Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer

January 17, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Re: Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (NCD CAG00450N)

Dear Ms. Jensen:

Ovarian Cancer Research Fund Alliance (OCRFA) is a 501(c)(3) nonprofit organization dedicated to expanding investments in ovarian cancer research and advancing policy?that improves access to treatment and care. OCRFA is the largest non-government funder of ovarian cancer research, and since 1998 has awarded more than $75 million to support 275 grants at 71 leading medical institutions.

Through programs and partnerships, OCRFA extends it reach locally and engages in communities nationwide to connect patients with the on the ground support they need. The Advocate Leaders program is OCRFA’s grassroots advocacy program that works at all levels of government to promote policies that advance ovarian cancer research and expand patient access to treatment and care.

As members of OCRFA’s Advocate Leaders program, we appreciate the opportunity to provide comments on the Centers for Medicare & Medicaid Services (CMS) Proposed National Coverage Determination (NCD) for Medicare Beneficiaries with Advanced Cancer. We commend CMS for recognizing the value of NGS technology and the growing role it plays informing clinical decision-making. However, we worry that the proposed NCD would adversely impact patient access to tests that utilize this valuable technology if finalized and urge CMS to expand the scope of coverage in any final determination.

To that end, we have two main concerns:

1. The proposed NCD only covers the cost of this test one time in patient’s lifetime – meaning that patients with a recurrence would not be covered for repeat NGS testing. This is insufficient, as tumors evolve over time and repeat sequencing is often necessary to monitor progress and inform treatment. Clinical trials now require sequencing of the tumor at many different points in time.

Furthermore, as NGS technology improves, it is likely that they will find more mutations or at least be able to validate some of the "variants of unknown significance" that some of us have seen in our genomic analysis. Repeat sequencing will be required when this happens.

The proposed NCD only covers Medicare beneficiaries with “advanced cancer”, meaning current, metastatic, or advanced stage IV cancer who have not been previously tested using the same NGS test and intend to seek further cancer treatment.” In other words, patients newly diagnosed with cancer or in earlier stages would not be covered for NGS testing. This is short-sighted and would exclude a broad segment of the patient population from the benefiting from advancements in precision oncology around early interventions and improved risk modification.

We appreciate this opportunity to comment and hope the agency will reconsider this proposal.

Sincerely,

Katie Maxwell, Advocate Leader
Bluffton, South Carolina
[PHI Redacted]

Tiffany Irving, Advocate Leader
Lynchburg, Virginia
Stage IV – [PHI Redacted]

Kimberly Richardson, Advocate Leader
Chicago, Illinois
[PHI Redacted]

Emily Caudill, Advocate Leader
Nashville, Tennessee
[PHI Redacted]

Apollo Kacsinta, Ph.D., Advocate Leader
Chula Vista, California
I lost [PHI Redacted] to ovarian cancer and now do cancer research at UCSD

Melissa Kritell, Advocate Leader
Findlay, Ohio
[PHI Redacted]

Kathleen Maxian, Advocate Leader
Buffalo, NY
[PHI Redacted]

Pam Dahlmann, Advocate Leader
Ann Arbor, MI
President/Founder, Michigan Ovarian Cancer Alliance

Kimberly Emory, Advocate Leader
Lithonia, Georgia
[PHI Redacted]

Katie Kimball, Advocate Leader
Minneapolis, Minnesota
[PHI Redacted]

Terri Gerace, Advocate Leader
Prairieville, Louisiana
[PHI Redacted]

Frieda Weeks, Advocate Leader
Liverpool, New York
Ovarian cancer advocate, [PHI Redacted] of bladder cancer survivor, [PHI Redacted]

Mary Phillips, Advocate Leader
Denver, Colorado
[PHI Redacted]

Rebecca Esparza, Advocate Leader
Corpus Christi, TX?
[PHI Redacted]

Tiffany Briggs, Advocate Leader
Anchorage, AK
[PHI Redacted]

Lynn Fallows, Advocate Leader
Edmonds, WA
[PHI Redacted]

Leslie Cancelliere, Advocate Leader
Lyndhurst, OH
[PHI Redacted] of 5-year survivor

Elise Daniel, Advocate Leader
Durham, New Hampshire
[PHI Redacted]

Jennifer Lane-Riefler, Advocate Leader
Marion, IN
Advocate, Health Professional, lost family member

Sharon Geiselman, Advocate Leader
Westfield, IN
[PHI Redacted]

Kristen Hovorka, Advocate Leader
Palmyra, PA
Caregiver, lost [PHI Redacted] to ovarian cancer

Amy Kay Lindh, Advocate Leader
Deer Park, WA
[PHI Redacted]

Mary Pegg, Advocate Leader
Spokane, WA
[PHI Redacted]

Janice Swierczek, Advocate Leader
Lawrenceville, NJ
President, Teal Tea Foundation, OCRFA Partner Member

Kerie Berkowitz, Advocate Leader
California
[PHI Redacted]

Janice L.B. Byrne, M.D., Advocate Leader
Salt Lake City, Utah
[PHI Redacted]
Utah Ovarian Cancer Alliance

Susan Leighton, Advocate Leader
Huntsville, Alabama
[PHI Redacted]
Lilies of the Valley Ovarian Cancer Support and Awareness

Laura Forte, Advocate Leader
Great Falls, Virginia
[PHI Redacted] battling stage 4 ovarian cancer from Bismarck, North Dakota

Jill Tanner, Advocate Leader
Owensboro, Kentucky
[PHI Redacted]

Marcie Paul, Advocate Leader
West Bloomfield, Michigan
[PHI Redacted], OCRFA research advocate?CDMRP and PCORI consumer reviewer, RPCI/UPCI SPORE Patient Advocate, Karmanos Cancer Institute Patient Advisory Council member

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As an academic molecular pathologist for over 20 years I am writing to express my opposition to the CMS proposal for National Coverage Determination for NGS. During my career molecular diagnostics has grown from a small field of highly specialized testing to a widely used testing modality invaluable for genetics, infectious disease,and more recently oncology. The oncology molecular testing my laboratory performs using NGS is used for diagnosis as well as treatment by directing therapy based on the pathogenic variant profile. We get frequent calls from oncologists requesting NGS tumor panel results on a patient because the patient has an appointment and the information is required for management. This testing is standard of care as cited in the current guideline document from NCCN among other groups and which are cited in this CMS-NCD document. .

I would like to take issue with several points related to the requirements for NGS laboratory developed procedures. The requirement for FDA approval is not necessary. CLIA”88 allows the development of tests within a laboratory. There is currently no established procedure to obtain FDA approval and the cost of such approval is prohibitive to academic laboratories from mid-size institutions like ours. In addition the process of FDA approval is not designed to regulate a rapidly changing clinical environment and Congress has agreed. A new mutation could be discovered and a drug identified for treatment before FDA approval is given for the previous version of the test. Isn’t this the essence of precision medicine- the care we want for our patients to provide the most current testing.

The Part B requirement of coverage with evidence development is not designed with academic molecular laboratories in mind. Molecular diagnostic laboratories carry out clinical testing on patient samples not research studies. The requirements are too narrow in scope and again not feasible for academic laboratories to comply.

Over the past year in the Journal of Molecular Diagnostics, guidelines have been published dealing with the validation of NGS testing, the classification of variants and most recently in Dec 2017 on the validation of the bioinformatics pipeline. These guidelines are comprehensive. Laboratories validating NGS oncology panels have done extensive validation testing many specimens at considerable expense to be able to provide quality testing results for patient care. Most academic laboratories participate in proficiency testing offered by the College of American Pathology. A recent article in JAMA Oncology by Kim et al published online December 14,2017 demonstrated that LDP and FDA approved tests performed equally well in proficiency testing comparing thousands of samples over multiple challenges.

In summary, if these rules are implemented the effects will be devastating to academic molecular laboratories and the patients we serve. I suggest before you take such a step that the committee who generated this report come and spend time in a molecular diagnostic laboratory and see what we do .

Thank you for your consideration.

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Questions for Commenters

1. Should the proposed NCD be expanded or narrowed by clinical conditions, test methodology to measure the same clinical biomarker, or clinical scenarios? If so, please provide supporting documentation, including peer-reviewed evidence, and a detailed analysis in support of your view.

A challenge here is that one clearly cannot demonstrate that using a specific drug targeting a specific mutation based on results from a specific test improves clinical outcomes (however defined) for EVERY permutation of drug, mutation, and test. So what is good enough? The design of the clinical study is guided by question we seek to answer. I’d propose that the central question we as a community are trying to answer is: When compared to the “standard of care”, does “tumor mutation profiling” (TMP) in patients with “recurrent, metastatic, or advanced stage IV cancer” improve health outcomes, broadly defined to include endpoints that address efficacy (e.g., ORR, PFS and/or OS), safety and quality of life. In addition, while this is obviously not required for a determination of “reasonable and necessary” for Medicare coverage, such a study could also at least characterize economic outcomes (e.g., total cost of care) for the TMP strategy versus standard of care. With this in mind, a study design like that described as version 2 by Prasad (PMID 29223937) and modified as necessary to address the desired intended use population and study endpoints seems appropriate and reasonable.

It is important to note though that TMP does not require NGS. Indeed, multiple other technologies, such as Sanger sequencing, ddPCR, MLPA, IHC, FISH, CISH, etc can and are being used today, generally in combination, to provide results for the 4 classes of alterations (i.e., SNVs, indels, CNVs, and rearrangements/fusions) tested for by F1CDx, as well as for MSI and TMB. Indeed, multiple papers compare the pros and cons of different technology platforms, whether in terms of accuracy, efficiency, or cost. (See for example, PMID 29165356 and 29061375 on BRCA testing, and PMID 29051321 for TMP.) An unintended consequence of limiting the test methodology to NGS will be to drive clinical testing, especially for LDTs, towards technology platforms that can differ meaningfully with respect to cost, analytical sensitivity and specificity, tissue consumption, turnaround time, etc.

Another important caveat is that demonstration of clinical and/or economic utility for a “personalized strategy” does not necessarily generalize to any methodology or combination of methodologies (e.g., NGS, ddPCR, MLPA, etc) used to execute that strategy because the analytical performance characteristics of these tests (most especially their respective limits of detection) as well as their tissue consumption, turnaround time, and cost structures will necessarily mean that the patients identified as eligible for targeted therapies and/or immunotherapies by these tests—and therefore the clinical and economic outcomes in those patients—will by definition differ (see Prasad reference above and especially PMID 27978570, 28431395, 27588476, and 29242909 comparing tissue- and blood-based TMP tests). The question is how different and whether these differences are clinically and/or economically significant? Our collective inability or unwillingness to answer these questions in a scientifically and clinically rigorous way is an unfortunate choice, whether implicit or explicit.

General Comments & Questions

1. Why must the patient have not been tested “using the same NGS test”? Tumor mutations are known to evolve over time (see PMID 29106415 and references therein) so a tumor sample from 3 months ago, especially with intervening treatment, may not be relevant to the patient’s current TMP and treatment.


2. Is the AV, CV, and CU data available in the NIH GTR reviewed or otherwise curated in any way? If the purpose of such registration is to provide transparency into such AV, CV, and CU data for both IVDs and LDTs, will the GTR achieve this goal?


3. Does this NCD apply to:
   1. “Liquid biopsy” (LBx) TMP tests, whether using NGS or not, for somatic mutation detection? An unintended consequence of limiting this NCD to tissue biopsy (TBx)-based tests may be to drive such TMP testing towards LBx approaches, for which there are now multiple reports of significant discordances, and unknown implications for patient safety and drug efficacy. (See, for example, PMID 27978570, 28431395, 27588476, and 29242909).
   2. TBx or LBx-based tests for germline mutation detection (e.g., BRCA), whether using NGS or not?
   3. TMP tests, whether using NGS or not, that test only tumor tissue? That test matched tumor and normal tissue?
   4. TMP tests, whether using NGS or not, for somatic or germline mutation detection in hematologic malignancies?
   5. ANY oncology test that uses NGS as part of its analytical methodology, or only those tests that use NGS for TMP, MSI, and/or TML for the purpose of therapy selection? For example, would this NCD apply to the OncoTypeDx Breast Recurrence Score, which may be used to decide whether to treat a breast cancer patient with adjuvant chemotherapy, if the test were to use NGS? (It currently does not.)


4. With respect to the CED requirements for LDTs and for FDA-cleared or approved IVDs without CDx claims, why is evidence for improvements in OS, PFS, and/or ORR appropriate for such tests when such data were not required for CDx claims for F1CDx (see P170019 SSED), for which approval appears to be based primarily on analytical concordance? Why is coverage and reimbursement proposed for “recurrent, metastatic, or advanced stage IV cancer” when the the CDx indications in P170019 are limited to NSCLC, melanoma, breast cancer, colorectal cancer, and ovarian cancer? If based on the additional clinical utility studies cited in the NCD, why are these applicable when many are (1) not specific to NGS-based oncology panels let alone to F1CDx specifically and (2) do not use OS, PFS, ORR, or PROs as endpoints? Note also the concerns expressed above about the generalizability of clinical utility claims based on ““personalized strategies”.


5. Analytic concordance to a companion diagnostic test with associated clinical outcomes is a reasonable surrogate for assessing clinical outcomes when drug selection is based on a new test (e.g., F1CDx), but ultimately incomplete without an understanding of the VAF (or equivalent) at which clinical response (however defined) is observed, and an assessment of analytic concordance between the new test and the original CDx at that VAF (or equivalent). (For example, at what VAF does a patient with an EGFR ex19 del, L858R, or T790M respond to the appropriate TKI? Alternatively, what were the ranges of VAF (or equivalent) at which clinical response was observed in the pivotal drug studies associated with the original CDx tests, such as P150047, and what is the analytic concordance between the new test and the original CDx at that VAF?)

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CellNetix Pathology and Laboratories is a large private pathology practice group and an affiliated laboratory located in Seattle, Washington, offering anatomic pathology services and appropriate ancillary testing, including immunohistochemistry, flow cytometry, and molecular testing for cancer and infectious disease, including several next generation sequencing panels for cancer. We examine over 200,000 specimens per year, and work with 25 hospitals across Washington State and in Alaska. Our major clinical partner is Swedish Medical Center, and we are a partner in the Swedish Cancer Institute’s (SCI) Personalized Medicine Research Program (PMRP) in Seattle. We have been participating intently in the field of precision medicine for the past 4 years. We have presented our research work at numerous national and international meetings, including ASCO and AACR. We are concerned that the proposed NCD for the FoundationOne CDx test will impede our ability to continue this work.

Since this NCD relies heavily on FDA approval status, it should be noted that there is strong evidence for the validity of laboratory developed testing (http://journals.sagepub.com/doi/full/10.1177/2374289517708309, https://jamanetwork.com/journals/jamaoncology/article-abstract/2665746?redirect=true). In addition to well-established professional standards for laboratory developed tests, each NGS test that we have validated, in our CAP and CLIA certified clinical laboratory, meets or exceeds quality criteria as described in the CAP checklist, the previously proposed Palmetto MolDx criteria (no long available online), and the previously proposed FDA draft criteria (https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm509838.pdf). We provide our validation data to any clinical user of our tests when requested. We have also been careful to meet all regulatory requirements regarding these tests. The SCI/PMRP program that we participate in correlates genomic and clinical data for patients who are tested there, with several aims, including trial matching, decision support, and outcomes tracking. The data is contained in a translational research database, which we have collaborated with SCI and a commercial partner to develop. As part of this program, we have participated for the past 3 years in a molecular tumor board, intended to provide a forum for discussion of interesting or problematic cases and to further the education of our clinical teams. We have been able to contribute greatly to this process due to our detailed knowledge of and experience with test performance and interpretation.

The proposed NCD will exclude coverage of our test based on lack of FDA approval, although we are meeting or exceeding all of the appropriate criteria for laboratory-developed testing according to CLIA and CAP, and in spite or our decision to participate in an organized and IRB-approved program for tracking patient outcomes. As a large private practice group, committed to providing excellent medical laboratory services to our clinical partners, we do not operate on venture capital investment, and do not have the resources to fund and support the FDA-approval process at this time. If, as a result of this decision, SCI is compelled to switch to the commercial FoundationOne CDx test, they will lose some of the involvement and expertise of our extremely knowledgeable and tightly-integrated pathology group, and the burden placed on our pathologists to support the SCI PMRP effort will increase, since we will need to make inferences from the commercial test, and to a large extent will need to reinterpret the results from a clinical standpoint for molecular tumor board purposes. The SCI program will also lose all access to the primary data.

We are not alone choosing to provide quality NGS cancer testing within our existing high-functioning medical community, as opposed to obtaining testing from a commercial vendor. These tests are currently being used to deliver high-quality, advanced cancer care across the country, including at virtually all major cancer centers and academic institutions (http://www.archivesofpathology.org/doi/pdf/10.5858/arpa.2016-0542-CP, https://www.ncbi.nlm.nih.gov/pubmed/?cmd=historysearch&querykey=1 ). Most of these institutions have chosen to provide this care locally to retain the involvement of their pathologists. As pathologists, we contribute medical laboratory expertise to the patient care effort, which is often most helpful in the setting of complex testing, as is under consideration here. We ensure that tissue is handled appropriately and that the correct test is performed. We are available to troubleshoot and to communicate directly with the clinician caring for the patient. Because we have access to the patient’s clinical record, and to the entire clinical team, we are able to correlate results and to draw inferences based on the complete clinical picture. Most of these efforts would be hindered if this decision were finalized.

NGS is a methodology, not a specific medical test. The proposed coverage, linked to the NGS cancer panel methodology, rather than to a specific biomarker or specific CPT code, is a break from the established process of coverage determination, which has previously been based on clinical utility of a specific diagnostic biomarker test, regardless of methodology or FDA approval status. This decision could reverse existing coverage determinations for proven biomarker tests used in hospitals across the country that employ NGS methodology, potentially disrupting care for many patients. Many labs, including ours, would need to revert to older technologies with less coverage and less accuracy, at an additional expense.

Additionally, an advantage of next generation sequencing technology is flexibility, enabling laboratories to adjust testing to clinical needs easily. This could include a change in a panel, or a change in sample type, or a change to a completely new assay. This works well in the current CLIA regulatory environment, where laboratories need only to complete a rigorous validation study to implement new biomarkers. The broadly restrictive nature of the draft NCD, including the requirement of the full FDA PMA process for each test, would discourage this accepted process and restrict access to the most clinically relevant testing in even the most advanced clinical centers. Development of new and innovative NGS-based tests would be restricted to commercial enterprises with extensive funding.

While we are encouraged by the recognition of the value of this type of testing for cancer patients, we are also hopeful that this draft NCD will be improved to address our concerns. We would be happy to contribute to this process if needed, with the aim of continuing to provide the best care possible for our patients.

Signed,

CellNetix Genomics Leadership Team
Kathleen Fondren, MBA, CEO
David Corwin, MD, President
Anna Berry, MD, Director of Genomics Programs
Danbin Xu, PhD, Technical DIrector of Molecular Diagnostics

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January 17, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Re: NCD CAG-00450N

Dear Ms. Syrek Jensen,

I applaud the decision linking NCD-level coverage to FDA clearance and approval of NGS testing. I am, however, concerned that the non-coverage section may limit access to comprehensive liquid biopsies for Medicare patients with metastatic lung cancer.

The draft NCD is unclear with respect the coverage for liquid biopsies. There are comprehensive liquid biopsies that are NYSDOH-approved, rigorously validated, and already in widespread clinical use, both in the community and at virtually all NCCN centers, including ours. While we applaud the decision linking NCD-level coverage to FDA clearance and approval, we are hopeful that CMS can find a solution to recognize the value of access to NGS-based liquid biopsies for lung cancer patients.

At the University California, San Francisco (UCSF) Helen Diller Comprehensive Cancer Center, we routinely order comprehensive liquid biopsy for patients with non-small cell lung cancer (NSCLC) at treatment-decision time points. We see many patients referred from outside institutions, whose tissue was not previously profiled for all FDA-relevant targets (EGFR, ALK, ROS1, BRAF).

Obtaining the original tissue obtained at outside care providers – usually months or years before – and scheduling and performing a repeat invasive biopsy to obtain more tissue, takes weeks to coordinate, leading to delays in patient care. Access to comprehensive liquid biopsy removes this barrier and allows for repeat sampling in patients as an alternative to invasive tumor biopsies.

In our experience at UCSF, comprehensive liquid biopsy has identified FDA-approved targets not previously identified in tissue, allowing access to approved targeted agents that, as you well know, have far better toxicity profiles and outcomes than cytotoxic chemotherapies. Beyond finding FDA-approved targets missed in prior lines, the comprehensive liquid biopsy tests we use, Guardant360 and other clinical commercial tests, also include the targets of key phase 2/3 trials that we run.

Thus, with a simple blood draw, patients in our clinic are comprehensively evaluated for all relevant targets with FDA-approved agents as well as genomically-directed clinical trials. I fear that the non-coverage section of the current NCD will create unnecessary obstacles to the widespread adoption of cancer genetic analysis of patient’s cancers. Improving clinical care, and decreasing the costs of that care, requires the use of this genetic information. Liquid biopsies are non-invasive. Covering liquid biopsies enhances the efficiency and timely care of cancer patients.

Sincerely,
Trever Bivona, MD, PhD
Department of Medicine, UCSF

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January, 17th, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Re: NCD CAG-00450N

Dear Ms. Syrek Jensen,

In my oncology practice at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, I see many patients with advanced cancer. The opportunity to order NGS testing on their tumor DNA and the availability of many targeted agents has changed lives for many of my patients. So I am very glad to see some aspects of this draft NCD. NGS testing in advanced cancer should be covered.

But the field is rapidly developing. It would be a mistake to adopt the draft NCD as is and exclude liquid biopsies from coverage. When CMS began this process more than a year ago, comprehensive liquid biopsies were still relatively new to the clinic. Evidence of their utility and validity was small but growing.

Today, multiple NGS-based liquid biopsies have been approved by the New York State Department of Health and top-tier medical journals regularly publish evidence of their effectiveness. I use the Guardant360 test regularly in my practice and my experience with it has been no different than using tissue-based NGS tests. Patients who are eligible for targeted therapies respond to the drug, as expected.

Although liquid biopsies have come a long way in the last two years, there is still no FDA-approved comprehensive, plasma-based tumor profiling test. Please amend the draft NCD to remove the exclusion of liquid biopsies.

Sincerely,

Young Kwang Chae, MD, MPH, MBA
Co-Director, Developmental Therapeutics Lurie Cancer Center
Northwestern University Feinberg School of Medicine

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Dear CMS,

I am Jonathan Nowak, MD, PhD, Instructor of Pathology, Harvard Medical School, and Associate Pathologist at the Brigham and Women’s Hospital in Boston. I am a board certified molecular genetic pathologist that works closely with my colleagues at the Dana-Farber Cancer Institute (DFCI) to care for patients with a wide variety of advanced solid tumors.

As should be evident to all, an understanding of cancer at a molecular genetic level is essential to refining our pathologic diagnoses, improving prognostic information and, perhaps most importantly, matching patients to the best type of therapy for their particular tumor. The advent of next-generation-sequencing, and its rapid and widespread adoption across many laboratories, both academic and commercial, in the country attests to the groundbreaking utility of this approach to treating cancer patients. I witness this utility nearly every day as I sign out cases, communicate with oncologist and participate in tumor boards where molecular results from the assays we have built in our CLIA-approved laboratory provide the backbone of treatment plans for patients at the DFCI. Moreover, as a researcher with specific expertise in pancreatic cancer, a highly incurable disease in most patients, I have been personally involved in guiding the care of a host of pancreatic cancer patients at the DFCI who have received treatment specifically based on findings from our NGS assay. Many of these patients had, or continue to have, remarkable responses to therapy. Notably, there are currently no specific FDA approved targeted therapies or molecular assays to guide the treatment of pancreatic cancer patients. Nevertheless, research that we are able to do as a result of our NGS assay may well pave the way for future testing indications in this cancer type.

Our laboratory has an extensive history of being at the forefront of molecular diagnostics and personalized medicine. Many molecular assays that are now standard of care for cancer patients were pioneered either in our laboratory, or in similar academic environments, often years become they became widely available as commercial assays. Moreover, some of our assays are specifically tailored to our patients with rare diseases visiting nationally recognized experts at our institution. As pathologists and physicians, we expect to be able to offer the best testing that can be specifically matched to OUR patient population. Often times this means development and validation of an LDT optimized for our patients and their particular spectrum of disease. We routinely employ this approach in a CLIA-approved environment, performing validation studies, engaging in proficiency testing, and publishing our methods in open, peer reviewed journals. We can demonstrate a track record of LDT performance that matches and, in many cases, exceeds the performance of commercial assays.

Given that CMS has already acknowledge the medical utility of NGS panels via the approval of assays from Foundation Medicine and Memorial Sloan-Kettering Cancer Center, and that numerous data and publications demonstrate excellent performance of LDTs compared to FDA-approved companion diagnostics, it is unclear why the proposed determination to cover only FDA-approved NGS assays was issued. If this misguided NCD is approved, the vast majority of NGS testing across the nation will be affected, and it is likely that the majority of labs offering NGS will cease to do so. The inability to offer rapid, and customized testing to local patient populations will almost certainly do more harm to patients than could be offset by theoretical gains for FDA approval. Importantly, LDTs for other indications are commonly reimbursed by CMS. It is not clear why NGS assays should be held to a different standard, nor why a near-monopoly on performing this type of testing should be awarded to the small number of labs with the capacity to seek FDA approval. Eliminating access to NGS-based LDTs will legitimately lower the quality of patient care that I am able to provide via LDTs at my institution, and I suspect this will be at the same at most other institution as well.

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My names is Mandie Hiznay and I am a a patient advocate with a [PHI Redacted] who is a 6 1/2 year Stage IV lung cancer Survivor. Thank you for the opportunity to provide comment on the National Coverage Analysis entitled ‘Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer’. Cancer patients all over the country are benefitting from new knowledge in the genomic causes and drivers of cancer, as evidenced by increased access to personalized therapeutics and care based on the genetic makeup of cancer. We are grateful for advances in diagnostic technologies, such as next generation sequencing, as it is one tool to obtain a more comprehensive genetic understanding of cancer. This technology is of particular relevance to lung cancer patients as it typically requires less tissue sample than separate sequencing of multiple genes. I thank CMS for recognizing the value of precision diagnostics in the care of cancer patients by proposing coverage for FoundationOne CDx (F1CDx). I support a positive coverage determination for the product reviewed in the Parallel Review program, F1CDx, however I have serious concerns about the broad scope of the proposed NCD. The proposed policy would limit cancer patients to 1 test per lifetime, which is not in line with the realities of personalized medicine based therapy for cancer patients. Also, the new policy will eliminate coverage for other NGS tests for advanced cancer patients enrolled in Medicare. These tests are currently being used to deliver high-quality, advanced cancer care across the country, including at virtually all major cancer centers and academic institutions. I support CMS’ proposal to cover the F1CDx test but urge CMS not to finalize the rest of the policy as it will result in several unintended negative consequences to cancer patients by erasing important medical advances and existing local coverage policies already in place. thank you for the opportunity to voice my concerns in helping to make lung cancer a chronically managed disease.

best, Mandie Hiznay

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Dear CMS,

As an academic pathologist and molecular diagnostic lab director performing LDT next generation sequencing sequencing of tumors at the Massachusetts General Hospital, I would like to express my concern with the proposed payment policy for cancer NGS. I believe the policy essentially gives Foundation Medicine a monopoly in this space, since there are no other FDA approved assays that have 5 or more genes clinically validated (i.e. Illumina and ThermoFisher Assays would not be eligible). I think the payment policy as proposed penalizes the many many labs performing safe and effective LDTs across the country, although this was likely not the intent. In the end the payment policy would undermine assays that have been validated by lab professionals under current FDA LDT guidance, and in our jurisdiction (MAC NGS) with a fair payment LCD.I propose a compromise where FDA-approved NGS would receive its own CPT code and be paid at an appropriate negotiated rate. CLIA assays that do not have FDA approval, but are properly validated according to CAP/CLIA guidelines could use current NGS CPT codes and paid off the CLFS gapfill rates. Any labs who received full PMA approval from the FDA could then be eligible to bill the other CPT, and presumably get paid at a higher rate. I think this approach is a compromise that would satisfy the majority of stakeholders.

Thank you for your consideration,
John Iafrate

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Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Blvd
Baltimore MD 21244

RE: Proposed Decision Memorandum for National Coverage Analysis (NCA) for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

Dear Ms. Jensen:

Guardant Health appreciates the opportunity to comment on CMS’ proposed national coverage determination (NCD) as described in the National Coverage Analysis for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer. CMS has set a high bar for test accuracy and utility, by requiring either FDA approval or FDA clearance. CMS also provides a clear and transparent path forward for coverage of NGS tests for companion diagnostic (CDx) indications. However, as proposed the NCD would have unintended and adverse impacts on patient access to standard of care cancer treatment as liquid biopsy is not a covered test under the proposal.

CMS must develop a coverage pathway for this important class of tests where tumor tissue is unavailable or patients are undergenotyped for all biomarkers with an FDA approved drug. Specifically, we are most concerned that the proposed language will deny access to the benefits of targeted therapies for advanced cancer patients for whom tissue genotyping is infeasible or incomplete for all targetable mutations. Without access to blood-based testing, the alternative for non-small cell lung cancer (NSCLC) patients is a repeat biopsy with high cost (averaging $14K) and risk (19% adverse event rate)¹ or being relegated to non-targeted chemotherapy that provide half the overall survival benefit of a genomically targeted therapy.^2–4 Insufficient tissue sample and risks associated with repeating tissue biopsies in advanced NSCLC contribute to widespread undergenotyping where published data finds that a minority of patients get tested for all targetable genes.^2,5

Currently, these patients are able to benefit from targeted therapies because NGS comprehensive liquid biopsies, such as Guardant360, provide accurate and reliable tumor genotyping information for all NCCN guideline-recommended targetable genes when tissue is unavailable. These guidelines currently recommend that “plasma biopsy should be considered” when repeat biopsy is infeasible.⁶ Because no FDA-approved NGS options for such testing exist, the current language will exclude all genomically targeted therapy options for these patients.

We believe it is possible to prevent such patient access issues with changes to the existing NCD language. We propose that the current policy be revised to exempt clinical scenarios in which genotyping is recommended but no FDA-approved NGS liquid biopsy test currently exists and could allow usual local Medicare Administrative Contractor coverage decisions with NYSDOH approval, to govern in such contexts. To this end, we advocate for the inclusion of a one-time, initial transition period that protects patient access to NYSDOH-approved NGS testing for a period of 2 years. (Note, such a strategy was effectively used by CMS in the June 8, 2012 NCD on Transcutaneous Electrical Nerve Stimulation for Chronic Low Back Pain, in which one coverage option was timed in advance to expire three years after publication of the final decision.) Such a transition period enable full coverage for testing under local carrier discretion and protects patient access to NCCN guideline-recommended precision medicine options while maintaining the spirit and intent of the original proposal.

Additionally, CMS provides a path to coverage for tests cleared by the FDA for analytical accuracy claims through a 510(k) pathway. We believe the ‘coverage with evidence development’ (CED) mechanism could be an appropriate vehicle by which analytically validated tissue-based tests could generate the clinical data necessary for clinical claims; however, the current proposed requirements for such CED coverage (Section B(2)(b)) are infeasible as written and we suggest an alternative plan for national laboratories to participate in CED:

• Guardant supports the CED process embraced by CMS. This process will ensure that data generation occurs when PMA tests are used off-label, and when 510(k) tests are used. In this spirit, CMS shares the vision of NCI, Institute of Medicine, and many oncology stakeholders that we can progress much further in the direction of a Learning Healthcare System in oncology.


• In order to ensure that liquid biopsy tests have the ability to enter CED, CMS must account for the fact that the 510(k) clearance pathway dependent on NYSDOH approval is only available for NGS using tissue platforms. CED for liquid biopsy tests should include NYSDOH approval for such tests.


• CED should and indeed must be based on principles of rational design and “Value of Information” in oncology. There should be individual CED plans that should be developed by each company applying for CED and approved by CMS which include a national linking of claims from the CMS National Database to lab data which will support universal core data analysis for clinical utility. We furthermore believe that such an approach employing rigorous analysis of real-world evidence would be groundbreaking in terms of vastly accelerating future beneficiary access to therapies matched with emerging biomarkers in a manner that is consistent with the spirit of the 21st Century Cures Act. An approach utilizing national claims data linked to laboratory data would be novel and powerful. The data could be verified with a physician survey data and/or a limited registry. This would make CED practicable, while still able to report on endpoints such as time-to-next-treatment and overall survival. The limited registry would provide a deeper dive into the data and could still be statistically designed and powered for meaningful knowledge.


• In regard to specific endpoints that should be included in CED, clinical endpoints should be assessed for treatments applied shortly after the NGS test result was issued, but not through multiple lines of therapy. One outcome measure that should be considered for assessment of real-world evidence is time to next treatment, TTNT. This measure is useful in incurable diseases like advanced cancer, is quantifiable for an individual line of treatment, and can be estimated from claims databases, for example.^7,8 On the other hand, assessment of tumor response according to RECIST does not reflect common clinical practice and would not be compatible with a registry.


• While we (Guardant Health) support reporting patient experience, validated PRO tools such as those used to assess targeted therapies in cancer patients are not appropriate for a diagnostic CED, would not provide additional value, and would become unnecessarily costly if collected over multiple time points for tens of thousands of patients.

Finally the limitation of once-in-a-lifetime NGS testing should be amended to testing at each progression. Both the NCCN NSCLC and breast cancer guidelines recommend repeat testing to recurrence or progression in advanced disease, as there are now acquired resistance mutations that are targetable with FDA-approved drugs, such as EGFR T790M or MET amplification in NSCLC or change in ERBB2 (HER2) status from not amplified to amplified in breast cancer.^6,9 These and other unintended consequences of the draft NCD can be avoided with changes to the existing proposal as outlined above.

In summary, while we believe this is an important and well-conceived proposal that will improve the delivery of health care in the years to come, the sudden, drastic, and relatively long-term non-coverage of liquid biopsy would lead to unintended but substantive patient harm in the short term and the existing CED requirements would prevent meaningful participation in this promising pathway. We propose changes above to each of the existing sections that would prevent unintended consequences, such as limiting patient access, while maintaining the intent and positive impact of the original proposal.

We greatly appreciate the efforts of you and your staff, and look forward to further discussion. Please let us know if we can be of any assistance or provide any further information.

Sincerely,

Richard B. Lanman, MD, Chief Medical Officer
Guardant Health, Inc.

Attachment 1: Information on Guardant360

Guardant360 is the leading plasma-based comprehensive genomic test. Launched in June 2014, we have performed over 50,000 tests in the United States alone and are used by 97% of National Comprehensive Cancer Network (NCCN) cancer centers. The Guardant Health lab is CLIA-licensed, CAP-accredited, and New York State Department of Health (NYSDOH)-approved. There are currently 50 peer-reviewed publications reporting experience with Guardant360, including two dozen external validation studies and 20 outcome studies in four major cancer types (excluding single patient case reports). The test has two indications:

1. Guardant360 is indicated in first line (up front) recurrent or advanced solid tumor cancers when genotyping is indicated but tissue is insufficient for genomic testing for the NCCN guideline-recommended genes targetable with FDA-approved drugs. Tissue insufficiency is a problem so serious that 30% of lung cancer patients are not even tested for EGFR or ALK, while ~90% remain untested for all seven NCCN recommended genes.² As a result, the majority of the nearly 20% of patients with targetable mutations remain “undergenotyped” and limited to receiving inferior treatment options. These cancers must be treated systemically and are generally stage IIIB/IV, i.e. not amenable to surgical resection.
2. Guardant360 is indicated in subsequent lines of treatment when patients were undergenotyped in the first line, or when cancer has progressed in order to identify a targetable resistance mutation with an NCCN guideline-recommended targeted therapy. Currently, NCCN guidelines recommend repeat genotyping at progression in breast and lung cancer6,9, and Guardant360 may obviate the need for repeat invasive tissue biopsy by finding a targetable ERBB2 (HER2) amplification in breast cancer or resistance mutation in lung cancer.^10,11 It has also been shown that metastases in gastric cancer may have different HER2 status than stomach tissue, and that when Guardant360 identifies HER2 status in blood that is discordant from stomach tissue, that the blood test is correctly identifying the HER2 status of the metastases in nearly 90% of cases.¹²

References:

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Thank you for the opportunity to review and comment on CMS’ proposed national coverage determination (NCD) entitled “Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N).”

I am a practicing molecular pathologist and an expert in the diagnosis of disease at the molecular level. I am commenting as private citizen. The laboratory that I work in does not perform next-generation sequencing (NGS) for clinical care, and I can therefore comment without conflict of interest. I am only interested in ensuring access to care for my patients – your beneficiaries.

NGS is a technology encompassing several different methodologies. NGS is used to sequence many genes simultaneously and has clinical applications for transplantation (matching donors and recipients), infectious diseases (identification of bacteria and viruses and identification of effective treatments), and oncology. In oncology, NGS allows healthcare professionals to identify specific genetic mutations that can be targeted by treatment and is useful not just for solid tumors (such as lung or colon cancer) but also for hematologic malignancies such as leukemia, multiple myeloma, and lymphoma. NGS is not a single test for a single disease even in patients with advanced cancer. I request the scope of the NCD be limited to payment coverage and non-coverage for the FoundationOne F1CDx test.

As drafted, this NCD will limit the ability of Medicare beneficiaries to obtain medically necessary testing. For example, there is no FDA-approved NGS test for leukemia and small laboratories will have trouble achieving the CED requirements of a registry. A leukemia patient will have no option for a covered test and will then be faced with the very real and very difficult decision about whether to pursue medically necessary testing or not. I already have patients who are reluctant to sign an advanced beneficiary notice for a potentially uncovered diagnostic test because of their financial circumstances. Within solid tumors, the NCD as proposed will limit a physician’s ability to select the best test for the individual patient. Physicians will choose the Medicare covered test if faced with a choice between it and a potentially more appropriate, less expensive, more targeted but uncovered test.

In summary, due to the need to ensure beneficiary access to medically necessary and appropriate testing and due to the fact that NGS is a technology incorporating different methodologies, I request that the proposed NCD be limited to payment criteria for the FoundationOne F1CDx test instead of serving as a general coverage determination for any gene panel test performed using NGS technology.

Sincerely,
Jennifer Laudadio, MD
Little Rock, Arkansas

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CMS Leadership
U.S. Centers for Medicare & Medicaid Services
7500 Security Boulevard, Baltimore, MD 21244

Dear CMS Leadership,

On behalf of Personal Genome Diagnostics, we thank you for providing this opportunity to comment and support of the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N).

Personal Genome Diagnostics (PGDx) empowers the fight against cancer by unlocking actionable information from the genome. We are committed to developing a portfolio of regulated tissue-based and liquid biopsy genomic products for laboratories worldwide. We strongly support the draft memo’s decision to cover FDA-approved companion diagnostics (CDx) and would like to specifically emphasize the rigorous manufacturing quality that is required to gain FDA approval. Importantly, FDA approved assays are analytically and clinically validated to provide standardized performance within the patient population; and specifically, in a decentralized product model, across any geographical location in any qualified lab. In addition, the clinical utility of the CDx is supported by the nature of its intended use with a given drug in the intent-to-treat population.

We also support the Coverage with Evidence Determination decision for additional NGS testing. It is an important distinction that evidence in the literature may speak to utility of a given biomarker, but not all tests built to detect these biomarkers are developed equally leading to disparate results among tests that undermine the goal for standardization. We fully support the industry and medical community uniting to prove the clinical utility of NGS, particularly beyond current CDx biomarkers. We believe participation in a robust trial registry will demonstrate the value of large NGS panels for innovation in patient care for diagnostics and new pharmaceuticals, however the current proposal language may be burdensome and restrictive, having the potential to limit patient access to testing.

PGDx proposes finalizing Section A coverage language with the following recommendations:

• Expansion of the Coverage language to include Complementary Diagnostics (either PMA or 510(k) approved). Complementary diagnostics, while not essential for the safe and effective use of a drug, provide valuable information on the risk/benefit determination for an individual patient with respect to a drug. For example, a patient who is biomarker negative may expect a 10% response rate while a patient who is biomarker positive may expect an 80% response rate. These differences are clinically meaningful and should be included in the coverage determination when a diagnostic is FDA cleared or approved for this use in the product labeling. Further, the clearance or approval for a complementary diagnostic indicates that the rigorous FDA analytical and clinical standards have been met for the assay, giving payors confidence to rely on the test results.


• Expansion of the proposed NCD to include repeat testing of a single patient over their disease course. This may include diagnosis in frontline to determine treatment, testing at treatment relapse to determine alternative therapy and/or testing in late stage disease to identify clinical trial opportunities.
  • Our primary research indicates ~20% of US physicians would order NGS testing for their patient two-times over their disease course and over 10% of physicians would order NGS testing 3 times or more. (Primary market research, Quintiles IMS, June 2017).
  • Actionable alterations are found in primary tumors, at local-regional relapse and in distant metastases. Genomic Evolution of Breast Cancer Metastasis and Relapse Cancer Cell 32, 169–184, August 14, 2017.
  • There are over 1500 open clinical trials listed in ClinicalTrials.gov that are actively recruiting participants for therapeutic intervention in relapsed disease. (https://clinicaltrials.gov/ct2/results?term=relapsed&cond=Cancer&Search=Apply&recrs=a&recrs=f&age_v=&gndr=&type=Intr&rslt=)


• Replacement of the Stage-specific language in Section A1a “recurrent, metastatic, or advanced stage IV cancer” with “recurrent, metastatic, or advanced cancer needing biomarker testing according to NCCN guidelines.” For example, testing of certain biomarkers may be recommended stages prior to metastatic disease (i.e., ERBB2 in breast cancer, see NCCN Guidelines https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf)


• The language of the NCD should be refined to uniquely identify the type of NGS technology being utilized (i.e., comprehensive genomic profile (CGP) testing (e.g., FM1CDx and MSKCC-IMPACT) and targeted “hotspot” panels (e.g., OncomineDx)), which may impact the value of the data being delivered to physicians in the report as well as help define future coding mechanisms that have yet to be established for CGP. Further, PGDx supports preferential tiered reimbursement towards CGP tests in the CED section of the proposal due to the ability of CGP technology to provide more comprehensive data for underserved patient populations in a real-world evidence setting
  • CGP identifies clinically relevant genomic alterations in 76% more cases than targeted hotspot testing. 10.1200/JCO.2016.34.15_suppl.e23120 Journal of Clinical Oncology 34, no. 15_suppl - published online before print.
  • Missed clinical benefit rate of specific EGFR alterations can be as high as 83% in some NSCLC cases. DOI: 10.1158/1078-0432
  • CGP detected alterations targetable by drug intervention (NCCN Guidelines) in 26% of patients that showed “no alteration” by standard of care test methods for lung adenocarcinoma. 10.1158/1078-0432.CCR-14-2683.

PGDx proposes further discussion and consideration prior to finalizing Sections B and C of the proposed coverage language with the following recommendations:

• Consideration to lessen the requirements of data submission for evidence determination. The CED requirements for reporting clinical utility are burdensome for the existing healthcare infrastructure (i.e., RECIST requirement). If the proposal is implemented as written, this may dramatically impact Medicare (and all) patient care. While we fully support tracking and providing proof of clinical utility for non-CDx NGS products and tests, we recommend either a lessening of the CED criteria or a grace period of 6-12 months to allow for current NGS service offerings to establish the necessary CED reporting infrastructure.


• Implementation of a tiered coverage and reimbursement model that promotes patient access to NGS testing. The current proposal language of Sections B and C may likely eliminate coverage of most Laboratory Developed Tests (LDTs). While LDTs do not meet the burden of clinical validity of FDA-approved IVD tests, they do provide patients with greater access to necessary testing. However, patients ultimately benefit from Labs or Companies who pursue the rigorous quality system, manufacturing, on market service and support and regulated post-market reporting that is required of IVD development. Patient access to FDA cleared or approved testing should not be impaired by cost issues that may disincentivize PMA or 510k development.

  A critical milestone ahead of demonstrating clinical utility of a drug or device is the establishment of clinical validity, or the ability of a test to predict a future clinical outcome. Importantly, basic CLIA validations of LDTs do NOT assess clinical validity of tests. However, FDA approved tests are obliged to demonstrate clinical validity in their premarket approval process. (Centers for Medicare and Medicaid Services. Laboratory developed tests (LDTs): Frequently asked questions. October 22, 2013. https://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/Downloads/LDT-andCLIA_FAQs.pdf.)

  Important distinctions between LDTs and FDA-cleared tests are the burden of analytical and clinical validity for the latter. For NGS tests, analytical validity is measured primarily through Limit of Detection (sensitivity), precision, accuracy & reproducibility (see ACMG Guidelines in Genetics in Medicine v15, 9 September 2013). Clinical validity requires additional testing in clinical cohorts of the intent to screen or intent to treat populations to determine whether the biomarker being tested is associated with a disease, outcome or the response to a treatment. Analytical validation studies can take 6 months or longer to conduct, whereas clinical validity studies vary and may take up to several years depending on the prevalence of the biomarker being validated and the type of clinical claim being stated.

• We also recommend the CED requirements for FDA-approved 510(k) assays (Section B2a) be less burdensome than those of non-FDA cleared or approved offerings (Section2b), since FDA-cleared assays have met the additional responsibility of proving clinical validity in addition to analytical validity.

Thank you again for the opportunity to comment, and please let us know if we may support your efforts in any aspect of policy development around CAG-00450N.

Sincerely,
Mary Padilla, MD

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Comment on CMS’ proposed Non-Coverage Determination (NCD) for Next Generation Sequencing (NGS)-based tests from the American Society of Cytopathology

The proposal for Non-Coverage Determination (NCD) for certain Next Generation Sequencing (NGS) testing has severe adverse unintended consequences that have come to the attention of the American Society of Cytopathology. CMS may not have been apprised of these consequences by other parties who have commented on the proposal. The adverse consequences of CMS’ proposal arise because of new effective patient care innovations for which an FDA-approval cannot practically be obtained.

Cytopathology is the field of medicine that strives to use the smallest possible biopsy for diagnosis. By minimizing the size of a biopsy, Cytopathology makes diagnosis safer for patients, it allows early detection of cancer, and it has enabled technologies outside our field for minimally invasive procedures. Two such mature technologies enabled by cytopathology include endoscopic ultrasound guided bronchoscopy (used for diagnosis and staging of the majority of lung cancers and endoscopic ultrasound guided endoscopic biopsy (used for diagnosis and staging of most pancreatic cancers as well as many other intra-abdominal malignancies. These technologies are safer and faster than previous technologies, with better outcomes. These technologies need to use cytopathology because the instruments themselves are too small to permit larger samples to be obtained.

Most FDA-approved methods were originally based on data from studies using large-size biopsies. However, in order to process and perform ancillary testing such as NGS on cytologic microbiopsies, it is frequently necessary to modify the procedures specified in the FDA-approval. As one example, large-size biopsies have been historically processed with formaldehyde, and therefore FDA-approved NGS protocols specify the use of formalin. However formalin has generally not been used in cytology. In addition to being highly toxic and carcinogenic, formalin decreases the quality of DNA for NGS testing such that more cells are needed to obtain a result with NGS if the material is formalin fixed compared to NGS performed on samples processed without formalin. Direct smears of microbiopsies, (cells deposited directly on a glass slide without any formalin or paraffinization), have also been documented in many intralaboratory validations to provide an excellent diagnostic substrate for NGS.

These and other modifications of FDA-approved tests that enable patients to have safer and more efficient minimally-sized biopsies are deemed “Laboratory-Developed Tests” (LDTs) by the FDA. LDT’s are specifically NOT covered in the CMS proposal. The CMS proposal will therefore lead to non-payment of NGS for patients having procedures that are safer and more effective. The magnitude is significant since the majority of advanced stage lung cancers (for which NGS has proved particularly useful) are now diagnosed using endoscopic techniques with cytopathology processing.

We understand that a major goal of CMS’ proposal is to limit the expenses of the government. CMS seems to agree that NGS can be a valuable test for patients. However CMS seems to assume that if an NGS test is not FDA-approved, it has no value. The productive evolution of the field of medicine has certainly occurred in individual laboratories developing LDTs without FDA approval. The CMS proposal is particularly problematic because there is no practical way for Cytopathology laboratories to apply for FDA-approval for the LDTs that enable NGS on microsized biopsies.

If CMS needs to make changes, we think that the changes should generally unleash the creative potential of health care sectors, such as Cytopathology, to develop cheaper and more efficient technologies that would then be able to compete with existing higher-priced methods. Such a productive and cost-effective evolution could be facilitated if there were changes in CLIA language, changes in the definition of LDT’s, and/or a new role for the FDA. One potentially useful change, in our opinion, would be to enable groups of laboratories to collaborate and collectively derive valid procedures that could be then be approved (possibly by a new FDA mechanism) for funding by CMS. The bureaucratic bar should be low to encourage competition, yet with an oversight that probably falls within the purview of the FDA to protect patient safety. It is clearly not possible for a capitated payment system to be the engine for driving cost-effective innovation: Molecular testing on cytology samples—and all of the promise that Cytopathology and affiliated technologies offer for greater cost effectiveness and safety—would definitely suffer if there were no direct reimbursement for our innovations.

Thank you for your consideration and the opportunity to reply to your proposal.

Respectfully,

Barbara A. Crothers, DO
President, American Society of Cytopathology

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Thank you for the opportunity to provide comment on the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N). I am a medical oncologist, specializing in the treatment of patients with lung cancer, and have witnessed firsthand the progress in personalized medicine and targeted therapy that has occurred over the last decade. The remarkable advances in survival in lung cancer have been made possible in large part due to the advances in molecular characterization of solid tumors, and I routinely seek molecular characterization of tumors for my patients. While I applaud the decision to provide coverage for an assay such as F1CDx, I believe the limitations placed on reimbursement in this proposed coverage determination could lead to many unintended consequences, including reduced access of Medicare beneficiaries to the standard-of-care testing that is so critical to identifying appropriate treatment and improving outcomes.

Notably, a requirement that assays must be FDA approved for coverage under this proposal would potentially result in a substantial reduction in the availability of testing at laboratories nationwide, including at academic institutions. While I do have concerns that the current system of oversight of laboratory testing leaves uncertainty regarding the quality of some laboratory testing, I do not believe that the FDA approval process is an acceptable universal solution. Requiring FDA approval for reimbursement will result in reduced availability of state-of-the-art testing, including testing driven by academic inquiry in conjunction with standard-of-care testing. Importantly, it could result in reduced availability of services at our local laboratory, on which I heavily rely not only for results for individual patients, but also for consultation across a wide spectrum of associated issues, such as the details of individual patient specimens, prioritization of specimen for competing priorities, considerations for unusual findings, among other topics. Reduced access to the testing services, and the accompanying consultative activities would be detrimental to the care of patients, in my experience.

An additional concern about this proposed coverage decision is uncertainty regarding the extent to which this policy would apply to NGS based cell-free DNA testing (so called ‘liquid biopsy’). Liquid biopsy is an excellent approach to look for potentially therapeutically targetable alterations, particularly in patients for whom biopsy is not feasible. Exclusions of this type of testing, as there is no currently FDA-approved test for liquid biopsy, could lead to dramatic patient harm.

I urge CMS to consider revising this proposed coverage determination to not focus on the FDA approval status of an assay, but rather the association between biomarkers and clinically meaningful information such as prognosis and predicting responsiveness to targeted therapy. High-quality testing should be covered regardless of FDA approval status, as this will best protect patient access to some of the most meaningful advances in oncology care in decades.

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January 17, 2018

Tamara Syrek-Jensen, JD
Director, Coverage and Analysis Group

Joseph Chin, MD, MS
Deputy Director, Coverage and Analysis Group

Katherine B. Szarama, PhD
Lead Analyst
katherine.szarama@cms.hhs.gov

RE: CAG-00450N Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer

Dear Ms. Syrek-Jensen and Drs. Chin and Szarama:

On behalf of XIFIN, Inc, we appreciate the effort of CMS to define a framework for validation and coverage of Next Generation Sequencing (NGS). The Coverage with Evidence Development (CED) framework of the proposed decision will establish NGS when ‘used as a diagnostic test for patients with advanced cancer meaningfully improves health outcomes through a prospective registry’ is a sound method to establish independent validation of NGS and standardization of coverage policies across the healthcare landscape [1].

XIFIN, is a healthcare information technology company that leverages diagnostic information to improve the quality and economics of healthcare across laboratories, physicians and patients. We respectfully request consideration of comments and observations that are directly related to how stakeholders will fulfill the requirements of data collection, aggregation, sharing and reporting with respect to the “prospective registry”, defined in Part (B)(2)(1). The CED describes approved registries that adhere to the criteria and parameters identified in Part (B)(2)(c)[1].

Understanding that the approved registry meets the description and standards described, with the intent of data sharing to evaluate outcomes in NGS, the following comments are proposed.

Comment #1: The Proposed Decision Memo states is (B)(2)(a)(ii, iii, iv, v) specifically outlines requirements for data collection, a portion of which is only available outside of the lab furnishing the test (e.g., claims, cancer type and stage and progression free survival to patient reported outcomes). The requirements for this type of registry are consistent with the CMS definition of a Qualified Clinical Data Registry (QCDR), an “approved entity that collects medical and/or clinical data for patient disease tracking to foster improvement in the quality of care provided to patients through reporting” the focus of which is to establish a high level of quality reporting [2]. The proposed NCD includes a detailed description and requirements for a prospective registry that are identical to the requirements for a QCDR and specifically, reporting of detailed patient level genomic and outcome data into a CMS approved format. In this memo, CMS has defined the NGS prospective registry as the vehicle to capture and report clinical and genomic results, data validation, reporting and quality, but has not stipulated any additional conditions to differentiate it from a QCDR.

Comment #2: Data sharing requirements through a prospective registry are described in section (B)(2)(c) but the text does not address a “governance framework” how data sharing models such as what is defined by long standing policies of the National Institutes of Health (NIH) and further by the Federal Health Information Technology Standards (FHIT) and the Office of the National Coordinator for Health (ONC) [3, 4, 5]. The FHIT, in collaboration with Federal entities including CMS, has developed standards for data collection and sharing. Moreover, since patient level clinical data will need to be tied to biomarker and genomic results not necessarily generated from the same laboratory the NGS tests were generated, successful data collection and sharing can only be facilitated by adopting existing Clinical Document Architecture (CDA) standards and the patient core data set that support interoperability as part of the prospective registry that are currently defined in the requirements for a QCDR (described in Comment #1) [6]. Federal entities and stakeholders have established methodologies and approaches to facilitate capture and linking of clinical data from treating physicians with genomic information generated from labs to track outcomes. To reduce duplicative efforts, and avoid confusion, CMS should make data sharing requirements consistent and aligned with existing, approved standards defined by HHS, ONC and FHIT.

Comment #3: Given the NCD data sharing requirements as part of a prospective registry, laboratories will be required to invest substantially to develop their own standard operating procedures that are aligned with existing FHIT and HHS-NIH data sharing and find a pathway to collect and maintain clinical data with biomarker and genomic results. Because of the onerous nature of data aggregation, along with retention and reporting can span several years, it is in the best interest of all stakeholders that CMS designate a standards-based quality registry as the de facto registry to ensure standardized reporting of data and outcomes.

Rationale: Laboratory investment to comply with the defined requirements to develop and implement a registry will be significant both from a human and financial resource position:

1. Labs do not necessarily have the in house expertise to understand and implement the data sharing requirements as defined in the draft NCD and would be forced to invest substantially to meet the requirements of developing and implementing a prospective registry for reporting data sharing.
2. Collecting and reporting outcomes requires a standard approach and stewardship over data, including tracking and reporting of false positive and false negatives. The question of accurate reporting across different entities as well as comparison of data and results across laboratories.
3. In the white paper “Medicare’s Universal NCD for Next Generation Sequencing in Cancer Patient: Understanding its Scope and Implications” Quinn introduces the challenge that commercial laboratories are not always affiliated within an integrated delivery network (IDN) (e.g., Intermountain Healthcare) and therefore, would have to invest heavily in an IT infrastructure to capture clinical or patient level data [7].
4. Alternatively, laboratories have the option of enrolling in the NCI National Clinical Trials track but as described in (a), the requirements are onerous and it is not clear how a laboratory would comply with aspects of the registry requirements (e.g., detailed genomic information clinical and patient reported outcomes).
5. With respect to item (c) it is not clear how a laboratory will work with treating physicians to enroll patients in NCI National Clinical Trials Network and how the link between clinical and diagnostic outcomes will be maintained for reporting.

Comment #4: Quality Improvement adherence to scientific integrity as defined by the Agency for Healthcare Research and Quality (AHRQ) Part B(2)(c) is cited as the underlying framework to support clinical research studies that meet the standards for establishing Coverage with Evidence Development (CED). AHRQ, through its description of Quality Improvement Registries (QIR)[ has highlighted the need for efforts that focus on data collection with quality improvement to continuously improve care. The methods and approach of a QIR interleave quality improvement around testing, unlike regular registries but very similar to a QCDR. CMS should consider a requirement that all information being collected be compared across all submissions by laboratories and measured against a composite score similar to the CMS QCDR. The differences between a traditional registry and a QIR can be thought of as how data are collected and what questions can be answered with the data.

Comment #5: Health and Human Services Office of Human Research Protections (OHRP) define Human subjects are defined as living individuals about whom an investigator (whether professional or student) conducting research obtains (1) Data through intervention or interaction with the individual, or (2) Identifiable private information. (45 CFR 46.102(f)) [8]. Moreover, Miller et al and others stress the ethics review and informed consent must balance clinical benefit and cost effectiveness including the overall effectiveness of NGS with the protection of patients in mind [9]. Aggregation of patient level data from across entities including laboratories and clinical facilities treating patients where identifiable patient information is generated will require a method to bind the information in the absence of patient consent. CMS should state clearly that Patient Safety and Institutional Review Board (IRB) oversight Part B(2)(c) obtaining consent is required and enforced where identifiable patient data generated.

As data scientist, researcher and former NIH funded investigator, I am of the strong opinion the long term impact of the NCD mandate will have on the future of NGS and treatment, strict adherence to standards of data collection and sharing must follow to achieve standardized real-world metrics. With enough resources, laboratories, clinics and hospitals can apply to CMS to become a prospective registry as outlined and discussed in the NCD but those very same entities should be required to observe standardized data sharing requirements, quality reporting and, above all else, the highest regard for patient safety, privacy and protections.

Respectfully,

Patricia Goede, MS, PhD

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January 17, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Dear Director Jensen:

Myriad Genetic Laboratories, Inc. is pleased to submit these comments on the Centers for Medicare & Medicaid Services’ (CMS’) Proposed Decision Memorandum for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N) (“Proposed Decision”). Myriad appreciates CMS’ efforts to develop national coverage policy for somatic multi-gene sequencing panels that use an NGS platform to test solid tumor samples in patients with advanced cancer. We support the agency’s proposal to cover nationally those in vitro diagnostics that the Food and Drug Administration (FDA) approves for companion diagnostic indications to specify FDA-indicated treatment options for a patient’s cancer.

In particular, we are writing to make the agency aware of additional FDA-approved tests referred to as “complementary diagnostics,” which should also be covered under the Proposed NCD. Like companion diagnostics, the analytical and clinical validity of complementary diagnostics is verified by the FDA through the required Premarket Approval (PMA) process. Complementary diagnostics, like companion diagnostics, are included in the FDA package insert labeling for the associated therapeutic anti-cancer drug or biological product. The FDA-approved complementary indications for these tests are based on data from clinical trials showing that the tests delineate subpopulations of patients into different benefit/risk categories for taking the therapeutic product. Based on this evidence of clinical utility and the established analytical and clinical validity of these FDA-approved complementary diagnostics, we respectfully recommend that CMS cover them nationally under the Final Decision in Section A if such tests are somatic multi-gene sequencing panels that use an NGS platform to test solid tumor samples in patients with advanced cancer.

Section A.2.a of the agency’s Proposed Decision requires that any test covered under the NCD be an “FDA-approved companion diagnostic.” The FDA has defined a companion diagnostic device in guidance as “an in vitro diagnostic device that provides information that is essential for the safe and effective use of a corresponding therapeutic product.”¹ The companion diagnostic device’s use is stipulated in the labeling of both the diagnostic and therapeutic product. The FDA has approved many tests as companion diagnostics, including Myriad’s BRACAnalysis CDx test for BRCA1 and BRCA2 germline mutations, which the FDA has approved as a companion diagnostic for LYNPARZA (olaparib).²

FDA has also approved several assays as “complementary diagnostics” through the same PMA regulatory process. The FDA has not formally defined the term “complementary diagnostic” in regulations or guidance, as it has for companion diagnostics. However, FDA appears to define a complementary diagnostic as an FDA-approved in vitro diagnostic that identifies a biomarker-defined subset of patients with a different benefit/risk profile than the broader population for which a therapeutic product is indicated, but which is not required to receive the therapeutic product. Under the Proposed Decision, FDA-approved complementary diagnostics would not be covered under Section A, although they would be eligible for Coverage with Evidence Development under Section B. We believe that CMS’ analysis in support of covering FDA-approved companion diagnostics also supports immediate coverage for complementary diagnostics.

As CMS notes in the Proposed Decision, FDA is responsible for evaluating the analytical and clinical validity of a diagnostic test. Specifically, CMS states: “FDA approval ensures that the device has been analytically and clinically validated in the population previously studied to support CMS to identify the patient health outcomes associated with the benefit of a specific therapeutic intervention as described on the FDA label.”

In vitro diagnostics that are classified as Class III medical devices are subject to FDA PMA under section 515 of the federal Food, Drug & Cosmetic Act and 21 CFR part 814. This is the most rigorous type of marketing review required by the FDA. Diagnostics approved under PMA are subject to the same requirements regardless of whether the associated therapy’s FDA-approved labeling includes a companion or a complementary diagnostic indication. FDA-approved diagnostics with complementary designations thus have demonstrated analytical and clinical validity identical to their companion diagnostic counterparts.

The determination as to whether a diagnostic receives a companion or complementary indication is rendered based on the drug’s performance in the specific trial population and is independent of the analytical performance and clinical validity of the diagnostic. For example, Myriad’s BRACAnalysis CDx³ test’s pre-market approval was recently supplemented to include a complementary diagnostic indication for ZEJULA (niraparib) in addition to its companion indication for LYNPARZA (olaparib). The approval of BRACAnalysis CDx as a complementary diagnostic for ZEJULA required the test to meet the same regulatory analytical and clinical validity standards as it did for the companion indication for LYNPARZA. The test’s receipt of a companion indication for LYNPARZA and a complementary indication for ZEJULA is due to the varying magnitude of benefit from the therapy shown in the clinical trial populations. This, in turn, largely resulted from the structure of the clinical trial – all comers in the ZEJULA trial as opposed to biomarker-positive patients only in the LYNPARZA trial. However, irrespective of whether a test like BRACAnalysis CDx is approved for a companion or complementary diagnostic indication, the analytical and clinical validation remains the same because the test is still going through FDA’s PMA process.

Because the FDA review process for drugs and biologics does not take into consideration the full therapeutic class effect or data outside the narrow clinical trial population, CMS must only look at the evidence of the subpopulations from the trial and apply this evidence more broadly to the Medicare population and the real world paradigm experienced by physicians in order to assess clinical utility of complementary diagnostics. Like companion diagnostics, complementary diagnostics show clinical utility by aiding in treatment selection. The data supporting this utility is generated in the FDA approval process and is evident in the therapeutic product’s patient management information as well as the intended use of the diagnostic device. In the Proposed Decision, the agency states that “diagnostic laboratory tests using NGS are most clinically useful for patients when the test reliably gives results that allow the patient and physician to make informed treatment decisions based on evidence-based interventions that improve health outcomes.” Just like companion diagnostics, complementary diagnostics also achieve this clinical application and benefit.

CMS explains in the Proposed Decision that in its clinical utility analysis, “[i]n order to provide evidence demonstrating improvements in health outcomes, we expect that the test will serve to directly manage the patient’s cancer in two different ways.” First, the test can directly manage the patient’s cancer when it is “essential for the use of one or more therapeutic interventions.” This language is clearly and directly applicable to companion diagnostics. By definition, companion diagnostics are “essential for the safe and effective use of a corresponding therapeutic product.” For this reason, even though the FDA does not determine clinical utility through its approval process of a diagnostic (that is CMS’ role), FDA-approved companion diagnostics are deemed to improve health outcomes and demonstrate clinical utility simply because they are required for the use of a drug that has been shown to improve health outcomes.

The Proposed Decision states that a test’s utility to directly manage a patient’s cancer can also derive from the ability of the “validated test [to] identif[y] patients in the same population who have been previously studied to benefit from such therapeutic interactions.” This statement holds true for complementary diagnostics. As noted above, the agency states in the Proposed Decision that FDA approval “ensures that the device has been analytically and clinically validated in the population previously studied” and that this “support[s] CMS to identify the patient health outcomes associated with the benefit of a specific therapeutic intervention as described on the FDA label.” The clinical utility data for tests that have been FDA-approved as complementary diagnostics, however, also support their value to improve health outcomes by identifying which particular patient populations are most likely to benefit from the approved therapeutic.

Complementary biomarkers are defined by their important role in identifying sub-populations likely to receive greater or lesser benefit from a therapy relative to the larger population for which the therapy is indicated. Although a complementary diagnostic is not a prerequisite for the safe and effective use of the therapy, it provides significant personalized genomic information that allows for more informed decision-making between a patient and provider as to the best course of treatment for each individual patient. The very fact that the outcomes data for the subpopulations from the clinical trial as identified by the complementary diagnostic are included in the therapy’s label supports the clinical utility of the diagnostic when used in a manner supported by those data.

Further, these diagnostics and their biomarkers are so significant in their clinical application that they require FDA approval (not clearance) to be included in the drug label. This is particularly important when an FDA-approved therapy carries significant side effects or where there is no clear standard of care for the therapy’s use. Like companion diagnostics, complementary diagnostics thereby also demonstrate clinical utility by “guid[ing] the selection of proven treatment,” and improving health outcomes by encouraging the use of therapeutics in subpopulations where the magnitude of benefit is likely to be greater than in other subpopulations based on risk/benefit information in the therapy’s label. As is the case with companion diagnostics, complementary diagnostics are used to guide treatment for patients to improve health outcomes because patients make more informed decisions on selecting treatments with demonstrated evidence of efficacy based on their tumor’s specific biomarkers.

Finally, the FDA-approved intended use of the complementary diagnostic may be the most compelling evidence of clinical utility to support national coverage by CMS. The combination of the outcome data for the biomarker subpopulations within the therapy’s label with the intended use of the FDA-approved device confirms that the biomarker status revealed by the test will change physician behavior to improve health outcomes for their patients, thereby validating the clinical utility of the complementary diagnostic.

Below are excerpts of the intended use statements of selected FDA-approved complementary diagnostics illustrating their associated clinical utility (emphasis added):

We applaud the agency for its groundbreaking decision to provide national coverage for somatic multi-gene sequencing panels that use an NGS platform to test solid tumor samples in patients with advanced cancer and that are FDA-approved with companion diagnostic indications. We believe that the rationale for the coverage in Section A of the Proposed Decision extends to FDA-approved complementary diagnostics along with companion diagnostics. FDA analytical and clinical validity standards are the same for both, and complementary diagnostics improve patient health outcomes by providing physicians and patients with more specific information on the likelihood of a patient succeeding on a therapy.

As such, we strongly recommend that in the Final NCD, CMS revise Section A.2.a of the Proposed Decision to read: “the test is an FDA-approved companion or complementary in vitro diagnostic.” This addition to the coverage decision will ensure Medicare beneficiaries with advanced cancer and their physicians have access to the full category of FDA-approved diagnostics associated with FDA-approved cancer therapies to inform critical treatment decisions in the course of their care. Furthermore, the inclusion of complementary diagnostics in the Final Decision will further the goals of personalized medicine without lowering the quality or evidentiary standards for determining analytical validity, clinical validity and clinical utility of these important tests.

Thank you for your consideration of these comments. Please do not hesitate to contact me at 202-449-7738 if you have any questions or need additional information.

Sincerely,

Kimberly J. Linthicum
Vice President, Government Affairs
Myriad Genetic Laboratories, Inc.

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On behalf of Johnson & Johnson (“J&J”), I am pleased to offer the following comments on the Centers for Medicare & Medicaid Services’ (CMS) Proposed Coverage Decision Memorandum (NCD) for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer.

Advances in science and technology are opening new horizons in healthcare and hold the promise of truly precise, personalized medicine. Today’s healthcare systems demand improved medical outcomes at lower costs, and patients deserve them. In this context, J&J drives this transformation of care at every stage in life, from wellness to illness. Our role within the life sciences spectrum is to put diagnostic technologies and solutions in the hands of healthcare providers to identify illness sooner, intervene earlier, cure people living with chronic diseases and potentially prevent diseases even before the onset of symptoms, as well as monitoring for disease management.

We support CMS’ proposed national coverage decision in recognition of the important role for genetic profiling to help identify the most effective therapies for patients with cancer. The information provided by NGS assays is an important tool to help clinicians and their patients make the best decisions. By signifying Medicare’s support of the role of NGS, CMS is providing critical support to the ongoing research and development in this area.

While we are supportive of the proposed decision to provide Medicare coverage for FDA-approved NGS companion diagnostic tests, we appreciate the opportunity to raise the following issues for consideration. NGS-based diagnostic testing holds great promise to advance personalized medicine to treat patients more effectively when they develop disease, and to potentially help prevent disease from developing. Therefore, we recommend several modifications to the proposed NCD to help ensure Medicare beneficiaries will have access to the benefits of future developments in this area.

CMS Should Ensure That Implementation Of This NCD Does Not Disrupt Care For Cancer Patients Or Future Innovations

The proposed NCD does recognize the evolving role of NGS to guide cancer treatment as it only provides for coverage with evidence development (CED) for tests that are: FDA-cleared or -approved but for which no companion diagnostic indication currently exists; or, the diagnostic laboratory test using NGS is provided within an NIH-NCI National Clinical Trial Network clinical trial.

We appreciate CMS’ position that it cannot assess the clinical utility of tests that cannot demonstrate evidence of analytical or clinical validity and are not developing evidence in the context of a clinical study. However, this issue must be balanced against the current utilization of NGS-based diagnostic testing that could potentially be disrupted for Medicare patients if the proposed NCD is implemented. We are supportive of policies that encourage evidence-based medicine, and we recognize the intent of the proposed NCD to provide such incentives through CED. However, we are also concerned the proposal will too abruptly end existing coverage for many NGS-based tests that are not FDA approved or cleared, including some for cancers for which FDA-approved NGS-based tests do not exist.

As we strongly believe that one company or organization alone will not forge the future of personalized medicine, we collaborate strategically with external partners who are leaders in their specific technological areas. In some cases, these partners may produce only a single test. To maintain a thriving and evolving diagnostics development ecosystem, CMS must proceed carefully and avoid an overly expansive non-coverage policy that could inadvertently eliminate small-scale developers of advanced diagnostic tests who are unable to comply with the proposed CED requirements.

CMS Should Amend This NCD So That It Does Not Preclude Coverage For NGS-Based Tests For Other Cancer Indications

CMS is suggesting that this proposed decision be focused entirely on oncology panels, and proposes that indications of cancer that are not noted explicitly in its decision are non-covered. We urge CMS to not preclude coverage for other NGS-based tests at this time for other indications of cancer.

There are a number of cancer conditions for which FDA-approved NGS tests do not exist, and for which lab-developed tests delivered by providers offer the most appropriate treatment pathways. The proposed NCD would not only disrupt care for patients with other cancer indications than those for the current list of FDA-approved NGS tests, but, by ending Medicare reimbursement, it would also likely disrupt the development of needed innovation and evidence generation for other tests.

CMS Should Allow Exceptions To Its Noncoverage For NGS As A Laboratory Diagnostic Test If The Patient Has Previously Received The Same Diagnostic Laboratory Test Using NGS

CMS reviewed the evidence to support the frequency of performing a diagnostic laboratory test using NGS and found the publications reviewed did not show that patients received multiple diagnostic laboratory tests using NGS. The analysis did not identify benefits of further diagnostic laboratory testing using NGS beyond identification of genetic alterations of the patient’s advanced cancer, which would lead the patient to select from companion therapeutic products, FDA approved anti-cancer agents, or enrollment into cancer clinical trials. Therefore, it proposed to only cover NGS as a diagnostic laboratory test if the patient has not previously received the same diagnostic laboratory test using NGS.

Once again, we urge CMS to exercise caution to avoid cutting-off future innovation by allowing flexibility for local contractors to allow NGS-based diagnostic tests to be covered when there is evidence of a medical benefit. As the science of NGS-based tests evolves, previously collected information will not provide accurate information if a patient subsequently acquires or develops new mutations. Including this kind of flexibility will help to prevent the NCD from becoming an obstacle to rapid advancement in the fight against cancer.

Laboratories’ Capacity To Generate Evidence

CMS also asked several questions intended to gather information about the implications of the proposed NCD on laboratories. One question related to the capacity of laboratories to assess analytical and clinical validity.

There are important limitations related to the fact that some disease conditions afflict only a small patient population. The lack of patients with such conditions can create burdens on independent laboratory test developers to meet the regulatory thresholds due to lack of samples. Perhaps CMS could consider a cut-off that would exempt small labs from general evidence requirements, and instead rely on CLIA certification and documentation of unmet clinical need.

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I’d like to thank CMS for the opportunity to comment on the proposed NCD for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer. I am a board-certified molecular genetic pathologist and the medical director of a CLIA-certified laboratory that provides laboratory developed NGS-based oncology testing. As part of a multidisciplinary team, I work closely with oncologist, pathologist, and other health care staff to provide appropriate, quick, accurate, and cost-effective testing that best enables our healthcare team to care for our patients.

The NGS-based testing performed in our laboratory is important to Medicare beneficiaries as it accurately, cost-effectively, and quickly identifies patients that may benefit from targeted therapy. Of the patients that underwent solid tumor NGS testing in our lab in 2017, greater than 90% received guidance on approved therapy for their cancer type, approximately 20% were identified for a clinical trial at our institution, while less than 3% received no therapy guidance at all as a result of testing. More importantly, 13% of patients tested on our focused solid tumor NGS testing went on to receive genomic-driven targeted therapy. We continue to monitor the largely positive response and outcomes for these patients. As these numbers suggest, we develop NGS-based testing that adheres to evidence-based guidelines outlined by professional societies, such as ASCO, NCCN, and CAP. However, under the proposed CMS coverage policy our testing would be excluded from coverage. Although FoundationOne CDx (F1 CDx) has clinical utility and we encourage its use under certain indications, it is not the only clinically acceptable test for advanced cancer patients. It should be noted that CMS’s proposed NCD will impose restrictive criteria on other tests, like the testing we provide, and is at odds with the local coverage policy we adhere to for NGS-based tests. Furthermore, it is important that NCD guidelines be evidence-based. Foundation medicine has postulated how its test may effect clinical trial enrollment or use of targeted therapy. However, no clinical trials or empirical evidence have been provided to show F1 CDx impact on patient care or outcomes, despite its relatively high proposed cost. The testing that we perform is tracked not only for its validity (we have compared over 60 patient samples with F1 CDX) but for its impact on patient care at our institution (as discussed above). This is fundamental to justify policy and control costs.

In conclusion, this proposed policy would have implications far beyond the F1 CDx test. It would impose very narrow criteria for coverage that would exclude many important laboratory-developed NGS-based tests that have similar clinical utility to Medicare beneficiaries at a much lower cost than proposed for F1 CDx. I urge revision of this proposed NCD be based on actual evidence on the impact on patient care and outcomes as well as cost considerations which will support coverage of wider-range of clinically useful NGS-based tests for advanced cancer care.

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January 17, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244
Submitted via email: tamara.syrekjensen@cms.hhs.gov and the NCA Docket at CAGinquiries@cms.hhs.gov

Dear Ms. Jensen,

I am an academic molecular pathologist at the University of Washington, where I co-direct the Genetics and Solid Tumors Laboratory that offers billable clinical NGS services to cancer patients, and has served as an advanced training environment for over 30 residents and fellows in this area of medicine since 2011. The thoughts expressed in this letter are my personal views and do not necessarily reflect those of my institution.

First off, thank you for the opportunity to comment on the draft national coverage determination (NCD) (CAG-00450N) which pertains to the FoundationOne CDx (F1CDx) test. My work, and the work of many additional faculty at our institution revolves around the development and clinical implementation of laboratory developed molecular testing procedures as billable clinical services for Medicare beneficiaries in the academic medical center setting. This work has included the development of several next-generation sequencing (NGS) based laboratory-developed tests (LDTs). Our ability to update and tailor these tests to our patient population needs helps us to provide the best possible cancer patient care. Specialized academic groups such as ours are an engine that drives quality and innovation in this emerging field, while also providing the careful training to residents and fellows that is critical for current and future diagnostic-medicine physicians.

If the current draft of the F1CDx national coverage decision is implemented, prohibiting Medicare reimbursement for currently available LDTs outside of narrow criteria, there are likely to be several detrimental effects for our cancer patients and academic institutions, both near-term and long-term.

1) It will limit innovation in this rapidly evolving field. My understanding is that FDA does not currently have a rapid or efficient process that allows for frequent updating of tests that is needed to include new genes/analytes to meet clinical needs. This aspect of medicine is handled well by the academic molecular pathology community and helps to ensure optimal care for our cancer patients.

2) Due to the high costs and lengthy time to FDA approval, it will concentrate effective monopoly power into a one or a few labs, driving up health care costs and limiting incentives for quality improvement for our cancer patients. NGS-based clinical diagnostic services have been in use for patient care for more than half a decade, and are increasingly central to cancer patient care. NGS-based laboratory methods are best provided by physicians and advanced diagnostics practitioners with access to detailed clinical information to inform our interpretations, and strong relationships with our cancer care providers. Requiring FDA-approval of NGS methods for Medicare reimbursement will limit where these services can be performed, effectively restricting testing. Costs for FDA approval of devices through the 510(k) or pre-market approval pathways were estimated at $31 million ($24 million spent on FDA dependent and/or related activities) and $94 million ($75 million spent on stages linked to the FDA), respectively, in an Avamed survey. These costs are prohibitively high for most academic medical centers. (SOURCE: https://www.advamed.org/sites/default/files/resource/30_10_11_10_2010_Study_CAgenda_makowerreportfinal.pdf)

3) It will limit medical training and education that is a critical mission of academic medical centers, and increasingly important for the future of health care as genomic medicine is used more broadly in practice. We have seen an effective monopoly before for key medical services and know the risks to medical training. BRCA1/2 testing was restricted to a single for-profit commercial lab until 2013, resulting in few medical students and residents outside of highly specialized areas being well-trained in this critical area of medicine. I anticipate a similar fate for NGS-based tumor testing will occur for our trainees if academic medical centers are no longer able to provide these services on a clinical basis as part of their training.

My recommendation to CMS:

1) Remove language regarding prohibition on reimbursement for NGS procedures used for clinical applications that is contained in the current draft F1CDx NCD. The restriction on the underlying methodology is beyond the scope of an NCD and is an unprecedented restriction on currently-available diagnostic methods. NGS is the widespread and currently dominant technology used in many different types of clinical laboratory methods that are currently reimbursed by Medicare, and to restrict reimbursement for these methods based on the FDA approval of a single test for a narrowly-defined patient population (advanced oncology patients), does not make sense.

2) Remove the requirement of FDA approval or clearance from the draft F1CDx NCD. This will allow existing methods to continue to receive Medicare reimbursement and provide optimal patient care at a local level, under the guidance of expert practitioners.

3) Provide language in the NCD stating that Academic Medical Centers that are already performing billable NGS-based tumor for Medicare Beneficiaries can be granted coverage. As training institutions, academic medical centers should be recognized for the critical services they provide for the not only patient care, but physician training.

4.) Exploration of the coverage with evidence model should be continued outside of the restrictions of the F1CDx NCD. The concept of a coverage-with-evidence model is an interesting approach to link reimbursement and clinical utility, but such a novel reimbursement approach is best served as a wider project to establish an appropriate policy – including such a requirement in a NCD addressing a single, narrow application seems out of place and is unlikely to be scalable across multiple applications. There are currently several not-for-profit registries and trials that should be considered as possible models that can be used to assess the implementation of coverage with evidence models.

The above recommendations will help to preserve the current innovation in the emerging field of precision oncology, facilitate training of the next generation of cancer providers, and most importantly, will ensure the best care for cancer patients and their families.

Thank you again for the opportunity to comment on this draft NCD. I would be pleased to provide any additional background that could be useful or otherwise be a resource for CMS in considering this important national coverage decision for our field.

Sincerely,

Colin C. Pritchard MD, PhD
Associate Professor
Head, Genetics Division
Co-Director, Genetics and Solid Tumors Laboratory
Department of Laboratory Medicine Box 357110
University of Washington
1959 NE Pacific Street
Seattle, WA 98195
cpritch@uw.edu
Desk: (206) 598-6131
Fax: (206) 598-6189

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This proposed decision for requiring FDA approval for NGS testing assays for cancer patients will have a detrimental effect on patient care, and stifle research and innovation in the rapidly evolving field of precision medicine.

Many hospitals, companies, and academic institutions across the country provide NGS testing to their patients in an already highly controlled and regulated manner. In many cases these tests have proved invaluable for directing patient treatment plans. The cost and time burden for achieving FDA approval will limit the availability and diversity of these tests by restricting providers to a few large companies able to achieve the capital for FDA testing. This will extremely limit the number of institutions able to contribute to innovation in the field, and lead to a stagnant “one size fits all approach” which is inappropriate in the field of precision medicine which is still rapidly evolving.

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January 17, 2018

Ms. Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mail Stop #S3-02-01
7500 Security Boulevard
Baltimore, Maryland 21244

Dear Ms. Jensen,

The Association of American Medical Colleges (AAMC) appreciates the opportunity to share with the Centers for Medicare and Medicaid Services (CMS) our comments on the Proposed Decision Memo entitled “Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N).” AAMC is a not-for-profit association representing all 149 accredited U.S. medical schools, nearly 400 major teaching hospitals and health systems, and more than 80 academic and scientific societies. Through these institutions and organizations, the AAMC represents nearly 167,000 full-time faculty members, 88,000 medical students, 124,000 resident physicians, and thousands of graduate students and postdoctoral trainees in the biomedical sciences.

The scope of the proposed national coverage decision (“Proposed NCD”) potentially impacts a growing number of diagnostic tests created using NGS, both those that are used in practice now and those that are being developed. The AAMC shares the concerns voiced by the academic medicine community and many others that limiting coverage for these patients for diagnostic tests to those tests approved or cleared by the U.S. Food and Drug Administration (FDA) could: 1) impede innovation; 2) increase the use of older or outdated technology; 3) result in Medicare beneficiaries receiving lower quality diagnostic testing; and 4) drive institutions to seek FDA approval for diagnostic tests when no such approval is now required and a national discussion about regulation of these tests is actively ongoing. Given the significant concerns with this proposed approach to determining coverage for diagnostic tests for patients with advanced cancer, the AAMC recommends that CMS delay issuing a final national coverage decision until the agency has an opportunity to receive and consider alternatives to limiting coverage to FDA-approved diagnostic tests developed using NGS technology.

By adding the significant hurdle of FDA approval to getting coverage for NGS-developed tests, CMS will create disincentives for creating and improving innovative tests for cancer patients. Academic medical centers and teaching hospitals provide innovative and cutting edge treatments for patients, and proven and precision diagnostic tests give providers information on which to make healthcare decisions. When providers have access to more advanced diagnostic tools, treatment decisions may be more effective and result in better outcomes with fewer delays caused by inaccurate or imprecise diagnoses. The AAMC shares CMS’ goals of ensuring that the diagnostic tests used to determine the course of treatment for all patients, including Medicare beneficiaries, are being deployed with confidence as to their clinical and analytic validity. CMS has long looked to FDA imprimatur as the method for allowing Medicare coverage. However, at a time of rapidly improving diagnostic testing that is necessary for personalized care, allowing only for FDA approval as a prerequisite to Medicare payment may be harmful to Medicare patients and limit innovation. This Proposed NCD could also limit the use of these diagnostic tests to those institutions or companies that have chosen to seek FDA approval.

Focusing this coverage decision on a technology underlying a test, not the test itself, may result in the unintended consequence of driving the creation or adaptation of similar diagnostic tests using older or other technologies. Underlying many of these concerns is the fact that NGS is not itself a test that leads to a diagnosis or provides results, but is a technology platform used to develop diagnostic tests. This proposed platform-based coverage decision is therefore very different than most national coverage decisions, even those that focus on specific technologies like positron emission tomography (PET) scans or magnetic resonance imaging (MRI). In those cases, the technology that is the focus of coverage decisions generates the image and is more analogous to the diagnostic test itself, not the NGS that was employed to create the diagnostic test.

The AAMC is concerned that this Proposed NCD could result in Medicare beneficiaries receiving less effective or advanced diagnostic tests, which could mean that they receive less than optimal treatment. Acquiring FDA approval of a single diagnostic test as a medical device is an expensive and lengthy process. Because FDA approval is not currently required for these tests, a decision to continue using the tests but not seek FDA approval could restrict the availability of these tests to those patients who are not covered by Medicare. This would result in more limited access to these diagnostic tools by Medicare beneficiaries and would create an economic obstacle to equitable care.

This proposed NCD pushes institutions to seek FDA approval for diagnostic tests when the current national discussion about how NGS-developed tests and other diagnostic tools should be regulated is unsettled. The breadth of the Proposed NCD has led to concerns at academic institutions about the impact on laboratory-developed tests (LDTs) developed using NGS technologies and offered by clinical labs at academic health centers. LDTs are not currently regulated by the FDA, although the labs which develop the tests are subject to regulation and inspection through the Clinical Laboratory Improvement Amendments (CLIA) overseen by CMS. Over the past several years, the debate about the FDA’s role in the regulation of LDTs, and what role CMS has or should have through CLIA, has played out across the agencies and is now in Congress. This discussion is relevant to the Proposed NCD, as it has raised questions about when FDA approval should be required, and through what mechanism such approval should be considered and granted. The suitability of the FDA’s medical device regulations for reviewing LDTs was called into question after the FDA released draft guidance in October 2014 on its proposed oversight of LDTs and in vitro diagnostic (IVD) tests using the existing device regulations. In January 2017, more than two years after the draft guidance was released and in the final days of the outgoing administration, the FDA announced that it would not be issuing final guidance on the regulation of LDTs and instead released a discussion paper synthesizing the FDA’s response to over 300 sets of comments to the draft guidance and setting forth its proposal for significant modifications that could be made to a future version of the agency’s efforts. This has left many questions about the FDA’s role with respect to LDTs unresolved. The pathway to FDA approval for LDTs using NGS is unclear to many institutions, especially following the FDA’s stalled 2014 draft guidance, 2017 white paper, and other guidance on NGS.

The AAMC is concerned that the Proposed NCD creates disincentives for creating innovative diagnostic tools, seeking out new technologies, and providing Medicare beneficiaries with opportunities for equitable care. The AAMC is grateful for CMS’ assertions that the goal of this proposed NCD is to initiate meaningful engagement with stakeholders in the community and to engage in a thoughtful process. We recommend that CMS continue to engage stakeholders and experts and consider delaying issuing a final national coverage decision until additional recommendations for demonstration of clinical and analytic validity can be presented to and analyzed by CMS. If the final national coverage decision is not delayed for further engagement with stakeholders, CMS should consider listing additional indicators of clinical and/or analytic validity that could be the basis for coverage. FDA approval could be included as one option for demonstrating the usefulness of a diagnostic test, but to require FDA approval for every covered test developed with NGS technology risks undermining the promise of better diagnostic tools.

We appreciate the opportunity to comment and would be happy to discuss these comments further. Please contact me or Heather Pierce, Senior Director for Science Policy and Regulatory Counsel at hpierce@aamc.org or (202) 478-9926 with any questions.

Sincerely,
Karen Fisher, JD
Chief Public Policy Officer

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SUBMITTED ELECTRONICALLY

Dear Director Jensen,

We thank you for providing this opportunity to comment on a proposed National Coverage Decision (NCD) regarding Next Generation Sequencing (NGS) analysis of tumors from patients with advanced cancer. We applaud CMS for proposing to provide coverage for next generation sequencing, which will give Medicare patients the opportunity to receive accurate, individualized, and effective care. We are glad that CMS acknowledges that NGS testing provides a clinical benefit to patients.

However, we have significant concerns about the scope and breadth of the proposed changes, as well as the speed with which the proposed changes are set to take effect. The proposed NCD limits coverage only to FDA-approved NGS tests, establishes very strict coverage criteria with regards to evidence development, and explicitly does not cover NGS tests that do not meet these criteria. We strongly urge CMS to reconsider the proposed limitations on coverage for NGS-based testing, which are overly restrictive and could dramatically reduce patient access virtually overnight.

Precision Medicine at Vanderbilt
Vanderbilt University Medical Center (VUMC) is internationally recognized as a leader in personalized medicine and precision cancer medicine. Examples of related activities include the development of innovative programs like VUMC’s Pharmacogenomic Resource for Enhanced Decisions in Care & Treatment (PREDICT), which uses patients’ genetic information to predict and prevent adverse drug side effects. MyCancerGenome, developed at the Vanderbilt-Ingram Cancer Center, is an internationally recognized precision cancer medicine resource that provides information about somatic mutations, therapeutic implications, and relevant clinical trials. Also of note, the Vanderbilt University School of Medicine Department of Pathology, Microbiology and Immunology has pioneered the use of Diagnostic Management Teams to ensure that physicians and patients get the complex clinical testing they need, while reducing unnecessary tests.

One Size Does Not Fit All
Indeed, we have incorporated multiple NGS panels into our testing algorithms at Vanderbilt, including large panels as discussed in this NCD, but also small panels, and plasma testing. We believe that there is no one size fits all NGS test for advanced cancers. We do not practice medicine in a vacuum at VUMC. Rather, we have multiple options, so that we can tailor testing to the patient, the sample, and cancer type in order to efficiently and cost-effectively provide patients and physicians the information that they need. In other words, we practice personalized medicine. The restrictions in this NCD would greatly damage our efforts to provide personalized cancer care to Medicare patients, including by potentially limiting use of Diagnostic Management Teams. These changes would undoubtedly reduce the quality of the care our Medicare patients receive.

NGS in Practice at Academic Medical Centers
There are currently only a handful of labs that can meet the proposed criteria, and it is unclear that they will be able to handle the volume of testing necessary without significant delays in return of results. Such delays will adversely affect patients’ treatment and outcome. Furthermore, when we at VUMC interpret NGS results, we have the entire clinical record at hand, which allows us to provide critical clinical and morphologic context to the data. This context is crucial in providing truly individualized medicine and is not available from distant commercial labs. Furthermore, we often test limited samples, such as fine needle aspirations, with an NGS test that is a much smaller panel and does not require nearly as much DNA as the large panels that were recently approved. The procedure to obtain this small amount of tissue frequently carries less risk, morbidity, and recovery time for the patient than a procedure to obtain the large amount of tissue necessary for the approved panels. If this NCD is approved, we will have to begin subjecting patients to much more invasive biopsies, with all the risk and adverse outcomes that entails, in order to get the necessary amount of tissue. Some patients will not be able to tolerate these procedures and may have to forego genetic testing altogether. Furthermore, most FDA approved tests are not validated for a wide variety of sample types, such as fine needle aspiration, pleural or cerebrospinal fluids, or DiffQuik stained slides. Use of these rarer sample types can greatly benefit patients, as they require much less invasive procedures to generate sufficient diagnostic material.

CAP/CLIA
Additionally, NGS is a technology, not a diagnostic test. This NCD focuses on a specific technology that is not tied to a specific biomarker. Previous coverage determinations have been based on clinical utility, independent of test methodology and regulatory approval. Thus, the proposed approach runs counter to established coverage determinations. Furthermore, requiring FDA approval for coverage is inconsistent with the FDA’s position on laboratory derived tests (LDTs), including the recent announcement that the FDA will not alter its position on enforcement discretion for LDTs. This NCD requires FDA approval for coverage, and thus establishes the FDA as setting the regulatory bar for acceptable clinical tests and thus the practice of medicine.

The proposed NCD will eliminate coverage for other NGS tests for advanced cancer patients enrolled in Medicare. The CLIA ’88 laws explicitly state that laboratories have legal rights to develop laboratory derived tests (LDTs). These tests are run with high quality at many academic institutions and reference laboratories, and the requirement for an FDA approved assay ignores oversight mechanisms that ensure the quality of LDTs. The oversight mechanisms include board certification, and re-certification, of pathologists, certification through the Clinical Laboratory Improvement Amendments act (CLIA), inspections by state Department of Health, inspections by the Joint Commission on Accreditation of Healthcare Organizations (JHACO), and inspections by the College of American Pathology (CAP). Indeed, CAP has published extensive guidelines for the validation of NGS LDT assays, checklists for laboratory inspection that require labs to show the clinical and analytical validity of NGS LDTs, and Cap requires that labs participate in regular proficiency testing. Indeed, a recent peer reviewed publication has demonstrated that oncology biomarker LDTs have comparable performance to FDA-approved assays. (Kim, A.S. et al. 2017, Dec 14, JAMA Oncology, Comparison of Laboratory-Developed Tests and FDA-Approved Assays for BRAF, EGFR, and KRAS Testing). We believe that rigorous CAP/CLIA oversight is effective in producing high quality LDTs, and request that the NCD be modified to include coverage for LDTs developed in a CAP accredited lab.

Myeloid/Lymphoid Testing
Importantly, this NCD does not discriminate between testing for solid tumors and testing for myeloid/lymphoid tumors, but specifically non-covers testing for myeloid/lymphoid testing. These malignancies are most common in the Medicare population. NGS testing has become an important component of diagnosis, prognosis and therapeutic decision making in this space. The panels that are approved are not suitable for testing these types of diseases, as they do not have the necessary gene content, nor can they be run on the required sample type. This NCD would likely prevent Medicare patients with myeloid and lymphoid malignancies from receiving standard of care diagnostics, and would certainly adversely affect their care and therapy.

Implementation Timeframe
We believe that the proposed timeframe for the implementation of this NCD, which is less than two months from its approval, will lead to significant confusion and disruption in the oncology and pathology space. Thus, alternatively, CMS should consider finalizing only Section A of the proposed coverage decision at this time, and start a new NCD process to study the appropriate coverage of NGS LDTs more broadly. That would allow for a more substantive dialogue with the relevant stakeholders. We believe this route would avoid significant confusion and disruption.

We also have concerns about the “NGS test once per cancer” proposal, which attacks the very basis of personalized medicine by proscribing the ability to monitor patients during and after treatment. We know that cancer evolves under selection, and there are multiple known resistance mutations to targeted therapies, such as gatekeeper mutations in EGFR in response to erlotinib or in ALK in response to crizotinib. Furthermore, there are now therapies that can treat some of these gatekeeper mutations. Identification of resistance mutations, and consequently changing from an ineffective to an effective therapy, is and will be a crucial use of NGS testing.

Potential to Stifle Innovation
Molecular diagnostics is rapidly evolving, as is our understanding of cancer mutations as biomarkers. Requiring FDA-approval will prevent laboratories from quickly responding to include new mutations, or modalities of testing. We believe that this draft NCD will stifle innovation, decrease, not increase, quality of testing, and have detrimental effects on patient care.

Sincerely,

Thomas Stricker, MD, PhD
Assistant Professor, Dept. of Pathology, Microbiology and Immunology

Adam Seegmiller MD, PhD
Associate Professor
Dept. of Pathology, Microbiology and Immunology
Vice Chair for Clinical Pathology
Director of Laboratory Medicine and Hematopathology

Mary Zutter, MD
Co-Leader, Host-Tumor Interactions Research Program
Louise B. McGavock Professor of Pathology, Microbiology and Immunology
Professor of Cancer Biology
Vice President for Integrative Diagnostics

Samuel A. Santoro, MD, PhD
Dorothy B. and Theodore R. Austin Professor and Chair
Dept. of Pathology, Microbiology and Immunology

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Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Centers for Medicare & Medicaid Services (CMS) Proposed National Coverage Determination for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

Dear Ms. Jensen,

Thank you for the opportunity to provide comments on the above referenced proposed National Coverage Determination. We are a group of oncologists at the University of Colorado who actively participate in patient care, test result review, and consultation across multiple specialties to deliver the best possible care to our patients. We are writing in response to the Centers for Medicare and Medicaid Services Proposed National Coverage Determination for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer. With these comments we are representing ourselves and not the University of Colorado. While we applaud the recognition that NGS based testing in oncology has value, we are concerned about the impact of this proposed NCD on the local practice of oncology, and anticipate this could compromise access to medically appropriate molecular testing for our Medicare patients.

At the University of Colorado, we routinely send testing performed to our local molecular pathology laboratories, which are CLIA accredited and CAP inspected. These labs test samples from hundreds of patients per year using laboratory developed NGS tests. By using a local laboratory, we are able to communicate directly with our Molecular Pathology team to triage, expedite, and implement cost-effective algorithmic approaches to testing. By testing locally, we can achieve better patient care by having detailed discussions about test results, the technology utilized for testing, how the quantity and quality of the biospecimen can impact how we view test results, the potential need for resampling, and therapeutic choices for the patient.

We are deeply concerned that the impact of the proposed NCD would be to eliminate the ability of our local laboratory to perform testing. Our local laboratories perform many standard-of-care tests for our patients using NGS technology, and if instituted as written, the NCD could lead to a non-coverage determination for testing for a significant portion of our patients. If this results in closure of our local laboratories, all local patients will suffer from the lack of immediately available testing, as well as the lack of ability for us to efficiently communicate with the laboratory about testing details.

We are also concerned that the section regarding Coverage with Evidence Development (CED) sets an unachievably high bar by excluding many clinical trials which are not part of the NIH-NCI Clinical Trials Network. Our local laboratories do not have the resources to comply with the requirements of the CED criteria, and we similarly do not have the resources to step in for essential components. For example, participating in an outcomes registry is well beyond the scope of our local laboratories, and we are unable to assist in providing outcomes data.

In summary, while we are glad to see the recognition of the critical importance of NGS based testing to precision oncology, we urge CMS to reconsider the proposed restrictions on coverage for NGS-based testing. The proposed coverage determination focuses on a technology rather than a specific biomarker, and NGS testing is widely deployed clinically at this juncture. Imposing these restrictions would rapidly destabilize the substantial progress in personalized medicine to date.

Sincerely,

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January 17, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed Decision Memorandum on Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG #00450N)

Dear Ms. Jensen,

The Association for Molecular Pathology (AMP) is pleased to offer comments on the proposed decision memorandum entitled, “Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer.” This National Coverage Analysis (NCA) was issued in conjunction with the Food and Drug Administration (FDA)’s approval of the FoundationOne CDx (F1CDx), an NGS-based test as an in vitro diagnostic (IVD). The test was reviewed as part of FDA and the Center for Medicare & Medicaid Services’ (CMS) Parallel Review Program, where the FDA approval process and the CMS evaluation for coverage occur concurrently. We thank CMS for granting an extension to the comment period to allow additional time to address this proposed policy.

AMP is an international medical and professional association representing approximately 2,300 physicians, doctoral scientists, and medical technologists who perform or are involved with laboratory testing based on knowledge derived from molecular biology, genetics, and genomics. Membership includes professionals from the, academic medicine, hospital-based and private clinical laboratories, the government and the in vitro diagnostics industry.

AMP has been very supportive of streamlining the approval and coverage processes and applauds CMS for their recognition of the value of precision oncology diagnostics in the care of cancer patients as evidenced by the positive elements of the proposed National Coverage Analysis (NCA). However, the policy as written is deeply flawed. The requirements for coverage are unduly narrow in scope. In many clinical scenarios gene mutation analysis for cancer is standard of care. That is why over a hundred laboratories today offer NGS-based testing that is used in the care of literally thousands of patients every year. The proposed policy would render most of the tests offered by those laboratories as not covered with widespread negative ramifications.

AMP recommends CMS refocus this policy so that is applies ONLY to FDA-approved NGS-based tests (such as the F1CDx assay) and does not apply to any other NGS-based test. Coverage for other clinically- and analytically- validated NGS-based tests should continue to be covered as determined by existing local coverage determinations (LCDs) administered by local Medicare Administrative Contractors (MACs). This approach will be much less disruptive, allowing ongoing coverage evaluation and clinical scientific progress to continue and for coverage policies to respond more quickly to changes in the science.

Today most academic centers, leading cancer institutions, and essential community cancer centers have Clinical Laboratories Improvement Amendment (CLIA) certified laboratories providing validated laboratory developed gene panels using NGS technology. This policy, if finalized would supersede existing local coverage policies for most of those tests and create barriers for Medicare beneficiaries’ access to clinically useful testing. The policy imposes two very narrow restrictions that threaten the viability and accessibility of those tests to Medicare beneficiaries. First, it effectively concentrates all NGS-based cancer testing to a limited number of commercial entities. It eliminates coverage or imposes severely restrictive coverage with evidence (CED) requirements for all other laboratory tests utilizing NGS for cancer. These tests are currently recognized as the standard of care in oncology diagnostics and are being used to deliver high-quality, advanced cancer care across the country. These tests meet or exceed CLIA standards, and/or other federal, state, professional practice standards, and provide clinically significant information for patients with advanced cancer. Many have demonstrated to be of highest quality by peer review through the College of American Pathology (CAP) laboratory inspection processes. This policy, by denying coverage to those tests, eliminates coverage for tests at leading academic center and cancer care programs in every jurisdiction, with the end result of a decrease in the quality of care being delivered to the sickest and most vulnerable Medicare patients being treated for cancer.

The policy is also flawed by recognizing coverage only for cancers with an FDA-approved companion diagnostic indication, i.e., lung, melanoma, breast, ovarian and colon cancers. There is clear scientific evidence, some provided below, that the value of NGS-based testing in cancer extends far beyond these first diseases for which coverage is granted. The existence of an FDA-approved companion diagnostic indication should not be an evidentiary standard required for coverage. Rather, the science and data should determine what care patients receive and what tests are reimbursed.

CMS should clarify that local MACs may continue to evaluate NGS-based tests to determine the scope of coverage within their individual jurisdictions for tests other than FDA-approved NGS-based IVDs. AMP offers the following detailed comments with supporting evidence to bolster our recommendation to refocus the scope of the final policy and highlight significant inconsistencies with current coverage and coding structures for molecular pathology procedures utilizing NGS-based platforms. Our aim remains to ensure that high-quality clinically-proven testing continues to be available broadly when appropriate. We welcome the opportunity to discuss the current state of molecular diagnostic testing, including NGS technology, with CMS to inform this and other future coverage policies.

Molecular diagnostics is a field dominated by NGS-based approaches and laboratories continue to migrate testing protocols to NGS-based platforms. For this reason, NGS has become the most frequently utilized laboratory method for standard-of-care for genomic tumor profiling. While individual gene mutations tests can provide essential information regarding genomic aberrations, NGS technology can provide cost efficient interrogation of a large set of genes simultaneously (Kulkarni, S et al). This testing strategy is critical for small specimens such as fine needle aspirates, which is the specimen most often obtained for characterizing lung tumors. Use of the technology can be found at more than 120 CLIA-certified clinical diagnostic laboratories that provide professional services for cancer diagnosis and treatment (Nagarajan, R et al).

NGS is not in itself a diagnostic test. Laboratory testing using NGS technology has applications in the management and treatment of patients with a variety of conditions including inherited diseases, infectious diseases, and cancer. While most samples are derived from solid tissue, NGS can be performed on liquid specimens, as well, and the benefits of non-invasive specimen collection will accelerate the development of non-solid tissue NGS applications.

By drafting a coverage policy based on broad applications of a specific methodology or technology platform, NGS in this case, rather than a specific diagnostic test, CMS sets policy incongruous with existing local and national coverage policies. CMS coverage decisions for precision medicine are based on the clinical utility (medical usefulness) of a proven effective biomarker/cancer subtype combination, independent of test methodology and whether a test has undergone FDA review. Some examples of local policies that address diagnostic testing for oncology include National Government Services coverage policy “Genomic Sequence Analysis Panels in the Treatment of Acute Myelogenous Leukemia (L36926)” and Palmetto MolDX’s “NSCLC, Comprehensive Genomic Profile Testing (L36143)” that covers both NGS-based and non-NGS based technologies that meet the stated criteria.

Specifically, AMP has significant concerns about applying the non-coverage portion of this policy to all NGS-based testing. The language within the non-coverage section of the policy (Section C) is very broad and can be construed to include NGS tests for conditions other than oncology. On page 75 of the NCA, CMS states that “Conditions other than oncology are outside the scope of this decision, therefore, we propose that only indications of cancer, other than those advanced cancers noted explicitly in our decision are non-covered.” We wish to point out that any attempt to expand the scope of this policy beyond oncology contradicts the wording in the NCA included above.

The approach CMS has taken with this NCA runs counter to how the American Medical Association (AMA) Current Procedural Terminology (CPT) coding for molecular pathology procedures was established and structured. The updated CPT codes for molecular pathology procedures (including genomic sequencing procedures (GSPs)) are method-agnostic; NGS is one of several methods that can be used to simultaneously analyze multiple genetic regions (CPT Professional Spiral 2018). For example, two laboratories may bill under the same genomic sequencing procedure CPT code to measure the same 12 genetic loci, with one laboratory assessing the genetic loci using NGS-based methodology and one laboratory using another technology. However, under the proposed NCD, the NGS-based assay would be non-covered under this NCD, despite the same CPT code used to bill for both procedures.

Use of NGS as a methodology is not limited to multi-gene panels. Assay of single analytes (e.g., IDH1, IDH2, EGFR, BRAF, KRAS, or NRAS) can be performed utilizing a variety of techniques, including, but not limited to PCR, Sanger Sequencing, and NGS. NGS-based testing is, therefore, also being utilized by laboratories when assessing for single analytes, genomic aberrations in 1-4 genes, and when larger panels are performed. Thus, the proposed NCA is incompatible with current coding structure and will likely create significant uncertainly for local coverage policies and laboratory billing across the country.

If finalized, the NCA will disrupt coverage for targeted cancer mutation panels established by existing local coverage policies. The scope of this NCA extends beyond coverage for the F1CDx test, which was the sole NGS-based test to have gone through the dual FDA-CMS review track. There is no precedent or justification for producing an overly broad, universal, and method-specific NCA in response to a voluntary proposal by a single company for a single test. By broadening the scope, CMS imposes restrictive criteria on other tests using a similar, but not identical, methodology that will, if finalized, supersede local coverage policy for NGS-based tests for solid tumor testing. By doing so, the proposed policy will eliminate coverage for other tests in active clinical use that utilize NGS platforms for advanced cancer patients enrolled in Medicare. These tests are currently recognized as the standard of care and are being used to deliver high-quality, advanced cancer care across the country. While some NGS based testing is restricted to clinical trials, there is extensive utilization of NGS-based testing in the clinical realm as evidenced by laboratories across the spectrum, including community medical centers, academic medical centers, and separate molecular pathology laboratories offering services.

Precision oncology is a medical practice that occurs at the local level, at the patient’s bedside, and in interactions between local healthcare professionals including molecular pathologists. The flexibility to triage urgent patient samples, to discuss in depth the findings at local tumor boards with a multidisciplinary team, provide medical education and training, and to participate in quality improvement initiatives specific to institutions will all be lost if testing is effectively centralized to one national laboratory as proposed by this NCA (Harada S, et al) (Bryce, AH et al) (Knepper, TC et al) (Tafe, LJ et al) (Erdmann J) (Schwaederle, M et al). To date, coverage of this technology has been determined by MACs, which provides opportunity for a coverage policy better suited to local needs and changes in the standard of care.

The difficulty and infrequency of modifications to national coverage determinations raises additional concerns. We are confident the rapidly-changing state of the science in this area will require frequent, multiple revisions of this policy if finalized as proposed. For these reasons, coverage of NGS-based testing is better suited at the local level through the ongoing LCD process.

As per long-standing policy, CMS should allow the MACs to continue to provide coverage for NGS-based tests that are used in CLIA accredited laboratories with appropriate analytical and clinical validation and that adhere to evidence-based guidelines. Numerous evidence-based guidelines written by professional medical societies have been published recently to ensure the delivery of high quality NGS-based testing services, bioinformatics driven technical and clinical interpretation, and clinical report generation, with additional evidence based guidelines also currently in development (Jennings, L et al) (Li, M et al) (Roy, S et al).

In all of these guidelines, clinical utility of a biomarker test is assessed independently of the test methodology. They address clinically significant information that can guide disease diagnosis, prognosis, monitoring, and/or therapy for patients (Joseph L, Cankovic M, Caughron S, Chandra P et al). When guidelines support the utility of a test, CMS should cover the test.

Evidence-based guidelines from the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH), Association of Molecular Pathology (AMP), CAP, and World Health Organization (WHO) support the clinical utility of molecular alterations in various diseases (Appendix A). Such alterations can also be detected by other non-NGS technologies, and as such, coverage policy should not be restricted to a specific method, but to the genetic alteration(s), cancer type, and targeted therapy combination that together defines clinical relevance. Coverage policies for laboratory developed testing procedures (LDPs), including those that utilize NGS technology, must be aligned with these evidence-based best clinical practices and cost-efficient patient care.

It is critical that Medicare cover tests that direct patient care and are deemed clinically relevant and useful by the team of treating physicians. Often, treating clinicians request laboratory testing for an indication not included in the label of the FDA-approved diagnostic and the off-label use of these tests, by definition, is the practice of medicine. Well-established clinical guidelines support the utilization of many NGS-based tests, including F1CDx, to guide patient care. The results from these tests are used in conjunction with other laboratory tests to inform clinical decisions, such as diagnosis, prognosis, disease monitoring, and often targeted therapy. AMP has included references for 42 articles that confirm the utility of these tests in clinical cancer care in Appendix B.

The NCA presents differing proposals for coverage based on whether a test has been FDA-approved or cleared. While FDA reviews a PMA application as a novel device, as part of a 510(k) submission, the test developer must demonstrate that the test is comparable to an already cleared predicate test, which has been demonstrated to be safe and effective. Thus, both FDA-approved and -cleared tests have successfully demonstrated that they are safe and effective as the term is applied by FDA. It is unclear why CMS has decided to withhold coverage for FDA-cleared tests unless additional evidence development requirements are met.

Worse, the preliminary NCA also disregards another responsibility of CMS: overseeing laboratories and LDPs. Clear legal guidelines for CMS’ oversight of LDPs exist currently and allow laboratories to pursue both FDA and non-FDA test development pathways. Inexplicably, CMS is proposing an overly broad, method-specific, universal non-coverage policy in this NCA based on an assessment from a different government agency, FDA, which violates statute preventing the regulation of medical practice, including laboratory physicians. Such a decision would represent a grave inconsistency that serve to harm providers and patients alike.

Every laboratory performing clinical testing is CLIA-certified by federal mandate. These requirements continuously assure laboratory performance standards and the tests’ accuracy and reliability over the entire lifetime of a test. As part of this certification, CLIA requires laboratory inspections, and additionally, those performing high-complexity tests must, under CLIA, undergo regular proficiency testing. Many laboratories obtain CLIA certification through accreditation by CMS-approved accrediting agencies, such as CAP or the Joint Committee on Hospital Accreditation. The standards of these accreditation programs must meet or exceed those of the CLIA regulations. The programs often go well beyond CLIA including more stringent requirements for proficiency testing, as well as documentation of clinical validity.

In summary, the NCA fails to acknowledge that there are other proven, time-tested federal government oversight entities responsible for verifying the accuracy and reliability of LDPs. Requiring FDA approval or clearance as a condition for coverage is inconsistent with the FDA’s position on enforcement discretion for LDPs including its 2016 announcement that it does not intend to finalize the draft guidance establishing a framework to regulate them. In fact, FDA officials have stated on numerous occasions that it would like Congress to legislate how the LDP pathway would be modernized. AMP supports modernizing the oversight framework for high complexity clinical laboratory developed testing services and procedures primarily through reform of the Clinical Laboratory Improvement Amendments (CLIA).

There are serious repercussions associated with exclusively accepting FDA as the only entity that can verify analytical and clinical validity. FDA review mandates that once a test is approved or cleared, no modifications can be made without submitting an application for additional review. This freezes a test in time and does not allow laboratories to modify their tests in light of new scientific understanding. The need to update a test is exceedingly common, as new information is constantly being identified which impacts the scope and technical specifications of individual testing. A recent comparison of LDPs and FDA approved assays for BRAF, EGFR, KRAS tests found 6,897 blinded proficiency testing responses that LDPs and FDA-approved companion diagnostics both performed well, with both test types exceeding 97% accuracy for all three cancer mutations (Kim, A et al). This study also found that more than 60% of participants using an FDA-approved companion diagnostic reportedly modified the assay to allow for a greater breadth of sample types, minimum tumor content, and instrumentation (Kim, A et al). This comprehensive study confirms that often times, the most current test offered is not the FDA-approved or -cleared test. As a result, this NCA may be promoting coverage of a test that does not fully meet patient care needs. An unintended consequence of this proposal would be to incentivize laboratories to shift away from NGS-based testing, despite its wide deployment nation-wide, and move backwards to single gene testing, which is not in the best interest of patients.

While the proposed NCD appears to allow for CED of certain LDPs using NGS technology that are provided to patients as diagnostic tests within the NIH-NCI National Clinical Trial Network clinical trials and that are registered in the NIH Genetic Testing Registry, this provision is unnecessarily restrictive. For example, laboratories cannot enroll patients in a prospective registry that tracks overall survival and patient reported outcomes. It is the treating oncologist, not the laboratory professional, who engages with the patient over the full course of their disease and recovery. Often when a sample is submitted to a laboratory, information regarding the registry status of the patient likely would not even be included. In addition, requiring that patients be enrolled in an NIH-NCI National Clinical Trial Network clinical trial would exclude patients who are enrolled in other relevant clinical trials or are obtaining testing in a clinical setting and not as part of a trial.

Thank you again for the opportunity to review and comment on this proposed policy. AMP urges you not to finalize this policy as proposed and instead, refocus this policy so that is applies ONLY to FDA-approved NGS-based tests, including the F1CDx assay, and not to any other NGS-based test, thereby preserving coverage for the NGS-based tests currently utilized by local laboratories and covered under local coverage policies. We welcome the opportunity to work with you to ensure CMS coverage policy supports this evolving field of medicine. Please direct your correspondence to Tara Burke, AMP Director of Public Policy and Advocacy, at tburke@amp.org.

Sincerely,

Kojo S.J. Elenitoba-Johnson, MD
President, Association for Molecular Pathology

References:
Jennings, L et al. Guidelines for Validation of Next-Generation Sequencing–Based Oncology Panels. May 2017.
CPT Professional Spiral 2018. American Medical Association. 2017
Harada S, et al. Implementation and utilization of the molecular tumor board to guide precision medicine. Oncotarget. 2017.
Bryce AH, Egan JB, Borad MJ, et al. Experience with precision genomics and tumor board, indicates frequent target identification, but barriers to delivery. Oncotarget. 2017 Apr 18.
Knepper TC, Bell GC, Hicks JK, et al. Key Lessons Learned from Moffitt's Molecular Tumor Board: The Clinical Genomics Action Committee Experience. Oncologist. 2017 Feb.
Tafe LJ, Gorlov IP, de Abreu FB, et al. Implementation of a Molecular Tumor Board: The Impact on Treatment Decisions for 35 Patients Evaluated at Dartmouth-Hitchcock Medical Center. Oncologist. 2015 Sep.
Erdmann J. All aboard: Will molecular tumor boards help cancer patients? Nat Med. 2015 Jul.
Schwaederle M, Parker BA, Schwab RB, et al. Molecular tumor board: the University of California-San Diego Moores Cancer Center experience. Oncologist. June 2014.
Kaul, K et al. The Case for Laboratory Developed Procedures. Academic Pathology. July 2017.
Kim, A et al. Comparison of Laboratory-Developed Tests and FDA-Approved Assays for BRAF, EGFR, and KRAS Testing. JAMA Oncol. December 14 2017.
Kulkarni, S et al. Clinical Genomics 1st Edition. October 1 2014.
Li, M et al. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer. J Mol Diagn. January 2017.
Nagarajan, R et al. A Window into Clinical Next-Generation Sequencing–Based Oncology Testing Practices. Arch Pathol Lab Med. December 2017.
Roy, S et al. Standards and Guidelines for Validating Next-Generation Sequencing Bioinformatics Pipelines. J Mol Diagn. January 2018.
Joseph L, Cankovic M, Caughron S, Chandra P et al. The Spectrum of Clinical Utilities in Molecular Pathology Testing Procedures for Inherited Conditions and Cancer. A Report of the Association for Molecular Pathology. J Mol Diagn. September 2016.

Appendix A

NCCN Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia. Version 3.2017. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf

NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. Version 2.2018. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

NCCN Clinical Practice Guidelines in Oncology. Myelodysplastic syndromes. Version 1.2018. https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf

NCCN Clinical Practice Guidelines in Oncology. Myeloproliferative Neoplasms. Version 2.2018. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf

NCCN Clinical Practice Guidelines in Oncology. Central Nervous System Cancers. Version 1.217. https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf

Arber Daniel A., Borowitz Michael J., Cessna Melissa et al. Initial Diagnostic Workup of Acute Leukemia: Guideline from the College of American Pathologists and the American Society of Hematology. Archives of Pathology & Laboratory Medicine. 2017 October.

Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. 2017.

Sepulveda AR, Hamilton SR, Allegra CJ et al. Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline from the American Society for Clinical Pathology. J Clin Oncol. 2017 May 1.

Appendix B

Pai SG, Carneiro BA, Chae YK, Costa RL, Kalyan A, Shah HA, Helenowski I, Rademaker AW, Mahalingam D, Giles FJ. Correlation of tumor mutational burden and treatment outcomes in patients with colorectal cancer. J Gastrointest Oncol. 2017 Oct

Pezo RC, Chen TW, Berman HK, Mulligan AM, Razak AA, Siu LL, Cescon DW, Amir E, Elser C, Warr DG, Sridhar SS, Yu C, Wang L, Stockley TL, Kamel-Reid S, Bedard PL. Impact of multi-gene mutational profiling on clinical trial outcomes in metastatic breast cancer. Breast Cancer Res Treat. 2017 Nov 24.

Furtado LV, Samowitz WS. Colorectal cancer molecular profiling: from IHC to NGS in search of optimal algorithm. Virchows Arch. 2017 May 27

Griewank KG, Schilling B. Next-Generation Sequencing to Guide Treatment of Advanced Melanoma. Am J Clin Dermatol. 2017 Jun.

Hamblin A, Wordsworth S, Fermont JM et al. Clinical applicability and cost of a 46-gene panel for genomic analysis of solid tumours: Retrospective validation and prospective audit in the UK National Health Service. PLoS Med. 2017 Feb 14.

Kyrochristos ID, Glantzounis GK, Ziogas DE, Gizas I, Schizas D, Lykoudis EG, Felekouras E, Machairas A, Katsios C, Liakakos T, Cho WC, Roukos DH. From Clinical Standards to Translating Next-Generation Sequencing Research into Patient Care Improvement for Hepatobiliary and Pancreatic Cancers. Int J Mol Sci. 2017 Jan 18.

Hynes SO, Pang B, James JA, Maxwell P, Salto-Tellez M. Tissue-based next generation sequencing: application in a universal healthcare system. Br J Cancer. 2017 Feb 28.

Surrey LF, Luo M, Chang F, Li MM. The Genomic Era of Clinical Oncology: Integrated Genomic Analysis for Precision Cancer Care. Cytogenet Genome Res. 2016.

Rozenblum AB, Ilouze M, Dudnik E, Dvir A, Soussan-Gutman L, Geva S, Peled N. Clinical Impact of Hybrid Capture-Based Next-Generation Sequencing on Changes in Treatment Decisions in Lung Cancer. J Thorac Oncol. 2017 Feb. Blumenthal DT, Dvir A, Lossos A, Tzuk-Shina T, Lior T, Limon D, Yust-Katz S, Lokiec A, Ram Z, Ross JS, Ali SM, Yair R, Soussan-Gutman L, Bokstein F. Clinical utility and treatment outcome of comprehensive genomic profiling in high grade glioma patients. J Neurooncol. 2016 Oct.

Fox AJ, Hiemenz MC, Lieberman DB, Sukhadia S, Li B, Grubb J, Candrea P, Ganapathy K, Zhao J, Roth D, Alley E, Loren A, Morrissette JJ. Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors. J Vis Exp. 2016 Sep 20.

Deans ZC, Costa JL, Cree I, Dequeker E et al. Integration of next-generation sequencing in clinical diagnostic molecular pathology laboratories for analysis of solid tumours; an expert opinion on behalf of IQN Path ASBL. IQN Path ASBL. Virchows Arch. 2017 Jan.

Grenader T, Tauber R, Shavit L. Next-generation sequencing in patients with advanced cancer: are we ready for widespread clinical use? A single institute's experience. Anticancer Drugs. 2016 Oct.

Søreide K, Watson MM, Lea D, Nordgård O, Søreide JA, Hagland HR. Assessment of clinically related outcomes and biomarker analysis for translational integration in colorectal cancer (ACROBATICC): study protocol for a population-based, consecutive cohort of surgically treated colorectal cancers and resected colorectal liver metastasis. J Transl Med. 2016 Jun 29.

Joseph L. The clinical utility of molecular genetic cancer profiling. Expert Rev Mol Diagn. 2016 Aug.

Szalat R, Munshi NC. Next-Generation Sequencing Informing Therapeutic Decisions and Personalized Approaches. Am Soc Clin Oncol Educ Book. 2016.

Kotelnikova EA, Pyatnitskiy M, Paleeva A, Kremenetskaya O, Vinogradov D. Practical aspects of NGS-based pathways analysis for personalized cancer science and medicine. Oncotarget. 2016 Aug 9.

Strom SP. Current practices and guidelines for clinical next-generation sequencing oncology testing. Cancer Biol Med. 2016 Mar.

Mantripragada KC, Olszewski AJ, Schumacher A, Perez K, Birnbaum A, Reagan JL, Mega A, Khurshid H, Bartley C, Lombardo A, Rossiter R, Papa A, Bakalarski P, Safran H. Clinical Trial Accrual Targeting Genomic Alterations After Next-Generation Sequencing at a Non-National Cancer Institute-Designated Cancer Program. J Oncol Pract. 2016 Apr.

Schwaederle M, Parker BA, Schwab RB, Daniels GA, Piccioni DE, Kesari S, Helsten TL, Bazhenova LA, Romero J, Fanta PT, Lippman SM, Kurzrock R. Precision Oncology: The UC San Diego Moores Cancer Center PREDICT Experience. Mol Cancer Ther. 2016 Apr.

de Abreu FB, Peterson JD, Amos CI, Wells WA, Tsongalis GJ. Effective quality management practices in routine clinical next-generation sequencing. Clin Chem Lab Med. 2016 May.

Chau NG, Li YY, Jo VY, Rabinowits G et al. Incorporation of Next-Generation Sequencing into Routine Clinical Care to Direct Treatment of Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. 2016 Jun 15

Kurzrock R, Colevas AD, Olszanski A et al. NCCN Oncology Research Program's Investigator Steering Committee and NCCN Best Practices Committee Molecular Profiling Surveys. J Natl Compr Canc Netw. 2015 Nov.

Pongor L, Kormos M, Hatzis C, Pusztai L, Szabó A, Gyorffy B. A genome-wide approach to link genotype to clinical outcome by utilizing next generation sequencing and gene chip data of 6,697 breast cancer patients. Genome Med. 2015 Oct 16.

Siu LL, Conley BA, Boerner S, LoRusso PM. Next-Generation Sequencing to Guide Clinical Trials. Clin Cancer Res. 2015 Oct 15.

Paweletz CP, Sacher AG, Raymond CK, Alden RS, O'Connell A, Mach SL, Kuang Y, Gandhi L, Kirschmeier P, English JM, Lim LP, Jänne PA, Oxnard GR. Bias-Corrected Targeted Next-Generation Sequencing for Rapid, Multiplexed Detection of Actionable Alterations in Cell-Free DNA from Advanced Lung Cancer Patients. Clin Cancer Res. 2016 Feb 15.

LeBlanc VG, Marra MA. Next-Generation Sequencing Approaches in Cancer: Where Have They Brought Us and Where Will They Take Us? Cancers (Basel). 2015 Sep 23.

Nikiforov YE, Carty SE, Chiosea SI, Coyne C, Duvvuri U, Ferris RL, Gooding WE, LeBeau SO, Ohori NP, Seethala RR, Tublin ME, Yip L, Nikiforova MN. Impact of the Multi-Gene ThyroSeq Next-Generation Sequencing Assay on Cancer Diagnosis in Thyroid Nodules with Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance Cytology. Thyroid. 2015 Nov.

Le Tourneau C, Delord JP, Gonçalves A et al. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. Lancet Oncol. 2015 Oct.

Gagan J, Van Allen EM. Next-generation sequencing to guide cancer therapy. Genome Med. 2015 Jul 29.

Damodaran S, Berger MF, Roychowdhury S. Clinical tumor sequencing: opportunities and challenges for precision cancer medicine. Am Soc Clin Oncol Educ Book. 2015.

Gallego CJ, Shirts BH, Bennette CS, Guzauskas G, Amendola LM, Horike-Pyne M, Hisama FM, Pritchard CC, Grady WM, Burke W, Jarvik GP, Veenstra DL. Next-Generation Sequencing Panels for the Diagnosis of Colorectal Cancer and Polyposis Syndromes: A Cost-Effectiveness Analysis. J Clin Oncol. 2015 Jun 20.

Cheng DT, Mitchell TN, Zehir A et al. Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology. J Mol Diagn. 2015 May.

Hagemann IS, Devarakonda S, Lockwood CM et al. Clinical next-generation sequencing in patients with non-small cell lung cancer. Cancer. 2015 Feb 15.

Saba NF, Wilson M, Doho G, DaSilva J, Benjamin Isett R, Newman S, Chen ZG, Magliocca K, Rossi MR. Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle. Head Neck Pathol. 2015 Jun.

Sehn JK, Hagemann IS, Pfeifer JD, Cottrell CE, Lockwood CM. Diagnostic utility of targeted next-generation sequencing in problematic cases. Am J Surg Pathol. 2014 Apr.

Chang F, Li MM. Clinical application of amplicon-based next-generation sequencing in cancer. Cancer Genet. 2013 Dec.

Bombard Y, Bach PB, Offit K. Translating genomics in cancer care. J Natl Compr Canc Netw. 2013 Nov.

Johansen Taber KA, Dickinson BD, Wilson M. The promise and challenges of next-generation genome sequencing for clinical care. JAMA Intern Med. 2014 Feb 1.

Cottrell CE, Al-Kateb H, Bredemeyer AJ et al. Validation of a next-generation sequencing assay for clinical molecular oncology. J Mol Diagn. 2014 Jan.

Mauer CB, Pirzadeh-Miller SM, Robinson LD, Euhus DM. The integration of next-generation sequencing panels in the clinical cancer genetics practice: an institutional experience. Genet Med. 2014 May.

McCourt CM, McArt DG, Mills K, Catherwood MA, Maxwell P, Waugh DJ, Hamilton P, O'Sullivan JM, Salto-Tellez M. Validation of next generation sequencing technologies in comparison to current diagnostic gold standards for BRAF, EGFR and KRAS mutational analysis. PLoS One. 2013 Jul 26.

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I am a Bioinformatician, with a PhD in Human Genetics from UCLA, at the Colorado Personalized Medicine Center. My work consists of developing, in collaboration with pathologists and genetics professionals, software for the analysis and visualization of Next Generation Sequencing (NGS) data within the context of a CLIA-certified laboratory. In addition, I am covered by Medicare and, thus, concerned with the quality, availability, and cost of NGS testing.

As a matter of law and policy, the proposal to require FDA approval of diagnostic laboratory tests is unnecessary, economically unsound, and harmful to innovation. Furthermore, it will deny coverage and/or choice of provider to Medicare patients.

CLIA certification has been and remains a robust and adequate regulatory framework to assure that testing by certified laboratories is both sensitive and specific, and is performed subject to rigorous good laboratory practices. CLIA certification provides a mechanism for smaller and academic laboratories to provide personalized and innovative tests in collaboration with pathologists and board-certified genetics professionals. As such, it is “the practice of medicine” and not subject to FDA regulation. Additionally, CLIA certification, while rigorous, is much less burdensome and costly than the notoriously expensive and inefficient process of obtaining FDA approvals. The record in this proceeding does not establish that CLIA is inadequate or inferior to FDA approvals. To the extent that there are any perceived shortcomings, these can best be addressed within the CLIA framework, not by imposing a poorly-matched FDA medical devices regulatory scheme.

In my experience with a small academic NGS lab, standards are rigorous, quality control is extensive, and in some cases a team of pathologists and bioinformaticians can quickly respond to outlier data and modify an analysis in real-time to provide a validated, life-saving report that goes beyond the norm. An FDA-regulated regime would lack such flexibility and personalization.

Requiring small and academic laboratories to obtain FDA approvals will impose enormous and unnecessary costs, with negligible, if any, benefits for patients or CMS. Requiring FDA approvals will inevitably lead to monopolies or oligopolies in the market for these tests, with consequently higher prices and lower incentives to innovate. In contrast, the current NGS laboratory testing market is highly competitive and innovative.

NGS testing is a relatively new technology, where many innovations by small and academic laboratories are being made each year. The current proposal would stifle this trend, and slow down advances in cancer diagnostics and treatment.

Concentration of NGS testing into a few behemoth corporations will mean that patients and their physicians will have few options for testing, testing will not take place within a local group of physicians who are close to the patients’ communities, and the cost of testing will increase.

Thank you for your consideration of these comments.

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I am a 5th year resident physician in pathology spending my entire year in the molecular laboratory. Throughout residency, and especially this year, I have learned the incredible value of NGS in patient care. And while NGS is a fantastic tool, if performed incorrectly it can lead to just as great of problems.

During training, I have been thoroughly educated on the importance of proper lab practices, quality control, lab certification, and lab management. In spending time in the lab, I have seen in person all molecular testing follow these strict guidelines.

The requirement of FDA approval of NGS will restrict and reduce patient access to high-quality patient care. Further, limiting patients to a single test per lifetime completely ignores the evolution of cancers, especially as their mutational profiles change in response to targeted therapy.

Thank you for the opportunity to comment on the proposal.

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January 17, 2018

Tamara Syrek Jensen, JD
Director, Coverage & Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mailstop S3-02-01
7500 Security Blvd
Baltimore, MD 21244

Dear Ms. Syrek Jensen,

On behalf of LUNGevity Foundation, the nation’s preeminent lung cancer nonprofit that funds research, provides education and support, and builds communities for the 222,500 Americans diagnosed with lung cancer each year and the 527,228 Americans living with the disease, we appreciate the opportunity to submit our comments in response to the “Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)” issued on November 30, 2017.

As a leading patient advocacy group that represents the voice and interest of the national lung cancer survivor community by accelerating research to patients that is meaningful to them, empowering patients to be active participants in their care and care decisions, and helping remove barriers to access to high quality care, LUNGevity applauds the Centers for Medicare & Medicaid Services (CMS) for proposing nationwide coverage for certain NGS tests for advanced cancer, including the FoundationOne CDx test, in this era of unprecedented scientific advancements in the diagnosis and treatment of lung cancer, particularly in the field of biomarker testing. Additionally, we applaud CMS and the Food and Drug Administration (FDA) for their joint efforts in the parallel review program, ensuring that patients receive timely access to FDA-approved products. While we applaud CMS for recognizing the importance of the NGS testing platform and the value of patients receiving high-quality tests to ensure optimal benefits in the proposed national coverage determination (NCD), we believe that a number of urgent concerns must be addressed prior to its finalization: lifetime limits on testing; coverage with evidence development (CED) clarification/modification, and patient access to liquid biopsy NGS testing. We have expanded on these concerns below.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, diagnosed in about 85 percent of people with lung cancer.^1,2 The complex nature of this disease requires personalized management plans for patients.² Since the discovery of the first epidermal growth factor receptor (EGFR) mutation in lung cancer in 2004, targeted therapies have become a major component of the treatment arsenal of NSCLC patients.^3-5 Now at least 10 driver mutations in adenocarcinoma have been identified (EGFR, ALK, ROS, RET, ERB2/HER2 mutations, ERB2/HER2 amplifications, MET amplifications, MET mutations, TRK, BRAF, KRAS).^6,7 In concert with the identification of an increasing number of targetable mutations is the development of novel, potent, and specifically targeted therapies. Currently, FDA-approved drugs for four mutations (EGFR, ALK, ROS1, and BRAF) are already in clinical practice, and several targeted therapies specific to other mutations are in clinical development.⁸ Access to high-quality, timely NGS testing is instrumental for matching patients to the appropriate targeted therapy and advancing precision medicine.

To ensure patient access to high-quality NGS testing and to ensure optimal benefits, we urge CMS to address the following concerns prior to finalization of the NCD:

• Lifetime Limits Impede Access Based on Outdated Science

  The draft NCD currently requires that patients have “not been previously testing using the same NGS test.” However, new evidence clearly establishes the value of multiple NGS tests in the duration of a patient’s treatment journey. An NGS panel at the time of diagnosis and subsequent NGS panels at progression on first- and subsequent lines of therapy fulfill similar and unique purposes.

  As against the traditional sequential testing algorithm for EGFR followed by ALK, an NGS panel at the time of diagnosis simultaneously checks for multiple clinically actionable mutations that help guide physicians to targeted therapies to treat NSCLC.¹² This, in turn, helps timely matching of the patient to the right targeted therapy should a targetable mutation be present. The National Comprehensive Cancer Network (NCCN) guidelines recommend multiplex testing such as NGS platforms for making treatment decisions.¹³ An NGS panel at the time of progression helps identify mechanisms of resistance or tumor heterogeneity after treatment with a targeted agent, often independent of the original driver mutation detected at the time of diagnosis. In the recent FLAURA trial of first-line osimertinib in EGFR-positive NSCLC, NGS assays at the time of progression helped identify additional mechanisms of resistance such as mutations in the PIK3CA and the MET genes.^14,15 Currently, drugs targeting the PIK3CA and the MET genes are in clinical development, suggesting that an NGS panel is ideal for determining the next line of treatment for an NSCLC patient who has progressed on a targeted agent.

  As stated above, new mutations in NSCLC are being discovered very quickly and limiting access to one test per a patient’s lifetime may be detrimental to their treatment and could prevent their physicians from not only identifying the accurate first-line targeted therapy that may save their life, but also impede access to subsequent lines of therapy.

  One of the crucial benefits of NGS testing is allowing a complete profile of the patient’s response to prior and post-therapy, and allowing novel classes of drugs to be offered to the patient as their tumor evolves. Offering an NGS panel at the time of diagnosis and at recurrence allows for identifying driver mutations that have drugs in clinical development, thereby allowing patients to be enrolled rapidly in clinical trials. This is especially crucial since NCCN guidelines suggest that clinical trials may often offer the best treatment option in first- and subsequent-line settings. ¹³

• The NCD’s Coverage With Evidence Development Requires Further Clarification

  The criterion for CED in the NCD is not well defined and does not indicate an endpoint that can be easily captured by treating physicians, how CMS intends to evaluate the data, or how the data may contribute to a future decision. We appreciate the importance of post-market data in providing valuable evidence of clinical utility; however, CMS must ensure that there are clearly defined guidelines and endpoints so the data collected from patients provides value. Further guidance is also needed on the process for CED, including patient consent, data collection, and who is responsible for the registry.

  Additionally, CMS must ensure that the CED process is not overly onerous for patients and physicians, so as to provide a disincentive for participation in the important process that can ultimately bring broader access to testing options. The CED stipulates the use of standard clinical trial endpoints such as Progression Free Survival, Overall Survival, and Objective Response Rate (as determined using RECIST criteria) for evidence development. While we understand that RECIST criteria are standardized metrics used to evaluate clinical trials, the use of these criteria may impede uptake of NGS platforms especially in the community setting, where 80 percent of lung cancer care is delivered in the US¹⁶ and physicians do not routinely use RECIST criteria to evaluate efficacy of treatment. Furthermore, RECIST criteria may not be relevant in certain subsets of NSCLC such as EGFR-positive NSCLC, which grow slowly and continue to respond to EGFR inhibitors even after progression.¹⁷ Instead, we recommend the use of surrogate real-world endpoints such as time-to-treatment failure or treatment change with a proper documentation of reasoning behind treatment failure/change (was the treatment changed due to toxicity or efficacy?).¹⁸ Including such real-world endpoints in the CED will not impose an undue financial burden on patients, physicians, labs, and manufacturers and incentivize adoption, data collection, or participation thereby driving innovation. As proposed, CMS appears to require extensive and burdensome CED even in common circumstances where the patient is not going to receive an on- or off-label targeted therapy, but rather a long-familiar chemotherapy because they had no druggable target.

  We suggest that CMS bring together a broad group of stakeholders, including but not limited to, health care providers, pathologist, patients, and patient advocacy groups, to inform the definition of appropriate criteria for the CED section before finalizing this section of the NCD. Additionally, we encourage CMS to consider the evaluation of well-qualified entities other than the FDA (e.g., the New York State Department of Health) when deciding whether adequate data exists to support the analytic validity, clinical validity, and/or clinical utility of a particular NGS test.

• The NCD Precludes Patient Access to Covered Liquid Biopsy NGS Testing

  The utility of liquid biopsies in the clinical management of lung cancer is unquestionable, because as many as 1 out of 4 NCSLC patients may be ineligible for a solid tissue biopsy.⁹ In her ASCO 2017 presentation on biomarker testing for lung cancer, LUNGevity Scientific Advisory Board member, Dr. Alice Shaw from Massachusetts General Hospital, pointed out that liquid biopsies may help in (1) initial detection of targetable mutations in advanced-stage NSCLC at the time of diagnosis, (2) identification of acquired resistance mutations and mechanisms of tumor heterogeneity in patients who have relapsed on targeted therapies, and (3) monitoring response to targeted therapies and predicting outcome in advanced-stage NSCLC patients.¹⁰

  At present, there are no FDA-approved liquid biopsy NGS tests. The draft NCD only proposes to cover such tests under extremely limited circumstances (e.g., if offered within the context of an NIH-NCI National Clinical Trial Network clinical trial). In contrast, a proposed Palmetto MolDX local coverage determination (LCD), which was proposed after careful consideration of the supporting data, would give many Medicare patients with NSCLC access to liquid biopsy NGS tests.¹¹ This access would effectively be eliminated if this draft NCD’s CED and non-coverage sections are finalized as proposed.

  We urge CMS not to preempt proposed local coverage determinations that would provide access to high-quality, lifesaving testing options for patients. The LCDs represent extensive and thorough review, public comment, and careful decision processes. Instead, CMS should consider the data submitted to the Medicare Administrative Contractors (MACs) in support of the local coverage determinations for inclusion in the NCD or provide an additional opportunity for clinical laboratories and manufacturers to provide supporting evidence before determining such tests as non-covered under the final NCD.

LUNGevity is grateful for the opportunity to comment on the “Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)” and is eager to work with CMS and FDA to continue to ensure that patients have timely access to high-quality biomarker testing. In addition, we encourage CMS to help foster an environment of innovation, which could include allowing covered access to laboratory developed tests that are the subject of favorable final or proposed LCDs while evidence development occurs for FDA approval/clearance.

Once again, we appreciate CMS’ attention to and proposed national coverage determination for this important testing platform for lung cancer patients; however, we encourage CMS to consider the areas highlighted above that could benefit from changes and additional clarification.

The recommendations outlined above can be discussed with my staff, myself, and LUNGevity’s Scientific Advisory Board, which is made up of some of the world’s leading experts in lung cancer biology, practice management, access to innovative medicines, and overall patient care. I can be reached at 240-454-3100 or aeferris@lungevity.org if you have any questions or would like to engage in further dialogue.

Thank you for your attention to this very important matter.

Sincerely,

Andrea Stern Ferris
President and Chief Executive Officer
LUNGevity Foundation

ABOUT LUNGEVITY:
LUNGevity’s mission is to improve outcomes for people diagnosed with lung cancer. Our goals are three-fold: (1) to accelerate research to patients that is meaningful to them; (2) to empower patients to be active participants in their care and care decisions; and (3) to help remove barriers to access to high quality care. We have the largest lung cancer survivor network in the country and actively engage with them to identify, understand, and address unmet patient needs. We also have a world class Scientific Advisory Board that guides the programs and initiatives of the organization. Additionally, we collaborate with other lung cancer patient advocacy groups and organizations, such as the American Lung Association and CHEST, who serve the lung cancer community.

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January 17, 2018

Department of Health and Human Services
Centers for Medicare & Medicaid Services
Department of Health and Human Services
P.O. Box 8013
Baltimore, MD 21244-1850

Dear Sir/Madam:

As the Medical Director and a practicing molecular genetic pathologist, I am submitting comments on behalf of the Genomic Medicine Program at the University of Vermont (UVM) Health Network, which welcomes the opportunity to comment on the proposed coverage decision for next Generation Sequencing (NGS) for Medicare beneficiaries with advanced cancer that was released on November 30, 2017.

Background

The Genomic Medicine Program at the University of Vermont Health Network is founded upon a CLIA-licensed, CAP-accredited clinical laboratory of which I serve as the Medical Director. In 2013, the Medical Center invested in next generation sequencing technology that would serve as the backbone technology used to perform laboratory developed genomic tests. The implementation of genomic medicine in our Network is rooted in the development of “care pathways”; genomically-informed clinical care involving strategic integration of the best genomic technology with people and processes beyond the laboratory to realize modern precision care for each unique patient. The five-year, Network-approved plan for this Program included the description of three care pathways, the first of which would serve advanced cancer patients with solid tumors incurable by surgery alone. The cancer care pathway is composed of a portfolio of tests, each test with content professionally curated by transdisciplinary cancer care clinical teams. The teams are composed of cancer specific professionals that include but are not limited to: oncologists, pathologists, radiation oncologists, and interventional radiologists. The genomic content of our cancer test has been vetted by the treating team as clinically relevant with references supporting this designation. Care pathway development additionally includes coordinated informatics and communication regarding patient care, patient samples, test results, and the resultant care planning thereafter. Fundamental to the Genomic Medicine Program at this institution is education. Genomic Medicine education that includes test utilization and result interpretation underlies every care pathway and the faculty/staff of the Genomic Medicine Laboratory are the professional educators. Every test performed in this laboratory is supported by pre-analytically, during analytical processing, and post-analytically. The latter is served by a genomic oncology tumor board. It is in the mission of this Program to educate our clinical colleagues, clinical trainees, researchers, ourselves and students of all levels about clinical applications of genomic testing.

The Food & Drug Administration (FDA) recently approved the FoundationOne CDx (F1CDx) NGS-based test as an in-vitro diagnostic. As part of the FDA’s and CMS’s Parallel Review Program, CMS then issued a proposed National Coverage Determination (NCD) relating to the F1CDx test.

While we are pleased that Medicare – whose payments policies are often adopted by commercial insurers – has in the proposed NCD recognized the value of precision oncology diagnostics in the care of cancer patients, the draft NCD has implications far beyond the F1CDx test. Specifically, the proposed NCD:

• limits coverage only to FDA-approved NGS tests with companion diagnostic indications;
• imposes very narrow criteria for coverage with evidence development; and
• makes explicit a policy of non-coverage for NGS tests if they do not meet the criteria listed in the NCD.

We have deep-rooted concerns over the scope and breadth of these proposed policies, especially the proposed exclusion of non-FDA-approved NGS tests from coverage. The negative impacts on care to our patients, and on the UVM Health Network’s academic and research mission, could be extensive. If finalized as written, it will likely limit access of our CMS patients to NGS testing and reduce incentives to develop validated NGS assays in laboratories like ours.

Genomically-informed cancer care is a medical practice that occurs at the local level. To be implemented successfully, it requires intricate and coordinated interactions between local healthcare professionals as described herein, the molecular pathologist serving as a fundamental member of the care team. Clinical benefits to CMS patients with advanced cancer is specifically derived from local “genomic-related” communication and includes: optimal tissue acquisition and triage of patient samples, post-analytical interpretation of genomic results at local tumor boards with a multidisciplinary team, and ongoing quality improvement initiatives. The delivery of genomically-informed cancer care as described herein cannot exist without a local laboratory offering genomic testing and thereby inherently educating. The laboratory and the molecular pathologists are central to successful practice of genomic medicine.

Lastly, next generation sequencing is a technology, not a diagnostic test. The NCD focuses on a specific technology and is not tied either to a specific biomarker or specific CPT code. This approach runs counter to established coverage determinations, which are based on the clinical utility of a proven effective biomarker, independent of test methodology and whether a test has received regulatory approval for marketing and labeling. If finalized, it will disrupt existing local coverage policies for more targeted panels and specific CPT codes. Academic laboratories such as ours are the national cornerstone of genomic medicine education of our current and future clinical workforce. The proposed NCD will effectively centralize this testing to one laboratory and this will undercut and stunt the implementation of precision oncology nationwide and severely limit clinically-informed used of genomic testing for cancer care in CMS patients in our region and beyond.

Thank you for the opportunity to provide comment on the larger potential negative impacts of the proposed National Coverage Determination for Next Generation Sequencing for Medicare Beneficiaries with Advanced Cancer. With my expertise and practical knowledge in developing a Genomic Medicine Program that serves this patient population, I gladly volunteer to serve as an educational resource for the Centers for Medicare & Medicaid Services.

Sincerely,

Nikoletta Sidiropoulos, M.D.
Medical Director, Genomic Medicine Program
Department of Pathology and Laboratory Medicine, University of Vermont Medical Center
Assistant Professor, Pathology and Laboratory Medicine
Larner College of Medicine at the University of Vermont

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To Whom It May Concern:

I am a molecular pathologist specializing in massively parallel sequencing (MPS, commonly referred to as next-generation sequencing or NGS). I am certified by the American Board of Pathology in Molecular Pathology, Anatomic Pathology, and Clinical Pathology. As a physician, my primary concern is for my patients, and the Center for Medicare & Medicaid Services (CMS) shares my priorities. Nevertheless, as a physician I believe it is my responsibility to convey that I have significant concerns about the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N).

I work at a major academic health center, with one hundred percent of my effort dedicated to patient care or training others in caring for their patients. I do not engage in research, other than efforts to improve the clinical testing we offer to our patients. Using four different MPS assays, we sequence approximately 4,000 specimens annually in our laboratory, a volume of testing that is steadily increasing and shows no sign of abating. For a significant and increasing proportion of our oncology patients, the identification of clinically relevant genomic changes by in-house MPS is already standard-of-care.

It is important to understand that MPS is a technique, not an assay. Like any other technique (e.g. PCR, MRI, microscopy), MPS can be employed in any number of ways, with the details optimized for specific clinical needs. For example, an assay can be designed for rapid results at the expense of sensitivity. Alternatively, an assay can be designed to include fewer genomic targets, lowering the cost per patient. At our institution, by offering a reflex assay for lower quality and quantity specimens, we have been able to reduce our rate of rejected specimens to roughly 3%, far lower than any commercial entity. We routinely make such considerations when developing and implementing assays in our laboratory. It would be inappropriate to restrict microscopy for use at specific magnifications, or to optimize an MRI machine for only metastatic cancer. Similarly, it is inappropriate to restrict MPS assays to the design decisions of remote commercial entities and institutions. Patient care is personalized and optimized by permitting individual institutions to offer clinically validated testing that best serves their specific patient populations.

Personalizing and optimizing the results of an MPS assay for a given patient also includes the interpretation and reporting of the data. It is natural to assume that the interpretation and output of MPS assays are analogous to single-mutation assays, simply with more findings. I believed as much before my formal training. This is a misapprehension – MPS is in many ways a sea-change from other forms of laboratory testing. As its name implies, MPS generates massive amounts of data for every patient – exponentially more than most other laboratory techniques. The output of the report focuses on the identified mutations, but in the appropriate clinical context, I can routinely address the following clinically-relevant concerns:

• Is mutation X really there?
• Was a mutation in gene Y missed?
• Could this mutation be native to the patient, rather than the cancer?
• Is the pattern of mutations significant?
• Could there be a misdiagnosis or multiple disease processes?
• Is the disease heterogeneous?
• Is there evidence the patient is responding to treatment?
• Is there any evidence of contamination?
• Is additional testing warranted?
• Is additional material available for testing?
• Do the results conflict with other laboratory findings, and if so, how can we resolve the discordance?

I can address these concerns because I have advanced training, access to the sequencing data and the patient’s medical record, and a detailed understanding of the performance characteristics of the assays we use. I care about the answers to the questions because these are my patients. Restricting reimbursement to entities with FDA-approved assays performed at a select few laboratories will dissociate analysis of patient data from appreciation and understanding of the individual patient. For optimal patient care, the performance, interpretation, and reporting of sequencing assays should be managed by a trained medical professional who is part of the patient’s health care team.

One of the dramatic advantages of MPS is the flexibility it offers to assays. The field of clinical genomics evolves constantly, with near-continuous discovery of new clinically relevant genes and mutations , and continual development of novel targeted therapies (as with larotrectinib, an inhibitor directed at NTRK fusion genes). New laboratory and computing tools also become available, permitting improved sensitivity, specificity, and detection of new, clinically relevant data (as with mutational tumor burden). Requiring FDA-approval locks MPS testing into what we currently know and are currently able to interrogate. In order to respond to dynamic changes in genomic medicine, laboratory professionals must be free to innovate appropriately.

As it happens, I recently authored a paper using clinical data to demonstrate some of the challenges imposed by FDA-approved assays. In “Genomic heterogeneity of ALK fusion breakpoints in non-small-cell lung cancer” (PMID: 29327716; DOI: 10.1038/modpathol.2017.181) we demonstrate that a laboratory-developed MPS-based oncology assay outperforms two FDA-approved companion diagnostics (FISH for ALK rearrangement and IHC for ALK protein expression). The MPS panel offers more clinically relevant data, with greater specificity and potentially improved clinical outcomes. Moreover, we show that the MPS data require a significant level of expertise to properly integrate into testing algorithms.

In summary, it is my opinion that the proposal by CMS is excessively restrictive, interfering with the delivery of personalized, high-quality care to my patients. It prevents me from offering a complete interpretation of my patients’ results; it prevents me from designing and delivering the assays that will best serve my patients’ needs; it prevents me from integrating new data and new testing as the field evolves. For the sake of my patients, I strongly urge CMS to reconsider this proposal.

Sincerely,
Jason N. Rosenbaum, MD
Assistant Professor, University of Pennsylvania Perelman School of Medicine
Attending Pathologist, Center for Personalized Diagnostics

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January 17, 2018

Seema Verma, Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Hubert H. Humphrey Building
200 Independence Avenue, SW
Washington, DC 20201

Dear Ms. Verma:

The five undersigned organizations request that you do not finalize the National Coverage Analysis entitled, Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer, as currently drafted. Our organizations are deeply concerned about the broad scope of the proposed decision memo and ask that the Centers for Medicare & Medicaid Services (CMS) further engage with stakeholders to better understand how this policy, if finalized, will impact the access of Medicare beneficiaries to tests utilizing NGS technology for cancer and other conditions.

Our groups represent patients and cancer care professionals and we support the goal of the Food and Drug Administration (FDA) and CMS’ Parallel Review program to streamline the approval and coverage processes. We also applaud the agency for recognizing the value of precision oncology diagnostics in the care of cancer patients by proposing coverage for FoundationOne CDx (F1CDx). To be clear, we do support a positive coverage determination for the product reviewed in the Parallel Review program, F1CDx, and hope CMS will move swiftly to implement its coverage.

However, the additional policy outlined in the proposed decision memo goes way beyond the focus of that product. It sets policy for the entire country with coverage so narrowly defined, that we are concerned that it would severely restrict patients’ access to other potentially lifesaving testing using NGS-based technology. Not only does the policy limit coverage to FDA approved NGS-based tests with companion diagnostic indications used in cancer, but it imposes very narrow criteria for coverage with evidence development for other FDA cleared or approved NGS based tests and makes explicit a policy of non-coverage for all NGS-based tests that do not meet the listed criteria. Furthermore, this would supersede existing local coverage policies finalized by Medicare Administrative Contractors (MACs) for most NGS-based tests that are currently being performed at academic medical centers, leading cancer institutions, and community cancer centers, further limiting Medicare beneficiaries’ access to necessary diagnostics.

The patients we represent and treat are benefitting from advances in the understanding of the genomic causes of cancer, both in increased access to targeted therapeutics and in innovative diagnostics that improve their ability to prevent cancer and monitor disease progression. Again, we support CMS’ proposal to cover (F1CDx) as it provides meaningful and actionable information for Medicare beneficiaries with advanced cancer. However, we believe CMS should not finalize the rest of the policy contained in the proposed decision memo and instead, convene a meeting with interested stakeholders to ensure that Medicare coverage policy enables patient access to valid and clinically relevant NGS-based tests without eliminating the importance of local expertise in this area or stifling innovation.

Thank you for your thoughtful consideration of this request. We look forward to working with you to improve this policy and protect Medicare beneficiary access to NGS-based testing that is valid and clinically relevant.

Sincerely,

Association of Community Cancer Centers
International Myeloma Foundation
Myeloma Crowd
National Organization for Rare Disorders
Susan G. Komen

cc: Honorable Mitch McConnell
Honorable Chuck Schumer
Honorable Paul Ryan
Honorable Nancy Pelosi
Honorable Orrin Hatch
Honorable Ron Wyden
Honorable Lamar Alexander
Honorable Patty Murray
Honorable Kevin Brady
Honorable Richard Neal
Honorable Greg Walden
Honorable Frank Pallone

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January 17, 2018

Tamara Syrek Jensen, J.D.
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Blvd
Baltimore MD 21244

Dear Ms. Jensen:

The American Lung Association appreciates the opportunity to submit comments on National Coverage Determination on Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N).

The American Lung Association is the oldest voluntary public health association in the United States. For more than 110 years, the American Lung Association has been working to save lives by improving lung health and preventing lung disease. In 2017, an estimated 222,500 people were diagnosed with lung cancer in the United States ¹ and sadly each year nearly 150,000 people die from lung cancer.² Thousands of lung cancer patients may benefit from NGS and we are pleased to support the Centers for Medicare and Medicaid Services (CMS) proposed National Coverage Determination.

With the development and approval of new targeted lung therapies, biomarker testing has become an important and integral part of a complete lung cancer diagnosis and is an important tool used in patient and physician decisions about appropriate treatment. The CMS National Coverage Determination represents a crucial step forward in increasing access to the benefits of precision medicine for people with lung cancer. Increasingly, advances in genomic technologies are used to understand the genetic changes driving cancer progression. Next generation sequencing (NGS) is among the most significant of these advances. The American Lung Association applauds CMS for taking this important step forward, and improving access to healthcare for those with lung cancer.

We know that currently many people with a cancer diagnosis do not receive biomarker testing. The increased availability of this test will allow patients and physicians to get a broad tumor profile that can help identify the best treatment option, which may include a clinical trial for their particular type of lung cancer. However, concerns remain regarding the single opportunity allowed for this important tumor testing. Firstly, it can be difficult to access a sizeable amount of lung cancer tissue or specimen. Initial attempts may not provide enough cancer cells for accurate tumor testing. It may be recommended that re-testing be done on a different specimen which could lead to clinically actionable results.

Secondly, tumors evolve over time and we are concerned that allowing only one test per lifetime can impact opportunities for additional precision medicine treatment. This would be especially important for patients who have failed treatment or who have a subsequent recurrence. Moreover, a patient may have a negative result early in disease progress, but can develop an actionable mutation later on. It is also possible for mutations to change over time and for patients to develop a new mutation which may indicate a different treatment. Testing should be allowed for each recurrence as it is crucial for bolstering long term survival. This may also be particularly important as additional therapies or clinical trials emerge that might be appropriate.

Lastly, it is important to note that a patient may present with two or more tumors. Molecular testing is the only way to determine if those tumors are related, the results of which may impact their stage and treatment. An additional consideration is the fact that is it possible for a patient to get more than one cancer in their lifetime. Limiting the number of tests a patient can get would negatively impact their care if they faced multiple cancers.

Limiting patients to one NGS test per lifetime is not in line with the realities of medical practice and can negatively impact patient outcomes but also the growth of future lung cancer precision medicine research.

Introducing NGS technologies into the current oncology setting for a wide range of patients has great potential to improve accessibility of these important tests, however the limit on the number of tests can introduce serious treatment barriers for many patients. The importance of testing, and linking with the proper personalized treatment, which extends patient survival, cannot be understated. We thank CMS for helping to advance the science behind lung cancer, which can increase survival for all patients and for the opportunity to share our comments.

Sincerely,

Harold P. Wimmer
National President and CEO

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Re: NCD CAG-00450N

Dear Ms. Syrek Jensen,

I am writing to voice my alarm at some of the restrictive elements of the proposed NCD covering NGS-based testing in advanced cancer. I welcome Medicare coverage of NGS testing. In fact, it is long overdue. But the draft policy would limit my choices for how I can care for Medicare patients. Please change it to address some of its obvious deficits.

I would contend that the introduction of comprehensive liquid biopsies has changed my practice as much as any therapy the FDA has approved in the last decade. Why? Liquid biopsies can obviate the need for an additional invasive biopsy when I don’t have enough tissue for proper testing.

The patients I have treated based on NGS liquid biopsy results have enjoyed the same benefits as those tested with tissue NGS: High response rates, better outcomes, and a far better quality of life on targeted therapy compared to cytotoxic chemotherapy.

The list of targeted therapies available to Medicare patients is long and growing. I want to make sure that each of my patients is on the best treatment. If the draft NCD is not altered to allow for coverage of NGS-based liquid biopsies, my patients will be forced to suffer through unnecessary risky procedures and sub-standard care.

You still have time to fix this. Please take this opportunity. As an expert in the field I can say that we are only seeing for now a tip of the iceberg of all the potential benefits that our patients can have, a review of Pubmed can easily show you a large number of publications about many different clinical benefits of liquid biopsies where NGS-based liquid biopsies are only the beginning.

Respectfully submitted

Luis E. Raez, MD FACP FCCP
Chief Hematology/Oncology &
Medical Director
Memorial Cancer Institute
Memorial Health Care System
Clinical Professor of Medicine
Herbert Wertheim College of Medicine
Florida International University

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On behalf of Facing Our Risk of Cancer Empowered (FORCE) and Living Beyond Breast Cancer, we are pleased to submit the following comments regarding the proposed National Coverage Determination (NCD) “Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer.”

We support the Food and Drug Administration (FDA) and Centers for Medicare and Medicare Services (CMS) Parallel Review program to streamline approval and coverage processes. We also applaud the CMS for recognizing the value of precision oncology diagnostics in the care of cancer patients. Our organizations agree that a positive coverage determination for coverage of FoundationOne CDx (F1CDx) is in the best interest of the Medicare population.

The proposed NCD, however, goes well beyond coverage of one test. It strives to establish a broad policy for coverage of all NGS-based tests. As such, it warrants close scrutiny. NGS testing is very complex. We support validating any test that impacts patient care to ensure safety, efficacy, validity and quality. Given that our organizations place a heavy emphasis on serving and supporting the patient population, our comments focus on access to care and the components of the policy that we are most qualified to address.

Coverage Clarifications
Stage: The proposed policy stipulates that the patient has “recurrent, metastatic, or advanced stage IV cancer.” Because certain cancers are referred to by the stage it was given at diagnosis, a stage III cancer may eventually become metastatic although it would remain a stage III diagnosis. Would these patients qualify for coverage based on the proposed NCD? We urge CMS to further elucidate these parameters to ensure that the greatest number of patients have access to the benefits of NGS testing.

Prior Testing:
The memo states that the patient qualifies for coverage if s/he has “not been previously tested using the same NGS test.” It is now understood that only a small proportion of the cancer cells that leave a tumor succeed at metastasizing to a distant organ. Importantly, metastatic cancers change genetically due to the natural progression of disease or in response to previous anti-cancer treatments. Even within single primary tumors there can be considerable genetic mutation heterogeneity (1). Consider the example of a resistance mutation that may be limited to one or a few loci: resistance to EGFR targeted therapies in cancer very frequently involves a single point mutation, and can possibly be overcome by merely switching to a different agent (2). Thus, we believe that limiting coverage to patients who have not previously tested using the same NGS test is a short-sighted approach. It is likely that many patients who were previously tested and whose cancer has genetically changed over time may benefit from additional testing—even with the “same NGS test.” We ask CMS to reconsider the coverage criteria to allow the use of NGS testing more than once to identify new mutations that may develop or be revealed during disease progression as these newly identified genomic changes may guide additional treatment.

Coverage in Earlier Cancer Settings
Personalized medicine should not be reserved for only those who have advanced or metastatic disease. The goal is to prevent cancer altogether, or to stop early stage disease from advancing. In colorectal cancer, for instance, there is considerable stage-independent variability in clinical outcomes. This variability underscores the need for prognostic and predictive biomarkers to guide therapeutic decision-making. Consequently, many colorectal cancer patients benefit from microsatellite instability testing before the cancer is advanced or metastatic. In the case of prostate cancer, the germline component to clinical NGS testing may have significant diagnostic and therapeutic utility, as demonstrated by the identification of pathogenic germline alterations in men with castration-resistant prostate cancer who respond to PARP inhibition (3). Or, the observation that many breast and prostate tumors in non-germline mutation carriers have tumors with BRCA-like features. These tumors may respond well to PARP inhibitors in the early cancer setting (4). We encourage CMS to explore the viability and utility of NGS testing in earlier cancer settings. This will serve the Medicare system by saving money on unnecessary or ineffective therapies, and the patient population by identifying the best treatment for each patient regardless of disease stage.

Coverage with Evidence Development
While the impetus for this NCD is parallel review and coverage of FoundationOne CDx, its scope goes far beyond one test. In fact, the proposed memo may be interpreted as a sweeping policy that could eliminate Medicare coverage for other types of genetic testing, both in oncology and in non-cancer indications. This is of great concern. The proposed NCD provides coverage with evidence development (CED) for FDA cleared or approved tests that are used in NCI approved clinical trials. The criteria in the CED section is very restrictive. It appears that most clinical genetic tests used today would not be eligible for coverage through this process. For instance, if the policy is broadly applied, BRCA genetic testing for women with a strong family history of breast or ovarian cancer would not be covered by Medicare unless it is provided through an FDA-approved companion diagnostic test or via a research study. Perhaps this is not the intent of the proposed policy but anything that may restrict patient access to potentially lifesaving tests raises concern for our organizations. We urge CMS to closely review the potential implications of this memo to ensure that it does not have broad repercussions for the patient community in regard to access to care and the potential benefits of precision medicine.

If the CED section is interpreted more narrowly, we believe the requirements are too burdensome, and will ultimately hinder timely use of NGS services to achieve the best health outcomes. The CED section requires that, “The patient is enrolled in, and the furnishing laboratory is participating in, a prospective registry that consecutively enrolls patients, adheres to the standards of scientific integrity and relevance to the Medicare population.” Theoretically, this seems reasonable but what if a registry does not exist for a specific cancer or tumor type? How will these patients gain access to the potential benefits of NGS testing? Additionally, reliance on RECIST criteria is problematic as this only applies to solid tumors. A large number of patients will be excluded from coverage if RECIST criteria is used. We understand and agree with the concept of collecting robust data that will inform the use of NGS to guide treatment decisions but with only 3% of cancer patients participating in clinical trials (less in Medicare population), CMS would be better served by reducing the burdens on patients and providers to improve participation and access to NGS testing. This might include review of the costs associated with participation, alternative methods of data collection (i.e. retrospective collection of data via chart audits and claims analyses), etc.

Beyond Tumor Testing
One area not addressed in this proposed policy is the broader possibilities and implications of genetic testing in oncology settings. There is definitely value in screening for genetic features in tumors to help guide treatment decisions but the promise of genetic testing and precision medicine is the ability to prevent cancer, or to diagnose it at an earlier stage when it is easier to treat. Tumor testing increases the opportunity to identify those with germline mutations, who may be at increased risk of other cancers, and whose results may inform family members of their potential increased risk of cancer. For example, tumor testing in 560 breast cancers revealed 33 patients with inherited BRCA mutations who did not know their status prior to the study (4). Ideally, all labs would be able to differentiate between somatic and germline mutations—and would report germline mutations found along with somatic mutations. This may not be feasible, however, so we suggest that CMS institute a policy on lab reporting of possible germline mutation findings. For example, for labs doing NGS testing where a germline mutation may be identified, CMS might stipulate that they meet one of the following requirements:

1. Labs with germline testing capabilities: Incorporate germline testing into the informed consent and reporting. Therefore, potential germline findings can be validated via a blood draw, saliva test, or pathology specimen to confirm or deny the germline status.


2. Labs without germline testing capabilities: Add reporting of suspected germline mutations, the significance of these gene alternations for the patient and family members, and the recommendation of additional genetic counseling and/or germline testing.

This fits within current Medicare policies on germline genetic testing as it only impacts individuals who have already been diagnosed with cancer. It would identify Medicare beneficiaries who may be more closely monitored for second primary cancers commonly associated with the identified germline mutation. Beyond Medicare, this would serve the broader good by facilitating cascade testing—providing useful information to family members who may also carry germline mutations.

Communication
CMS asked, “how can the information in this proposed NCD be clearly communicated to health care practitioners, patients, and their caregivers…?” We believe that it is crucial to develop health care provider and patient-facing materials explaining the nuances of the policy regarding the testing itself, coverage for Medicare beneficiaries, etc. Beyond the traditional Medicare communication channels, it would be wise for CMS to work with patient and health care professional organizations to disseminate the information in a variety of formats which may include web-based content, a flyer, pamphlet or brochure available in PDF format for download and printing, and infomercials or webinars for specific patient and provider populations.

In summary, we support a positive coverage determination for FoundationOne CDx (F1CDx). However, we have significant concerns regarding the broader implications of the NCD, especially the Coverage with Evidence Development policy as outlined. As such, we do not believe the NCD should be approved and finalized without significant revisions. A thoughtful, measured approach must be taken when contemplating policies that have the potential to broadly impact the patient community and its access to care. The NCD must be carefully crafted to account for new tests that come to market as well as new indications for existing tests and therapies. Can the policy easily evolve? Will it serve the needs of the community now and in the future? We urge CMS to work with industry and patient groups to develop its policies and programs related to molecular and genetic testing—and find workable solutions for all parties involved.

Thank you for you for the opportunity to contribute to this important discussion.

Sincerely,

Lisa Schlager
Vice President, Public Policy
FORCE: Facing Our Risk of Cancer Empowered

Jean Sachs, MSS, MLSP
Chief Executive Officer
Living Beyond Breast Cancer

FORCE: Facing Our Risk of Cancer Empowered is the only national nonprofit organization representing people and families affected by hereditary breast, ovarian cancer, and related cancers. FORCE programs provide education, support, advocacy and research to empower those affected by hereditary cancer to make informed decisions about their health, including decisions surrounding genetic counseling and testing.

Living Beyond Breast Cancer (LBBC), founded in 1991, is a national nonprofit education and support organization serving women and families affected by breast cancer. LBBC's mission is to connect people impacted by breast cancer with trusted information and a community of support.

1. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012; 366:883–92.
2. Jänne PA, Yang JC-H, Kim D-W, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372:1689–99
3. Robinson D, Van Allen EM, Wu Y-M, Schultz N, Lonigro RJ, Mosquera J-M, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015; 161:1215–28.
4. Davies H, Glodzik D, Morganella S, et al. “HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.” Nature Medicine. 2017; 23(4): 517-525.

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January 17, 2018

Seema Verma, Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Hubert H. Humphrey Building
200 Independence Avenue, SW
Washington, DC 20201

Re: Proposed Decision Memorandum for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

Dear Ms. Verma:

Thank you for the opportunity to submit comments on the National Coverage Analysis’ proposed decision memorandum for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N). Invitae is a leading genetic information company specializing in NGS-based genetic testing for hereditary cancer and many other clinical indications. We believe that the proposed decision memorandum is overly broad and would have the unintended consequence of depriving tens of thousands of Medicare patients of hereditary cancer testing that they currently receive under Medicare LCDs in accordance with clinical guidelines that inform their management. We also believe that the proposed decision memorandum would negatively impact the rapidly evolving market for NGS-based somatic solid tumor testing and ultimately deprive patients of critical oncology testing. We therefore respectfully request that you do not finalize the proposed decision memorandum in its current draft form.

Foundation Medicine submitted an application to the Food and Drug Administration (FDA) and Centers for Medicare and Medicaid Services’ (CMS) Parallel Review program that streamlines the approval and coverage processes for its product, FoundationOne CDx (F1CDx). We view Foundation Medicine’s FDA approval and subsequent proposed positive coverage determination to be a significant contribution to the field of precision medicine and one that could accelerate patients’ access to targeted therapeutics and create opportunities for better disease management in oncology. However, we strongly oppose CMS’s policy unrelated to F1CDx proposed in the National Coverage Analysis.

The scope of the proposed decision memorandum goes well beyond coverage for the F1CDx test. In making the scope overly broad, CMS imposes restrictive criteria on other NGS-based tests that will, if finalized, supersede local coverage determinations (LCDs) for NGS-based tests including those finalized by Palmetto’s MolDx Program, which was created in 2011 and specializes in overage processes for molecular diagnostics, including NGS-based diagnostics. We believe that the paths for coverage set forth by CMS in the proposed decision memorandum should not be the only paths for coverage for other NGS-based somatic tests. As currently drafted, the proposed decision memorandum would effectively eliminate reimbursement for other NGS-based somatic solid tumor test providers. We request that CMS narrow the scope of the National Coverage Analysis to focus solely on the product requesting a national coverage determination, F1CDx, for the reasons set forth below.

First, the national coverage analysis conflicts with current FDA policy regarding the regulation of laboratory developed tests (LDTs). In November 2017, the FDA announced that it will not finalize a draft guidance requiring premarket review to LDTs. Instead, the agency is working with Congress to implement a new regulatory paradigm that ensures high quality diagnostics balanced with fostering innovation and maintaining patient access. In 2017, the FDA also down-classified NGS-based tests for autosomal recessive diseases and cleared an NGS-based test for tumor profiling via the 510(k) process, which created a predicate for other LDTs that would enable review via the 510(k) pathway. Given the shifting regulatory landscape for diagnostics in the United States, we are concerned that CMS proposes to finalize a national coverage policy that is very difficult to modify or revoke, that will most certainly be outdated once Congress enacts legislation, and that in the interim fails to reflect current FDA policy on oversight. We recommend that CMS not finalize this policy until the regulatory uncertainty is addressed by Congress, the FDA, and other stakeholders.

The reality that the proposed decision memorandum’s policy conflicts with current regulatory policy is most concerning when considering the lack of clarity in the noncoverage section. Based on the language in the proposed decision memorandum, it is reasonable to conclude that the noncoverage policy applies to all LDTs as well as 510(k)-cleared tests that do not fall under the CED section. Additionally, this noncoverage section could apply to all diagnostics, including genetic testing for hereditary conditions known as germline testing, and not just those performed on tumors in late stage cancer patients. The vast scope of this noncoverage policy could result in Medicare beneficiaries no longer having coverage for NGS-based tests that determine risk of hereditary cancer, disorders in cardiology, neurology and pediatrics, as well many other indications. For example, early-stage breast cancer patients would no longer be covered for NGS-based genetic testing to help guide treatment decisions even though it has been concluded that it should be covered under the Palmetto MolDX program.(1) It is alarming that in one proposed decision memorandum, CMS could effectively eliminate coverage for the vast majority of NGS-based tests for patients throughout the United States. Germline testing plays a significant role in decision-making around oophorectomy and mastectomy in breast cancer patients. Prophylactic bilateral mastectomy and oophorectomy in breast cancer patients has been proven to reduce the risk of recurrence and prolong life and has been standard of care for > 10 years.(2) In a recent study using SEER data, 80-85% of breast cancer patients with a positive BRCA1 or BRCA2 test choose with their surgeon to have bilateral mastectomies, twice the frequency for women without a positive test.(3) Extrapolating from incidence data that we have received from private payers, we believe that between 400,000 and 500,000 patients are tested annually in the United States for hereditary breast and ovarian cancer alone.

The somatic testing field is currently evolving rapidly, both in terms of the technologies being used and the markers being evaluated to profile tumors and identify treatment options. The requirement that laboratories pursue the FDA PMA pathway for coverage without evidence development would stifle these advancements. While we believe that the path outlined by the NCD provides a useful avenue for providers seeking FDA approval and Medicare reimbursement, insistence on a single path will inevitably inhibit innovation and make testing more costly. Outside the context of companion diagnostics, FDA pre-market approval is less appropriate for other NGS-based somatic solid tumor tests, particularly those that seek to profile patients at earlier stages. FDA clearance through the 510(k) process is also problematic for other NGS-based somatic solid tumor tests under the proposed decision memorandum for the reasons set forth below. By effectively limiting coverage to a handful of providers who could use approval as a means to justify comparatively high prices, CMS is effectively inhibiting innovation in a rapidly evolving market and ultimately harming patients by depriving them access to critical oncology testing. Therefore, we believe that CMS should not bar other NGS-based somatic solid tumor tests from coverage.

Additionally, it remains unclear as to why the national coverage analysis focuses on a genomic technology platform instead of the clinical utility of the information provided by that test and its implication for treatment and patient care. Often times, the same genomic marker, variant, mutation, etc. can be detected and identified using multiple types of tools such as Sanger sequencing, RT-PCR, and NGS. NGS is not a new technology. In fact, it has been used in clinical testing since 2009.(4) A laboratory may opt for one technology over another for numerous reasons (e.g. equipment already being used in the lab, sample quality, detection ability based on clinical context, etc.), and the impact of that test result for the patient’s care remains the same regardless of which platform was utilized. Yet, CMS proposes a national coverage policy applied to one technology, NGS, instead of focusing on the utility or whether the testing procedure is reasonable and necessary per CMS’s purview. This type of technology-based approach should not be applied to molecular testing. Moreover, this approach conflicts with other policy, such as Palmetto MolDX’s “NSCLC, Comprehensive Genomic Profile Testing (L36143)” which covers both NGS-based and non-NGS based technologies.(5) CMS should seek stakeholder input on the utility of such tests and also consider the LCDs already approved.

Finally, while the national coverage analysis does provide a route to coverage, via coverage with evidence development (CED), for FDA-approved tests that do not meet the coverage criteria, FDA-cleared tests, and LDTs, the criteria for CED is unreasonable, overly restrictive, and fails to reflect the current practice of clinical oncology. Restricting the use of a diagnostic laboratory test to use in an NIH-NCI National Clinical Trial Network clinical trial disregards the fact that currently, NGS-based somatic solid tumor testing is performed frequently outside of a clinical trial. Even if the test is provided within a trial, laboratories do not have readily available access to the types of data required including overall survival, objective response rate, and other health outcomes. The test is one very significant component of the overall patient’s care, but the treating physicians and not the laboratory health professionals, are the ones with access to the data required by the CED. We recommend that CMS not finalize this policy and if the agency wishes to proceed with CED, that it modifies the criteria to reflect the state of the field and current clinical practice guidelines and approaches to care. Furthermore, CMS should clarify at what point sufficient evidence has been collected to warrant coverage.

Given the scope of the policy contained in the proposed decision memorandum, its failure to reflect the current state of the field, its negative impact on patients and other unintended consequences as outlined above, Invitae strongly requests that CMS not finalize the policy as written. Instead, we recommend that the agency convene stakeholders to learn about the use of genomic technologies in cancer and other indications, including both germline and somatic solid tumor testing, the utility of those diagnostics, and how they contribute to improved outcomes for Medicare beneficiaries. As stated above, we oppose the policy contained in the memorandum unrelated to F1CDx. In conclusion, we recommend that CMS modify the CED section and remove the noncoverage section completely.

Thank you for your attention to our comments and we would be happy to provide additional guidance or answer any questions you may have.

Sincerely,

Sean George, Ph.D.
President and Chief Executive Officer

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Tamara Syrek Jensen
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop # S3-02-01
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

Dear Ms. Jensen:

Roche Diagnostics Corporation (“Roche”) is pleased to submit comments regarding the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N). Roche Diagnostics is part of one of the world's leading research-oriented healthcare organizations — the Roche Group. Roche develops innovative products and services that address the prevention, diagnosis and treatment of diseases and medical conditions. As a global leader in the fields of diagnostics and pharmaceuticals, we believe personalized health care will transform lives, improve patient outcomes and reduce costs of care.

In summary, we support the Agency’s efforts to establish national coverage for Food and Drug Administration (FDA)-approved NGS testing when performed for its companion diagnostic indications (CDx), and we agree that FDA approval provides the requisite considerations to result in coverage of these tests. We also ask that CMS consider expanding the covered patient indications included in the proposed memo given the significant promise in care management for many types of cancer patients.

As you proceed in the finalization of this decision memo, we respectfully ask that you consider the following questions and comments on the draft NCD. For your consideration, we have organized our comments into the following categories:

1. Comments on Covered Indications
2. Comments on Coverage with Evidence Development (CED)
3. General questions and requests for clarification of language
4. Coverage for new tests and indications

In the proposed decision memo, CMS describes the coverage indications for full coverage (Section A in the proposed decision memo) and tests covered under CED [Sections B(2)(a) and B(2)(b)]. For both Section A and B, a patient must meet the following criteria:

(a) Recurrent, metastatic, or advanced stage IV cancer;
(b) Not been previously tested using the same NGS test; and,
(c) Decided to seek further cancer treatment (e.g., therapeutic chemotherapy)

In addition, in Section A, the diagnostic laboratory test using NGS must meet the following criteria:

(a) Test is an FDA-approved companion in vitro diagnostic;
(b) Test is used in a cancer with an FDA-approved companion diagnostic indication; and,
(c) Test provides an FDA-approved report of test results to the treating physician that specifies FDA-approved treatment options for their patient’s cancer.

We offer the following comments on some of the above referenced covered indications for your consideration:

• It is our understanding that patients can meet this criterion if he/she has recurrent cancer and/or metastatic cancer and/or advanced stage IV cancer. In other words, the patient does not have to meet all three criteria. We are concerned, however, that this language could be misinterpreted to require that patients have cancer that is recurrent, metastatic, and advanced IV stage cancer. To clarify that a patient can meet this criterion if he/she has recurrent cancer, metastatic cancer and/or advanced stage IV cancer, we encourage CMS to list each condition option on a separate line in the final decision memo.
• With the inclusion of this language, it is our understanding that the NCD does not address coverage for NGS testing for patients with earlier stage cancer. Use of NGS testing in earlier stage patients may have a potentially greater impact upon survival, outcomes, and quality of life.¹ Use of NGS (including blood biopsy) for at-risk patients enables earlier detection, intervention and behavioral changes to improve patient prognosis.^2,3 As such, we request that CMS broaden the indication to cover testing performed on patients with earlier stages of cancer.

• As drafted, the proposed policy does not cover any subsequent testing with the same NGS test. We disagree with this coverage limitation. The restriction on coverage for repeat NGS testing would negatively impact patient care by removing access to NGS tests used in the active monitoring of cancer progression or resistance mutations for Medicare beneficiaries. The genetic profile of a tumor may change during the course of diagnosis and treatment; the ability to test serially using NGS test would allow for more informed treatment management.⁴ More specifically, active monitoring for resistance mutations via NGS has been demonstrated for EGFR and ALK+ NSCLC for tissue and plasma samples.^5,6,7 We respectfully request that CMS allow NGS coverage for repeat testing when used for on-going monitoring.

• The proposed policy limits the use of the NGS test to a cancer with an FDA-approved companion therapy. In practice, however, newly released clinical oncology data may prompt guideline listings and spontaneous adoption prior to FDA-indicated approval. For example, the National Comprehensive Cancer Network (NCCN) in its biomarker compendium and clinical guidelines do not restrict use of FDA-approved companion diagnostic indications for the diagnosis of advanced stage or metastatic cancer. Given the restrictive nature of the proposed policy, we encourage CMS to allow for NGS testing without the requirement for approval as a companion diagnostic, consistent with current practice and NCCN guidelines.

In the proposed decision memo, CMS allows for CED for NGS as a diagnostic laboratory test when (a) performed in a CLIA-certified laboratory, (b) ordered by a treating physician, and (c) specific criteria on the indications and clinical data registry are met. We believe that CMS should initiate CED only as an alternative to otherwise limiting coverage. Specific circumstances under which we believe CED is appropriate include:

• When the alternative is national non-coverage based on limited evidence but the direction of that evidence shows clinical benefit;
• When there is considerable non-coverage at the local level, creating a de facto national non-coverage policy;
• When the final NCD will be more restrictive than the current FDA-approved labeled indication, as signaled by the draft NCD; or
• Prior to removing coverage for an item or service that was previously covered by Medicare.

Additionally, we have a number of concerns regarding the requirements for CED as outlined in the decision memo. Specifically, we believe that the CED study requirements appear too onerous and too prescriptive to demonstrate the clinical utility of the test.

We have outlined a few considerations and questions for CMS as it finalizes this memo:

• Under the proposed memo, the test is non-covered if not FDA-approved or does not meet the requirements for coverage with evidence development. How does CMS intend to handle tests that were previously covered prior to this policy but will be denied coverage once implemented as there was insufficient time to get approval for CED studies?
• The CED pathway outlines detailed requirements for the type of trial (prospective), the registration (NIH Genetic Testing Registry), and the required outcomes tracked per each intervention (e.g., overall survival, progression free survival, and objective response rate consistent with RECIST). These requirements are not only overly prescriptive but also financially taxing. Specifically, each patient would require full informed consent and tracking all outcomes listed in section B.2.a.v could make the registry cost and time prohibitive. Product lifecycles, reimbursement levels, and returns on investment may not support the resources necessary for the clinical trial requirements outlined in this proposed decision memo, thus stifling future NGS innovation. We recommend that CMS establish high level baseline requirements for the trials but give the labs the flexibility to determine how they can best meet those requirements.
• We encourage CMS to consider the Special Fraud Alert issued by the Office of Inspector General (OIG) in June 2014 which addresses payments made to physicians for submitting patient data to a registry or database, answering patient questions about a registry or reviewing registry reports. The proposed CED pathway in the decision memo relies heavily on registry participation, however the Special Fraud Alert creates restrictive parameters under which labs and physicians can interact in relation to registry data. We suggest that CMS coordinate with OIG to relax those criteria and ensure registry accessibility in the CED pathway.
• The proposed decision memo does not outline how a test “graduates” from CED after an appropriate amount of evidence has been collected on the outcomes. What are the criteria for moving to full coverage from coverage with evidence development? We recommend that CMS engage with stakeholders in the laboratory community to clearly outline the process.

In reviewing the memo, there are a few points that were unclear and would benefit from further clarification in the final memo. Specifically, we raise the following questions:

• Does this NCD apply to NGS testing on tumor tissue as well as liquid biopsy? As written, the draft policy applies to “NGS” testing for advanced cancer and is therefore arguably broad enough to apply to liquid biopsy NGS tests. However, the CED section of the draft NCD specifically requires measurement of the patient’s objective response consistent with Response Evaluation Criteria in Solid Tumors (“RECIST”), which only applies to solid tumor clinical trials and therefore suggests the agency may not have intended to include hematologic applications liquid biopsy in the scope of the NCD.
• How would emerging NGS test applications be addressed by this decision? As written, the proposal does not appear to consider hematologic or hereditary cancers and it is unclear whether/how new NGS tests related to those types of cancers would be impacted by this NCD.
• To what extent would this NCD impact the existing local coverage determinations or other policy decisions on NGS tests?⁸ While we understand that the provisions of an NCD prevail insofar as an NCD and LCD are not consistent with each other, the impact of the NCD on existing LCDs is not clear because the intended scope of the NCD may be narrower than current clinical practice.
• What elements of the test report and results must require FDA approval for coverage? Would analysis and interpretation of results provided as raw data be considered part of the “test report” as envisioned by CMS? CMS states that the test must provide “an FDA-approved report” and that it will cover NGS, “including the test results”, but the endpoint of a “report” or “result” is not clearly defined.
• If the clinical interpretation portion is considered separately from the “wet lab”/analytic portion, would subsequent clinical interpretation of the raw data output from the original “wet lab” portion be deemed non-covered? CMS states that a test is non-covered if the patient has been previously tested using the same NGS test, however it is unclear whether subsequent interpretations of the raw data are considered the same test. Discovery of new biomarkers may necessitate repeated interpretation of the original raw data output.
• If new NGS tests are approved for an intended use that is not explicitly addressed in this proposed policy (e.g., in patients with early stage cancer, for cancer detection, for cancer treatment monitoring), would NGS be deemed non-covered under this policy? Insofar as such uses are non-covered, what would be the appropriate pathway for pursuing coverage?

In finalizing the decision memo, we request that CMS respond to these questions.

As currently written, the NCD would automatically cover new cleared or approved companion diagnostic indications for tests that have already been approved by FDA for other indications (as companion diagnostics). Local Medicare contractors may find it difficult to stay abreast of changes in the FDA-approved labeling for the NGS tests, however, there may still be significant delays in access to medically-necessary testing as the contractors update their claims processing systems. We encourage CMS to establish a standardized process to quickly inform local Medicare contractors of new FDA-approved NGS tests. This would facilitate the dissemination of accurate, up-to-date information regarding the extent of Medicare coverage for FDA-approved NGS tests.

We appreciate the Agency’s careful consideration as it has developed this proposed decision memo on NGS testing. As noted above, we support the Agency’s efforts to establish national coverage for FDA-approved NGS testing when performed for its CDx indications. As the Agency proceeds with finalizing this coverage policy, we ask CMS to address the questions raised and to consider our comments above. Specifically, we ask CMS to:

• Broaden the indications to cover testing performed on patients with earlier stages of cancer and for repeat testing when used for on-going monitoring;
• Allow for NGS testing without the requirement for approval as a companion diagnostic, consistent with current practice and NCCN guidelines;
• Engage with laboratory stakeholders on the CED process to address the concerns regarding the specific requirements; and,
• Establish a process to communicate accurate, up-to-date information regarding the extent of Medicare coverage for FDA-approved NGS tests.

We appreciate your consideration of our comments. Please contact Russell Ring at (202) 347-1789 or Russell.Ring@roche.com if you have any questions.

Sincerely yours,

/s/
Russell C. Ring
Vice President, Government Affairs
Roche Diagnostics Corporation

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January 17, 2018
Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

CG# 00450N

Dear Ms. Jensen,

I am writing to express my disagreement with the “Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)”. As the director of a large CLIA licensed hospital molecular pathology laboratory, I have great experience in designing, validating, running and interpreting the types of assays under discussion in the proposed NCD.

Although there are many reasons to believe that this coverage determination would harm Medicare-covered cancer patients, I focus my objections on Clause C. Non-coverage for Next Generation Sequencing tests which do not meet the criteria for Coverage or Coverage with Evidence Determination. I find this to be profoundly anti-competitive and harmful to the development of the NGS lab testing industry, including academic laboratories that are incubators for the development of new tests. While the goal is for all cancer patients to receive FDA approved or cleared NGS tests, or to be tested in an appropriate clinical trial, this is currently not true for the vast majority of cancer patients. Thus, this decision will deprive many patients of the opportunity to be tested and appropriately treated based on tests established and validated over many years in CLIA-licensed and appropriately inspected labs, and used to assign, in our case, many hundreds of patients to appropriate therapy. Alternatively, these patients will be driven to testing at a single large commercial provider with no realistic alternative. I am unable to find any other NCDs in the genetic testing arena which explicitly prohibit payment for non-covered assays. I urge you to abandon this proposed national coverage determination.

Sincerely,

Christopher D. Gocke, M.D.

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January 17, 2018

Ms. Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mail Stop #S3-02-01
7500 Security Boulevard
Baltimore, Maryland 21244

Dear Ms. Jensen,

Please accept these comments from the American Clinical Laboratory Association (ACLA) on the proposed decision memo titled "Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)" (Proposed NCD). ACLA is the leading trade association representing clinical laboratories throughout the country, including national, regional, and local laboratories that provide testing for Medicare beneficiaries every day. ACLA member companies have a direct stake in ensuring that laboratory testing that uses NGS technology is available when a Medicare beneficiary’s physician determines that it is medically necessary for treatment of the beneficiary.

ACLA supports Foundation Medicine’s original request for an NCD for comprehensive genomic profile testing for the management of cancer in patients with solid tumors that are metastatic, including Stage IV and recurrent tumors, with FoundationOne CDx™ (F1CDx). To that end, should CMS limit the NCD to Foundation Medicine’s original request as ACLA And other stakeholders recommend, the title of the NCD would need to be modified to reflect limiting the decision to this narrow, product-specific scope: the F1CDx test. However, if CMS extends the scope of the Proposed NCD beyond positive coverage of the F1CDx test, the NCD must be re-characterized and limited to tumor-based somatic multigene NGS oncology panels, because the evidence that CMS cites in the body of the Proposed NCD is limited to such panels. As proposed, the scope of the NCD would reach far beyond the evidentiary support for it. If CMS elects to limit the NCD to tumor-based somatic multigene NGS oncology panels (consistent with the evidence the agency reviewed), the process and final NCD would benefit from CMS opening up a separate NCD to address this category of tests to allow more time for engagement with stakeholders.

ACLA is deeply concerned that the real-world effect of the NCD, were it to be finalized, would be a de facto requirement that each laboratory test using NGS technology would need to be approved or cleared as a medical device by the U.S. Food and Drug Administration (FDA) before it is covered by Medicare. The fact that the FDA has not reviewed and opined on the validity of a laboratory test using NGS technology does not mean that evidence of the test’s scientific validity is non-existent. Most tests using NGS technology are laboratory-developed tests (LDTs), and there are multiple ways that laboratories show evidence of an LDT’s scientific validity, other than submitting the test to the FDA for review. Application of FDA’s current medical device review process to LDTs would impede innovation in tests using NGS technology. Whatever the eventual scope of the NCD, CMS must allow Medicare coverage for tests using NGS technology that are validated in ways other than through FDA medical device review.

Despite the extension of the comment period, stakeholders have not had adequate time to review and understand the full implications of what would be non-coverage for all but a small handful of laboratory tests that use NGS technology – an important factor in the acceleration of personalized medicine. Finalizing the NCD as proposed effectively would "slam on the brakes" with respect to advances that have allowed clinicians to tailor medical treatment to the individual characteristics of each patient. If CMS were to proceed with finalizing an NCD for laboratory testing that uses NGS technology that is broader than Foundation Medicine’s initial request, ACLA urges the agency to do so only after the agency has consulted with the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC), the Clinical Laboratory Improvement Advisory Committee (CLIAC), as clinical experts who develop and use laboratory testing using NGS technology, laboratorians, patients, and other stakeholders.

ACLA objects to several aspects of the Proposed NCD, as drafted. The Proposed Decision (Section I) is inconsistent in some respects with statements made in the background section and the sections on the history of Medicare coverage, general methodological principles, evidence, and CMS analysis. Furthermore, we find it problematic that the Proposed NCD would base coverage or non-coverage on the technology used to perform the test, rather than on the purpose of the test, as other NCDs do. These issues deserve more study and discussion between CMS and various stakeholders before the agency proceeds with an NCD involving NGS testing beyond tumor-based somatic multigene NGS oncology panels.

Next Generation Sequencing refers to a technology platform whereby an entire human genome – or specific areas of interest – can be sequenced rapidly to detect deletions of DNA, large genomic deletions of exons or whole genes, and rearrangements in genes. An NGS platform can sequence millions of small fragments of DNA simultaneously. Bioinformatics analyses are used to synthesize the fragments by mapping the individual reads to the human reference genome. Simply put, NGS is not a class of tests – it is a methodology that is used with a laboratory process to answer specific questions to aid in management of a patient’s disease.

NGS has not entirely taken the place of traditional Sanger sequencing, but it is far faster, can be more cost-efficient, allows for simultaneous interrogation of the entire genome, and can be used with samples with low-input DNA. Instead of sequencing a single DNA fragment, an NGS platform extends this process across millions of fragments in parallel. Sanger sequencing may require additional assays to be performed (e.g., fluorescence in situ hybridization (FISH)) to identify mutations beyond the region of interest, whereas NGS can yield the full spectrum of genomic variation in a single run. Sanger sequencing depends on knowledge of the gene or region under investigation, but NGS is unselective and can identify novel mutations and disease-causing genes.

Laboratory testing using NGS technology has applications in the management and treatment of patients with immunodeficiencies, infectious diseases, cancer, and cardiomyopathies. While most samples are derived from solid tissue, NGS can be performed on liquid specimens, as well, and the benefits of non-invasive specimen collection will accelerate the development of non-solid tissue NGS applications.

Laboratories use NGS platforms with analytically and clinically-validated LDTs and with commercially-available kits that are cleared or approved by the FDA. In many cases, LDTs yield better and more up-to-date results than FDA-approved kits. A recent peer-reviewed study published in the journal Molecular Diagnosis & Therapy assessed mutations detected in EGFR, KRAS, and BRAF genes using an LDT that combines NGS with confirmation by Sanger sequencing and compared it with mutations that could be detected by FDA-cleared test kits. The study found that significantly more mutations in these genes are detected when the LDT combining NGS and Sanger sequencing was used than when FDA-cleared kits were used. The study’s authors stated that rapid advances in analyzing molecular abnormalities make it difficult for FDA-approved test kits to keep pace and remain the standard in patient care and oftentimes, FDA-approved tests become outdated quickly.¹ Another study, published in JAMA Oncology in December 2017, compared performance of LDTs and FDA-approved assays for EGFR, KRAS, and BRAF testing. The study included 6,897 College of American Pathologists (CAP) proficiency testing responses and found 97 percent accuracy across both FDA-approved assays and LDTs. Authors also noted that more than 60 percent of study participants using FDA-approved assays modified the approved assays to broaden clinical practice, rendering them LDTs.²

Testing using NGS technology most often is ordered by a treating physician,³ but a pathologist also may order such testing. This may be the case, for instance, when a pathologist has examined a tissue specimen and determined that a patient has cancer; the pathologist may consult with the treating oncologist and suggest use of testing using NGS technology to identify molecular abnormalities, and the pathologist may be the physician to place the order. The collaborative approach does not remove the treating physician from management of the patient’s condition, but rather involves a pathologist with expertise in laboratory testing using NGS technology in that management. Sometimes it may be necessary to perform the same laboratory test using NGS technology more than once on the same patient, or it may be necessary for a patient to have a different NGS test, in order for a treating clinician to determine an appropriate course of treatment. Cancer is a heterogeneous and dynamic disease that may be characterized by multiple sub-clones existing in the same tumor or across disease sites. Mutations also may evolve through incomplete DNA replication or as a result of treatment. For example, EGFR mutations in exon 20 or T790M have been shown to develop after EGFR inhibitor therapy, and mutations in HER2 may evolve after anti-HER2 therapy.⁴ Repeat testing after therapy and sampling of tumor tissue from different disease sites should be covered by CMS. This would allow physicians to evaluate treatment response, identify potential new actionable mutations in the current tumor environment, and in the case of sampling from a different disease site, identify actionable mutations that did not exist in the "primary" tumor.

Foundation Medicine’s November 17, 2017 letter requested initiation of a national coverage analysis for comprehensive genomic profile testing with F1CDx in patients with metastatic cancers and who are seeking treatment for one of 10 tumor types: bladder, breast, colon, carcinoma of unknown primary (CUP), colon/rectum, endometrial, NSC lung, melanoma, ovary, pancreas, and stomach/gastric.⁵ However, the Proposed NCD has a far broader scope than the scope of the request and of the evidence CMS cites in Section VII of the Proposed NCD. The evidence CMS cites to address health outcomes in Medicare beneficiaries focuses almost exclusively on tumor-based multigene panels, yet we understand that the scope of non-coverage in the Proposed NCD would reach any test using NGS technology that does not meet certain criteria. Until and unless CMS reviews evidence relevant to other kinds of laboratory tests using NGS technology, it is inappropriate for the agency to issue an NCD that extends beyond tumor-based somatic multigene NGS oncology panels. CMS should change the title and scope of the NCD accordingly.

ACLA appreciates that CMS recognized that the initial 30 day comment period was inadequate for a proposal with such a potentially large impact on treatment for Medicare beneficiaries and that it extended the comment period. But the longer comment period still has not been adequate for ACLA and other stakeholders to fully vet and respond to the Proposed NCD (especially given the holidays in the middle of the comment period). If CMS believes that it would be appropriate to develop an NCD regarding coverage for testing using NGS technology, it should do so only after adequate consultation with the clinical and laboratory experts who develop and use the technology, not beforehand. Many of the questions CMS asks in the Proposed NCD are conceptually complex and cannot be answered without more time and effort than is allowed in the short comment period – even one that has been extended.

CMS states that it did not consult with the MEDCAC about the Proposed NCD, which would have given stakeholders an additional opportunity to communicate their viewpoints to CMS and to the Committee. CMS notifies stakeholders two months in advance of a MEDCAC meeting about the topics to be discussed and how a member of the public can participate and present information to the committee. CMS’s own guidance states that it refers issues to the MEDCAC "when presentation, public discussion, and clarification of the appropriate scope for the technical review, a preferred methodological approach, or a clinical management issue would benefit future NCDs," when "dissemination of a technology may have a major impact on the Medicare program, the Medicare population, or the clinical care for specific beneficiary groups," or when "obtaining the perspective of affected patients and caregivers (e.g., the degree of perceived benefit, subjective assessment of risk, or burden of side effects) through public comments and voting representation on the panel may be relevant."⁶ Use of NGS testing for Medicare beneficiaries meet these criteria, and the agency should have taken the time to consult with the MEDCAC on the issues included in the Proposed NCD. The fact that MEDCAC meets only a few times each year is not a sufficient reason to withhold a Proposed NCD from MEDCAC consultation if a topic is appropriate for presentation before the committee, as this is.

We are not aware that CMS "consulted with appropriate outside clinical experts," which is required under statute when CMS does not consult with MEDCAC.⁷ CMS also said it "did not request an external Technology Assessment on this issue." It does not appear that CMS consulted with CLIAC, whose charter includes giving advice and guidance to HHS on general issues related to improvement in clinical laboratory quality and laboratory medicine practice and on specific questions related to possible revision in CLIA standards.⁸ The laboratory experience and expertise of CLIAC’s membership would add immeasurably to CMS’s decision-making process. As it stands, CMS risks developing a far-reaching NCD without adhering to procedural requirements included in the statute and without the benefit of expert input from the laboratories and clinicians that work on the cutting edge of NGS testing and technology. For these reasons and others, the scope of the NCD should be no broader than tumor-based somatic multigene NGS oncology panels.

We believe that finalization of the Proposed NCD with its overbroad scope would hamper the development of innovative testing using NGS technology and would deprive Medicare beneficiaries of currently-available laboratory tests. Nevertheless, if CMS proceeds to finalize some version of the Proposed NCD, we urge the agency to address a number of serious issues presented the draft.

CMS cannot finalize an NCD regarding testing using NGS technology without recognizing the scientific validity and value of LDTs that are currently available and that currently provide actionable information to physicians treating Medicare beneficiaries. ACLA takes issue with the agency’s insinuation in the Proposed NCD that only FDA-cleared or –approved tests are fully validated and that a test using NGS technology that is an LDT cannot "provide assurance to treating physicians and patients that the test is scientifically valid before they rely on the results for selection of cancer treatment." The fact that the FDA has not reviewed and opined on the validity of an LDT does not mean that evidence of its scientific validity is non-existent. ACLA maintains its long-held view that LDTs are not "in vitro diagnostics" or "medical devices", as defined in the Federal Food, Drug, and Cosmetic Act and its implementing regulations, and therefore are outside of the scope of the FDA’s current regulatory authority.

Laboratory-developed tests are diagnostic services that are developed, validated, and performed by highly-trained professionals within a single clinical laboratory entity. Physicians routinely depend on LDTs to make crucial medical decisions about the best course of treatment for their patients. Laboratories that provide LDTs are subject to comprehensive regulation by CMS itself, by state regulators, and in many instances by CAP, the world’s largest association comprised exclusively of board-certified pathologists and which accredits thousands of laboratories. Laboratories regulated by CMS under the Clinical Laboratory Improvement Amendments (CLIA)⁹ and implementing regulations are required to be CMS-certified, and many are state-licensed, as well. Those certifications and licensure requirements work to ensure that laboratories provide accurate information to physicians using methodologies appropriate for patient care, and that laboratory testing processes are supervised and performed by qualified personnel.

CLIA includes extensive requirements for laboratories to verify or establish a test’s analytical performance characteristics before offering it and reporting patient results based on the test. CLIA regulations require that laboratories that use LDTs, that modify FDA-cleared or –approved tests, or that use a test system for which the manufacturer did not provide performance specifications, must establish the following performance characteristics before reporting patient test results: accuracy, precision, analytical sensitivity, analytical specificity to include interfering substances, reportable range of test results for the test system, reference intervals (normal values), and any other performance characteristic required for test performance.¹⁰ CLIA regulations also require a laboratory director to ensure that test methodologies have the capability of providing the quality of results required for patient care, which is the case only when they are clinical relevant for the patient populations being tested (i.e., are clinically valid).¹¹ Clinical validity also is ensured by accreditation by an approved third-party accreditation organization such as CAP, whose goals include ensuring that tests are analytically and clinically valid, that there is patient safety and patient access to testing, and that there is innovation and improvement of LDTs.¹² Currently, approximately 8,000 laboratories are CAP-accredited.¹³

Precisely because LDTs are not required to undergo premarket FDA-clearance or -approval as devices, laboratories are able to innovate and improve their services rapidly and continually. Laboratories thus have the flexibility and technical expertise to adapt in real time to the latest scientific advances in NGS technology. Laboratory tests using NGS technology can be modified and improved rapidly, and indications for use may be expanded without altering any test processes or analytic standards. Yet under the FDA’s current medical device review paradigm, many innovative modifications would require additional FDA review before use, which would add considerable unnecessary time and costs to the process, without evidence that the additional time provides higher quality testing or better patient care. Moreover, we are concerned that the FDA does not have the resources it needs to conduct reviews on the submissions it receives currently for laboratory tests, let alone all laboratory tests using NGS technology. Effectively restricting Medicare coverage to FDA-cleared or –approved tests not only would deprive Medicare beneficiaries and their physicians of the most advanced diagnostic information available—in many cases, where no FDA-cleared or –approved test exists, Medicare beneficiaries and their physicians would be deprived of actionable diagnostic information altogether.

In the list of questions for commenters to address in the Proposed NCD, CMS acknowledges that laboratories may use various methods to assess the analytical and clinical validity of tests, other than waiting for the FDA to determine the scientific validity of a test. One such approach involves pre-market review and approval by the New York State Department of Health (NYSDOH) of LDTs offered to New York State residents. NYSDOH reviews LDTs for both analytical and clinical validity, and according to SACGHS, an estimated 75 percent of the genetic tests offered in the United States are subject to New York State oversight.¹⁴ The FDA recently recognized the value of NYSDOH oversight by designating it as an approved third-party reviewer of certain FDA regulatory submissions and by accepting certain submissions to the NYSDOH to inform FDA’s decisions. Another approach is for CMS to continue to rely on Medicare Administrative Contractors’ (MACs’) assessment of whether a laboratory test using NGS technology should be covered by Medicare, given its analytical and clinical validity and clinical utility. The MACs invest tremendous time and effort learning about test methodology and usage before issuing a positive Local Coverage Determination (LCD), and this avenue should remain available to laboratories seeking coverage of a test using NGS technology.

While the Proposed NCD appears to allow for Coverage with Evidence Development (CED) of certain LDTs using NGS technology that are provided to patients as diagnostic tests within the NIH-NCI National Clinical Trial Network clinical trials and that are registered in the NIH Genetic Testing Registry, this provision is unnecessarily restrictive. ACLA has shared its concerns with CMS in the past about CED, and our concerns have not been allayed by the Proposed NCD. CMS’s CED research may collect new evidence in the long-run, but restricting coverage for Medicare beneficiaries outside of CED clinical trials is short-sighted.

In contrast to the typically direct relationship between a therapy and health outcomes, the relationship between a laboratory test and a health outcome usually is indirect or is very difficult to ascertain in a reasonable period of time with traditional trial designs. The appropriate standard for a clinical laboratory tests is not necessarily tied to a patient outcome – this does not yield useful information about the analytical or clinical validity of a test. It is rare (and impractical) for a laboratory to conduct prospective randomized clinical trials to show that a molecular test has clinical utility; this usually can be deduced from other available evidence about changes in physician behavior without the considerable time and expense inherent in clinical trials. Coverage of new tests could be delayed by years if CMS accepts only published studies from peer-reviewed journals of prospective randomized clinical trials, or, in the absence of such studies, refuse to accept other evidence of clinical utility.

For laboratories, CED is unworkable and inappropriate as proposed. Many laboratories do not have the resources to participate in NIH-NCI clinical trials. And laboratories oftentimes do not have access to data that are required by a registry, such as overall survival, progression-free survival, objective response rate, and patient-reported outcomes. Thus, for many laboratories, the "choice" to use CED for an LDT using NGS technology, in lieu of FDA-approval or –clearance, is not a real choice.

As we explain above, there are circumstances in which a pathologist may order an NGS test for a Medicare beneficiary, after examining a specimen and consulting with other members of the treatment team. The pathologist is not the "treating physician," as that term is commonly understood in the Medicare context. Therefore, coverage for testing using NGS technology should not be limited to tests ordered only by the treating physician.

ACLA supports coverage of FoundationOne CDx™, but we do not believe that CMS should finalize the Proposed NCD as drafted. The time that stakeholders have had to consider the Proposed NCD and respond to it is woefully inadequate, and the agency has failed in its duty to consult with the public, clinical experts, MEDCAC, and CLIAC before issuing the proposal. To the extent that CMS extends this NCD beyond the initial request from Foundation Medicine, the NCD would benefit from a longer period of stakeholder engagement for input on coverage of different kinds of laboratory tests using NGS technology. CMS’s restrictive conditions of coverage for other tests using NGS technology, amounting to blanket non-coverage, would be a severe impediment to development and use of cutting-edge tests using NGS technology for cancer and other indications – especially those tests that are LDTs – and would deny Medicare beneficiaries access to innovative, scientifically valid, and medically necessary testing that has the potential to reduce overall healthcare costs by avoiding therapies that either will not work for or could be harmful to a Medicare beneficiary.

Thank you for your consideration of ACLA’s comments.

Sincerely,

Paul Sheives
Vice President, Reimbursement & Regulatory Policy
American Clinical Laboratory Association

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January 17, 2018

Tamara Syrek Jensen, J.D.
Director, Coverage & Analysis Group
Centers for Medicare & Medicaid Services
Mailstop S3-02-01
7500 Security Blvd.
Baltimore, MD 21244

Sent electronically

Dear Ms. Syrek Jensen:

The Personalized Medicine Coalition (PMC), a multi-stakeholder group comprising more than 200 institutions across the health care spectrum, appreciates the opportunity to submit comments regarding the Centers for Medicare & Medicaid Services (CMS)’ Proposed Medicare Coverage Decision Memorandum for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer.

Personalized medicine is an evolving field that uses diagnostic tools to identify specific biological markers, often genetic, to help determine which medical treatments and procedures will be best for each patient. By combining this information with an individual’s medical history, circumstances, and values, personalized medicine allows doctors and patients to develop targeted prevention and treatment plans.

Personalized medicine is helping to shift the patient and provider experience away from trial-and-error and toward a more streamlined process for making clinical decisions, which will lead to improved patient outcomes, a reduction in unnecessary treatment costs, and better patient and provider satisfaction. As noted above, PMC’s members are leading the way in personalized medicine and recommend that patients who may benefit from this approach undergo appropriate testing and tailored treatment as soon as possible during their clinical experiences.

In recent years, NGS technologies have played an essential role in advancing our understanding of altered genetic pathways involved in human cancer. PMC appreciates CMS’ recognition that NGS is an important technology for identifying cancer patients who may benefit from a specific treatment path, and we applaud CMS’ work with the Food and Drug Administration (FDA) to accelerate coverage for the FoundationOne CDx (F1CDx) through the Parallel Review Process. We commend the agencies on their approval and preliminary coverage for the F1CDx. High quality, validated genomic profiling assays accelerate patient access to precision approaches to cancer diagnosis and treatment. PMC supports timely finalization of the National Coverage Determination (NCD) for the F1CDx and encourages CMS to continue allowing product developers to pursue Parallel Review as a voluntary process.

We sense growing enthusiasm for the diagnostic innovation upon which personalized medicine depends. In order to capitalize on this opportunity, stakeholders must work toward agreement on a framework that lays out clear paths to coverage and payment, which in turn will encourage the investment that the field requires. Those policies will accelerate the pace of advancement in both diagnostics and personalized medicine. We appreciate therefore CMS’ interest in putting in place guidance that will shape an industry with great potential to improve patient care and make the health system more efficient.

We are concerned, however, that the scope of the proposed decision memo for this National Coverage Analysis (NCA) interferes with current established care pathways and removes the flexibility some test developers have to quickly bring NGS technologies to market outside of the Parallel Review Process. We believe that both allow patients and providers to benefit from personalized medicine technologies. Our comments pertain to how the proposed policy, as written in the decision memo, would affect coverage for clinical testing services already employed in patient care and those that will be developed in the future, as well as the potential burden patient, providers, and product developers will face under the proposed coverage with evidence development (CED) requirements. PMC respectfully asks that you consider the following comments as you finalize this proposed decision memo and we would be honored to serve as a resource to CMS as you contemplate the implementation of broader coverage policies for diagnostic laboratory tests using NGS.

Many of PMC’s members will present their own responses to CMS and will actively advocate for those positions. PMC’s comments are designed to provide feedback so that the general concept of personalized medicine can advance, and are not intended to impact adversely the ability of individual PMC members, alone or in combination, to pursue separate comments with respect to the proposed decision memo on NGS for Medicare beneficiaries with advanced cancer or related issues.

Under Section A of the proposed decision memo, to be granted full coverage patients must have recurrent, metastatic, or advanced stage IV cancer; cannot have been previously tested using the same NGS test; and must have decided to seek further cancer treatment. This language does not address coverage for NGS testing in patients with cancer at earlier stages. However, use of NGS-based testing, including liquid biopsies, in patients with earlier stage cancer may have an even greater impact on survival, outcomes, and quality of life. If CMS moves forward with finalizing the NCA for other diagnostic laboratory tests using NGS in addition to the F1CDx test, the agency should consider broadening the NCA to include coverage of testing performed in patients facing earlier stages of cancer and allow more than one test in an individual’s lifetime to account for potential recurrence.

Section A of the proposed decision memo also describes the criteria for full coverage of a diagnostic laboratory test using NGS. PMC understands that the NCA will only extend full coverage to tests if they are FDA-approved companion in vitro diagnostics; are used in cancers with FDA-approved companion diagnostic indications; and provide FDA-approved reports of test results to the treating physicians specifying FDA-approved treatment options. We agree that tests meeting these criteria should receive full coverage but also acknowledge concerns raised by the American Medical Association and others in the medical community that the proposed national coverage criteria are restrictive and run counter to processes firmly established in medical practice.

Current local coverage determinations are based on the clinical usefulness of proven biomarkers independent of test methodologies and the status of their regulatory approval for marketing and labeling. Clinicians rely on research findings to help them assess and understand a given patient’s disease and to guide treatment decision-making. Thus, in practice, new clinical oncology data often prompts guideline revisions and spontaneous adoption prior to FDA-indicated approval to allow physicians to provide patients with the best care based on the most up-to-date findings. The NCA will supersede these existing local coverage determinations, which currently provide coverage for clinically valid and medically necessary testing services. In addition, the criteria requiring an NGS-based test to have FDA approval for companion diagnostic indications would limit the ability of providers to use NGS tests that are recommended in clinical guidelines.

Diagnostic tests performed in clinical laboratories are reviewed using well-accepted processes for determining the analytical and clinical validity of tests and are subject to ongoing review by accreditation bodies and through statute. They are often included in prevention, screening and treatment guidelines for specific conditions that are developed by professional societies, the Agency for Healthcare Research and Quality (AHRQ), and the United States Preventive Services Task Force (USPSTF). If the proposed scope of coverage is not modified, the NCA will lead to blanket non-coverage determinations for many of these tests and services moving forward, making it difficult for patients to access care that reflects the most up-to-date science. A representative cross-section of PMC’s membership urges CMS to modify the criteria for full coverage to better reflect established patterns of reimbursement and adoption of diagnostic testing in clinical practice.

In 2013, PMC provided feedback to CMS on the agency’s revision of CED guidance. At that time, PMC called on CMS to maintain the use of CED only in circumstances where it would expand access for Medicare beneficiaries. PMC was concerned that the 2013 guideline revision signaled CMS’ intent to utilize CED more regularly for new technologies and services and that CED could be applied in a manner that impedes access to care by restricting the ability of providers to make decisions in the best interest of individual patients.

The Coalition’s comments to CMS on CED also recognized that experience was gained from prior CED efforts. We observed that collaboration among stakeholders during the early stages of defining CED study designs, research protocols, and coverage decision-making was essential to successful implementation of CED. PMC’s contention that broad participation throughout the CED process was particularly important in relation to personalized medicine, where science and clinical practice rapidly evolve and external expertise on appropriate research questions and study designs would be necessary.

Section B of the decision memo details the criteria for diagnostic NGS-based laboratory tests that would be considered for coverage under CED. CED is proposed when NGS tests for advanced cancer are FDA-cleared or -approved but no companion diagnostic indications currently exist. These tests must be registered in the National Institutes of Health (NIH) Genetic Testing Registry, and patients and furnishing laboratories must participate in a prospective consecutive registry, answering questions designed to compare patient outcomes, patient clinical characteristics, and initial clinical validation of the tests. CED is also proposed for NGS tests that are not FDA-cleared or –approved, but coverage would be limited to participants in National Cancer Institute (NCI) clinical trials. We understand that these tests would be required to be registered in the NIH Genetic Testing Registry; be part of a trial in the NCI Clinical Trial Network; adhere to CED standards of integrity; have a written analysis plan; and address the same questions in the criteria for FDA-cleared or -approved tests designed to compare patient outcomes, patient clinical characteristics, and initial clinical validation of the tests.

In keeping with PMC’s earlier comments to CMS in 2013 on its CED guidance, we believe the proposed CED criteria detailed for NGS diagnostic laboratory tests in advanced cancer are too restrictive, exclude alternative methods for data collection, burden study participants, and limit patient access. We doubt this was CMS’ intention and we call on you to convene patients, providers, product developers, laboratories and other stakeholders to develop consensus on solutions to major issues impacting the larger community. We specifically recommend discussion of the need for flexibility in meeting CED requirements through the use of alternative data sources, the level of evidence sufficient for successful completion of CED and transitioning to full coverage, and how CMS plans to treat a gap in coverage for tests that were reimbursed prior to the NCA but will subsequently be denied coverage until a CED study is approved and underway.

In summary, PMC recognizes and appreciates CMS’ work with the FDA to reduce the time between FDA approval and Medicare coverage of the F1CDx through the voluntary Parallel Review Program. We urge you to finalize the NCD for this test, but strongly urge revision of the decision memo as it pertains to other tests using NGS technology for cancer if they are to be included in the final NCD. When revising the decision memo, we respectfully ask that CMS:

1. Prioritize testing using NGS technologies that aid in clinical care across numerous cancer types and stages by continuing to allow tests that do not meet the criteria in Section A to receive coverage.


2. Modify the scope of coverage proposed in the decision memo to minimize the effect it will have on reimbursement for clinical testing services already employed in the care of patients with early and advanced stage cancer, as well as tests that will be developed in the future.


3. Convene patients, providers, product developers, laboratories and other stakeholders to develop consensus on solutions to major issues with the proposed CED requirements.

Thank you for considering our comments. PMC welcomes the opportunity to serve as a resource for you in continuing to shape this policy so that it more effectively achieves the goal we share with CMS of delivering appropriate, efficient, and accessible health care to patients. If you have any questions about the content of this letter, please contact me at 202-589-1769 or cbens@personalizedmedicinecoalition.org.

Sincerely yours,

Cynthia A. Bens
Senior Vice President, Public Policy

CC:Joseph Chin, M.D., M.S.
Deputy Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services

JoAnna Baldwin, M.S.
Senior Technical Advisor, Coverage and Analysis Group
Centers for Medicare & Medicaid Services

James Rollins, M.D., Ph.D.
Director, Division of Items and Devices
Centers for Medicare & Medicaid Services

Lori Ashby, M.A.
Director, Division of Medical and Surgical Services
Centers for Medicare & Medicaid Services

Carl Li, M.D., M.P.H.
Lead Medical Officer
Centers for Medicare & Medicaid Services

Katherine B. Szarama, Ph.D.
Lead Analyst
Centers for Medicare & Medicaid Services

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I am writing to oppose the proposed national coverage determination being considered by the Centers for Medicare and Medicaid Services. I am a professor in a highly regarded academic institution and the director of a molecular diagnostic laboratory that performs genetic and genomic testing for patients nationwide. The majority of molecular genetic tests available are laboratory developed tests (LDTs) which go through the rigor of CAP and CLIA guidelines. Next generation sequencing-based tests now allow us the ability to test for a multitude of genes simultaneously and this technology impacts our ability to perform precision/personalized medicine. LDT’s are no less superior to FDA approved tests and indeed have the advantage of being able to be developed in time with the identification of new disease genes and improve on existing tests – thereby improving diagnostics of genetic conditions. By mandating that only an FDA-approved test will be reimbursed will severely impact the lives of millions of patients, as this will mean that all testing must be performed in a very narrow set of labs. This will destroy the advances made in personalized care and create a monopoly in genetic testing strategies. This will not be to the benefit of patients.

I urge the Centers for Medicare and Medicaid Services to discard this national coverage determination and instead rely on the input of those with the highest level of expertise in this area such as the American College of Medical Genetics and Genomics (ACMG), Association for Molecular Pathology (AMP), and organizations that the CMS has empowered to determine accreditation standards for laboratories, such as CLIA. We need to tred very carefully in this area and make changes in a fashion that improves on LDTs and does not affect patient’s access to high quality genetic and genomic testing.

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Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Dear Ms. Jensen:

Thank you for the opportunity to comment on the National Coverage Analysis ‘National Coverage Analysis (NCA) Tracking Sheet for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)’. I am a molecular pathologist and laboratory director at the University of Colorado Department of Pathology; these comments represent my opinion and not that of the University of Colorado.

I am encouraged by the recognition by CMS that multi-analyte testing in oncology, such as can be achieved using NGS-based technology, is of value. Despite ongoing lags in reimbursement for this service nationally, laboratories, in particular academic molecular laboratories, have recognized that multi-analyte testing, when feasible, is often the best solution for evaluating an individual patient’s tumor sample to assess best treatment options. In some cases, this includes exploration of only well-characterized biomarkers which influence decisions as part of standard of care, while in other cases, these well-characterized biomarkers are combined in panel format with exploratory markers which may facilitate clinical trial enrollment. The latter approach has become common across the country, particularly at academic molecular laboratories nationally, and are similar in approach to the recently approved F1CDx assay. Institutions across the country have continued to perform this testing despite the gaps in reimbursement, further supporting the idea that multi-analyte testing, particularly in selected tumor types, is now considered standard of care.

The NCA, if finalized, would formalize a non-coverage policy for the vast majority of testing being performed today for Medicare beneficiaries, as laboratories across the country have largely adapted much of routine testing to NGS-based platforms. This would significantly disrupt care that is being routinely provided as standard of care. The proposed approach to coverage of NGS-based tests is contrary to a long-established history of using local coverage determinations, and further focuses on testing approval from the United States Food and Drug Administration (FDA) as a major determinant for full coverage.

While it is understandable that CMS views FDA approval as an indicator of the quality of testing, it belies the entire history of laboratory medicine to suggest that this is the only acceptable metric for quality and validity in testing. Laboratory medicine is built on the foundation of continuous quality improvement, and practitioners in this field are highly trained specialists who understand the intricacies and nuance of individual assays. FDA approval of an assay, whether a packaged product for distribution to laboratories or an assay performed in a single facility, is but one approach. However, a vast spectrum of clinical guidelines have been established as the progression from single-analyte testing to NGS-based testing has become more widespread. This includes clinical guidelines on the validation of NGS-based testing, interpretation of variants, as well as systematic reviews to delineate which biomarkers are clinically meaningful. By restricting coverage to only FDA approved assays, CMS would in effect indicate that an entire field of medicine, i.e. laboratory medicine, is only of value if their medical work product is FDA approved. Laboratory professionals do far more than implement FDA approved assays, and CLIA regulatory language specifically provides for the required quality metrics for non-FDA approved assays.

It is, however, evident that some financially driven laboratories have exploited the longstanding CLIA approach to LDTs for monetary gain. This proposal may represent an effort to reduce reimbursement to such entities, however I believe the likely consequences of this proposal will lead directly to patient harm, including to Medicare beneficiaries. If CMS is concerned that existing regulatory frameworks are not sufficient to identify which testing is of clinical value, it should consider and embrace the idea that there are multiple pathways to strengthen such oversight without requiring the burdensome and oftentimes scientifically detrimental step of FDA approval for all assays.

I can provide numerous examples of cases in which identification of a biomarker in an unusual but LDT-validated specimen type (which would certainly not be included in any FDA approval) or for an unapproved indication has led to dramatic patient benefit. Other laboratory directors around the country can undoubtedly do the same. We exercise our medical judgment to determine how the limitations of the testing we understand so well can be applied to novel situations, leading to answers for patients, improvements in their therapy selection, and direct patient benefit.

While I have at my disposal many such examples, I will provide one here to more fully illustrate the point. Recently, we were provided a small biopsy sample from a patient with non-small cell lung carcinoma, a patient who had never smoked cigarettes. The sample was very scant, and while we were able to gain sufficient nucleic acid to assess for mutations using a small NGS-based panel, the sample was insufficient for our parallel RNA based NGS panel for the detection of gene fusions (and almost certainly would have been quantitatively insufficient at larger commercial laboratories). We identified that at the time of surgery, a DiffQuik stained touch preparation was created, a sample type validated in our laboratory. Rather than simply release our results for fusion testing as a suboptimal specimen, we requested and were granted permission to utilize the stained slide (particularly given the patient’s non-smoking status and absence of other identifiable alterations), and testing of the material extracted from it demonstrated the presence of a ROS1 fusion. The patient was initiated on targeted therapy within 4 days and is responding to the therapy. It was through our clinical knowledge and integration with the patient’s medical history, enabled by local practice, combined with technological advances in the laboratory under a LDT framework, that we were able to achieve an answer regarding targeted therapy for this patient. This type of patient care would be considered invalid by the proposed NCD, despite clear patient benefit. Ultimately, personalized medicine truly is personalized – laboratories have the ability to adapt to limitations of specimen quantity and quality, and can issue reports with appropriate disclaimers regarding the confidence provided around positive and negative findings. This is the practice of personalized laboratory medicine. To suggest through this proposed NCD that this practice of medicine is not valid because of lack of FDA approval undermines the individual patient success stories generated every day in laboratories across the country.

Much to my surprise, this proposed NCD focuses on a technological platform, rather than a specific biomarker. Suggesting that an entire platform for testing should be subjected to different reimbursement strategy than others belies the reality that a platform is merely a methodology, a means to an end. I and many others view NGS instrumentation to be like any other instrumentation in a molecular pathology laboratory – a tool for which it is critical to understand the advantages and limitations of the technology itself, for which monitoring and maintenance are paramount, and for which assay and sample metrics can be used to inform clinical interpretation of findings. Issuing a NCD for all NGS technology because one company submitted for parallel FDA-CMS review of an NGS assay is not justifiable given how widely NGS is already used by academic cancer centers in a manner consistent with published guidelines and standard of care.

I am also encouraged to see CMS embrace an approach that considers reimbursement under a coverage with evidence development (CED) strategy. While I believe that such strategies are critical for the understanding of evolving biomarkers, I am concerned that the CED requirements as proposed in this NCA are extremely stringent and frankly unachievable by many laboratories, including those at academic institutions. In our setting, our laboratory has no way of knowing upon specimen receipt whether the patient is included in a prospective registry that meets the proposed CED requirements, and we have no ability to enforce that such a registry would be completed to CMS’ satisfaction. Furthermore, to even be eligible for this pathway, any testing offered would have to be FDA cleared (of offered only through limited NIH-NCTN trials). For many reasons beyond the scope of this letter, it is functionally impossible for my laboratory (and the vast majority of academic laboratories) to get FDA clearance for our many assays, and even if I could pursue such clearance, it would prevent me from continuing to evolve and improve the performance specifications of assays that are the central focus of my day to day care of patients. As highlighted by the above example, the ability to provide these services constitutes medical care that changes outcomes for patients, and preserving the ability of laboratories, particularly academic laboratories, to provide this care is essential for patients to achieve the promise of personalized medicine.

In summary, I believe that while it is a step in the right direction to provide reimbursement for multi-analyte testing such as that achieved using NGS platforms, the overly restrictive nature of this NCA would result in rapid and significant patient harm. I respectfully request that CMS consider: 1) applying the constraints of this NCD only to FDA-approved assays and 2) eliminating all language that indicates non-FDA approved assays would be non-covered. Determination for coverage for non-FDA approved assays should continue to be established through the Local Coverage Determination process as NGS technology continues to mature. This will allow for continued progress in the remarkably rapidly evolving field of personalized medicine.

Sincerely,

Dara L. Aisner, MD, PhD
Director, Colorado Molecular Correlates Laboratory
Associate Professor
Department of Pathology
University of Colorado
dara.aisner@ucdenver.edu

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My name is Glen Melby. [PHI Redacted]

The treatment [PHI Redacted] received is directly related to the genetic testing performed. As the new drugs improve [PHI Redacted] chances for survival, so also will continued genetic research being done with cancer cells. I hope to always have access to the best science has to offer. If further genetic testing will allow [PHI Redacted] to keep fighting, I hope that option is available [PHI Redacted]

Thank you for the opportunity to provide comment on the National Coverage Analysis entitled ‘Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer’. Cancer patients all over the country are benefitting from new knowledge in the genomic causes and drivers of cancer, as evidenced by increased access to personalized therapeutics and care based on the genetic makeup of cancer. We are grateful for advances in diagnostic technologies, such as next generation sequencing, as it is one tool to obtain a more comprehensive genetic understanding of cancer. This technology is of particular relevance to lung cancer patients as it typically requires less tissue sample than separate sequencing of multiple genes. I thank CMS for recognizing the value of precision diagnostics in the care of cancer patients by proposing coverage for FoundationOne CDx (F1CDx). I support a positive coverage determination for the product reviewed in the Parallel Review program, F1CDx, however I have serious concerns about the broad scope of the proposed NCD. The proposed policy would limit cancer patients to 1 test per lifetime, which is not in line with the realities of personalized medicine based therapy for cancer patients. Also, the new policy will eliminate coverage for other NGS tests for advanced cancer patients enrolled in Medicare. These tests are currently being used to deliver high-quality, advanced cancer care across the country, including at virtually all major cancer centers and academic institutions. I support CMS’ proposal to cover the F1CDx test but urge CMS not to finalize the rest of the policy as it will result in several unintended negative consequences to cancer patients by erasing important medical advances and existing local coverage policies already in place.

Sincerely,
Glen Melby

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America’s Health Insurance Plans (AHIP) appreciates the opportunity to comment on the national coverage analysis for NGS for Medicare beneficiaries with advanced cancer.

While the new diagnostic test - F1CDx™ - may help to identify a number of different genetic tumor mutations that may benefit from Food and Drug Administration-approved targeted treatment options (at this point in time: fifteen), the majority of genetic mutations identified by the F1CDx remain under investigation. Therefore, the significance of these mutations remains incompletely understood and there is no currently approved therapy to treat patients based on the identified gene mutation. Proponents of the F1CDx argue that the comprehensive test provides patients and health care professionals access to extensive genetic mutation information in one test report, potentially avoiding duplicative biopsies. They also argue that the test may help patients and their physicians determine candidacy for cancer clinical trials. Nonetheless, evidence that the test (in its entirety) will result in informed cancer treatment decisions that improve health outcomes has not yet been demonstrated, and the variants of unknown significance may potentially lead to unnecessary work-up and possible harm (e.g., anxiety/stress, radiation exposure from imaging, work-up, complications from procedures).

Additionally, we urge CMS to also consider other NGS tests that may also be available. For example, NantHealth has also developed a platform to diagnose alterations in an individual’s cancer. Like F1CDx, these tests are promising, however remain unproven and therefore share some of the uncertainties described above. We recommend CMS evaluate these products while making coverage with evidence development determinations.

AHIP is the national association whose members provide coverage for health care and related services. Through these offerings, we improve and protect the health and financial security of consumers, families, businesses, communities and the nation. We are committed to market-based solutions and public-private partnerships that improve affordability, value, access, and well-being for consumers.

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I agree entirely with Dr. Karen Kaul's below commentary:

The recently proposed national coverage determination from CMS is, simply put, bad for patient care. The commercial vendor who worked with the FDA and CMS to obtain clearance did not develop the methods or quality systems utilized (which are in use in clinical laboratories across the country) but did have the financial resources to accomplish this approval. Few academic and community hospital labs will be able to pursue this approval in this era of cost containment, particularly if reimbursement for these services is further obstructed. Furthermore, the large gene panel that was approved, and proposed to be covered by this NCD, will not be suitable for many samples, many types of cancer, and certainly not biopsies or aspirates. Sending the representative tumor block may negate performance of other studies needed for appropriate patient care. Uncertain reimbursement for local laboratories will preclude performance of these critical studies at many centers, leaving them to await results from a remote laboratory not likely to be able to handle the testing volumes. Advances in the field made by local and academic laboratories will be hindered as institutions seek to trim costs and unreimbursed services. Certainly, the robust academic discussions that are so much a part of modern management of oncology patients, and the training of our residents, fellows, and colleagues, will lessen with the reduction of these important procedures to a send-out commodity. Precision laboratories are fundamental to precision oncology and are an important part of patient care; it is critical that they be performed according to quality standards in a variety of settings and centers, and that they be able to contribute to ongoing advances as well.

There is no evidence that FDA’s newly established Breakthrough Device Program will lead to improved testing quality. In fact, it may be argued that the collective comparisons currently made between labs through the College of American Pathologists and other proficiency testing programs more broadly raise quality, particularly when coupled with adherence to laboratory performance standards for NGS. There is a great need to increase quality improvement opportunities available to labs, and especially to collect outcomes data on the impact of this testing in a way that helps us all improve patient care. The public needs would be served best by insuring reimbursement of NGS to facilitate access to service, and to provide a minimally burdensome program to collect the needed data (about quality and outcome) from laboratories, by building on the current CLIA programs. Data-driven consensus guidelines addressing such issues as appropriate timing, sample types, assay coverage and detection sensitivities should be developed. With only a single reimbursed provider for these services, advances in the field will be stymied.

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January 17, 2018

Ms. Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mail Stop #S3-02-01
7500 Security Boulevard
Baltimore, Maryland 21244

Submitted electronically

Dear Ms. Jensen,

We at the University of Iowa Hospitals and Clinics (UIHC) and the Holden Comprehensive Cancer Center are deeply concerned that the CMS Proposed National Coverage Determination for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer will negatively impact the care that we provide to Medicare beneficiaries.

UIHC is owned by the state of Iowa and has is Iowa's only comprehensive academic medical center and NCI designated comprehensive cancer center. We are an 811-bed hospital that annually admits more than 36,000 patients for in-patient hospital care of which one-quarter to one-third are Medicare beneficiaries. We represent more than 200 outpatient clinics and care areas and accommodate around 1 million clinic visits each year. Our molecular pathology laboratory in the CLIA accredited Emory Warner Clinical Laboratories in the Department of Pathology provides clinical molecular diagnostic procedures including multiple gene panels using NGS to support local and regional oncologists in the care of cancer patients for biomarker indications driven by professional society guidelines and the latest clinical research.

We believe there are several problems with this draft policy.

1. Next generation sequencing, or NGS, is a technology and is not a diagnostic test. Performing DNA and/or RNA sequencing is relatively straight forward and NGS or other molecular technologies for sequence analysis are performed by over a hundred CLIA-licensed clinical laboratories every day across the country. Molecular Testing using NGS technology and performed in CLIA accredited laboratories that adhere to evidence-based guidelines from the leading subject matter experts, especially as guidelines developed by professional societies, including AMP, CAP, ASCO, ASH, WHO and NCCN should be acknowledged as important for the care of Medicare beneficiaries. The evidence that you site in the draft policy in many instances has been the foundation for laboratory-developed and clinically-validated procedures using NGS technology for cancer mutation detection.
2. As written this policy is focused on this specific technology and has not tied the coverage or non-coverage to either a specific biomarker or a specific CPT code. This approach runs counter to established coverage determinations, which are based on the clinical utility of a proven effective cancer mutation biomarker independent of test methodology. If finalized, it will disrupt existing local coverage policies for indicated molecular cancer mutation specific CPT codes and their disease indications. Furthermore, the FDA has not yet published the approval letter for the Foundation Medicine F1CDx assay so that we know what indications are being covered by CMS.
3. The coverage with evidence development (CED) requirements within the draft policy is unmanageable. Our laboratory does not have the capabilities to meet these CED requirements of enrolling patients in a prospective registry that tracks patient outcomes. It is the treating physician, not the laboratory health professional, who engages with the patient over the full course of their disease and recovery. This sort of clinical outcomes research should be hypothesis driven and in the absence of such is a considerable waste of time and money. Even if labs were structured to be able to meet the CED requirements as written, they exclude other relevant clinical trials by requiring only NIH-NCI trials. Further, we do not believe these requirements will be HIPAA compliant.

We appreciate and support the goal in providing effective cancer care for Medicare beneficiaries through the recognition of the value in profiling their tumor specimens for mutations using assays like the Foundation Medicine F1CDx test. However, this policy as written will have many negative consequences for beneficiaries who are or will need mutation profiling for identification of valuable life extending treatment options for which testing is already being provided by our molecular pathology laboratory.

We request that you limit the scope of this NCD only to the F1CDx test or other like companion diagnostic assays with the appropriate CPT and ICD-10 codes AND acknowledge the valuable cancer mutation profiling using NGS methods performed in laboratories like ours by removing the reference to these tests as “NGS tests” so that we can continue to provide appropriate care for all of our cancer patients including Medicare beneficiaries.

Thank you for the opportunity to comment. We look forward to working closely with you in the near term to address these issues.

Sincerely,

Jennifer H. Vermeer
Assistant Vice President for Health Policy and Population Health

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Thank you for allowing me to provide my comments on this national coverage determination. It is encouraging to learn that CMS is considering a policy that may provide a framework for consistent payment of next generation sequencing panel testing for Medicare recipients. However the current scope of the NCD is concerning; in particular the requirement for FDA approval is onerous and in all likelihood would lead to a centralization of NGS for cancer testing to a few commercial laboratories that can afford the labor, time and financial costs of seeking this approval. This will have a dramatic negative effect on smaller labs, in particular those in the academic hospital setting. These labs are operating within the confines of a clear regulatory framework provided by CLIA, with routine inspections from organizations with expertise in lab quality and management (JCAHO, CAP); FDA approval is not a prerequisite for delivering clinically useful and reliable molecular results. By stating that CMS will not reimburse non-FDA approved assays, smaller labs that offer NGS based testing will be punished for providing a cost-effective and efficient approach to delivering what is today considered to be essential information for the management of the tens of thousands of patients diagnosed each year with lung and colon cancer, melanoma, and brain tumors, among many other cancer types. Ultimately, this will lead to delays in delivery of essential molecular information to oncologists and promises to undermine innovation in biomedical sciences, by introducing barriers to clinical trial enrollment and blocking the free exchange of information between patient-facing physicians and the laboratory scientists who are interpreting critical results in the context of an individual patient's disease. I hope that CMS will reconsider this proposal and recognize the value of the multitude of laboratory developed procedures currently in use and already demonstrated to provide reliable and clinically impactful information.

References:
Sholl et al. JCI Insight. 2016 Nov 17;1(19):e87062.
Muller et al. J Thor Oncol. 2017 Oct; 12(10):1503-11.
Aisner et al. Clin Canc Res. 2017 Dec 7 (epub).

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Foundation Medicine submitted on November 17, 2017, a request to the Centers for Medicare & Medicaid Services ("CMS") for a national coverage determination as part of the Parallel Review process for the FoundationOne CDx device ("F1CDx"), an advanced cancer screening test employing next generation sequencing technology. CMS issued the Proposed Decision Memorandum for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N) (the "Proposed NCD") on November 30, 2017. The period for public comment was initially limited to thirty days, ending on December 29, 2017, but was extended until January 17, 2018. We submit the following comment for your consideration.

Caris MPI, Inc., doing business as Caris Life Sciences ("Caris"), is a pioneer in the advancement of next generation sequencing ("NGS") technology and its use in personalized medicine and is a leading developer and provider of molecular profiling tests that aid physicians in determining appropriate cancer treatment for specific patients. Our laboratory, which is located in Arizona, is certified under the Clinical Laboratory Improvement Amendments of 1988 ("CLIA"), is accredited under ISO 15189:2012 and by the College of American Pathologists, and holds state clinical laboratory licenses for California, Florida, Maryland, New York, Pennsylvania, and Rhode Island.

Over the past decade, we have developed four primary NGS panels for assessing cancer tissue, one of which includes 592 genes from solid tumors using the same biomarkers included in the F1CDx platform, plus additional important biomarkers not included in the F1CDx. Since 2013, Caris has tested tens of thousands of tumor tissue samples per year and prepared reports to help physicians determine which therapies will produce the greatest, most durable response in patients with malignant forms of cancer. Medicare – and, in many cases, Medicaid – covers a significant number of these physician-ordered tests. However, under the Proposed NCD, our NGS panels would lose already established Medicare coverage because they are not cleared or approved by the Food and Drug Administration ("FDA").

We realize that CMS has received a significant amount of criticism over the proposed NCD because it requires NGS panels to have FDA approval for national Medicare coverage, creates unduly restrictive CED requirements for FDA-cleared tests, and permits reimbursement for such testing only once in a patient’s lifetime. Although we agree with some of the concerns expressed in the comments CMS has received to date, we commend CMS for recognizing the need for expanding Medicare coverage for NGS testing and access to such testing for Medicare beneficiaries with advanced cancers. We understand it is challenging to differentiate between NGS panels in a way that promotes use of legitimate, validated, and effective testing, especially when there are 28,614 genetic tests employing NGS available from CLIA-certified laboratories as of March 2017, and 3,122 of these tests assess mutations in multiple genes.¹

While we believe that conditioning coverage or CED for NGS testing on FDA approval or clearance is overly restrictive because the vast majority of these tests are laboratory developed tests ("LDTs") that do not require FDA oversight, we recognize the value of using the FDA review process as a way for CMS to distinguish NGS tests and to easily categorize them as applied to cancer testing. However, FDA review, especially in the context of premarket approval ("PMA"), is a long and laborious process. Clinical laboratories that create and provide LDTs employing NGS technology should have an opportunity to engage with FDA in a meaningful way before CMS uses FDA review pathways to determine national coverage criteria for NGS cancer testing, particularly in light of the fact that FDA has only approved or cleared five NGS tests for use in cancer treatment.

Our proposed phase-in process addresses the desire to establish consistent national coverage for validated, effective NGS testing for advanced cancers while utilizing the local Medicare coverage determinations already applicable to NGS LDTs to provide a bridge to national coverage that maintains sufficient Medicare patient access and that is supported by strong evidence. To that end, we propose that in addition to addressing the application for Foundation Medicine’s F1CDx, that CMS should allow clinical laboratories time to submit NGS LDTs for FDA review and premarket approval or clearance. CMS should also separately consider national coverage for individual NGS tests on a test by test basis.

We understand that in accordance with the Parallel Review process, CMS seeks to issue an NCD for the F1CDx in vitro diagnostic device which received FDA approval on November 30, 2017. Rather than creating a broadly applicable national coverage structure for NGS advanced cancer testing based on the F1CDx request, we propose that CMS narrow the current NCD to the F1CDx device, as requested by Foundation Medicine in its November 17, 2017 letter, and explicitly state that all other NGS tests for advanced cancers may continue to receive coverage and reimbursement through existing local coverage determinations ("LCDs"). This initial phase of implementation would allow CMS to fulfill its desire to issue an NCD as part of the Parallel Review of F1CDx but would maintain patient access to NGS LDTs that have met the rigorous criteria for coverage established by certain Medicare Administrative Contractors ("MACs").

After issuing the F1CDx specific NCD, CMS should engage with other NGS providers and create an appropriate process to allow clinical laboratories the opportunity to submit NGS LDTs for FDA review and premarket approval or clearance, a process that can take years, depending on the clinical trial requirements and collaborative interactions with FDA throughout the review. This is consistent with FDA’s most recent proposal for a phased-in approach to regulating LDTs, which would require premarket review of new LDTs that FDA has identified as moderate risk after three years.² In light of FDA’s recent recognition of NGS analytical and clinical validity methods other than its own PMA or 510(k) review, such as review by the New York State Department of Health ("NYSDOH"), an FDA-accredited third-party reviewer, we also recommend that CMS consider broader options to determine analytical and clinical validity beyond the FDA review process.

FDA issued a draft guidance entitled Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) (the "LDT Draft Guidance")³ on October 3, 2014. The LDT Draft Guidance adopted a risk-based phase-in approach that gradually applies the regulatory and approval structure for in vitro diagnostics to LDTs, starting with the tests that pose the highest risks. This phase-in period spans nine years, a recognition by FDA that any shorter period would significantly impact diagnostic test availability and severely impact the health care system. FDA received over 300 comments on the LDT Draft Guidance and held a public workshop in 2015 to discuss the potential consequences of the proposed regulatory framework, and ultimately decided against issuing a final guidance implementing the framework for LDT regulation.

FDA’s recent LDT policy position is that traditional premarket review by FDA is not the only feasible method for confirming analytical and clinical validity of an LDT. CMS has itself cited nineteen studies that utilize NGS LDTs that FDA did not clear or approve and nine studies in which no sequencing method was used (meta-studies) or which do not clearly identify the sequencing method used. CMS should continue to consider evidence of clinical utility that is not based solely on FDA review criteria.

Caris is pleased that CMS has decided to take on the challenge of creating national Medicare coverage for NGS advanced cancer tests and determining the criteria a test must meet before receiving national coverage and reimbursement. Like others who have commented on the Proposed NCD, we believe that CMS is attempting to accomplish too much at once and should take a more measured approach to NGS technology in light of the number of validated NGS LDTs currently in use to determine appropriate cancer treatments for Medicare beneficiaries. CMS should adopt a gradual phase-in approach to NGS cancer testing by (1) limiting the proposed NCD to the F1CDx device only, (2) maintaining existing coverage, and (3) considering national coverage for individual NGS tests on a tests by test basis.

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January 16, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Re: NCD CAG-00450N

Dear Ms. Syrek Jensen,

Weill Cornell Medicine (WCM) is committed to excellence in patient care, scientific discovery and the education of future physicians in New York City and around the world. The doctors and scientists of WCM are engaged in world-class clinical care and cutting-edge research that connect patients to the latest treatment innovations and prevention strategies. Through a robust partnership with our hospital affiliate NewYork-Presbyterian (NYP), WCM faculty provide comprehensive patient care at NYP/ Weill Cornell Medical Center, NYP Lower Manhattan Hospital and NYP Queens as well as in the outpatient setting in physician offices across the City.

As the doctors and scientists of WCM, we applaud and thank the Centers for Medicare and Medicaid Services (CMS) for acknowledging the value of advanced oncology diagnostics for patients suffering from oncological diseases. Technological advances in the last decade have dramatically changed the ways in which physicians treat such patients, and the future holds even more promise. To that end, we write to express our strong reservations and concerns regarding the proposed National Coverage Decision (NCD) issued November 30 (NCD CAG-00450N) and appreciate the opportunity given by CMS to do so.

While the catalyst for issuing the proposed NCD was the parallel approval of Foundation Medicine’s FoundationOne Test (F1CDx), the outcome of this decision has very broad implications that go well beyond F1CDx. Specifically, the proposed NCD would limit Medicare coverage of Next Generation Sequencing (NGS) tests only to those with companion diagnostic indications that have been approved by the Food and Drug Administration (FDA), limit NGS technology to patients with advanced cancer, impose exceedingly narrow criteria for Coverage with Evidence Development (CED) and explicitly exclude any NGS tests that do not meet the precise criteria listed in the NCD. At a time when both the Legislative and Executive Branches of Government agree on advancing the speed with which therapies, technology and devices reach patients, this proposal is inconsistent and would be an impediment to advancing such goals.

We understand and deeply respect the FDA’s critical role in protecting the public, but are very concerned this proposed NCD would effectively establish the agency as the regulatory bar for acceptable clinical tests. The Clinical Laboratory Improvement Amendments (CLIA) regulate laboratory testing and require clinical laboratories to be certified by their state as well as CMS before they can accept human samples for diagnostic testing. Laboratories here at WCM, as well as many others at academic medical centers across the nation, have withstood the rigorous requirements associated with obtaining and maintaining CLIA certification. With this certification, WCM and NYP’s Joint Clinical Genomics Initiative has advanced NGS tests such as EXaCT-1 (https://pathology.weill.cornell.edu/clinical-services/molecular-and-genomic-pathology/clinical-genomics-laboratory/exact-1-whole-exome), and CGMP_50 (https://pathology.weill.cornell.edu/clinical-services/molecular-and-genomic-pathology/clinical-genomics-laboratory/50-gene) from bench to bedside. CGMP_50 detects mutations in lung, colorectal, thyroid, brain and melanoma cancer. EXaCT-1 Whole Exome Sequencing scans over 21,000 genes to detect mutations that drive all cancer types at all stages. Care teams that include oncologists, pathologists and many others, use these NGS tests for diagnosis, prognosis, and therapeutic decision making for the benefit of patients. They are also just two examples of NGS tests that have been approved by New York State Department of Health’s (NYSDOH) Clinical Laboratory Evaluation Program (CLEP) due to their proven analytical validity and clinical utility. This proposed NCD would effectively supersede local policy determinations significantly restricting the current common practice of offering these important NGS tests to patients. We recommend that appropriately validated, NYSDOH approved NGS assays be explicitly considered to meet the requirement for coverage under this NCD and the requirement for a companion diagnostic indication be removed.

In addition to NYSDOH approved tests currently offered to our patients, there are others that are very close to progressing to the clinical setting, such as Oncomine (https://pathology.weill.cornell.edu/clinical-services/molecular-and-genomic-pathology/clinical-genomics-laboratory/oncomine) and Myeloid (https://pathology.weill.cornell.edu/clinical-services/molecular-and-genomic-pathology/clinical-genomics-laboratory/myeloid). The advancement of these assays represents millions of dollars of both investigator-initiated and industry-sponsored trials. The unreliability of government appropriations for research requires WCM scientists to obtain funding from other sources. This does not degrade quality, outcomes or validity, but rather is illustrative of the need for scientists to pursue alternative methods to advance treatment and cures to patients. For this reason, we recommend the CED include a broader allowance for investigator-initiated and industry-sponsored trials and impose less restrictive and onerous compliance requirements. As the cancer genomic landscape is ever changing and personalized medicine continues to bourgeon, CMS should not be constricting the further advancement of NGS technology.

Lastly, it is unclear the degree to which additional scientific evidence, other than that provided in support of the F1CDx application, was reviewed in advance of making this determination as it precludes an entire segment of NGS tests that can be used to benefit non-advanced cancer patients. We have included supplemental information that provides evidence of the validity and utility of such tests (via email). As history has shown, it is exceedingly difficult to modify an NCD once it has been adopted. In an attempt to make this NCD as inclusive and beneficial as possible, we recommend CMS conduct a more expansive analysis to ensure Medicare beneficiaries are receiving access to the most advanced technologies by not limiting access to NGS tests to those that have advanced, recurring or metastatic cancer.

We again thank and applaud CMS for taking this critical step toward bringing advanced care technologies to patients, but caution the speed and breadth of this proposal. We encourage you, Ms. Syrek Jensen, and the Agency to consider WCM a resource. We stand ready to provide any additional information to aid in making this landmark decision as inclusive and beneficial to patients as possible.

Sincerely,

\s\
Daniel M. Knowles, M.D.
David D. Thompson Professor
Weill Cornell Medical College
Chairman of Pathology and Laboratory Medicine
Weill Cornell Medicine
President and CEO
Weill Cornell Medicine Physician Organization
Pathologist-in-Chief
New York-Presbyterian-Weill Cornell Medical Center

\s\
John P. Leonard, M.D.
Interim Chairman, Joan and Sanford I. Weill Department of Medicine
Interim Physician-in-Chief, New York-Presbyterian Hospital/Weill Cornell Medical Center
Richard T. Silver Distinguished Professor of Hematology and Medical Oncology
Associate Dean for Clinical Research
Associate Director, Sandra and Edward Meyer Cancer Center

\s\
David M. Nanus, MD
Chief, Hematology and Medical Oncology
Associate Director for Clinical Services
Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine
Ronald P. Stanton Clinical Cancer Program at New York-Presbyterian
Director of New York-Presbyterian Hospital - Weill Cornell Medicine Healthcare Services Cancer Program

\s\
Olivier Elemento, PhD
Director, Englander Institute for Precision Medicine
Associate Director, Institute for Computational Biomedicine
Co-Assistant Dean for Scientific Computing
Co-Leader, Genetics, Epigenetics and Systems Biology Program, Meyer Cancer Center

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January 17, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Mail Stop S3-02-01
Baltimore, MD 21244

Dear Ms. Syrek Jensen:

Bristol-Myers Squibb Company (BMS) appreciates the opportunity to submit the following comments on the Centers for Medicare & Medicaid Services' (CMS's) Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N) (Proposed National Coverage Determination (NCD)).¹ The Proposed NCD would provide for national Medicare coverage of certain FDA-approved NGS diagnostic tests for patients with recurrent metastatic and advanced stage IV cancer.² It would also provide for coverage with evidence development (CED) for certain FDA-approved or cleared NGS diagnostics for patients with certain cancers who are enrolled in qualifying registries and for certain other diagnostics for patients with certain cancers that are part of certain clinical trials.³ Coverage for all other NGS diagnostics would not be available.⁴

BMS is a global BioPharma company whose mission is firmly focused on discovering, developing, and delivering innovative, transformational medicines for patients with serious diseases. We are a leader in oncology care, developing breakthrough immuno-oncology therapies that improve long-term survival and quality oflife for people living with cancer. BMS has been at the forefront of pioneering personalized medicine and patient-specific approaches to life-threatening diseases such as cancer. We are firmly committed to providing high-quality, cost-effective care for patients, including through support of the development of personalized medicine, particularly in the cancer space.

BMS applauds CMS for taking steps to ensure that NGS, a tool that is particularly helpful in the area of personalized medicine, is covered nationwide as diagnostic laboratory tests are used increasingly to improve and guide patient selection of treatments and care in the cancer arena. BMS also supports CMS's proposal to cover FDA-approved clinical diagnostic companion NGS tests without evidence development. However, there are a few points that BMS believes CMS will need to address before it finalizes this NCD including:

• Modifying the proposed NCD to ensure that NGS is covered for all stages of cancer where the NGS is FDA approved as a companion diagnostic.
• Clarifying the proposed NCD to ensure that other NGS tests are covered for all stages of cancer under CED.
• Modifying the proposed NCD provisions with respect to coverage of FDA-approved or cleared NGS through registries under CED to increase flexibility and reduce the burden on providers seeking to comply with the NCD and provide beneficiaries access to these tests.
• Modifying the proposed NCD provisions with respect to coverage of other NGS through clinical trials to increase flexibility and ensure that a broader range of clinical trials are eligible for coverage through these provisions.
• Modifying the proposed NCD to delay the noncoverage provisions so that existing coverage of NGS diagnostic tests can continue while the registries and clinical trials needed for CED are developed and to provide uninterrupted coverage for laboratory developed NGS tests covered under existing local coverage determinations (LCDs) until they receive FDA approval.
• Adopting a process governing the transition of FDA-approved NGS from CED to full coverage.
• Adopting a thorough communications strategy for disseminating information about the final NCD, to include working even more closely with Medicare Administrative Contractors (MACs) and applicable provider organizations.
• Clarifying that the final NCD does not limit coverage to a single NGS test in a patient's lifetime.
• Modify the proposed NCD to ensure that NGS is covered in new cancers when supported by NCCN or other approved compendia in order to be consistent with coverage for cancer drugs.

These comments are addressed further below.

CMS proposes to cover FDA-approved companion diagnostic NGS without further evidence development for patients with recurrent, metastatic, or advanced stage IV cancer, when used under certain conditions.⁵ CMS indicates in the Proposed Decision Memo that "[b]ased on the evidence [it] reviewed, patient characteristics most likely to benefit from molecular diagnostic tests are patients having recurrent, metastatic, or advanced stage IV cancer . . ." and that "we propose that NGS as a diagnostic laboratory test be covered for patients with recurrent, metastatic or stage IV cancer."⁶ BMS supports this proposal and applauds CMS for its efforts to ensure that companion clinical diagnostic NGS testing is covered for Medicare patients. These tests are a key component of moving towards an era of precision medicine, where the right treatments are administered to the right patients at the right time.

However, BMS also believes that this proposal takes too narrow a view of existing evidence regarding the benefits of NGS diagnostic testing for cancers of other stages and that, consistent with CMS's request for comment on whether the NCD should be expanded or narrowed by clinical conditions, CMS should expand the NCD to cover any FDA-approved NGS companion diagnostic products regardless of cancer stage to avoid having to continually update the NCD in future.

Even among the research that CMS reviewed to draft the proposed NCD there is an indication that other stages of cancers might benefit from NGS. For example, CMS cites a 2014 study by Plimack et.al. title "Accelerated methotextae vinblastine, doxorubicin, and cisplatin is safe, effective and efficient for neoadjuvant treatment for muscle-invasive bladder cancer," which reviewed the effect of NGS in a study population of patients with stage III and stage IV cancers.⁷ Another analysis by Schrock et. al. titled "Pulmonary Sarcomatoid Carcinomas Commonly Harbor Either Potentially Targetable Genomic Alternations or High Tumor Mutational Burden as Observed by Comprehensive Genomic Profiling" looked at patients using NGS in Stages IB, IL III and IV of cancer.⁸ While studies on the use of NGS testing for stage IV cancer may be more common currently, we are beginning to see evidence of how it is useful for other stages of cancer as well. In addition, as new NGS companion diagnostics are developed and approved, their use for earlier stages or other categories of cancer may become more and more common. If CMS does not wish to continuously update its NCD to reflect these new developments, then it should expand the proposed NCD now to ensure that any NGS companion diagnostic test approved by the FDA, no matter the stage or type of cancer, is will be covered when used consistent with the approvals.

On the face of CMS' s proposal, it appears that CED would apply more broadly than coverage without evidence development, because it would apply to NGS for recurrent, metastatic or advanced cancers, without explicitly limiting it to stage IV cancers. ⁹ However, in the text of the proposed decision memorandum CMS defines "advanced cancer" as being limited to stage IV, metastatic and recurring cancers, such that it appears that there is no coverage available under the entire NCD for other stages of cancer.¹⁰ BMS asks that CMS clarify the stages of cancer it intends to cover under CED and, if it did intend to limit CED to recurring, metastatic and stage IV cancers, that it expand CED to cover any NGS used for cancer diagnostic testing, for the reasons described above.

BMS appreciates CMS's proposal to cover FDA-approved NGS diagnostic tests provided to patients included as part of patient registries that meet certain criteria. However, the extensive list of requirements that CMS provides for registries to qualify for coverage under the NCD would mean in practice that very few current registries, if any, will likely be eligible for CED on the date that the proposed NCD is finalized. Instead, stakeholders will have to modify existing registries or establish and develop new ones that conform to CMS's extensive list ofregistry requirements. These requirements would result in a significant lead time for any registries to be established that would qualify under the proposed NCD's CED requirements. And for stakeholders to do so to address a particular cancer or condition would be incredibly burdensome, both to establish the first registries that qualify under the NCD and to establish future registries. Most important, beneficiaries would not have access to new NGS until these registries are established and providers are prepared to participate in them.

Therefore to further expand the scope of the NCD, and make it feasible to accommodate new NGS in the future, BMS asks CMS to reduce the list of requirements for NGS diagnostic tests to qualify under CED when provided to patients in certain registries and make it more flexible. For example, CMS proposes to require registries to track "patient-reported outcomes using measurement develop to evaluate symptomatic toxicity in patients on cancer clinical trials." Although we agree that measurements of quality of life are important, we also recognize that it can be difficult to collect data on patient-reported outcomes, particularly from patients with advanced cancers. We recommend that CMS either not require information on patient-reported outcomes or seek minimally burdensome methods of collecting information on patients' quality of life.

BMS also urges CMS to adopt a clear pathway for FDA-approved tests to move from CED to full coverage. CMS should clarify the type and amount of evidence that would be sufficient to move to full coverage and adopt a process for FDA-approved NGS to make that transition. The NCD as currently drafted does not address this process at all.

BMS appreciates CMS's proposal to cover other NGS diagnostic tests when provided through certain clinical trials. However, BMS is again concerned that the NCD, in limiting the eligible clinical trials to those listed in the National Institutes of Health (NIH) National Cancer Institute (NCI) National Clinical Trial Network, may be drawing the scope of CED coverage in this category too narrowly. CMS may inadvertently fail to cover under CED some of the most valuable clinical trials for the development of NGS diagnostic testing, which may be conducted by organizations not be participating in the Network due to the burdens associated with doing so. The also Network excludes all investigator sponsored research (ISR) and investigator sponsored trails (ISTs), meaning that the NGS clinical trials that are most commonly tied to the potential development and expanded use of FDA-approved drug therapies would not be covered by the NCO. BMS believes that CMS therefore should expand coverage to include trials provided through academic medical centers, regardless of whether they are participating in the NIH-NCI National Clinical Trial Network, and should generally redraft the NCD to ensure that it covers a broader range of clinical trials on NGS.

In addition, CMS should broaden coverage of NGS in clinical trials to accommodate trials with more expansive inclusion criteria than those in the NIH NCI National Clinical Trial Network. The patient coverage criteria for clinical trials in this Network are unnecessarily narrow, making these trials underinclusive of the diversity of cancer patients that CMS would ideally cover under the NCD for NGS testing. For example, NCI-MATCH is limited to patients with an ECOG performance score of 0-1. Sicker patients , those with ECOG scores of 2 or more, are excluded.¹¹ BMS also believes that these trials do not always sufficiently account for racial and ethnic diversity in their selection of patients.¹² For CED to be effective in encouraging continued study of how NGS diagnostics can best be used to treat patients, CMS needs to ensure that covers clinical trials under the NCD that are sufficiently broad to cover a variety of patient types and cancers, consistent with the Medicare beneficiary population.

Under the proposed language, CMS seems to be considering eliminating coverage of many NGS tests currently covered under existing LCDs. This is because CMS proposes that all tests that do not meet the criteria in CMS' s coverage or CED categories would not be covered. Therefore, any test currently covered under an LCD that does not meet the criteria of one of these two categories would not be covered as CMS s NCD would supersede local MAC decisions.¹³ At the same time, and as discussed above, it would take 6-12 months to develop registries and clinical trials that would satisfy the CED portions of the NCD.

Many NGS tests that are currently covered by Medicare Administrative Contractors (MACs) therefore would lose coverage without any coverage pathway available to obtain coverage under the NCD in the short term.

BMS urges CMS to modify the language in the NCD regarding noncoverage of NGS to ensure that any NGS diagnostic test covered under an existing LCD continues to be covered for a reasonable amount of time after the NCD is finalized to allow registries and clinical trials to develop to provide alternative coverage of NGS tests under CED. BMS believes that a reasonable amount of time would be 6-12 months. CMS need not delay the effective date of the noncoverage provisions with respect to any NGS not currently approved by an LCD.

In the interim, BMS also urges CMS to proceed with implementation of the provisions of the NCD that expand coverage of NGS tests. Permitting immediate coverage of FDA-approved companion NGS tests would allow CMS to continue to support the development of precision medicine techniques. Permitting coverage of certain other NGS tests through CED would incentivize further evidence collection and efficient and timely development of registries and clinical trials that meet the requirements of the NCD.

CMS should take extra steps to notify providers about coverage for NGS diagnostic tests should it finalize the proposed NCO given that the NCD could supersede or would at least overlap with existing LCDs on the same issue. CMS should work with MACs to develop a more thorough communications process than usual for doing so and should also make sure that it develops a thorough communication process for disseminating this information to practitioners through provider organizations, particularly those focused on treatment of cancer, those that might have existing cancer registries that could potentially be eligible for CED, and those that work with academic medical centers and clinical trial providers.

BMS urges CMS to remove the once per lifetime coverage limits for patients' use of NGS testing. Setting prescriptive coverage limitations could be problematic as the science of oncology treatment is evolving rapidly. As NGS tests are the gateway to personalized medicine and individual patient treatment plans, these tests are likely to become a standard part of the treatment pathway for many tumors. Therefore, as patients face tumor recurrence or metastasis, NGS testing will likely become an essential tool for oncologists to ensure that they make the most informed treatment decisions for their patients.

BMS urges CMS to ensure alignment of coverage of NGS testing with CMS' current policies for oncology drug coverage. In certain instances, NGS tests may not be approved as a companion diagnostic however, such testing may be strongly recommended to identify the most appropriate treatment pathway for a patient. In such cases, BMS recommends that CMS align coverage for the NGS test to all clinically validated uses in additional cancers as may be published by the National Comprehensive Cancer Network (NCCN) or other compendia approved by CMS for identifying covered uses of anticancer chemotherapeutic drugs.¹⁴

BMS thanks CMS for its consideration of these comments, and appreciates CMS' s intent to ensure adequate coverage of NGS diagnostic tests. However, BMS also urges CMS to ensure that the final NCD provides flexible coverage and CED guidelines for NGS diagnostic tests as these tests continue to evolve, and does not preclude coverage of any existing NGS already covered by LCDs. If you would like to discuss any of these comments, please do not hesitate to contact at Amy Demske at (202) 783-8665. We look forward to continuing to work with CMS on these important issues and appreciate CMS's efforts to make NGS diagnostic tests available to patients thus far.

Tamar Thompson
Executive Director
Federal and State Payment

Footnotes:

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Thank you for the opportunity to offer comments on the “Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)”.

The proposal to cover oncology testing with NGS platforms is a move in the positive direction, and I applaud your thoughtful approach to this. There are, however, a some serious concerns:

1. NGS is not a “test” but a technology, that can be used for single gene assays, multigene discrete output assays and only, rarely, for multiplexed assays with a single indexed output using a proprietary black-box algorithm. The proposal of non-coverage of “NGS as a diagnostic laboratory test” when the criteria 1 or 2 of the NCD are not met, creates the following problem: The NGS platform is currently used not only for large panels, but also for focused single gene/small panel assays important not only for the management of metastatic/recurrent disease, but also for initial diagnosis, classification and staging. The non-coverage decision will force academic laboratories to switch to less efficient non-NGS assays for this testing. Therefore, this NCD should address only large-scale, large-panel, whole exome or whole genome assays. Single gene, or small-panel assays should be excluded from this NCD, and these assays should be considered equivalent whether they use NGS or non-NGS methodology.
2. CLIA oversight of non-indexed discrete-result LDPs, is an established mechanism to ensure test quality. Furthermore, laboratories in New York State are overseen by the CLEP, CLIA/CLEP laboratory developed , and 510-K cleared assays that identify the same discrete genomic alterations as designated CDx assays and meet the appropriate technical quality standards, provide the same information as designated Cdx assays, and restricting coverage to FDA-approved CDx assays provides no benefit to Medicare beneficiaries. The inability to modify an FDA assay is a double-edged sword, and in many instances can delay clinically significant improvements necessary for improved patient management., and even delay access to new genomically directed therapies.
3. Finally, with respect to coverage under CED: the language is extremely rigid. Limiting coverage under 2b only to trials under the NCI NCTN creates a very high barrier to participation by most laboratories. Often, participation in these trials and, indeed, obtaining consent to participate in clinical trials is contingent upon the results of these assays. This creates a Catch-22 situation for labs. Criteria for CED should be broadened to an intent to participate by the ordering physician, when patients have failed standard of care therapy. When tests become standard of care for the choice of therapy in specific situation, this should be recognized and the assays covered, after trials have been completed, with the understanding that LDPs used under the CED will continue to remain LDPs after successful clinical trials.

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While it is encouraging to see that CMS recognizes the use and utility of next-generation sequencing (NGS) for treatment of cancer patients, there are several aspects of its proposed decision memo that raise significant concerns.
The most troubling aspect of the proposal is the limitation of reimbursement to FDA-approved assays. This will have a chilling effect on molecular laboratories in academic medical centers which, by and large, do not have the financial resources to carry out the years-long clinical trials required to obtain FDA approval. Furthermore, these laboratories perform their testing primarily on their own patient populations and may not be able to enroll sufficient patients with specific tumor types to demonstrate clinical utility. The end result of this is to eliminate options for NGS cancer testing, where only a few large commercial labs (perhaps only one) will perform testing on all oncology patients. Certainly most academic hospital laboratories will be forced to discontinue in-house NGS testing, despite being the standard of care in many institutions. Although the proposal permits testing in the context of NCI trials, the majority of patients undergoing NGS testing, even at tertiary care academic medical centers, are not participating in trials and are getting testing as part of standard care. Continuation of this beneficial practice will be financially non-viable if there will be no opportunity for reimbursement. Not only will patients be deprived of potentially superior testing, but there will also be a loss of tremendous amounts of data which have been the source of much of the rise of precision medicine.

The distinct and favorable treatment of FDA-approved assays in the proposal is not supported by data. There is a long history of laboratory-developed tests (LDTs) performed in academic hospital laboratories for care of the hospital’s own patients. Indeed, in our institution, out of necessity (due to an absence of FDA-approved options) and for cost containment, most molecular testing for cancer is done using LDTs. Regulation of LDTs under existing CLIA and state laws as well as guidelines, accreditation and proficiency testing from professional organizations such as the College of American Pathologists, the Association for Molecular Pathology, and the American Society of Clinical Oncology have ensured that the vast majority of LDTs for cancer perform robustly and to a standard comparable to that of FDA-approved diagnostic tests. This has recently been shown for EGFR, KRAS and BRAF testing by Kim AS et al in a study published in JAMA Oncology in December, 2017. Guidelines for the performance of NGS tests have been published and provide a framework for continued high performance of LDTs using this methodology. Oncology NGS tests developed by academic medical institutions primarily for their own patients can and do perform as well as FDA-approved testing and should be reimbursed.

Finally, the tying of FDA approval to reimbursement will have unintended consequences that will impede CMS’s goal of improving healthcare. Because FDA-approved assays cannot be altered, there is a disincentive to modify an existing test to incorporate new methodologies or scientific discoveries, even if these were to improve the technical performance or clinical utility of the assay. Secondly, the proposal is limited to NGS testing, while older, less efficient technologies are not addressed and may continue to be reimbursed by CMS. Laboratories will be given an incentive to use these technologies in order to retain payment for their services, depriving patients access to potentially superior testing. Another limiting effect of the proposal is the requirement (for reimbursement) that an NGS test may be performed only once, only for a specific list of tumor types, and only in “advanced” cancer. This ignores important aspects of cancer biology, where tumors evolve in the course of treatment, necessitating re-testing to identify the cause of drug resistance and possible remedies. Restricting payment to a small list of tumors will exclude a large segment of oncology patients, many of whom will harbor targetable mutations identical to those seen in the on-label list. In metastatic cancer, the original tumor may be unknown, excluding these patients as well. Lastly, while there are patients with metastatic disease who certainly warrant a designation of advanced cancer, there are highly aggressive tumors, such as some soft tissue sarcomas, which have poor prognoses even in the absence of systemic metastasis.

CMS has recognized that NGS testing is a critical component of treating patients with cancer, and for that we are relieved. However, the draft proposal limiting reimbursement to FDA-approved assays will have a negative impact on the overall care of oncology patients in this country through restrictive access, promotion of status quo testing, and elimination of academic molecular testing labs from participation in this testing.

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January 16, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Dear Director Syrek-Jensen:

On behalf of Biocept, Inc. we appreciate the opportunity to comment on the Proposed Decision Memorandum for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N), issued by Centers for Medicare & Medicaid Services (CMS) on November 30, 2017.

Biocept, Inc. (“Company”) is a San Diego-based provider of liquid biopsy testing services. The Company was established in 1997 and has developed minimally-invasive, blood-based methods to detect cancer related molecular biomarkers (e.g., protein expression, gene fusions, gene amplifications, and oncogene mutations) utilizing circulating tumor cell (CTC) and circulating tumor DNA (ctDNA). Biocept’s pipeline is focused on leveraging NGS and other advanced technologies to support more informed physician decision-making and improved patient outcomes.

We would like to acknowledge the progress that CMS has made towards developing national policy for personalized medicine in oncology. We feel that this draft National Coverage Decision (NCD) solidifies the movement towards advancing molecular profiling and further revolutionizing the treatment of cancer. To that end, we would like to suggest a few modifications to the NCD to ensure increased patient access to medically appropriate testing, leading to improved outcomes for Medicare beneficiaries.

The FDA has approved multiple, novel, gene-specific targeted therapies over the past few years, with dozens of new cancer therapies currently in development. In order to benefit from these targeted therapies, oncologists require molecular testing for characterization of the patient’s cancer for selection of the best possible therapy. Despite the availability of molecular tests with demonstrated evidence, for example EGFR assays for Non-Small Cell Lung Cancer (NSCLC), a large percentage of patients do not receive the appropriate testing and are left without the opportunity to receive targeted therapies.¹ Biocept is gravely concerned by this paradigm of care.

The following comments are intended to address areas in the NCD proposal that we believe may inadvertently limit patient access and compromise quality of care for Medicare beneficiaries. We would like the agency to consider:

• Include coverage in the NCD for NGS based Laboratory Developed Tests (LDTs) that meet defined technical assessment standards and include medically appropriate markers with established utility (e.g., EGFR, KRAS, BRAF, ALK, ROS1) that are considered standard of care today - whether offered as individual tests or as a targeted “hot spot” panel that includes only clinically actionable genes.
• Institute transparent Analytical (AV) and Clinical Validity (CV) standards, for NGS markers that are medically appropriate, in guidelines and have an approved targeted therapy (e.g., NSCLC – EGFR, BRAF, ALK, ROS1)
• Create an additional tier of requirements, coverage and pricing structure for emerging genes within the large multi-gene NGS panels that are not medically appropriate but promising
• Clarify which registries will quality for CED
• Identify approved entities in addition to the FDA and NYSDOH that can provide authorized technical assessments so as not to unduly restrict the approval process (e.g., CAP or AMP).
• Provide coverage for assays that achieve FDA 510K clearance without a CED requirement
• Clarify the type of NGS testing that the NCD applies to (e.g., somatic, solid- tissue, large multi-gene panels). Do not include liquid biopsy NGS testing in the NCD as the clinical evidence reviewed by CMS and the FDA was limited to solid tumor tissue tests.

Lastly, we would like to acknowledge the effort that the Coverage and Analysis Group has made towards advancing the goal of personalized medicine for patients by providing resources for molecular profiling and further revolutionizing the treatment of cancer.

Thank you for your time and consideration.

Sincerely,

Mike Nall
Chief Executive Officer

Veena Singh, M. D.
Senior VP and Senior Medical Director

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January 17, 2018

Ms. Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
U.S. Department of Health and Human Services
7500 Security Boulevard
Baltimore, MD 21244

Dear Ms. Jensen:

On behalf of the American Society of Clinical Pathology (ASCP), I am writing to provide comment on the proposed National Coverage Determination for the FoundationOne CDx (F1CDx) next generation sequencing (NGS)-based test. While ASCP supports coverage of novel diagnostics that can improve the ability of physicians to treat patient diseases like cancer, we are concerned that this proposed NCD could undermine the ability of clinical laboratories to provide patients and their providers with the diagnostic services that may be best-suited to their medical needs, delivered via laboratory developed tests (LDTs). Consequently, we urge CMS not to include any provisions or policies in its final NCD that would adversely affect the coverage of other clinical laboratory tests, including LDTs, that are currently covered by local coverage determinations (LCDs).

The ASCP is a 501(c)(3) nonprofit medical specialty society representing over 100,000 members. Our members are board certified pathologists, other physicians, clinical scientists (PhDs), certified medical laboratory scientists/technologists and technicians, and educators. ASCP is one of the nation’s largest medical specialty societies and is the world’s largest organization representing the field of laboratory medicine and pathology. As the leading provider of continuing education for pathologists and medical laboratory personnel, ASCP enhances the quality of the profession through comprehensive educational programs, publications, and self-assessment materials.

ASCP appreciates the efforts of the FDA and CMS to recognize advanced oncology diagnostics that enhance patient care via companion diagnostics. The FoundationOne test can detect 324 genetic mutations and two genomic signatures in solid tumors. It is only the second test to be reviewed under the Food and Drug Administration and CMS Parallel Review Program, which allows device makers to request a simultaneous, overlapping review by the two agencies to reduce the time between a marketing decision by FDA and a national coverage determination by CMS. According to the FDA, the test can help identify patients with five specific tumor types and could benefit from 15 targeted therapies already approved by the agency.

While we are supportive of providing coverage to this test, ASCP is deeply troubled with the implications that this NCD could have beyond this particular test, such as for those LDTs which perform the same function. In its NCD, CMS proposes to limit future coverage of NGS-based tests with companion diagnostic indications and other potentially tests to those that are FDA-approved and also sets in place very narrow criteria for Coverage with Evidence Development (CED). Because the NCD imposes a no-coverage policy for tests that do not satisfy the criteria outlined in the NCD, CMS would not reimburse novel NGS LDTs (and possibly other laboratory methodologies) developed by clinical laboratories and academic medical centers for in-house use.

Under the proposed NCD, clinical laboratory tests would have to obtain FDA-approval to receive Medicare reimbursement. While this requirement is focused on NGS-based tests, it is hard to believe that this requirement would not ultimately affect other laboratory services. This proposal is not sound policy as it could prevent LDTs (and not just those that perform a similar function) from securing Medicare coverage.

LDTs are developed, validated and used for in-house purposes and have been well-integrated into standard practice for diagnosing and managing disease, and informing decisions about lifestyle and behavior. These tests are enabling improved prevention, diagnosis, treatment and disease management and prevention for an array of common chronic conditions such as cancer, heart disease, and diabetes, as well as rare genetic disorders and infectious diseases. They are indispensable tools in the practice of medicine.

The Clinical Laboratory Improvement Amendments of 1988 (CLIA) was crafted purposely to enable and encourage clinical laboratories to develop and utilize their own innovative laboratory testing protocols/systems. CLIA is an appropriate regulatory oversight scheme that focuses on the accuracy and reliability of the testing process, with specific requirements for analytic quality control, proficiency testing, testing personnel qualifications, laboratory test reports, and documentation of standard operating procedures. The CLIA model has also been aided by the development of consensus guidelines, such as those that exist specifically for the validation and performance of NGS on tissue specimens.

Moreover, to ensure that laboratories adhere to these requirements, data are reviewed through rigorous inspections performed under the auspices of CLIA. This framework has allowed timely and appropriate introduction of innovative testing into practice, and has been instrumental in providing quality patient care. As numerous published studies have demonstrated, LDTs have a solid track record of advancing patient care safely and effectively. As a result, ASCP believes that CLIA, not FDA, provides the most appropriate regulatory oversight scheme for most LDTs.

Conditioning Medicare coverage of laboratory tests on whether they are FDA-approved would undermine the ability of clinical laboratories to develop innovative diagnostics. As Karen Kaul, MD, PhD¹ noted in a recent blog post to CollabRx.com, the gene panel proposed for approval here “will not be suitable for many samples, many types of cancer, and certainly not biopsies or aspirates. Sending the representative tumor block may negate performance of other studies needed for appropriate patient care.” It is important that CMS be aware that many of the advances establishing NGS as an important laboratory technology occurred as a result of research performed by academic medical centers and other clinical laboratory sites to develop for their own LDTs. These advances benefitting patients, providers, and the medical diagnostic industry would be lost if CMS and/or FDA impose requirements that disincentivize innovation within clinical laboratories.

The FDA’s-approval only requirement would be particularly problematic for infectious disease testing as many LDTs have preceded the availability of FDA-cleared or approved assays, often by many years. This concern also relates to low-volume tests, such as those for rare disorders, which have historically been developed at smaller laboratories and academic medical centers. Creating disincentives to innovation could present significant risks to the public health by increasing the time needed for assay development during pandemics and other emerging infectious disease scenarios.

As CMS is aware, the FDA-approval process is extremely expensive, resource-intensive and time consuming. Requiring tests to be FDA approved will slow down the process of developing diagnostic devices. It would also disincentivize smaller clinical laboratories and academic medical centers from engaging in advanced research to improve available diagnostics. CMS should be aware that many of the advances establishing NGS (as a critical tool to improving patient care) are the product of molecular pathologists and scientists working in academic and large community hospitals. This NCD’s attack on LCDs will hurt patient care as the lack of predictable reimbursement will stymie the development and use of these critical tools.

This NCD requires clinical laboratories, test developers and other entities seeking Medicare coverage of their NGS companion diagnostics to satisfy CMS’ CED requirements, which outlines requirements for participation in clinical trials and access to patient outcomes data. Under the proposal, CMS would generally allow coverage for NGS-based tests approved by FDA under the Pre-market Approval (PMA) process. However, both PMA approved tests used off-label and 510(k) approved tests would need to participate in NCA-sponsored clinical trials to obtain coverage.

Such a mandate, however well-intentioned, could pose insurmountable obstacles for many clinical laboratories at the forefront of diagnostics development. Many lack the financial resources and staff to engage in clinical studies. Similarly, many laboratories lack access to the patient outcome data required by the NCD. Without reasonable alternatives, the proposed CED provisions would harm innovation and patient care. ASCP believes that the NCD’s CED requirements are too prescriptive and onerous and would prove harmful to patient care.

In addition to the concerns outlined above, ASCP is also troubled with the broad and restrictive scope of the NCD, which effects testing far beyond the coverage of the FoundationOne CDx (F1CDx) NGS-based test. First, we should point out that NGS is a technology, not a diagnostic test, and thus this NCD has far-reaching implications for the entire spectrum of laboratory tests using this methodology. We also note that CMS’ NCD strays from past convention that has focused on specific biomarkers or HCPCS codes without regard to the test methodology or its FDA approval status.

One feature of NCDs is that they supplant local coverage decisions (LCDs) that allow LDTs to receive reimbursement under the Medicare program. Thus, this proposed NCD would disenfranchise patients currently being served by the hospital-based and independent clinical laboratories that are currently receiving reimbursement under Medicare for similar NGS-based tests. Further, since the FoundationOne test is the first and only FDA-approved comprehensive genomic profiling test for all solid tumors that has been covered under a preliminary NCD from CMS, this NCD has the potential to create monopolies and/or oligopolies, and not just for this test but others as well. This directly diminishes innovation, increases healthcare costs, and delays the development of laboratory tests—all of which is detrimental to patient care. Also alarming is that this NCD may harm Medicare beneficiaries currently receiving advance cancer diagnostics at academic medical centers and cancer treatment centers in the United States.

ASCP does not believe that it is necessary or appropriate to use a NCD specific to one NGS-based test to recast the Medicare coverage landscape for other tests. Moreover, such a tactic seems contrary to the Administration’s policy with regard to development of regulatory policies. We note that Executive Order 12866 states that “Federal agencies should promulgate only such regulations² as are… made necessary by compelling public need (emphasis added)…” Given that the term laboratory developed tests appears once in the background section of the NCD, the Agency has clearly not demonstrated that a compelling need exists for such a policy.

ASCP must point out several issues specific to CMS’s coverage plans. CMS’ coverage decision is drafted to include all oncology test indications and all cancer patients, but later states that non-advanced cancer patients are exclude from coverage of any type of NGS-based genomics test. This suggests that NGS-based testing for non-advanced cancers is not medically necessary, which potentially causes patient harm at a point in time where accurate diagnoses and treatments are most effective. ASCP urges CMS to correct this to allow coverage of all individuals with cancer.

ASCP is also concerned that the NCD seems to suggest that Medicare may not provide coverage for BRCA Risk NGS testing. Medicare currently provides coverage for women with a history of breast cancer. There are several methodologies currently used for this type of tests. Frequently, however, the technology used for this testing is NGS. Currently, however, there are no FDA-approved or cleared tests for germline mutations. Our reading of the rule is that the NCD would not allow for coverage of BRCA Risk Testing by NGS, and may require testing using an alternative technology, such as Sanger sequencing. According to a study by Hyung Seok Park et al. entitled Next-generation sequencing of BRCA1/2 in breast cancer patients: potential effects on clinical decision-making using rapid, high-accuracy genetic results “NGS yielded comparably accurate results to Sanger sequencing and in a much shorter time with respect to BRCA1/2 mutation identification. The shorter turnaround time and higher accuracy of NGS may help clinicians make more timely and informed decisions regarding surgery or neoadjuvant chemotherapy in patients with breast cancer.” We do not believe that it is CMS’s intent to restrict coverage for these tests and urge CMS to ensure that coverage for these services is not threatened by the final NCD.

In closing, we note that companion diagnostics are not products, but a collaborative process involving the patient, his or her clinicians, the diagnostic team and other health care professionals. Optimum patient care requires the ability and flexibility to analyze patient specimens, the need to discuss findings with local tumor boards and to be involved in quality improvement initiatives within the treating institution. This type of care, however, can be diminished when coverage determinations require testing to be performed at a single centralized laboratory, far removed from the patient. Such a development would be troubling and seems plausible, if not likely, under this NCD. Laboratory services account for only 2 percent of health care costs in the United States, but their influence is far greater.

As a result, ASCP believes that CMS should try to incentivize the development of novel and advanced laboratory tests, not disincentivize them. Consequently, ASCP urges CMS to limit approval to the FoundationOne CDx. CMS should not include any provisions or policies that would establish broad coverage policies affecting other clinical laboratory tests or services, including but not limited to those that are currently covered by local coverage determinations (LCDs). ASCP encourages CMS to revise the proposed NCD to remove those provisions applicable beyond the FoundationOne CDx.

ASCP appreciates the opportunity to comment on this proposed NCD. If we can be of any assistance, please contact me or Matthew Schulze, Director of the ASCP Center for Public Policy at 202-408-1110 (x 2905) or Matthew.Schulze@ASCP.org.

Sincerely,

James L Wisecarver, MD, PhD
President, ASCP

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Tamara Syrek Jensen, JD
Director, Coverage & Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop S3-02-01
7500 Security Boulevard
Baltimore, MD 21244–1850

Re: Comments on Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG #00450N)

GRAIL, Inc. (GRAIL) is pleased to provide comments on the Centers for Medicare & Medicaid Services (CMS) proposed decision memo for Next Generation Sequencing (NGS) for Medicare beneficiaries with advanced cancer (CAG #00450N). GRAIL’s mission is to detect cancer early, when it has the greatest potential to be cured. Given the potential importance of such medical innovation to patients, GRAIL encourages CMS to consider policies that help advance such innovation.

In this letter, we provide comments regarding a particular aspect of the proposed decision memo: our concern that the proposed draft language for the referenced National Coverage Determination (NCD) is overbroad and may limit access to important life-saving technologies for early-stage cancers, i.e. those cancers that are not metastatic, stage IV, or recurrent. In particular, the proposed language on non-coverage indications appears to foreclose any decision-making at the local contractor level for NGS testing for early-stage cancers. We urge CMS to revise the NCD section on non-coverage to make clear that the provision is limited to advanced cancers and that local contractors may develop coverage determinations on appropriate NGS used for early-stage cancers. This clarity is important to medical innovation around early-stage cancer detection. GRAIL is not commenting on other aspects of the proposed decision memo in this letter.

As background, GRAIL is a clinical-stage life sciences company using the power of high-intensity sequencing (including NGS), population-scale clinical trials, and state of the art computer science and data science to enhance the scientific understanding of cancer biology and develop blood tests for early-stage cancer detection. Although GRAIL’s tests are still in development, we are presently conducting clinical trials with tests that utilize NGS. Our comments on the CMS proposed decision memo relate to future coverage for NGS testing for early cancer detection.

Summary of Comments

If CMS does not provide clarity, the proposed language in Appendix D, Section C of the NCD—“Nationally Non-Covered Indications”—could be a potential impediment to beneficiary access to coverage for NGS testing used for early-stage cancers. The title of the proposed decision memo addresses NGS for “advanced cancer.” But the memo’s proposed terms may be viewed as speaking to and precluding any consideration of NGS technologies for early cancers. Without further guidance to Medicare Administrative Contractors (MACs), these contractors may determine that any NGS testing for indications other than those listed can only be covered if CMS develops new or revised NCDs. Funneling all decision-making to the national level may lead to a slow uptake of important life-saving technologies at cancer stages when they are most likely to result in a cure. This will result in a chilling effect on innovation and negatively affect the public health.

We request that CMS clarify in its final decision memo and NCD that the scope of non-coverage criteria applies only to diagnostic testing focusing on advanced cancers and does not pertain to NGS for: (1) tests focusing on early-stage cancers, or (2) early/preventive cancer screening tests (that is, non-diagnostic tests). By clarifying the language of the proposed Section C, CMS will leave open the door for future NGS coverage policies to be developed at the appropriate national and local levels for tests for screening, preventative, and early stage cancers that are vitally important to the public health.

Comments

We understand that Foundation Medicine, Inc. (Foundation Medicine) sought an NCD for “comprehensive genomic profile testing for the management of cancer patients with solid tumors that are metastatic, including Stage IV and recurrent, with F1CDx.” Foundation Medicine stated that such comprehensive genomic profile testing falls under the Medicare benefit category for “diagnostic laboratory tests.” This narrow request did not seek NCD coverage addressing other indications or falling under other benefit categories, such as: (1) NGS technology for early-stage cancers, or (2) NGS technology for cancer screening.

In the draft NCD language at Appendix D of the proposed decision memo, CMS suggests that established evidence is sufficient to cover NGS as a “diagnostic laboratory test” for advanced cancer if several conditions are met. One of these conditions is that the patient has “recurrent, metastatic, or advanced stage IV cancer.” In Section C of Appendix D, “CMS proposes non-coverage of NGS as a diagnostic laboratory test when patients do not have the above-noted indications for cancer or when the test does not meet the above-noted criteria.” GRAIL is concerned that the draft language of Section C is so vague and overbroad, as currently drafted, that it could prevent MACs from evaluating newly-developed evidence and extending coverage to tests focusing on early-stage cancers, even when the new evidence otherwise is reliable and shows clinical and analytical validity, as well as clinical utility.

In Section C, CMS uses the term “diagnostic laboratory test,” but does not address possible future coverage of preventative or screening tests. Nor does CMS distinguish diagnostic tests for early-stage cancer indications from “the above-noted indications” for advanced cancers. We urge CMS to clarify that its silence in addressing tests focusing on early-stage cancers should not be interpreted as meaning these tests will never be covered. Rather, such tests may be addressed under other coverage determinations through NCDs or local coverage determinations developed by the MACs.

Also, CMS reached this particular NCD proposal based upon Section 1862(a)(1)(A) of the Social Security Act, which does not address early/preventive cancer screening tests or tests focusing on early-stage cancers that may qualify for coverage under other parts of the Act. For example, CMS may determine to proceed with an NCD to address preventive or screening uses for NGS if the U.S. Preventive Services Task Force reviews and assigns an “A” or “B” grade to a specific NGS indication. At that time, CMS may solicit evidence specific to its analysis. Opening a new national coverage analysis at that time would permit the Agency to focus on the specific technology and indications rather than as a catch-all approach taken here.

From a public health perspective, it would be detrimental to deny the possibility of any future coverage of early/preventive cancer screening tests or tests focusing on early-stage cancers. NGS tests offered at earlier stages of cancer or before a cancer metastasizes may have particularly promising outcomes, because the earlier cancers often are smaller and easier to treat. Denying coverage for such tests would also have a chilling effect on this vitally important public health space.

In sum, we ask CMS to clarify in its final decision memo and NCD that NGS used for treating and/or managing early-stage cancers are not the subject of the NCD, including the non-coverage provisions in Section C.

Proposed Revisions to the Proposed NCD’s Non-Coverage Section

To address the need for flexibility in decision-making for early-stage cancers, GRAIL recommends that CMS amend the proposed language of Section C as follows:

CMS proposes non-coverage of NGS as a diagnostic laboratory test for advanced cancers when patients do not have the above-noted indications for cancer or when the test does not meet the above-noted criteria.

We also recommend that CMS clarify in its final decision memo that its coverage determination does not foreclose coverage for tests focusing on early-stage cancers or early/preventive cancer screening tests (non-diagnostic), which may be addressed with separate coverage determinations, including, as applicable, local coverage determinations developed by MACs.

Thank you for the opportunity to comment on this important proposal from CMS. As mentioned earlier, GRAIL’s comments are focused on the specific issue described herein; GRAIL is not providing comments, including by omission, on other aspects of the proposed decision memo at this time. GRAIL looks forward to serving as a constructive partner on this issue and would be happy to meet with CMS to discuss the company and its technology and how we envision NGS will continue to evolve for diagnosing and managing early cancers. Please do not hesitate to contact us if you have any questions.

Sincerely,

Ken Drazan
President, GRAIL, Inc.

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I am writing to you regarding your recent National Coverage Decision (NCD) (CAG-00450N). I am the Medical Director of OncoMetrix Laboratory, a part of Poplar Healthcare in Memphis, TN. Poplar Healthcare is a national anatomic and molecular pathology laboratory servicing thousands of treating physicians throughout the United States. Our staff of over 40 surgical pathologists receive well over 1,000 cases daily for histologic diagnosis. Many of these cases also require additional molecular diagnostic testing for characterization of malignant tumors, as deemed appropriate by treating oncologists, who use these results for patient management. Our laboratory has developed and validated both individual gene mutation assays and next generation sequencing panels for solid tumors. These panels have been validated under CLIA and CAP specifications using specimens and data from our community physicians. Our pathologists identify the area of the tumor to be sequenced and oversee the entire process from beginning to end and are in contact with both the surgeon and the treating oncologist. The proposed NCD would prohibit our lab from completing these tests. These assays would not be covered by CMS and would limit a Medicare beneficiaries’ access to such tests. This essentially would force labs like Poplar Healthcare to discontinue this valuable service and limit the testing to a very limited number of labs that have undertaken the FDA approval process.

Secondly, the proposed NCD will inhibit innovation and growth in the laboratory sector if CMS required laboratories to go through an FDA approval process before ever receiving reimbursement for esoteric testing. Few labs have the resources for this undertaking. In addition, NGS technology is changing the way we practice medicine. Our laboratory is offering or developing assays for prenatal testing, carrier screening, microbiome characterization and supporting precision medicine. By requiring FDA approval for NGS assays for reimbursement would shut down this development in our laboratory and countless other labs, thus again limiting innovation and access for Medicare beneficiaries. Poplar Healthcare is a CLIA-certified and CAP-accredited laboratory. We submit to the rigorous standards of these bodies to regulate and oversee both our clinical validations and day-today test performance. We believe that clinically validated assays under CLIA and CAP regulations should continue to be able to seek reimbursement from CMS. This testing should stay in the local community where physicians discuss and coordinate care. It will greatly affect patient care if these tissues are required to be sent away from the pathologist overseeing the case and sent perhaps out of state to a single facility approved under this NDC.

On behalf of Poplar Healthcare (CLIA# 44D0915029), I request that you reconsider the language in the current NCD. It is too broadly restrictive and will shut down innovation in labs like Poplar Healthcare that were performing next generation sequencing technology. In addition, it is inconsistent with the FDA’s position on enforcement discretion for laboratory developed testing procedures. I am available to help with crafting new language that will address the concerns raised by myself and my industry colleagues.

Sincerely,

Mihaela Onciu, MD
Medical Director, OncoMetrix Laboratory
Poplar Healthcare
3495 Hacks Cross Road
Memphis, TN 38125

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The American College of Medical Genetics and Genomics (ACMG) welcomes the opportunity to comment on the proposed National Coverage Determination (NCD) for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer. Our 2000 members are clinicians who evaluate, diagnose, and treat patients with genetic disorders, and laboratory medical geneticists who perform genetic and genomic testing. Our guiding principles regarding genetic and genomic testing policy are to ensure that:

ACMG applauds CMS for recognizing the importance of genomic testing in the care of cancer patients. Further, consistent with the above principles, we support FDA approval and the NCD for the FoundationOne CDx (F1CDx) test. We are, however, concerned that the NCD proposes a coverage policy that has implications well beyond the F1CDx test. It appears that the proposed NCD process would deny coverage for many currently available and widely-used NGS technology-based tests by restricting coverage only to FDA approved or cleared companion NGS tests or, alternatively, would establish a restricted category of tests which would receive coverage based on evidence development. This expansion in the proposed coverage policy would significantly and harmfully reduce patient access to vital tests and treatment by eliminating coverage for many NGS tests for cancer patients enrolled in Medicare.

Moreover, we have additional concerns regarding the NCD and its reliance on FDA approval which, de facto, establishes FDA regulation of NGS-based tests. First, nearly all NGS-technology-based tests are Laboratory Developed Tests (LDTs), over which the FDA currently exercises enforcement discretion but has not yet produced final guidance or rule-making defining how they would propose to regulate LDTs. Consequently, FDA cannot currently regulate LDTs. Second, it has been widely reported that there are over 60,000 genetic and genomic tests currently available clinically. Exactly how many of these use NGS technology has not been published, but is it reasonable to estimate that more than 1000 are NGS-based. Even if the FDA were to develop an acceptable process for regulating NGS-technology-based tests, it is impractical to assume that the agency has the capacity to review such a large volume in a timely fashion. Finally, ACMG's position regarding oversight of NGS testing has been widely published and made clear in public comments at several FDA workshops. In our view, NGS-based testing is analogous to medical imaging, wherein the platform is a medical device, but the tests performed are not devices. Our position has supported CLIA modernization, rather than imposition of a new regulatory scheme.

Further, even if the FDA were to develop and publish a reasonable process for evaluating NGS-technology-based tests, we have serious concerns that tests for rare disorders would all but disappear. Most are sui generis, low-volume tests, and laboratories which perform these niche tests would be hard pressed to go through the expense of FDA clearance let alone approval. Patients and their physicians would consequently lose access to these critical tests.
Requiring FDA clearance or approval would also stifle innovation and potentially harm patients. One example regards testing for BRAF mutations, which can be targeted by a specific drug. The only FDA approved test kit for BRAF targets a single mutation in the gene. Research has identified other mutations in BRAF which can be targeted by the same drug. However, because it is time-consuming and expensive to re-submit an application for an expanded BRAF test kit to the FDA, the only way a patient currently can have testing for these additional mutations is through the use of an LDT. FDA regulation of LDTs would further impede progress in precision medicine, and patients would suffer the unintended, but foreseeable, consequences.

In summary, while the ACMG supports CMS’s decision to cover F1CDx, we do not support the expanded scope of the proposed NCD as written. We suggest that CMS and FDA engage stakeholders in a public process to ensure that physicians and their patients realize all the benefits of precision medicine.

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BIO COMMENTS RE: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

The Biotechnology Innovation Organization (BIO) appreciates the opportunity to comment on the Centers for Medicare and Medicaid Services’ (CMS’) National Coverage Analysis (NCA) and proposed decision memo for Next Generation Sequencing (NGS) for Medicare beneficiaries with Advanced Cancer. BIO is the world's largest trade association representing biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO’s members develop medical products and technologies to treat patients afflicted with serious diseases, to delay the onset of these diseases, or to prevent them in the first place. In that way, our members’ novel therapeutics, vaccines, and diagnostics not only have improved health outcomes, but also have reduced healthcare expenditures due to fewer physician office visits, hospitalizations, and surgical interventions.

Diagnostic technologies, such as NGS testing for cancer diagnosis and treatment, play a pivotal role in personalized medicine, allowing an individual’s genetic profile to guide decisions regarding prevention and treatment of serious health conditions. The availability of high-quality molecular profiling advances access to the most appropriate course of therapy in a more expeditious and efficient manner. Providing coverage for technologies and tools that advance patient access to the most appropriate course of treatment helps to improve health outcomes and reduce overall healthcare spending in the short- and long-term.

BIO is encouraged by CMS’ development of an NCA for NGS. Coverage of NGS is a critical step forward in advancing diagnosis and ensuring patients with advanced cancer receive the most appropriate course of treatment for their given health condition. High quality, validated genomic profiling assays accelerate patient access to precision approaches to diagnosing and treating cancer. Further, we are pleased to see the Parallel Review Program being employed, as it advances our shared goal of ensuring expedited patient access to new medical treatments and technologies, and we commend the Food and Drug Administration (FDA) and CMS on the approval and preliminary coverage for F1CDx. BIO supports CMS coverage and reimbursement for validated NGS testing as it reduces barriers to access, helps to ensure safe and effective use of medicines for patients with serious diseases.

BIO appreciates the development of coverage policies founded on clinical evidence and data and thanks CMS for the opportunity to provide comments on the NCA and proposed decision memo. We support the coverage of NGS testing for solid tumor genetic profiling. We believe it is imperative to balance coverage for NGS solid tumor genetic profiling with providing an appropriate pathway for coverage of additional NGS testing that represents a positive benefit to patients across disease states and care delivery through the NCD. We ask that in clearly providing coverage for NGS testing in stage IV solid tumor testing, CMS consider updates to the National Coverage Determination (NCD) that will advance additional coverage of NGS testing to advance patient access to the most appropriate course of treatment for their given health condition by doing the following:

• CMS should ensure that CED registry requirements have a low administrative burden that encourages developers of NGS tests to provide additional technologies to patients. The CED requirements as outlined in the proposed decision memo may inadvertently discourage certain laboratories or developers from participating, as Medicare reimbursement may not adequately account for the associated data collection and other requirements needed to assert CED. We ask that CMS not attempt to duplicate the efforts of the FDA through use of CED by using the requirements only when there is otherwise limited coverage. Further, while the genetic testing registry serves a critical role in research and efforts to improve patient health, its submissions are voluntary and therefore may create additional burden without added scientific value.(1) BIO ask CMS to work with stakeholders to appropriately address this process to ensure it further advances access to treatments and technologies for vulnerable cancer patients.


• CMS should provide an appropriate pathway for coverage of NGS tests that have additional clinical utility in patient care, but are either not associated with an FDA approved companion diagnostic or treatment,(2) or do not meet the specific criteria in the NCD based on testing (solid tumor v. liquid biopsy) or cancer type. BIO supports demonstration of appropriate clinical use and advancement of clinical trials that improve the safety and efficacy of cancer treatment. We urge CMS to consider a separate threshold to allow coverage of FDA-approved NGS tests that may not currently have a companion diagnostic or treatment.


• CMS should consider how to incorporate Laboratory Developed Tests (LDTs) where they may have potential benefit for patient-specific care and treatment needs where appropriate evidence thresholds are met. Currently, there are instances in which NGS LDTs exist for cancer diagnosis and treatment, but FDA-approved NGS tests do not exist. For patients afflicted with such cancers, NGS LDTs can serve a role in assessing the most appropriate treatment pathways for a patient’s specific disease state and healthcare needs.

BIO appreciates the opportunity to comment on this NCA and proposed decision memo and supports advancing coverage for NGS testing in a manner that ensures patients are able to access technologies that drive use of the most appropriate care plan and course of treatment for each patient’s given condition. We believe this NCA is an important step toward addressing unmet patient need and opens an opportunity to begin a national stakeholder dialogue on how to further advance access to more personalized approaches to treatment through use of diagnostic technologies, and ask CMS to continue to engage on that front. Should you have any questions, please do not hesitate to contact us.

(1) The Genetic Testing Registry website notes that “NIH does not independently verify information submitted to the GTR; it relies on submitters to provide information that is accurate and not misleading. NIH makes no endorsements of tests or laboratories listed in the GTR. GTR is not a substitute for medical advice.”

(2) Or equivalent platforms that use sequence specific results in the profiling of personalized medical testing results. For example, tests can be used to determine the risk-benefit profile of continued treatment – disease recurrence, progression, death – but are not specific to predicting the utility of a specific type of treatment. For example, testing PIK3CA mutation status of tumors in women with human epidermal growth factor receptor 2 (HER2) –positive metastatic breast cancer. In particular, women with tumors harboring a PIK3CA mutation had worse progression-free survival compared with women with PIK3CA wild-type tumors regardless of treatment group. While not NGS testing, other NGS platforms do test for these and other mutations.

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By Electronic Delivery at: www.regulations.gov

Ms. Seema Verma
Administrator
Centers for Medicare & Medicaid Services (CMS)
Department of Health and Human Services
7500 Security Blvd.
Baltimore, MD 21244-8013

RE: Comments on the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

Dear Administrator Verma:

The Alliance of Dedicated Cancer Centers (“ADCC” or “Centers”) is pleased to submit comments related to national coverage for Next Generation Sequencing. The ADCC is comprised of 11 institutions that have a singular focus on treating cancer patients; unlike other hospitals that care for patients suffering from any condition. Our institutions are at the forefront of innovations in the field of cancer, with a shared commitment to discovering and implementing the most effective treatment strategies for patients living with, or at risk for, cancer and are committed to delivering the highest standard of cancer care and achieving the best outcomes for our patients. We appreciate your consideration of our comments. If you have any questions or would like to discuss these comments with us, please do not hesitate to contact me (215.266.3497, karen.bird@adcc.org) or our consultant on technical issues—Ms. Jugna Shah (215.888.6037, jugna@nimitt.com). Many thanks in advance for your consideration of our comments.

Sincerely,

Karen Bird
Executive Director

Introduction

Molecular pathology tests are the gateway to personalized medicine and have already significantly improved oncology care by allowing physicians to more effectively manage patients using targeted drug therapy regimens. As the field evolves, molecular pathology testing will continue to serve as a cost-effective approach to help reduce overall treatment costs by ensuring that the “right” therapies (i.e., the most effective therapy for the patient) are used as first-line treatments and therapies that lack efficacy are avoided. Therefore, access to molecular pathology testing is important at the “right” time early in their cancer course to achieve optimal efficacy. Achieving these positive outcomes requires up-front investment since these complex tests involve costly reagents, consumables, and equipment, and require the involvement of highly trained personnel. Therefore, designing proper coverage policy and associated payment is essential.

Many of the ADCC’s member centers use Next Generation Sequencing (NGS) panel-based tests, through which multiple genes are tested rather than relying on single analyte testing. Panel-based testing enables us to analyze more types of genetic abnormalities than do conventional DNA sequencing technologies (i.e., single analyte testing). Panel-based testing also provides a comprehensive picture of the full spectrum of genetic changes in the patient’s cancer. Additionally, because panel-based testing allows multiple and different genes to be evaluated simultaneously, it is more cost-effective than separate sequential testing for individual mutations. Additional cost savings and reduced risk to patients stem from the fact that panel-based testing requires less tumor tissue, which means that fewer invasive biopsy procedures have to be performed.

Local availability of these assays allows each ADCC institution to provide needed rapid response and customized interpretations of the genomic findings afforded by a full review of the medical record. NGS allows cancer genomes to be profiled in a large number, quickly, and with a high level of sensitivity. The use of larger panels is a more reliable way to detect changes in the number of copies of each gene (i.e., gene amplifications or losses), which often represent targetable genetic alterations. The genes covered by these tests include all “actionable targets”—genes that can either be targeted with drugs or provide clinically relevant information about the disease if they are altered. Specifically, these NGS tests include identification of genes for which there are associated FDA-approved therapies.

Comments on the Draft NCD

As written, the proposed decision memo will exclude all ADCC academic molecular pathology laboratories from receiving payment (without evidence development) for NGS tests since coverage would be tied directly to FDA test approval as a companion diagnostic. The Centers’ own molecular pathology laboratories run NGS tests that identify the same genetic mutations that FDA-approved companion diagnostics identify—ones associated with specific FDA-approved therapies. Therefore, it does not make sense to limit coverage to FDA-approved companion diagnostics when other tests are already being done that are able to provide healthcare professionals with the same information.

Further, the vast majority of NGS tests furnished by our academic molecular pathology laboratories would be ineligible to obtain coverage with evidence development (CED) under the proposed policy—and it may be unrealistic for the tests to meet the criteria even if they are eligible. Only one of our center’s tests, MSK-IMPACT, offered by Memorial Sloan Kettering Cancer Center (MSKCC), would be eligible for coverage under the first category of CED, which provides CED for FDA-cleared or -approved tests with participation in the NIH Genetic Testing Registry. Thus, MSKCC’s other tests and the rest of the ADCC’s tests would not be eligible to obtain coverage even under the CED category.

Although tests that have not opted to obtain FDA clearance or approval may theoretically be eligible for coverage under the second category of CED, very few tests could practically meet these criteria. The second category of CED requires tests that are not FDA-cleared or -approved to be furnished to patients enrolled in an NIH-NCI National Clinical Trial Network clinical trial and an NIH Genetic Testing Registry. First, NGS tests are rarely provided as part of a clinical trial. Instead, NGS testing is performed in order to identify clinical trials that may offer possible further therapeutic options for beneficiaries who have exhausted conventional therapies. Furthermore, many therapeutic trials are run outside of the NIH-NCI National Clinical Trial Network clinical trials program, and access to such industry-sponsored or institutional trials remains vital for the care of advanced cancer patients and to optimally assess the utility of the therapy and the validity of the genomic biomarkers being used as trial entry criteria. Therefore, if the CED for these tests is limited to instances in which they are provided within an NIH-NCI National Clinical Trial Network clinical trial, then the access to non-FDA cleared or -approved tests would be extremely limited.

Second, it is unclear whether CMS will identify one registry, or whether individual registries would qualify. Individual registries would make synthesis of data more difficult. The answers to the questions posed may depend on the characteristics of the test. For example, more comprehensive tests find more potentially actionable variants than less comprehensive tests and the results also depend on the variety of tumors being tested. To further develop the body of evidence regarding specific genetic mutations, one registry should be operated on a national level with clear endpoints. Key stakeholder and clinician input will be necessary in developing the registry and identifying endpoints. We encourage CMS to evaluate existing registries and identify a professional organization to lead efforts to coordinate data collection and present an executable analysis plan to address CED questions. Lastly, the NCD should outline the pathway from CED to permanent coverage and establish clear timeframes for this process. There is limited precedence regarding items and services moving from CED to full coverage. The proposed NCD language is vague, stating only that data should be available “in a form and manner specified by CMS upon request.” The criteria and timeframe for graduating laboratory developed tests (LDTs) to permanent coverage should be outlined.

Because the proposed policy virtually excludes tests that do not have FDA authorization, academic molecular pathology laboratories, and many other sponsors of LDTs, will be compelled to seek FDA-authorization for their NGS tests. FDA will likely receive a high volume of pre-submission inquiries and then applications in a short timeframe—above and beyond the agency’s projected workload for which they are staffed. For academic laboratories in particular, the FDA clearance process will largely be unfamiliar, time consuming, and resource-intensive. Although FDA recently announced its accreditation of the New York State Department of Health (NYSDOH) as a FDA third-party reviewer of in vitro diagnostics, most of our institutions have not had reason or opportunity to engage with the NYSDOH previously, meaning that the NYSDOH would need to conduct new reviews for their submissions. More broadly, it is unclear whether FDA and the NYSDOH currently have the capacity to review the substantial volume of submissions likely to result from this proposed policy. Of course, if this route to coverage or CED proves to be untenable, it would mean that beneficiaries would not benefit from these tests, particularly those offered by academic medical centers.

Moreover, although the proposed NCD appears to rely on FDA’s role in regulating LDTs, FDA’s approach to and authority over such tests is currently unclear. In early 2017, FDA announced that it would not issue final guidance on LDTs at that time to allow for further public discussion on an appropriate oversight approach. Until the FDA pathway is more established, CMS should provide alternative criteria for NGS tests that are not yet FDA-cleared or -approved. Notably, much of the evidence supporting the clinical utility of NGS outlined in the proposed NCD derives from publications from the ADCC centers and other academic molecular laboratories based on high-quality LDTs used for molecular profiling. In fact, academic pathology departments and their associated clinical laboratories have been intimately involved in the non-commercial development and implementation of LDTs used for patients cared for in their institutions. Many of the scientific and clinical discoveries that underlie and allow for the development of LDTs have been made first in academic departments of pathology, in close development and collaboration with clinical caregivers and cancer researchers. These laboratories that innovate and develop LDTs obtain the level of CLIA licensure that demands the highest level of quality and safety. In addition, laboratories owned and operated by hospitals must meet hospital accreditation standards to satisfy the Medicare conditions of participation requirements. Finally, many academic medical centers obtain the College of American Pathologists (CAP) certification. These requirements ensure that laboratories with these levels of certification operate with the standards required to appropriately and successfully develop LDTs. In addition, it is contradictory that LDTs are not considered adequate for standard of care testing but such tests can be covered as part of an NIH-NCI National Clinical Trial Network clinical trial. Similarly, research testing can be paid for under this decision memo if part of an NIH-NCI National Clinical Trial Network clinical trial, but the same test would not be covered if a LDT is used for standard of care testing in a companion diagnostic disease indication.

Indeed, some of these tests would otherwise be covered under Local Coverage Determinations (LCDs), such as those from Palmetto-MolDx, Noridian, Novitas, and National Government Services. For example, National Government Services has issued an LCD providing coverage for a targeted genomic sequence analysis panel of 5 to 50 genes in certain beneficiaries with advanced non-small cell lung cancer. To ensure that there is a sufficient time period for sponsors to qualify for the new criteria for coverage, and to avoid disruptions of services for beneficiaries who are currently eligible for coverage of these tests, the NCD should include an appropriate transition period during which tests covered under an LCD would continue to be covered under the current terms of the applicable LCD.

Although coding and payment are not germane to this coverage policy, these issues logically follow after coverage. The ADCC urges CMS to take steps to clarify how it will operationalize coding and payment for these tests. First, as CMS is aware, the Protecting Access to Medicare Act (PAMA) established a new category of tests known as “Advanced Diagnostic Laboratory Tests” (ADLTs). However, the process for applying for ADLT designation and the assignment of a unique HCPCS code remains unclear, despite the PAMA provisions relating to payment for laboratory tests taking effect on January 1, 2018. To ensure beneficiary access to these tests, CMS should issue further guidance to facilitate coding and payment.

Summary and Conclusion

We applaud the proposed establishment of a national coverage policy for NGS for Medicare beneficiaries with advanced cancer. However, the coverage policy should better reflect the clinical utility of NGS panels. We strongly urge CMS to revise the proposed NCD to provide coverage without evidence development for tests that identify genetic mutations associated with specific FDA-approved therapies and to revise the CED requirements to better reflect current use of NGS tests. CMS should establish alternative criteria for LDTs to qualify for coverage until the FDA pathway is well-established, and a transition timeframe for sponsors of LDTs covered under LCDs to meet the coverage criteria and continue to provide for access and coverage. In the absence of an existing national registry, the ADCC encourages CMS to develop or identify a national registry that can be used to meet the CED registry requirements.

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January 16, 2018

Tamara Syrek-Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Dear Ms. Jensen:

NeoGenomics Laboratories wishes to provide CMS its comments on the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N). As a member of the American Clinical Laboratory Association (ACLA) NeoGenomics also supports ALCA’s public comment letter to CMS on this matter.

NeoGenomics is a premier cancer diagnostics laboratory company serving oncologists, pathologists, pharmaceutical companies, academic centers, and others with innovative diagnostic, prognostic and predictive testing. We believe precision medicine is a critical component in controlling cancer, and we provide precision testing through our network of Clinical Laboratory Improvement Amendments (CLIA)-certified, College of American Pathologists (CAP)-accredited facilities across the U.S.

We wish to thank CMS for extending the public comment period until January 17, 2018 allowing for comprehensive comments. We believe CMS should limit the scope of the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N) to Foundation Medicine’s FoundationOne CDx comprehensive genetic profiling test (F1CDx) based on its November 17, 2017 request for CMS to initiate a national coverage analysis (NCA).

We propose that CMS not finalize the NCD as written to allow for additional time to solicit and consider a wide-range of stakeholder input before issuing a coverage decision relating to NGS tests other than F1CDx.

Our comments on the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N) as written relates to the following points:

The proposed NCD appears to limit coverage to NGS as a diagnostic laboratory test "when ordered by a treating physician".

We believe CMS should reword "when ordered by a treating physician" to "when ordered by a member of the treating physician’s multidisciplinary medical team" (which may include multiple clinical specialists such as: clinical oncologist, surgical oncologist, pathologist, etc.)

The development of targeted therapies has brought with it implications with regard to tissue sampling and processing. Notoriously small diagnostic biopsy specimens that previously were required for confirmation of malignancy and tumor subtyping now must also be sufficient for molecular testing in order to complete the diagnostic assessment.¹

Ideally, treating physicians and pathologists will work together as part of a multidisciplinary team to select appropriate molecular testing and optimize patient management. While the treating physician may initially order molecular testing, a pathologist may also appropriately order molecular testing to avoid delays in identifying actionable mutations and potential delays in initiation of targeted therapy.¹

"With personalized medicine has come the development and clinical application of molecular testing in lung cancer. As the majority of patients never progress to surgical resection, the diagnostic small biopsy or cytology specimen has become a precious resource from which the surgical pathologist must aim to maximize diagnostic yield. Surgical pathologists have become the guardian for these limited precious samples, evaluating specimen adequacy, ensuring that appropriate processing techniques are applied, selecting suitable slides or blocks, enriching the tumor proportion by microdissection if required, and interpreting and providing timely results to the multidisciplinary team."

Pathologists play a similar role in the care of patients with other solid tumors and hematological cancers.

In addition to identifying targetable mutations, such as in breast cancer, pathologists often play a critical role as the one who monitors the response to treatment by analyzing molecular biomarkers and the changing molecular profile of the cancer during treatment.²

A 2014 Journal of Clinical Pathology article titled Guidance for laboratories performing molecular pathology for cancer patients states that while it is most often the oncologist that orders molecular testing, "multiple medical disciplines (e.g., surgery, oncology or pathology) may request molecular analysis to define a treatment strategy for individual patients." "In many cases, a multidisciplinary team (tumor board) will make the decision to request a test. The requesting process should ensure that the request is made appropriately, and that every patient who needs a test is offered one in a timely manner. This is one of the most difficult aspects of operating a molecular pathology laboratory.

It is important to ensure that tests are requested on all patients who need one, but equally important that unnecessary tests are not performed."³ A physician multidisciplinary approach to determining appropriate testing allows each specialty physician to lend their expertise to the decision making process, test requisitioning and producing actionable benefit to patients.

Advancements in oncology are identifying patients who may be effectively treated before the cancer becomes metastatic. New agents are beginning to be studied in non-metastatic cancer. We do not feel that coverage should be limited to those who have recurrent, metastatic or advanced disease. This point is particularly critical with the recent advances of lung cancer screening finding lung cancers at an earlier, more treatable stage. Having patients matched to appropriately targeted treatments earlier in the treatment paradigm is more patient-centric and may prevent advanced disease and be more cost effective.. In addition, not all patients with low-stage disease can be treated optimally by local therapies, due to co-morbidities and other factors. These patients must have additional options, including appropriate targeted therapies.

It is well-documented that cancer is a dynamic disease and during the course of disease, generally cancers become more heterogeneous and multiple subclones may exist in the tumor. Therapy may lead to selection of one subclone over the other and re-testing is frequently needed to evaluate cancer after relapse or progression. Furthermore, secondary mutations may evolve after exposure to treatment. For example, EGFR mutations in exon 20 (e.g., T790M mutation) may develop after initiating therapy with an EGFR inhibitor. Mutations in the HER2 gene may evolve after anti-HER2 therapy. As a result of this heterogeneity, the bulk tumor might include a diverse collection of cells harboring distinct molecular signatures with differential levels of sensitivity to treatment.

This heterogeneity might result in a non-uniform distribution of genetically distinct tumor-cell subpopulations across and within disease sites (spatial heterogeneity) or temporal variations in the molecular makeup of cancer cells (temporal heterogeneity).⁴

We believe repeat testing may be necessary for monitoring the efficacy of therapy, for confirming therapeutic response and for predicting relapse. Therefore, there are appropriate instances where retesting, using the same NGS test, is beneficial and actionable to the patient management team.

NeoGenomics vigorously opposes limiting coverage in this NCD to FDA-approved companion in vitro diagnostic tests only.

Our vast test menu of Laboratory Developed Tests (LDTs) are developed by leading experts in the field of molecular pathology; are validated to the highest standards for analytical and clinical validity⁵ and are performed by professionals in our CLIA-certified laboratories. Additionally, our labs are accredited by CAP and maintain compliance with rigorous state regulations and licensing requirements. Each of our molecular tests undergoes regular proficiency test challenges.

Advances in molecular diagnostics are rapidly evolving, making it difficult for FDA-approved testing kits to maintain pace and remain the standard of care, especially in oncology. This is demonstrated by a 2017 published peer-reviewed study comparing mutations detected in EGFR, BRAF and KRAS using a clinically validated LDT using NGS, with confirmation using Sanger sequencing, with mutations that could be detected by two FDA-cleared kits (. cobas v2 and therascreen) for these three genes. The results showed:

1. Significantly more mutations in EGFR, BRAF and KRAS genes are detected when using a clinically validated LDT for analyzing tumors than with FDA-cleared kits.
2. Significant improvement in mutation detection technology renders FDA-cleared kits inadequate for routine clinical testing.
3. Detected mutations that were missed by FDA-cleared tests may have significant impact on the clinical decision to treat or not to treat.⁶

Another study compared the performance of LDTs and FDA-approved companion diagnostics (FDA-CDx) using proficiency testing (PT) samples provided by the College of American Pathologists Molecular Oncology Committee. CAP is a well-known provider of external PT materials used by laboratories to fulfill the CLIA requirement for assessing analytical validity of clinical assays during initial development and ongoing clinical use.

Results from the study showed comparable accuracy and performance between LDTs and FDA-CDx. Of 6897 proficiency testing responses, both LDTs and FDA-CDx exceed 97% accuracy combined across all comparable molecular oncology proficiency testing samples. Importantly, results also showed that the majority of laboratories who purchased an FDA-CDx kit are, in fact, using them as LDTs. More than 60% of participants using FDA-CDx kits report modifying the approved procedures to broaden clinical practice, rendering the tests LDTs. Interestingly, LDTs outperformed FDA-CDx kits with BRAF p.V600K with an acceptability rate of 88% v. 66.1%.⁷

Requiring FDA approval for all NGS based testing is not currently feasible. The current pathway for FDA approval is arduous, expensive, time consuming, and unnecessary for those tests which have been analytically and clinically validated. By the time a test is FDA-approved or cleared, the genes on that panel may already be outdated, which means those patients are no longer receiving standard of care treatment. Also, FDA approved tests often require modification by experienced Medical Laboratory Physicians; sometimes an extra gene needs to be added, or sometimes the test procedure needs to be modified slightly to improve test performance.

Any change in an FDA-approved test, no matter how small, changes the test classification from FDA-approved to an LDT. Every CLIA certified and CAP approved laboratory already undergoes a rigorous validation process when introducing or modifying an LDT assay, including NGS testing, under existing CAP and CLIA standards. We believe requiring FDA oversight of this process is unnecessary, redundant, costly, impractical, and would limit patient access to state-of-the-art NGS testing.

At this time, LDTs are not mandated to undergo FDA approval or clearance. As a result, labs like NeoGenomics are able to change, adapt and validate our vast LDT test menu to take advantage of real-time advancements in oncologic discovery and NGS technology. This provides Medicare beneficiaries with the most current, actionable and reliable testing.

If CMS’s concern is primarily ensuring analytical and clinical validity of LDTs, we suggest utilizing CAP, CLIA and NYSDOH clinical laboratory regulations and guidelines that are already in place. We believe these regulations and guidelines are sufficiently rigorous and have proven to ensure that laboratories offer accurate and quality testing.

The FDA’s role in regulating LDTs remains limited today. In 2016, the FDA decided not to finalize its previously issued guidance on regulation of LDTs and the Agency continues to practice enforcement discretion to this day. As a result of this ongoing enforcement discretion, laboratories have not pursued FDA approval for the vast majority of NGS LDTs.

In fact, on January 11, 2018 in his All Hands Meeting related to the 2018 FDA Roadmap, Dr. Gottlieb, Commissioner of the Food and Drug Administration, stated: "I’m also hopeful that in 2018 we’ll continue to work with Congress to fashion a more modern and efficient approach to how we can assure the analytical and clinical validity of laboratory developed tests. As with other areas of new technology, when it comes to LDTs, we need to fashion a regulatory approach to these innovations that’s tailored to the novel profile of these products."

An NCD which limits NGS coverage to only FDA approved companion in vitro diagnostic tests will prevent patient access to the majority of NGS tests available today.

We strongly oppose an NCD which limits coverage only to tests which have been FDA-approved, or approved only for companion diagnostics when provided as part of a clinical trial with Coverage with Evidence Development (CED). By limiting coverage of NGS tests only to those that are FDA-approved companion in vitro diagnostic tests versus LDTs, CMS will limit access and delay care for Medicare beneficiaries. The CED process is protracted and expensive. Additional questions arise as to how CED would work for those diagnostic tests for rare cancers, many of which are vitally important to the beneficiary to determine an actionable plan of treatment. In the case of rare cancers, the number of cases is too small for a laboratory to devote the substantial resources necessary for the FDA approval process. We also believe that additional clarity for CED participation timeframes would be helpful?

If CMS elects to finalize Sections B of the Proposed Decision, we request that CMS provide a more viable CED process for LDTs that have been analytically and clinically validated. As written in this Proposed Decision, all LDTs, regardless of the level of evidence for analytical and clinical validity, will only be covered through NCTN clinical trials.

6. Evidence Section:

The Evidence section of the Proposed Decision Memorandum indicates that CMS only reviewed clinical literature and data with respect to solid tumor tissue testing in developing the Proposed Decision. In Section II, the Agency specifically states "for this NCD analysis, we are proposing coverage for any next generation sequencing diagnostic testing with the scope of this review limited to patients with advanced cancer." Since the scope of the review is limited to patients with advanced cancer, we believe CMS lacks sufficient basis to determine that NGS-based testing should be non-covered in other situations (i.e., for patients who do not have recurrent, metastatic or advanced cancers).

Furthermore, as the proposed NCD is written, it is not entirely clear if the intent is to limit coverage of NGS testing only to patients with advanced solid tumors, as there is no mention of use on hematological disorders. If this is indeed the intent of the proposed NCD, NeoGenomics is strongly opposed. In addition to hematological disorders, NGS has been shown to have clinical applications across multiple other diseases that affect Medicare beneficiaries; including, visual and hearing disorders, and cardiovascular disease.⁹ Limiting coverage only to patients with advanced solid tumors will unnecessarily limit access to otherwise actionable care for many Medicare beneficiaries suffering with hematologic disease.

In Summary, NeoGenomics believes:

• CMS should bifurcate this proposed decision and proceed with the Agency’s determination of coverage for Foundation Medicine’s F1CDx separate from NGS.
• CMS should allow coverage decisions to be made at the Medicare Administrative Contractor (MAC) level through the Local Coverage Determination process (LCD) currently in place.
• CMS should postpone finalizing the proposed NCD as it relates to NGS testing beyond F1CDx to allow for appropriate in-depth stakeholder input, potential MEDCAC meeting, and external subject matter experts input.
• CMS should reword "when ordered by a treating physician" to "when ordered by a member of the treating physician’s multidisciplinary medical team".
• CMS should provide equal coverage for NGS LDTs that have undergone the proper analytical and clinical validations.
• CMS should not prohibit repeat testing as there are appropriate situation where this is valid.
• CMS should not limit NGS testing to only recurrent, metastatic, stage IV advanced cancer, but should include other clinical applications as noted above.
• CMS should not limit the NCD to solid tumors only; rather, CMS should expand to all clinical applications, as noted above or should have multiple NCD’s that address other clinical application.
• CMS should remove non-coverage language.

We thank CMS for the opportunity to provide our comments on the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N). If CMS should have questions related to our comments, please do not hesitate to contact us at 239-284-8571.

Respectfully submitted,

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January 17, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Re: Proposed Decision Memo “Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)”

Submitted electronically

Dear Ms. Jensen:

On behalf of Washington University in St. Louis and its School of Medicine, I am writing to comment on the National Coverage Decision (NCD) proposal regarding Next Generation Sequencing (NGS), NCD CAG-00450N. I would like to thank CMS for the opportunity to provide feedback on this NCD, which we see as an important acknowledgement of the importance of next generation sequencing (NGS) in advancing precision medicine in oncology diagnostics. I hope this serves as a first step in a broader attempt by CMS to put regulatory guidance in place for other such applications.

The Washington University School of Medicine operates a physician group practice that consists of approximately 1,400 providers covering 76 different specialties and subspecialties. As a member of the Association of American Medical Colleges (AAMC), we fully support their comments as submitted on January 17. We would like to expand on one issue and raise a second.

First, by limiting Medicare coverage to an FDA-approved diagnostic, the NCD will severely restrict the usefulness of this policy. Oncology genomic diagnostics is a field that is quickly evolving. Doctors and their patients desire the best possible care, and as we move into an era of precision medicine, they need to have tests for the latest approved drug biomarkers. In this rapidly changing field, medicine must be nimble and adaptable, and a traditional FDA-approval pathway for many diagnostic tests may not be appropriate in many cases. We believe NGS diagnostic tests performed by CLIA-certified labs should be permitted, as the environment and standards within a CLIA lab are equivalent to FDA-approved assays in cross-assay comparisons. We recognize that the NCD offers another pathway under section B (Coverage with Evidence Development), which may allow for non-FDA tests. However, the criteria to qualify for this pathway are exceptionally onerous and not likely to be achievable in most situations.

Second, by requiring the NGS test to have been ordered by the treating physician, CMS may inadvertently be limiting the NCD in such a way that fails to recognize how advanced oncology services are provided. At our cancer center, an individual patient’s care is overseen by a team of physicians, including oncologists, pathologists, and several other specialties. There are often valid and important reasons why a pathologist who is part of this team may see the need to order an NGS diagnostic test, but under the NCD, that may not be possible as the pathologist is not usually considered the “treating physician.” We recommend CMS revise the NCD and replace the term “treating physician” with “treatment team” or “physicians on the treatment team.”

The NCD represents an important milestone in precision medicine, and this policy will be a model going forward. For these reasons, we strongly encourage CMS to acknowledge the potential of precision medicine by crafting an NCD that is both flexible and that acknowledges the reality of advanced medical practice. We recommend that CMS continue to engage stakeholders and delay finalizing the NCD until additional recommendations for demonstration of clinical and analytic validity can be presented to and analyzed by CMS.

If there is any further way I can be of assistance in this matter, please let me know. Thank you again for the opportunity to comment on this important matter.

Sincerely,
David H. Perlmutter, MD
Executive Vice Chancellor for Medical Affairs and Dean
Washington University School of Medicine

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January 17, 2018

Tamara Syrek Jensen, JD
Director, Coverage & Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mailstop S3-02-01
7500 Security Blvd
Baltimore MD 21244

Dear Ms. Syrek Jensen:

The Advanced Medical Technology Association (AdvaMed) and AdvaMedDx are pleased to offer the following comments on the Centers for Medicare & Medicaid Services’ (CMS) Proposed Coverage Decision Memorandum for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer.¹ We applaud the joint effort of the Food and Drug Administration (FDA) and CMS to reduce the time between FDA approval and Medicare coverage through the Parallel Review program. At the same time, we have some feedback regarding the current NGS NCD proposal, which are described in greater detail below.

AdvaMed member companies produce the medical devices, diagnostic products, and health information systems that are transforming health care through earlier disease detection, less invasive procedures, and more effective treatments. AdvaMedDx functions as an association within AdvaMed, and its member companies produce advanced in vitro diagnostic tests that facilitate evidence-based medicine, improve quality of patient care, enable early detection of disease and often reduce overall health care costs. Our membership includes manufacturers engaged in the development of innovative diagnostics that support the advancement of the public health, including next generation sequencing-based technologies. Throughout this letter, AdvaMed refers to both AdvaMed and AdvaMedDx.

AdvaMed has long supported the use of sound evidence to inform medical care. We have been supportive of the voluntary Parallel Review program, and we agree with the program’s objective to provide timely access to innovative medical technologies to patients and improve the quality of the overall health system.

We applaud CMS for moving quickly to propose national coverage for certain NGS applications upon FDA-approval of related tests. It is clear that both FDA and CMS contributed significant and thoughtful deliberation in the review of this technology for approval and coverage purposes.

AdvaMed recognizes that there is a critical public health role for companion diagnostic tests in supporting safe and effective use of therapeutic products; and we support access to these important tests that play an integral role in personalized medicine. We strongly support the Parallel Review process as a way to close the gap between FDA approval and CMS coverage, particularly in cases where a more efficient process supports an important public health need.

As we have stated previously, we are hopeful that lessons learned from the parallel review program can be applied to other new and innovative devices and technologies; and we look forward to working with CMS and our member companies toward the continued success of the program.

We appreciate the opportunity to provide constructive comments on the proposed decision memorandum. Our primary concern is that the decision is drafted in a way that may cause confusion with respect to future uses of NGS technology for other conditions or disease states. NGS is a tool that can be used for a number of applications, from hematology/oncology, to immunology, and more. It is unclear whether, in the case of this proposed coverage determination, the use of NGS is intended to include all applications of NGS, or whether it is limited to solid tumor gene profiling for Medicare beneficiaries with advanced, recurrent, or metastatic cancer at a single time point. As written, it may exclude other potential uses for NGS technology, such as initial diagnostic assessment, tracking diseases longitudinally, or where companion designation of a test is not plausible.

CMS should clarify whether the scope of this national coverage determination was intended to be tailored to a specific use of NGS technology, and whether other NGS applications would fall under its scope.

Future uses of NGS for other indications and disease states, outside of solid tumors in oncology, will require specific and careful consideration and input from an array of stakeholders, including physician specialty societies and diagnostic test developers. AdvaMed supports coverage of additional uses of NGS in the hope that it can be used more frequently in the future.

We appreciate CMS’ recognition of this important technology for tests indicated for use with patients with advanced cancer. However, we are concerned that the proposed definition of “advanced cancer” as described by this NCD could inappropriately narrow coverage for patients for FDA approved NGS-based companion diagnostics as CMS has defined advanced cancer as “recurrent, metastatic or advanced stage IV cancer.” Yet, the tests covered by the proposed NCD are indicated to aid in identifying patients who are eligible for targeted therapies regardless of the stage of cancer and/or recurrence.

CMS should clarify that coverage also would apply when consistent with the approved companion diagnostic test. For example, coverage should not be foreclosed for a patient with advanced stage III cancer, when consistent with the FDA approved or cleared test.

Again, AdvaMed supports CMS’ proposed decision to cover the NGS-based diagnostic tests for patients with advanced cancer that are described in the NCD, but we would appreciate such clarification so as not to inadvertently exclude other appropriate patient populations.

CMS is proposing coverage with evidence development (CED) for NGS diagnostic tests for use in the management of patients with advanced cancer where 1) the test is FDA-cleared or -approved but for which no companion diagnostic indication currently exists, or 2) the test is not cleared or approved by the FDA. For the first category, the FDA-cleared or –approved test must be registered in the NIH Genetic Testing Registry and the patients must be enrolled, and the laboratories participating in, a prospective registry that consecutively enrolls patients, meets other criteria and is designed to answer specific CED questions. For the second category, coverage would be limited to tests provided to patients within an NIH-NCI clinical trial meeting specific criteria. AdvaMed members have concerns that the data registry and clinical trial requirements are overly prescriptive and that CMS should allow for alternative mechanisms for data collection apart from the prescribed trial. Additionally, this requirement is restrictive as it implies that the only demonstrated and validated application of NGS is in a single-use case.

AdvaMed encourages CMS to take the necessary time to finalize the CED portion of the NCD and ensure thoughtful consideration as it could result in unintended consequences. CMS could consider finalizing Section 1 of the proposed NCD, with the clarification that the scope of the decision applies only to a specific use case of NGS technology (solid tumor, multi-gene profiling), and that this NCD does not apply to all NGS use cases at this time.

CMS could then pursue coverage with evidence development for the above categories or other categories along a separate track from the initial coverage decision, and take advantage of input from a variety of relevant stakeholders with expertise and knowledge of NGS.

Again, AdvaMed supports the use of rigorous evidence to inform patient care. We recognize that CMS may require CED to generate additional evidence when the agency believes the available evidence regarding a promising medical technology or procedure is not sufficient to support broad, national coverage. We also agree that coverage contingent on the development of additional evidence may allow certain beneficiaries access to innovative medical technologies and treatments where the alternative is non-coverage.

At the same time, AdvaMed believes that when CMS incorporates CED into a National Coverage Determination, the Agency should strive to:

As CED generates evidence supporting the use of a new innovation or services, Medicare’s coverage policies should reflect these outcomes while minimizing additional administrative burdens and simplifying program requirements where possible.

Thank you for the opportunity to provide these comments. Please feel free to contact me or Chandra Branham, JD, Vice President, Payment & Health Care Delivery Policy, at cbranham@advamed.org if you have any questions concerning these comments.

Sincerely,

/s/
Donald May
Executive Vice President
Payment & Health Care Delivery Policy
AdvaMed

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The OHSU Knight Cancer Center (KCI) has been designated by the National Cancer Institute as a Comprehensive Cancer Center, the agency’s highest distinction. KCI is internationally recognized as a leader in cancer research and treatment, as well as a pioneer of personalized cancer medicine. The institute is a part of OHSU who employs over 15,000 people which includes some of the world’s leading researchers and physicians in the tireless care of over 303,000 patients each year. Critical to KCI’s cutting-edge precision approach, are its own laboratory-developed Next Generation Sequencing (NGS) diagnostic tests, which are rigorously clinically- and analytically-validated in accordance with federal requirements outlined in the Clinical Laboratory Improvement Amendments (CLIA) statute, and CAP laboratory inspection requirements.

OHSU applauds CMS for their recognition of the value of precision oncology diagnostics in the care of cancer patients, as evidenced by the proposed National Coverage Determination (NCD) issued in conjunction with the FDA approval of Foundation Medicine Inc.’s F1CDx. However, the draft NCD proposes a coverage policy that has implications far beyond the F1CDx test. In making the scope overly broad, CMS imposes restrictive criteria that supersede local coverage policy and will effectively eliminate coverage for other NGS tests for advanced cancer patients enrolled in Medicare. The F1CDx test has clinical utility for certain indications, but it is not the only clinically acceptable test for patients with advanced cancer, nor is it the only test that has been demonstrated to be of high quality by peer review.

The NCD requirement of achieving FDA approval for coverage is inconsistent with the FDA’s position on enforcement discretion for laboratory developed testing procedures (LDPs), including its 2016 announcement that it does not intend to finalize the draft guidance establishing a framework to regulate LDPs. Rather, the NCD requirement of FDA approval for coverage establishes the FDA as determining the regulatory bar for acceptable clinical tests and thereby the practice of medicine. As a regulatory bar, FDA approval is impractical or impossible for most laboratories to reach, including those in many leading academic medical centers and cancer programs. Laboratories cannot sustain clinical services without reimbursement, and therefore would have to stop offering NGS-based tests to patients with advanced cancer.

CMS coverage policy for Medicare beneficiaries should not exclude entire categories of testing (i.e., those that use NGS technology), when such testing is performed in CLIA-accredited laboratories and adheres to evidence-based guidelines developed by leading scientists and subject matter experts and endorsed by medicine’s preeminent professional societies, including AMP, CAP, ASCO, ASH, WHO, and NCCN.

Precision oncology is a medical practice that occurs at the local level, at the patient’s bedside and in interactions between local healthcare professionals including molecular pathologists. The flexibility to triage urgent patient samples, to discuss in depth the findings at local tumor boards with a multidisciplinary team, and to participate in quality improvement initiatives specific to institutions will all be lost if testing is effectively centralized to one lab by the NCD as written.

Furthermore, NGS is a technology and is not a diagnostic test. The NCD focuses on a specific technology and is not tied either to a specific biomarker or specific CPT code. This approach runs counter to established coverage determinations, which are based on the clinical utility of a proven effective biomarker, independent of test methodology and whether a test has received regulatory approval for marketing and labeling. If finalized, it will disrupt existing local coverage policies for more targeted panels and specific CPT codes.

In areas where science is advancing rapidly, good coverage policy must remain nimble to adapt to advances in understanding and application to good patient care. Because NCDs are difficult to modify, they can be a barrier to rapidly-advancing medical practice. Therefore, we urge CMS to reconsider the implementation of this policy.

As you look to finalize the coverage determination, please consider the additional feedback below, provided in response to the specific “Questions for Commenters” posed in the Proposed Decision Memo.

Thank you very much for your consideration of our feedback on your proposal. Please do not hesitate to contact Abby Tibbs at tibbs@ohsu.edu if you have any questions.

Questions for Commenters to Address:

Q 1: Should the proposed NCD be expanded or narrowed by clinical conditions, test methodology to measure the same clinical biomarker, or clinical scenarios? If so, please provide supporting documentation, including peer-reviewed evidence, and a detailed analysis in support of your view.

A 1: We strongly recommend that CMS narrow this policy so that it applies only to the F1CDx assay, and not to any other NGS-based test. Coverage for these other clinically-and analytically-validated NGS-based tests should continue to be regulated, as per long-standing CMS precedent, by existing local coverage determinations (LCDs) administered by local Medicare Beneficiary Administrators.

Q 2: How do laboratories assess analytical and clinical validity? Based on laboratory experience, how long does it take to compile data demonstrating analytical and clinical validity, such as what would be submitted to the FDA or the New York State Department of Health? What are the variables that affect the duration of this time?

A 2: There are standard processes for test validation (analytical and clinical) recommended by AMP and CAP. If carried out properly these should meet NY state requirements.

Q 3: Would the approach (es) used currently in laboratories be similar to the approach used in this proposed NCD for the FDA to analytically and clinically validate a diagnostic laboratory test? Are there other possible approaches? If so, please provide supporting documentation, with peer-reviewed evidence, and a detailed analysis in support of the approach, including the number of tests using such an approach.

A 3: We strongly recommend that the existing regulations that mandate how a diagnostic test is to be stringently analytically and clinically validated, as detailed under the well-vetted federal CLIA law, be similarly applied to diagnostic tests that employ NGS methodologies. Every laboratory performing clinical testing is, by federal mandate, CLIA-certified. The stringent policies of the CLIA statute continuously assure high-quality laboratory performance standards and each test’s analytical and clinical performance characteristic over the entire lifetime of a test. As part of this certification, CLIA (or a federally-deemed partner) conducts laboratory inspections, and additionally, those performing high-complexity tests, must, under CLIA, undergo regular proficiency testing. Many laboratories obtain CLIA certification through accreditation by CMS-approved accrediting agencies, such as the College of American Pathologists (CAP) or the Joint Committee on Hospital Accreditation. The standards of these accreditation programs must meet or exceed those of the CLIA regulations. These programs often go well beyond CLIA including more stringent requirements for proficiency testing, as well as documentation of clinical validity.

Q 4: How do laboratories assess clinical utility? With regard to the proposed NCD, what would be examples of circumstances in which coverage would be adequately addressed by a local Medicare Administrative Contractor (MAC) including the ability to identify clinical utility of specific tests?

A 4: OHSU generally does not assess clinical utility; however, assay equivalence (analytically) should be all that is required if there is already an FDA-approved panel for the same gene targets.

Q 5: How can the information in this proposed NCD be clearly communicated to health care practitioners, patients, and their care-givers in addition to our existing communications through listservs, coverage updates, and outreach and education materials?

A 5: The important message to communicate to all stakeholders is that this policy would supersede existing CMS local coverage policies for NGS-based tests and limit Medicare beneficiaries’ access to a single laboratory and single test, which would be quite deleterious to patient care. This policy concentrates testing to a single entity, and will eliminate coverage or impose severely restrictive coverage with evidence (CED) requirements for all other tests utilizing NGS technology for all advanced cancer patients enrolled in Medicare. These tests are currently being used to deliver high-quality, advanced cancer care across the country as part of standard of care in oncology diagnostics. While we agree that the F1CDc test has clinical utility for certain indications, it is absolutely not the only clinically validated test for patients with advanced cancer, not is it the only test that has been demonstrated to be high quality by peer review and offered through existing regulatory oversight, e.g., the CLIA and CAP laboratory inspection processes. This policy as proposed would have a severe negative impact on extremely vulnerable Medicare beneficiaries by eliminating coverage for clinically valid and medically necessary testing services currently being used to deliver high quality cancer care across the country, including at virtually all major cancer center and academic institutions.

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January 17, 2018

Tamara Syrek Jensen, J.D.
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

Dear Ms. Jensen,

Thank you for the opportunity to review and comment on CMS’ proposed national coverage determination (NCD) entitled “Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N).” As the world’s largest organization of board-certified pathologists and leading provider of laboratory accreditation and proficiency testing programs, the College of American Pathologists (CAP) serves patients, patient-facing healthcare providers, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide.

Members of the CAP are experts in molecular pathology, and the CAP appreciates CMS’ effort to provide national coverage for precision medicine offered by next generation sequencing. However, the CAP is concerned that the proposed NCD constitutes an anomalous attempt to specify the medically reasonable and necessary clinical utilization of an entire family of methodologies (“Next Generation Sequencing”), rather than more appropriately addressing the detection of specific genetic mutations that are clinically relevant. The implementation of the proposed NCD criteria would have profound adverse and immediate consequences for access to therapies by Medicare beneficiaries, and treating physician’s ability to order medically necessary tests. Future development of test-based cancer therapies would also be impacted.

First and foremost, next generation sequencing is not a diagnostic test for which a NCD can reasonably be promulgated, but an extremely general family of laboratory methodologies. The medically reasonable and necessary applications of NGS vary by patient condition, and established usage is evolving rapidly. With regard to detecting acquired mutations in specific cancer genes, NGS methodologies are often used in “gene panel” tests that simultaneously sequence multiple “actionable” genes that can be the target of precision medicine drugs of direct therapeutic (and in some instances diagnostic) relevance to particular cancer sub-types. NGS methodologies thus facilitate the simultaneous sequencing of multiple genes of relevance to a cancer sub-type in a single, efficient, cost-effective and specimen-conserving process.

The appropriate diagnostic lab test to be assessed for clinical utility by CMS should be the target gene or genes being interrogated for mutations. The presence or absence of mutations in such specific genes, not the methodology used to detect their alterations, is what determines the sensitivity of a patient’s tumor to targeted cancer therapies.

All previous Medicare coverage decisions related to detecting cancer gene mutations that may predict responses to targeted therapies have been applied appropriately to diagnostic testing, irrespective of methodology, for detection of mutations in specific subsets of genes and cancers. These coverage decisions quite appropriately apply to all instances of a test that will detect these targetable mutations for precision oncology, irrespective of methodology. This proposed NCD constitutes a misguided attempt to determine clinical utility of an entire family of methodologies, rather than appropriately to provide coverage for the detection of the specific genetic mutations that are clinically relevant.

Moreover, upon urging of both governmental and private payers, the American Medical Association (AMA) has moved to develop molecular pathology Current Procedural Terminology (CPT) codes that are method agnostic, focusing on identifying specific genetic analytes and disease/syndrome-specific testing¹. Creating a NCD that addresses NGS methodologies rather than specific tests jeopardizes efforts to meaningfully codify clinically valid tests, including those that use NGS methods.

CMS proposes non-coverage of NGS as a diagnostic laboratory test when patients and tests do not meet the criteria outlined in the proposed NCD. However, the definition of the service provided in this proposed NCD is inconsistent with both the existing CPT codes designed to describe such services and the philosophy of CPT surrounding molecular testing in general, and multiplexed multianalyte assays in particular. The current construct of molecular pathology CPT codes has strongly advocated being analyte specific and “method agnostic” (i.e. codes should not refer to specific analytical methodologies) in order to accurately describe the analytical services provided, while encouraging development and adoption of the most clinically effective and cost-efficient testing.

The preamble to the Genomic sequencing procedures (GSP) section of CPT 20181 states:

“Genomic sequencing procedures (GSPs) and other molecular multianalyte assays GSPs are DNA or RNA sequence analysis methods that simultaneously assay multiple genes or genetic regions relevant to a clinical situation. They may target specific combinations of genes or genetic material, or assay the exome or genome. The technology used for genomic sequencing is commonly referred to as next generation sequencing (NGS) or massively parallel sequencing (MPS). GSPs are performed on nucleic acids from germline or neoplastic samples. Examples of applications include aneuploidy analysis of cell-free circulating fetal DNA, gene panels for somatic alterations in neoplasms, and sequence analysis of the exome or genome to determine the cause of developmental delay. The exome and genome procedures are designed to evaluate the genetic material in totality or near totality. Although commonly used to identify sequence (base) changes, they can also be used to identify copy number, structural changes, and abnormal zygosity patterns…..The analyses listed below represent groups of genes that are often performed by GSPs; however, the analyses may also be performed by other molecular techniques (polymerase chain reaction [PCR] methods and microarrays). These codes should be used when the components of the descriptor(s) are fulfilled regardless of the technique used to provide the analysis, unless specifically noted in the code descriptor. [Bold type added for emphasis]…..The assays in this section represent discrete genetic values, properties, or characteristics in which the measurement or analysis of each analyte is potentially of independent medical significance or useful in medical management.”

It is immediately apparent that the services described by the GSP codes cannot be equated with “NGS tests” since they are not performed exclusively using NGS methodologies. Furthermore, the spectrum of clinical scenarios addressed by the GSP-described services exceeds that described in this proposed NCD (e.g. prenatal testing for genetic abnormalities or inherited predisposition to malignancy). Categorical non-coverage of NGS as a diagnostic laboratory test when patients and tests do not meet the criteria outlined in the proposed NCD will be problematic when these services are performed and reported using the available GSP codes. It is critical for CMS to understand and correctly apply the established HIPAA-required coding structure in developing coverage determinations as it has in the past. This departure from that practice in the proposed NCD jeopardizes the entire system of coding for these services and would require creation of an expensive, time-consuming, unfamiliar, and unnecessary new coding system.

A particularly notable element in the GSP preamble is the statement:

“The assays in this section represent discrete genetic values, properties, or characteristics in which the measurement or analysis of each analyte is potentially of independent medical significance or useful in medical management.”

This statement reflects the AMA’s consistent efforts to codify in CPT specific testing services as specifically as possible as regards the results of the analysis, whether described as individual analytes or as elements of well-defined test panels. It is important to recognize that novel technologies, such as NGS, make it feasible to include in test panels many analytes of variable clinical value and utility. We encourage caution in attempting to codify, and develop coverage policies, for such services by linking them to established testing services (i.e., companion diagnostic tests), which in most circumstances are performed as single analytes. To do so results not only in a sub-optimal evaluation of the NGS-based tests, such as the one specifically addressed by this proposed NCD, but also creates a highly disruptive environment for the performance of other molecular pathology services and the CPT codes used to describe them.

The CAP supports coverage of actual tests, which identify particular analytes or mutations that have clinically demonstrable utility, and has no wish to impede access to Foundation Medicine, Inc’s test. However, we are opposed to the conflation that all diagnostic services using NGS-based technologies are in any sense “a test” for purposes of determining clinical utility, or that they are in any way equivalent as “tests”. The proposed NCD would have the effect of arbitrarily excluding providers from using this entire family of genomic sequencing procedures because of loss of coverage.

The proposed NCD raises several issues that are well beyond the scope of traditional NCDs. The coverage limitations outlined in the proposed NCD are unprecedented. CMS is attempting to establish conditions of coverage for an entire family of methodologies, which is a significant departure from the statutory requirements for Medicare to cover reasonable and necessary items or services based on existing evidence.

It is well established that clinical validity and analytic validity are two routine and required processes that must be assessed and confirmed in any CLIA-accredited laboratory. To limit coverage to only those specific panels that are FDA-approved or cleared will deny many patients access to these high-quality lifesaving tests.

CMS should rewrite the policy to explicitly define payment criteria for the specific test (i.e., FoundationOne F1CDx test) which was the only test reviewed under the FDA-CMS parallel review process. CMS should not attempt to generalize the NCD as a coverage determination for other test panels based on use of a shared methodology, many of which target a completely different set of cancer sub-types and/or genetic mutations than the Foundation Medicine, Inc., test. Specific genes and/or mutations in certain cancer sub-types are the appropriate testing target for regulatory oversight – certainly not the entire class of diagnostic tools that utilize related methodologies.

Additionally, not all actionable mutations require an extensive or costly NGS panel. This policy will undoubtedly restrict beneficiary access to the care that their treating physician feels is most appropriate. Allowing the treating physician to assess the results of a test that is not in an FDA-approved/cleared panel is strictly analogous to appropriate off-label prescribing of FDA-approved pharmaceuticals. Clinicians should be allowed to use testing that they feel they understand well enough to choose and apply in the clinical care of their patients. Restricting testing in a fashion more rigorous than the actual therapeutics that testing will guide represents an unreasonable interference in the practice of medicine.

A precedent for Medicare coverage of NGS assays already exists through local coverage determinations (LCDs). Medicare Administrative Contractors (MACs) have developed LCDs that provide coverage for the treatment of non-small cell lung cancer, acute myelogenous leukemia, and myelodysplastic syndromes.^2,3,4 These LCDs, which were developed using traditional local coverage development processes, define reasonable and necessary criteria, are solidly evidence-based policies supported by multiple professional practice guidelines, and were written with substantial input from recognized professionals in multiple institutions.

The coverage with evidence development (CED) criteria that the proposed policy prescribes will restrict use by most providers. It is not practical to require labs to submit patient information to a registry because of the limitations laboratories face in accessing patient records. Registries should focus on evaluation of information of test results and not on the type of methodology.

In summary, the CAP strongly recommends that the policy be rewritten to explicitly define payment criteria for the FoundationOne F1CDx test, rather than generalized as a global coverage determination for other gene panel tests that happen to use NGS methodologies similar to that of the Foundation Medicine, Inc., test.

Thank you again for the opportunity to comment on this proposed NCD. The CAP welcomes the opportunity to work with CMS to address these important issues that affect the medical care of beneficiaries. Please direct questions to: Nonda Wilson (202) 354-7116 or nwilson@cap.org.

REFERENCES

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January 17, 2018

Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Medicare & Medicaid Services
Mail stop #S3-02-01
7500 Security Blvd
Baltimore, MD 21244-1850

Dear Director Jensen:

On behalf of Genomic Health, Inc., I am submitting comments regarding CMS’ Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer. Genomic Health, Inc. is the world's leading provider of genomic-based diagnostic tests that optimize cancer care, including addressing the overtreatment of the disease, one of the greatest issues in healthcare today. With its Oncotype IQ® Genomic Intelligence Platform, the company is applying its world-class scientific and commercial expertise and infrastructure to lead the translation of clinical and genomic big data into actionable results for treatment planning throughout the cancer patient journey, from diagnosis to treatment selection and monitoring.

Our comments focus on the following key points:

1. We support extension of Medicare coverage to the FoundationOne CDx™ test.
2. We recommend CMS limit the scope of the Final Decision to only address coverage of solid tumor based somatic multi-gene oncology sequencing panels performed on tissue specimens using an NGS platform that have received FDA premarket approval as a companion diagnostic.
3. In the Final Decision, we request CMS enables laboratory developed tests (LDTs) approved by the New York State Department of Health (NYSDOH) to pursue CED under the same conditions as proposed for FDA cleared or FDA approved NGS tests.
4. We suggest CMS modify the CED criteria and scope in the final determination to be feasible for a wide variety of NGS tests and labs to ensure the ability to generate clinical evidence that supports expansion of Medicare coverage.

In addition, we will respond to the following questions asked by the Agency in the Proposed Decision memorandum:

• Question #1: Should the proposed NCD be expanded or narrowed by clinical conditions, test methodology to measure the same clinical biomarker, or clinical scenarios?
• Question #2: How do laboratories assess analytical and clinical validity? How long does it take to compile data demonstrating analytical and clinical validity, such as what would be submitted to the FDA or the New York State Department of Health? What are the variables that affect the duration of this time?
• Question #3: Would the approach(es) used currently in laboratories be similar to the approach used in this proposed NCD for the FDA to analytically and clinically validate a diagnostic laboratory test? Are there other possible approaches?

Acceptance of the FoundationOne CDx™ into the parallel review process continues to establish this process as a compelling route to regulatory approval and simultaneous national coverage for all types of medical technologies. We believe, based on the analysis presented in the Proposed Decision, that Medicare coverage is appropriate for the FoundationOne CDx™ test. We agree with CMS’ conclusion in the Proposed Decision that NGS PMA approved companion diagnostics have demonstrated, by virtue of the FDA review process, analytical and clinical validity. In addition, we agree that the reference to use of a companion diagnostic in the FDA labeling for an approved therapeutic establishes clinical utility for the test. As most FDA approved NGS companion diagnostics performed on tissue specimens are already covered for Medicare beneficiaries via local coverage determinations, granting national coverage to these tests ensures uniform access by Medicare beneficiaries to critical tests that will facilitate improved therapeutic decision making in advanced cancer patients.

While we support CMS’ extension of coverage to the FoundationOne CDx™ and to solid tumor based somatic multi-gene oncology sequencing panels that use an NGS platform and have received FDA premarket approval as companion diagnostics, we believe the agency, in the Final Decision, should clarify the process by which coverage will be implemented for new tests that receive FDA approval as companion diagnostics. We recommend that coverage be effective for newly FDA approved NGS companion diagnostics on tissue specimens upon their FDA approval date. CMS should consider working with FDA to establish an automatic process that would allow notice of FDA approval of a new NGS tests to be quickly communicated to CMS and to the Medicare Administrative Contractors (MACs) to ensure prompt coverage and patient access.

• Limited public input has resulted in an unprecedented level of non-coverage

During a parallel review process, CMS undertakes a more streamlined approach to a national coverage analysis because the parallel review usually seeks CMS’ assessment of a very narrow question, typically a specific technology. In this case, the request was to review a single NGS FDA approved companion diagnostic specific to tissue specimens for patients with advanced cancer. Despite the very narrow request from Foundation Medicine and the limitations on public input to the coverage analysis conducted as part of parallel review, CMS has chosen to expand the Proposed Decision well beyond the single test to an entire class of NGS diagnostic tests. The result is establishment of very broad non-coverage of a large class of tests without sufficient public input.

When CMS opens a national coverage analysis (NCA) that is not part of parallel review, there are two opportunities for public input.¹ When the NCA is opened, CMS will seek public comment to address the key questions the Agency plans to address in a draft decision memo. This public comment period allows key stakeholders such as clinicians, patient interest groups, and industry to provide data and insight to CMS that will strengthen the coverage analysis the Agency must complete. Then, when the draft decision memorandum is posted, the second public comment period allows CMS to gather additional insight into how the proposed coverage may impact the provision of and access to care. The two opportunities for public comment are critical to ensure the implications of a broad coverage determination are well understood by CMS as well as by external stakeholders. In addition, CMS will often consult the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) as part of a coverage analysis. A MEDCAC consultation gives stakeholders an additional opportunity to communicate their viewpoints to CMS about the potential impact of NCDs, particularly NCDs that address broad categories of medical care as this Proposed Decision does. Expanding the NCD beyond a review of just the FoundationOne CDx to include all NGS tests has resulted in an extraordinarily broad coverage determination, including an unprecedented level of non-coverage, despite remaining unexplored impacts to patient care.

Within the decision memorandum, CMS has posed several questions to the public that are complex and far-reaching. These questions are well considered but require an appropriate amount of time and consultation with stakeholders and experts to develop comprehensive responses. Clearly, for CMS, issues regarding the impact of NGS technology on Medicare beneficiaries remain, and these issues could be considered by MEDCAC and further understood based on public input that can be garnered during a typical coverage determination process. The nature of these questions speaks to the lack of stakeholder involvement in the development of the Proposed Decision, as these are precisely the questions the Agency should investigate prior to drafting a coverage determination, not afterward. We recommend the Agency limit the scope of the coverage decision to only address the establishment of coverage for FoundationOne CDx and should consider how to engage the public in addressing these questions prior to finalizing any other elements of the Proposed Decision.

• Applying Proposed Decision to a broad definition of NGS tests is not supported by evidence

Based on the clinical evidence cited in the Proposed Decision, CMS completed a thorough review of the available data for tissue based NGS tests. The analysis supports establishing coverage for FDA approved solid tumor based somatic NGS tests. However, the NCD does not cite any published evidence, despite its availability, for liquid based NGS tests in advanced cancer. Given the lack of cited publications, CMS cannot have made a full assessment of the available clinical evidence for liquid based NGS testing and it is inappropriate for the scope of this NCD to include any NGS tests other than solid tumor based tests in advanced cancers that CMS reviewed. We recommend that CMS specifically state, in the Final Decision, that the scope of the NCD is limited to tissue based NGS tests and that liquid based NGS tests are specifically outside the scope of the NCD.

The Proposed Decision is generalized to the use of NGS as a technical platform for diagnostic tests. This is a view of NGS technology that is inconsistent with the approach to other laboratory sequencing technologies and applications. There may be some tumor sequencing applications (e.g. Tumor Mutation Burden) where the only feasible approach is NGS and where there is little pre-existing data to support its use. However, for assessing panels of gene variants that have already established clinical relevance, other technologies (e.g. PCR approaches) can be used but NGS may be more efficient. For these uses, there is not a valid reason why NGS should be required to show higher levels of clinical evidence development than other technologies. Rather than focusing on the technology, coverage determinations should focus on the specific clinical application of the technology to determine what level of evidence is sufficient to demonstrate clinical validity and clinical utility. In drafting such a broad coverage determination, CMS seems to be assuming that all NGS tests are the same regardless of specimen type or clinical application when that is clearly not the case. With increased public input, the Agency would have received insight to the variety of potential applications of NGS testing in advanced cancer and understood the limitations such a broad NCD would place on patient access to innovative testing.

Given the unprecedented limitation on public engagement for a national coverage determination of this breadth, we believe it is appropriate that CMS narrow the scope of the coverage determination to address only the extension of coverage to FDA approved solid tumor based somatic multi-gene oncology sequencing panels that use an NGS platform. We request the non-coverage determination and establishment of CED criteria for other tests using NGS platforms be excluded from the Final Decision to allow for increased public input on the coverage of these tests.

Limiting CED for laboratory developed tests (LDTs) that do not have FDA approval or clearance to only NIH-NCI National Clinical Trials Networks studies is unlikely to generate the clinical utility data CMS expects and will significantly limit patient access to innovative lab tests that may not be available via the FDA approval or clearance process. The NCTN likely does not have the infrastructure to accommodate multiple additional studies to evaluate LDTs. In addition, typical studies within NCTN may not be designed appropriately to assess clinical utility of a diagnostic test, so inclusion of a LDT in one of these studies will not result in the clinical utility data CMS is seeking. The likely results are clinical evidence that does not advance coverage and the continued restriction of patient access.

Currently, there are LDTs available to patients that provide test results specific to FDA approved therapeutic interventions. The analytical and clinical validity of these LDTs in the patient population appropriate for that FDA approved therapy have been established via the CLIA and NYSDOH approval processes. Given the rigor of the NYSDOH process and its recent designation as a third-party reviewer in support of FDA 510K clearance, we believe that LDTs approved by NYSDOH should be permitted coverage via CED under the same conditions as a FDA cleared test. The Journal of the American Medical Association Oncology recently published a study by Kim et al. comparing proficiency testing of laboratory developed tests and FDA approved companion diagnostics. The study found “no differences overall between FDA-CDs and LDTs in assay performance…with an average of over 97% accuracy from both types of assays”² The study also noted that 60% of study participants using an FDA approved companion diagnostic modify the assay effectively rendering it a laboratory developed test. Given the conclusions of Kim et al. that FDA approved companion diagnostics and LDTs have comparable performance and that many FDA approved assays are modified by the performing lab, CMS should view FDA cleared tests and LDTs equivalently and allow them to pursue the same path for CED.

We agree with CMS’ expectation “that studies conducted under a CED NCD will produce evidence that will lead to revisions to Medicare coverage policies.”³ To successfully produce such evidence, however, the CED requirements must be feasible for all labs to participate in. We encourage the Agency to promote less burdensome study designs then those currently in the Proposed Decision to ensure development of evidence to support revision of Medicare coverage policies.

The relationship between a laboratory test and health outcomes is usually indirect. The test guides a treatment decision and the outcome results from that treatment decision. The appropriate standard to evaluate a clinical laboratory test cannot always be tied to patient outcomes. Clinical design constraints make it rare for a laboratory to be able to conduct prospective randomized clinical trials to show demonstrate clinical utility. Clinical utility for known genetic variants in cancer is usually deduced from other available evidence enabling efficient patient access to new tests with no compromise on patient safety. As currently written, the CED criteria require that approved CED registries track “Objective response rate, definition must be consistent with the Response Evaluation Criteria in Solid Tumors.” Requiring this degree of outcomes monitoring is not aligned with the typical design of a clinical registry and it poses a burden on the CED process that does not increase the likelihood of developing clinical utility data for NGS tests. For example, collecting clinical outcomes of overall survival, progression free survival, and objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) would require extensive third-party monitoring, auditing and review of diagnostic scans to ensure sufficient rigor. This presents significant administrative burden to patients and providers that are uncharacteristic in observational registries. Such burdens have been shown to affect patient enrollment in the registry as well as representation of the findings from the study population to the full target population. Essentially, the CED requirements set forth in the proposed NCD are likely to introduce significant selection bias. If the intent of CED is to gather more real-world evidence of clinical utility with the goal of expanding Medicare coverage, then CED requirements should not introduce unnecessary administrative burden that could impact patient enrollment and the generalizability of the data. In the Final Decision, we recommend CMS allow the laboratory, when designing the study for CED, to determine the outcome measure most appropriate for the test and indicated patient population.

To ensure efficient and appropriate data collection via CED, we recommend CMS streamline the process for approval of CED studies. The agency should establish a list of criteria, based on consultation with stakeholders, that a study must meet to be eligible for CED. Approval of CED studies would be effective upon the laboratory or sponsor’s certification of compliance with the criteria. Such self-certification of CED study protocols will allow efficient development of studies as well as patient enrollment to ensure the generation of clinical evidence to support expansion of Medicare coverage. The establishment of less burdensome CED requirements, like more appropriate registry designs and outcomes measurement tools that are determined upon consultation with stakeholders after the NCD is finalized, will facilitate broader participation in CED and faster generation of evidence to expand Medicare coverage.

While Genomic Health supports Foundation Medicine’s initial request for coverage of the FoundationOne CDx via the FDA/CMS parallel review process, we believe CMS should not finalize the proposed NCD as written. CMS has chosen to establish an extraordinarily broad coverage policy without benefit of full public input or adherence to its own national coverage analysis process. The significant limitation of LDTs to pursue CED only through a small number of clinical trials without direct applicability to the development of clinical utility data effectively denies Medicare beneficiaries access to innovative testing and provides no clear avenue to pursue national coverage. In addition, the CED criteria, as currently written are likely to prevent the generation of clinical evidence CMS expects for NGS tests pursuing CED. Given the significant flaws in the draft NCD, we recommend the following:

• CMS should finalize national coverage of the FoundationOne CDx™ test
• CMS should narrow the scope of the NCD to FDA approved solid tumor based somatic multi-gene oncology sequencing panels that use an NGS platform.
• CMS should allow LDTs approved by NYSDOH to pursue CED under the same conditions as FDA approved or cleared NGS tests.
• CMS must modify the CED criteria and scope in the final determination to be appropriate and feasible for a wide variety of NGS tests and labs to ensure generation of clinical evidence that supports coverage expansion.

Thank you for your consideration of our comments.

Sincerely,
Phillip Febbo, MD
Chief Medical Officer

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On 1/17/2018, at 12:48 pm

Dear Sir or Madame:

In reference to, Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-450-N), please note that I oppose requiring laboratories to use FDA-approved companion assays. Allowing such singular monopoly would destroy NGS-based laboratory develop testing assays that are both analytically and clinically just as sensitive and specific as FDA-approved tests. This proposition is an abomination set to destroy small and moderate size business in the Anatomic Pathology space. Shame on the legislators for allowing this proposition to be placed on the table for consideration. Take myself as an illustrative example, if you don't think that I can't write, perform, and interpret high-complexity molecular genetic pathology testing after sixteen (16) years of higher education, two advanced degrees, and four board certification, then, well, I should just apply for working for one of the large corporations. Finally, here is a thought for you, if you want to decrease spending in medicine and improve quality of care, why don't you revamp and make 510(k) pathway more stringent; https://www.nytimes.com/2018/01/13/opinion/sunday/can-your-hip-replacement-kill-you.html.

Again, what an abomination to have this proposal on the table.

With respect,

Nemanja

Assistant Professor of Pathology
Dermatopathology and Molecular Genetic Pathology Clinical Services
University of Florida Health Pathology Laboratories
4800 SW 35th Drive
Gainesville, FL 32608
Office: (352) 627-2225
Pager: (352) 413-8196 ?
Email: nemanja@ufl.edu

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[PHI Redacted]

Thank you for the opportunity to provide comment on the National Coverage Analysis entitled ‘Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer’. Cancer patients all over the country are benefitting from new knowledge in the genomic causes and drivers of cancer, as evidenced by increased access to personalized therapeutics and care based on the genetic makeup of cancer. We are grateful for advances in diagnostic technologies, such as next generation sequencing, as it is one tool to obtain a more comprehensive genetic understanding of cancer. This technology is of particular relevance to lung cancer patients as it typically requires less tissue sample than separate sequencing of multiple genes. I thank CMS for recognizing the value of precision diagnostics in the care of cancer patients by proposing coverage for FoundationOne CDx (F1CDx). I support a positive coverage determination for the product reviewed in the Parallel Review program, F1CDx, however I have serious concerns about the broad scope of the proposed NCD. The proposed policy would limit cancer patients to 1 test per lifetime, which is not in line with the realities of personalized medicine based therapy for cancer patients. Also, the new policy will eliminate coverage for other NGS tests for advanced cancer patients enrolled in Medicare. These tests are currently being used to deliver high-quality, advanced cancer care across the country, including at virtually all major cancer centers and academic institutions. I support CMS’ proposal to cover the F1CDx test but urge CMS not to finalize the rest of the policy as it will result in several unintended negative consequences to cancer patients by erasing important medical advances and existing local coverage policies already in place.

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First, I would like to thank CMS for the opportunity to comment on the proposed decision memo on NGS coverage for Medicare beneficiaries with advanced cancer (CAG-00540N). I appreciate the opportunity to comment on this issue, as a laboratory director, ABMGG-certified in Clinical Molecular Genetics, Cytogenetics, and Ph.D. Medical Genetics, serving the Portland metropolitan region in Oregon and Southwest Washington. Our Molecular Pathology laboratory offers laboratory-developed tests that have been extensively validated and clinically vetted per CAP, CLIA, and ISO 15189 guidelines. We have recently validated a laboratory-developed NGS oncology panel that will be offered to our patients that either have metastatic disease or have been refractory to standard chemotherapy treatments. Since healthcare delivery is LOCAL, our patients rely of our hospital laboratory to provide these basic clinical services in order to get treated quickly and appropriately. More importantly, our validated pan cancer panel is “necessary and sufficient” providing coverage for the 12 most actionable and targetable genes in which variants can provide a plan of action for the patient. This will allow a more economical approach to NGS testing. The current proposal whereby NGS testing is FDA-approved and associated with one company will produce a monopoly, and will jeopardize the efforts of hundreds of CLIA and CAP-accredited laboratories that are trying to care for the specific needs of their patients.

It is also important to note that FDA-approval is not necessary for the clinical utility and validity of NGS testing. Our molecular laboratories have been developing tests for decades and have fully documented the success and utility of these endeavors. FDA-approval is difficult, costly, and only allows the approved entity to obtain monopoly on the market. There has been NO data to suggest that FDA-approved tests in oncology are superior in performance. In fact, several publications have address this very issue and the data show equivalent results and more flexibility from LDTs (Kaul KL et al., 2017 and Kim AS et al., 2017).

In addition, the development of LDTs by local hospital laboratories ensures the timely transfer of specimens from the hospital to the laboratory therefore ensuring rapid results to the patient for treatment initiation. With the oncology testing and patient care rapidly evolving, laboratories are able to nimble adjust to the addition of newly validated NGS to increase patient care. To this end, FDA-approval cannot possibly be compatible with such a vastly evolving field.

I would like to urge CMS to reconsider this proposal and allows Medicare Beneficiaries to get coverage for testing performed in their local accredited laboratories.

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January 17, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Re: NCD CAG-00450N

Dear Ms. Syrek Jensen,

I support many of the policies put forth in the draft NCD referenced above. However, some language in the draft may limit my choices for how I care for Medicare patients and should be changed.

In my lung cancer practice, I order NGS testing for most of my patients, and frequently more than once. I have seen the dramatic benefits of this approach first hand. Patients who are eligible for targeted therapy can avoid unnecessary treatment with chemotherapy and instead receive less toxic, easier to administer targeted therapy drugs that are highly effective. Furthermore, retesting these patients at the time of resistance to targeted therapies can provide critical information about mechanisms of resistance to therapy and can frequently inform second line and beyond treatment decisions.

If the draft NCD is adopted without revision, a large percentage of my Medicare patients could lose access to the benefits of these drugs. In the past two years, comprehensive liquid biopsies have become an important tool for conducting this testing and have found targetable mutations in many patients whose tissue was insufficient for testing. Furthermore, the patients I have treated based on liquid biopsy results have experienced the same benefits as the patients who were tested with tissue.

As written, the draft NCD would exclude comprehensive liquid biopsies, as well as testing patients more than once. By limiting access to this important new technology, I am concerned that the new policy may prevent my Medicare patients from receiving the best treatment. I hope you can create a reasonable path for covering comprehensive liquid biopsies and ensure all Medicare patients have access to this important test.

Thank you for the opportunity to comment on this matter,

Collin Blakely MD, PhD
Assistant Professor
Thoracic Medical Oncology
UCSF Helen Diller Comprehensive Cancer Center

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This is a brief summary of comments submitted by PDF with illustrations and graphics.

CMS should be applauded for its bold effort to transform Medicare oncology care to a learning healthcare system. However, the NCD rules lead to a number of serious unintended consequences. It would be far better to develop a program in the way the Oncology Care Model was developed, with town halls, requests for information, and selection among proposals and fully vetted options against clear and explicit goals during a year of development.

1. Forbidden coverage in non advanced patients has perverse effects. Germline testing unrelated to somatic mutation drug selection is blocked (e.g. BRCA syndromes and Lynch syndromes) if it is performed by NGS but not if performed by worse methods. Clinically important classes of tests are in non advanced patients (e.g. Oncotype and other prognostic tests) and these would become noncovered solely if and because they are migrated to NGS platforms for accuracy, speed, and efficiency.

2. LDT tests are covered only in NCI trials. For one example, there are multiple recorded drug-gene combinations where the FDA has approved the drug prior to a PMA test (cetuximab/KRAS; crizotinib/ROS1; Keytruda/MSI). Each case involves tens of thousands of patients (!) where FDA was happy to have drug approval based on then-existing LDTs. This will no doubt happen again sometimes. In well known areas like germline testing, leukemia panels, and liquid biopsy panels (for limited scenarios) there are no PMA tests yet and in germline sequencing even future tests may be non PMA FDA reviewed tests. These are scenarios where the PMA rule makes no sense and is a bad fit.

3. In some ways, perversely broad coverage is created. A hospital could run five, $300 gene tests on Monday ($1500), and the FMI F1 test would be covered on Tuesday. The FMI test might be validated for ONE gene, in a cancer, a gene known to be negative, but the F1 test would still be covered with no CED. Under CED, F1 testing will be covered in millions of patients with "recurrent" skin cancers so long as any kind of therapy was being considered. (Cancers of all types are covered if recurrent but not advanced or metastatic.)

4. Large numbers of patients will be pushed into CED that doesn't make sense. For example, leukemia patients would be required to have RECIST tumor size imaging. Many stakeholders have criticized the CED plan. I would say it bears no relationship to learnings from the hundreds of published papers on "value of information" in medical research. See my PDF comment. Broad use of pairing genomic information with drug records & timelines (Pt B & D) would be a vast, powerful step forward that would make us the envy of the world. Additional CED could be focused and targeted and based on specific questions and research power. Use of PRO to discriminate diagnostic sequencing tests is not sensible. For example, patient PRO will not vary based on the brand of PET scanner used, the brand of sequencing test, or the brand of thermometer used to diagnose a fever.

SOLUTIONS

1. CMS should limit scope to "solid cancers, for somatic mutations for drug selection, in tissue samples." These avoids large numbers of problems and aligns the NCD to the data reviewed. The NCD remains a large, powerful, landmark NCD. 90% of cancers are solid cancers; the whole PMA/CED structure is based on somatic mutation drug selection; and 95% or more of panel tests are and will be based on tissue.

2. CED should be limited and rationalized. Where a protocol for $500M of CED would be laughed out of the NCI if it was a grant proposal (with vague aims, poor methods, and limited value), it shouldn't be required spending by CMS either.

3. Provide a two year window for LCD coverage alongside the (corrected) NCD coverage and NCD CED pathway. This is less crazy than it sounds. Other NCDs say "In addition to this NCD, local coverage may be created." MACs have been rigorous and frugal with molecular tests. NYS approval could be required. Small specific targeted 1861(a)(1)(A) situations could be removed from pointless CED. Another weakness of the current CED is that patients are launched into literally years of burdensome, costly CED based on day of testing, even if the same gene/drug is FDA approved the next day.

4. Consider a CED channel for liquid biopsy. This needs to be handled separately because FDA has created PMA and 510(k) channels for tissue based mutations but continues to work on liquid biopsy rules. Note that OTHER tests (including FMI's test) were covered prior to PMA approval, and this continues to occur (e.g. MSI testing today). NYS approval and CED (appropriately managed) are adequate controls at this time.

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Coordinated Comments from a University of Texas System Molecular Diagnostics Laboratory Coalition on CMS Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

January 16, 2018

A coalition of molecular diagnostics laboratories at The University of Texas MD Anderson Cancer Center (MD Anderson), The University of Texas Southwestern Medical Center (UTSWMC), and The University of Texas Medical Branch (UTMB) at Galveston thank the Centers for Medicare and Medicaid Services (CMS) for the opportunity to comment on this National Coverage Determination (NCD) proposal. All three of these institutions have major programs in molecular diagnostics that include patient care, research, training and education that will be impacted adversely if this Decision Memo is adopted in its present form. In addition, these laboratories are representative of academic molecular diagnostics laboratories throughout the United States.

MD Anderson is the top-rated and largest cancer center in the US and provides extensive precision therapy standard-of-care for cancer patients and enrollment on integral marker therapeutic clinical trials. In 2017, over 8,000 patients participated in at least one therapeutic clinical trial. These trials include investigator-initiated and industry trials that employ the Clinical Laboratory Improvement Amendments (CLIA) and New York State Department of Health-accredited MD Anderson Molecular Diagnostics Laboratory, as well as National Cancer Institute (NCI) National Clinical Trials Network clinical trials, e.g. the NCI-MATCH (Molecular Analysis for Therapy Choice) precision medicine trial (1) that uses the Lab for testing national participants. The patient population that is enrolling in these trials has a large majority of patients with advanced cancer who seek effective therapy and/or contribute to the development of new targeted agents. The Lab served 974 patients age 65 years or over during 2017.

UTSWMC is one of three NCI designated Comprehensive Cancer Centers in Texas. UTSWMC relies extensively on the ability to rapidly and efficiently generate genomic data in CLIA-validated clinical laboratory settings via next-generation sequencing (NGS) technologies for patient care, research and the training of PhDs and MDs. Indeed, these efforts have led to the recent development, validation and deployment of a state-of-the-art NGS test that is larger, more sensitive and has greater predictive accuracy than that currently offered by the FDA-approved Foundation Medicine test. These efforts and the associated benefits they bring to the care of Medicare, non-Medicare and charity patients at UTSWMC’s three hospitals are profound and would be imperiled by these proposed provisions. Beyond patient care, the institution’s mission of training will be negatively impacted as it will be unable to share and teach these technologies with medical students as well as residents and fellows. UTSWMC annually produces among the largest resident MD graduating classes in Texas. Any reduction in this critical resource will negatively impact the entire state health care delivery system.

UTMB has a molecular diagnostics laboratory that addresses multiple diagnostic needs, including the genetic characterization of cancers. UTMB’s patient demographics include Medicare patients, as well as a large percentage of Medicaid patients and patients within the correctional system in the State of Texas. It is absolutely essential for a healthcare institution with such a highly diverse patient population to use the results from molecular studies to improve the speed and the accuracy of the diagnosis and identify the correct treatment option. Reductions in molecular testing will most certainly result in costly mistakes that will negate any apparent benefits.

All three institutions support fully the NCD proposal for the Foundation Medicine and Memorial Sloan Kettering Cancer Center Food and Drug Administration (FDA)-approved assays, but request that the other provisions of the Decision Memo be removed.

The NCD as proposed has a flawed premise in its development, namely that next-generation sequencing (NGS) is a test. Instead, NGS is a widely applied methodology that is used in a large number of tests for patients with advanced cancer. Local Coverage Determinations have been successful in bringing evolving molecular diagnostics to cancer patients, including Medicare beneficiaries.

The NCD if implemented would have profound negative effects on cancer care for Medicare beneficiaries and cancer patients in general. The requirement for FDA approval of a test for Medicare reimbursement would immediately impact the financial viability of molecular diagnostics laboratories throughout the US. This financial problem would persist until FDA approval is obtained for assays in those labs that can afford the time and expense of the approval process. As a result, implementation of the NCD would have major adverse impact both short-term and long-term on the care of Medicare beneficiaries with advanced cancer at academic institutions by limiting their access to state-of-the-art therapies that are currently supported by the rapid turnaround times of our high-quality on-site molecular labs. There are no commercial vendors, including the FDA-approved vendor, that can rapidly provide the standard-of-care testing that our oncologists demand for these very ill patients who require short turnaround time to initiation of therapy.

In addition, advances in precision medicine that are occurring in academic molecular diagnostics laboratories through their innovative support of targeted therapies and prognostic biomarkers would be slowed dramatically, including progress in development of targeted anti-cancer agents in the pharmaceutical pipeline. The ability of the labs to make new discoveries into the genetic causes of cancer and how to treat current and future cancer patients who have these alterations in their tumor would be impaired greatly. As a result, future development to improve the genetic testing that supports rational therapy selection for patients in the era of precision oncology would be attenuated.

The costs associated with shipping and tracking outsourced specimens when added to the expense of purchasing commercial services from an external lab would require significant fiscal resources and negatively affect health care costs for Medicare beneficiaries. The costs of obtaining FDA approval would further increase the costs for in-house labs.

The locked-down nature of FDA-approved assays would prevent progress in investigator-initiated and pharmaceutical industry clinical trials. Rapid modification of gene panels to add emerging targets and prognostic and predictive genetic abnormalities and to delete poor-performing biomarkers is required as new therapies become available. The requirement for FDA approval will greatly prolong activation of clinical trials and slow the pace of new drug development as new versions of existing assays undergo the FDA approval process rather than validation for CLIA compliance.

The Coverage with Evidence Development (CED) requirements cannot be met by the vast majority of academic molecular diagnostics laboratory due to the informatics infrastructure that would have to be developed and the personnel resources required to complete the CED process.

Academic laboratories are the training ground for the next generation of laboratory scientists. The training programs for residents and fellows in laboratory sciences, including those directly involved in patient care in Genetics and Pathology, would be negatively impacted because instruction and hands-on exposure to the technologies required for precision medicine would be severely constricted. This situation would affect innovation on a nationwide scale and mortgage the future of precision medicine.

For the stated reasons, we ask that CMS approve the NCD component for the Foundation Medicine and Memorial Sloan Kettering Cancer Center assays and eliminate the other components of the NCD until a task force can be convened to consider the wide-ranging implications. Analysis of options by a group such as one from the National Academy of Medicine should include the medical, societal and financial aspects of the regulatory and reimbursement process to inform constructive decisions.

Thank you for your consideration and we are happy to discuss these comments in greater detail

Regards,

Stanley R. Hamilton, M.D.
Head, Division of Pathology & Laboratory Medicine
Frederick F. Becker Distinguished University Chair in Cancer Research
The University of Texas MD Anderson Cancer Center
1515 Holcombe Boulevard |Unit 85
Houston, TX 77030
shamilto@mdanderson.org

Michael Laposata, M.D., Ph.D.
Professor and Chairman
Department of Pathology
The University of Texas Medical Branch-Galveston
301 University Blvd.
Galveston, TX 77555-0419
milaposa@utmb.edu

James S. Malter, M.D.
Professor and Senator Betty and Dr. Andy Andujar Distinguished Chairman of Pathology
5323 Harry Hines Blvd.
UT Southwestern Medical Center
Dallas, TX 75390-9072
james.malter@utsouthwestern.edu

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January 17, 2018

VIA Electronic Mail to: CAGinquiries@cms.hhs.gov

Tamara Syrek Jensen
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop # S3-02-01
7500 Security Boulevard
Baltimore, MD 21244-1850

Dear Ms. Jensen:

On behalf of Foundation Medicine, Inc. (“FMI”), the developer of the FoundationOne CDx™ comprehensive genomic profiling test (“F1CDx”), and in follow-up to our request for a National Coverage Determination (“NCD”) for comprehensive genomic profile testing with F1CDx, I am pleased to submit comments regarding the above-captioned proposed decision memo. Consistent with the approach we took in our formal request for an NCD, these comments focus exclusively on the impact of the proposed decision memo on Medicare coverage for F1CDx.

In summary, we strongly support the proposed Medicare coverage framework for F1CDx. The issuance of a proposed decision memo represents a critical step in the parallel review process. By publishing a draft NCD that establishes appropriate Medicare coverage for F1CDx on the same day that the FDA announced its approval of the test, CMS has substantially reduced the usual interval between FDA approval and Medicare coverage for breakthrough, innovative new technologies. We thank CMS for its diligence and guidance throughout this process, and look forward to working with the agency to finalize an NCD that establishes appropriate coverage for F1CDx.

In the ensuing comments, we respectfully encourage the agency to consider some minor modifications and/or clarifications to the draft NCD. For your consideration, we have organized our comments into three groups:

• General comments on the proposed decision memo;
• Comments on specific aspects of the proposed decision memo; and
• Comments responsive to the five questions CMS posed in the proposed decision memo.

We strongly support the Medicare coverage framework for F1CDx that is set forth in the proposed decision memo. Consistent with the clinical evidence summarized in our formal request for an NCD, the proposed decision memo recognizes F1CDx as medically reasonable and necessary for the management of cancer patients with solid tumors that are recurrent, metastatic, or advanced Stage IV when comprehensive genomic profile testing is ordered to inform patient management by the treating physician. If finalized as proposed, the NCD would cover F1CDx for all solid tumor types, either through full coverage or via Coverage with Evidence Development (“CED”), and ensure that Medicare beneficiaries nationwide have access to high-quality, broad genomic profile testing with F1CDx, which expeditiously, efficiently, and accurately identifies patients who may benefit from biomarker-driven commercially available therapies and/or be eligible to participate in therapeutic clinical trials.

In the proposed decision memo, CMS describes two types of coverage – full coverage (section A in the proposed NCD language) and tests covered under CED (section B). We offer the following comments on each type of coverage, respectively:

We strongly support the proposal to cover F1CDx for indications that fall within its FDA-approved labeling. The FDA’s review and approval of F1CDx establishes the analytic validity and clinical validity of the test for its approved uses, and the reference to FDA-approved testing in the labeling of FDA-approved therapeutics supports the clinical utility of F1CDx for such uses.

We offer the following comments for your consideration:

• The draft NCD requires that patients have “recurrent, metastatic, or advanced stage IV cancer.” With respect to this language, we encourage CMS to:
  • Delete the word “advanced”. The National Cancer Institute’s (“NCI’s”) “Dictionary of Cancer Terms” defines “advanced” cancer as “cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment.”¹ Similarly, on its “Cancer Staging” webpage, NCI describes “stage IV” cancer as “cancer that has spread to distant parts of the body.”² As such, medical professionals may find the use of both “advanced” and “stage IV” in the NCD as clinically redundant or confusing, and some may view this standard as requiring the existence of more than one of these terms in medical documentation.
  • Add the words “relapsed” and “refractory”. F1CDx’s FDA approval covers tests performed on solid tumor samples only. However; it is our understanding that CMS intends for the NCD to apply to coverage for patients with hematologic malignancies as well. Please note that when compared to the terms referring to solid tumors, the analogous terms generally used to describe the natural history of many hematologic malignancies are “relapsed” and/or “refractory”.³
  • Clarify that patients need not have all of the above-described conditions to be eligible for coverage. It is our understanding that patients can meet this criterion if they have any one of the above-referenced disease states, not all listed disease states. We harbor some concerns that contractors may misinterpret this language as currently phrased as requiring ALL not ANY of the listed disease states, and propose that CMS list each separate disease state on a separate bulleted line in the final NCD. Consistent with the revisions requested in the first two sub-bullets, the list could read as follows:
    “a. Patient has cancer that is:

    • Recurrent; OR
    • Metastatic;OR
    • Relapsed; OR
    • Refractory; OR
    • Stage IV.”
  • Section B of the proposed decision memo (i.e., the coverage under CED section) also includes the “recurrent, metastatic, or advanced stage IV cancer” language. We make the same recommendations here.
  • Note – for ease of reference, this correspondence will continue to reference the “recurrent, metastatic, or advanced stage IV cancer” language that currently appears in the draft NCD instead of the revised, bulleted language we proposed above. Insofar as CMS agrees to make the changes we proposed in the final NCD, our comments should be read as equally applicable to the revised coverage list.
• It is our understanding that CMS intends to limit full coverage for F1CDx to those disease indications for which it is itself FDA-approved. The NCD to our reading is vague on this point, stating that F1CDx is covered if it is “used in a cancer with an FDA-approved companion diagnostic indication”. One possible interpretation of this language is that the NCD does not explicitly require that the approved indication be F1CDx’s approved indication, and therefore leaves open the possibility that F1CDx would be covered if another test obtains FDA approval for a companion diagnostic claim that references a gene or variant for which F1CDx has been validated but not approved. Insofar as our understanding is accurate, we encourage CMS to revise the NCD to clarify that F1CDx is only covered to the extent that “the test is used in a cancer for which that specific test has an FDA-approved companion diagnostic indication.”
• In the future, we intend to seek additional FDA approval(s) for F1CDx for companion diagnostic claims relevant to conditions that are not currently included in our FDA-approved labeling. As currently drafted, the NCD would automatically cover F1CDx for newly-approved indications. The individual contractors, however, may find it difficult to stay up-to-date with changes in the FDA-approved labeling for F1CDx. To facilitate the dissemination of accurate, up to date information regarding the extent of Medicare coverage for F1CDx, we encourage CMS to maintain a website that identifies FDA-approved companion diagnostic tests and the specific indication(s) for which such tests have been approved.⁴

We also strongly support the proposal to cover F1CDx under CED for conditions falling outside its current FDA-approved indications for use, provided it is implemented in a manner that limits the burden on patients and providers. As evidenced by the clinical data provided in support of our formal request for an NCD, substantial clinical data supports the performance of F1CDx in patient population(s) that are not currently included in our FDA-approved labeling. F1CDx testing helps ensure appropriate, evidence-based therapeutic utilization in patient populations for which there are no FDA-approved companion diagnostics (e.g., bladder cancer, pancreatic cancer). Conditioning coverage for F1CDx for such indications on participation in CED strikes an appropriate balance between facilitating access to F1CDx while ensuring CMS can ultimately avail itself of the robust data necessary to evaluate the clinical utility of F1CDx in these populations. In parallel, to the extent that F1CDx obtains expanded FDA-approval for other companion diagnostic claims in additional tumor types, that would constitute adequate evidence of clinical utility moving those tumor types from CED to full coverage per the NCD.

In the proposed decision memo, CMS lists five questions on which it seeks public input. Below, please find our response to each of these questions. (Note – the text of your questions appears below for ease of reference.)

As outlined above, we respectfully request that the clinical conditions addressed in the draft NCD (i.e., “recurrent, metastatic, or advanced stage IV cancer”) be revised to (a) delete the word “advanced” (to minimize the potential for provider confusion) and (b) add the words “relapsed” and “refractory” (to use terminology that is more commonly used to describe hematologic malignancies).

The test methodology addressed in the draft NCD (i.e., NGS) is appropriate. The clinical data we submitted in support of our formal NCD request related to the performance of F1CDx, which is an NGS-based test. Our request did not include data relevant to any test performed with any other methodology.

The clinical scenarios addressed in the draft NCD (i.e., that the patient must have decided to seek further treatment, and that the results will be used by the patient’s physician in patient management) are appropriate, and consistent with our understanding of the Medicare regulatory requirements for coverage of diagnostic testing services.⁵

We assess analytical validity consistent with College of American Pathologists (“CAP”), CLIA, state clinical laboratory (e.g., New York State (“NYS”)), FDA, and third-party payer (e.g., Palmetto MolDX) requirements. We assess clinical validity consistent with NYS, FDA, and third-party payer requirements.

In our experience, it takes at least three years to develop, submit, and facilitate FDA’s review of the analytical and clinical validity data required to earn FDA approval as a companion diagnostic. (Note – this estimate does not include any time spent up front to facilitate compliance with FDA’s quality systems regulation (“QSR”).) For purposes of the FDA’s evaluation of F1CDx, we spent:

• ~1 year planning our validation studies, meeting with FDA to confirm that our study design(s) were sufficient to meet the agency’s requirements (upon submission of a premarket approval (“PMA”) application), and executing facility and process validation;
• ~1 year executing and writing summaries of our analytical validation studies; and
• 2 years executing our clinical validation studies (note, this number can be highly variable between products and indications, depending on the rate at which patients enroll in the studies and the length of the expected follow-up period, among other factors);

We prepared the PMA application for F1CDx while we completed the analytical and clinical validation studies, and completed and submitted the application within one month of finalizing the last validation report. FDA approved our application for F1CDx approximately six months after we initially submitted the PMA application to the agency. The duration of FDA’s review may vary, though, depending on the number, nature, and extent of any issues the agency raises and requires to be addressed, as well as whether the test is designated a “breakthrough” device by the FDA.

Similarly, it takes approximately 2.5 years to develop and take a test through the approval process in NYS. After completing the initial development of F1CDx, it took us 3-6 months to validate and document the validation of the test, and 1-2 months to prepare the application for submission to NYS. NYS then takes 18-24 months from the date it receives an application to approve a new test. The length of the review period is substantially influenced by the initial delay in the state’s consideration of the application (due to the substantial backlog of applications) as well as the amount of time it takes to respond to substantive questions from NYS review staff.

The MolDX program allows Palmetto to evaluate the analytical and clinical validation of molecular diagnostic tests. With respect to analytical validity, the MolDX program maintains detailed analytical performance specifications specific to comprehensive genomic profiling. These specifications require clinical laboratories performing such tests to meet certain general laboratory standards (e.g., licensure/accreditation, participation in proficiency testing), as well as detailed pre-analytical, analytical, and post-analytical testing requirements.⁶ MolDX also requires laboratories to provide detailed information regarding the studies that establish the clinical validity of such tests.⁷ The MolDx “Covered Tests” database includes 29 coverage articles describing covered assays, at least 5 of which explicitly address tests that are run on NGS platforms.⁸

The MolDX program utilizes a well-defined process to evaluate the clinical utility of molecular diagnostic tests, which it relies upon when deciding whether to cover a specific test. In addition to the “traditional” pathway to establishing clinical utility – under which MolDX reviews each clinical utility trial submitted as part of a dossier, assigns a study-specific evidence grade as well as an overall level of evidence grade depending on the nature of the trial(s) and their clinical relevance – MolDX has established an expedited clinical utility review pathway for FDA-approved companion diagnostics and tests that have already been formally reviewed by a MolDX-designated specialty society or other group and are recommended as the “standard of care,” respectively.⁹

Clinical laboratories also undertake independent efforts to establish the clinical utility of their assays. For example, we participate in decision impact and patient outcomes studies, the results of which are ultimately published in the peer-reviewed literature. We also partner with biopharma companies that are running clinical trials to identify patients that may be most likely to benefit from a specific therapy.

The information in the proposed NCD can be clearly communicated to stakeholders via the following channels (in addition to those explicitly referenced in the question):

• Develop and maintain a website that lists tests covered under the NCD (and the covered indications for each such tests);
• Engage stakeholders (e.g., patient and provider organizations) on social media (e.g., Twitter, YouTube, Facebook);
• Give interviews to trade press;
• Enlist Medicare Advantage plans to actively inform their provider networks of the NCD (e.g., provide language for inclusion in provider newsletters, facilitate the adoption of NCD coverage directly into plan medical policies by offering appropriately formatted documents, etc.);
• Encourage inclusion in relevant professional guidelines (e.g., NCCN, ASCO); and
• Incorporate into the CMS Oncology Care Model and other value-based programs.

Please contact Gary Martucci at 1-610-256-9182 (or by e-mail at gmartucci@foundationmedicine.com) if you have any questions regarding this request. We look forward to working with you and your staff to finalize this NCD by the statutory deadline of February 28, 2018 and expanding the access of this testing to Medicare beneficiaries with advanced cancer.

Sincerely yours,

Vincent A. Miller, MD
Chief Medical Officer
Foundation Medicine, Inc.

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January 17, 2018

Tamara Syrek Jensen, JD
Director, Coverage & Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mailstop S3-02-01
7500 Security Blvd
Baltimore, MD 21244

Re: Coverage of NGS tumor panels-CAG-00450N

Dear Ms. Jensen,

The American Cancer Society Cancer Action Network (ACS CAN) appreciates the opportunity to submit comments regarding the national coverage decision (NCD) of Next-Generation Sequencing (NGS) diagnostic tests for cancer. ACS CAN, the nonprofit, nonpartisan advocacy affiliate of the American Cancer Society, supports evidence-based policy and legislative solutions designed to eliminate cancer as a major health problem. As the nation’s leading advocate for public policies that are helping to defeat cancer, ACS CAN ensures that cancer patients, survivors, and their families have a voice in public policy matters at all levels of government.

Progress in cancer treatment increasingly involves the use of targeted therapies designed only to work within populations of cancer patients with very specific genetic abnormalities. These targeted therapies often do not work absent the required genetic signature, making the accurate diagnosis of mutations within a tumor absolutely critical. Initially, diagnostic tests probed single genes matched to single drugs, but as the number of targeted therapies increased, the approach of testing a tumor using multiple single gene tests has become burdensome and inefficient. Such an approach is often time consuming and at times may not even be feasible because of limited tumor samples available. The advent of next-generation sequencing (NGS) panel testing has marked an important turning point in cancer diagnosis and treatment, allowing comprehensive tumor genetic data to be collected all at once, providing patients and their providers with information to drive treatment choices.

ACS CAN commends CMS for the positive coverage determination of Foundation One’s F1CDx FDA-approved companion diagnostic test. Up to now, coverage for NGS panel tests has been inconsistent, and patients have often been faced with paying for such testing out of their own pockets. We also support the decision to extend coverage to any FDA-approved NGS cancer panel companion diagnostic rather than a single vendor’s test. This approach ensures that any NGS cancer panel test obtaining FDA approval as a companion diagnostic will be automatically covered by CMS, without requiring any additional review which might delay patient access. It is important that a patient can trust the results from their diagnostic test, and FDA approval ensures that a test’s clinical validity has been verified by a third party.

The second component of the NCD details categories of diagnostic tests that will be contingently covered with requirements for data collection. This coverage with evidence development (CED) allows FDA-approved tests that lack companion diagnostic designation to be covered, and it allows non-FDA approved tests to be covered as part of a National Cancer Institute (NCI) clinical trial. In both cases the tests must be in the National Institute of Health’s (NIH’s) genetic testing registry (GTR) and the patients tested must be in a patient registry that is able to track patient outcomes. We are very encouraged that this decision provides a way for patients on NCI trials to benefit from NGS testing, which has been a longstanding challenge.

The CED patient registry requirement ensures that data is being collected that could lead to full FDA approval or unconditional CMS coverage, while still providing coverage during the data collection process. We encourage CMS to be mindful of the cost and burden associated with such registries and tailor registry requirements to ensure that the necessary data will be collected to analyze test performance, while at the same time avoiding any unnecessary requirements that might dissuade test developers from utilizing this coverage pathway.

ACS CAN has concerns regarding the implementation of the non-coverage component of the NCD. While coverage of NGS cancer panels has been fairly sparse, some NGS cancer panel tests appear to currently enjoy some level of coverage as a result of formal local coverage determinations (LCDs) or informal CMS policies. We strongly support the overall movement of the marketplace toward FDA-approved NGS cancer panels, but we are also concerned about continued patient access to NGS cancer panel testing during the transition toward the requirement to be FDA-approved. The proposed non-coverage would begin in 90 days and to the degree that some tests previously being covered, this transition would occur relatively rapidly with little time for individual practices to adjust or NGS panel test developers to create transition plans toward either full FDA approval as a companion diagnostic or establishment of the appropriate patient registries needed to comply with CED requirements. We believe that to the extent an NGS cancer panel test is currently being covered by CMS under current policies, or have an active coverage determination underway, these tests should continue to be covered for a period of time while test developers and oncology practices transition to the new policy. This period should not be seen as an opportunity for tests to newly qualify for coverage under pre-NCD policies, but rather for tests that have demonstrated a history of coverage pre-NCD or are currently in a coverage determination process to continue to be reimbursed for a finite period.

Lastly, we would like to suggest CMS consider modifications or exceptions to the patient restrictions that are part of the NCD. Under the current proposal a patient is eligible to be tested only once at a late stage of disease, yet genetic mutations in cancer are dynamic. Treatment itself can place selective pressure on a tumor and cause it to evolve, meaning that the genetic makeup of a tumor may differ over time and the genetic makeup of metastases may differ from the primary tumor [1]. Restricting the patient to one single opportunity for testing would not capture these changes, and we recommend CMS consider the allowance of retesting after a medically appropriate interval. Furthermore, while genetic tumor testing is currently indicated in late stage or metastatic cancers, this is simply a reflection of the current science. If NGS tumor panel testing were to become medically appropriate in earlier-stage disease, the proposed non-coverage portion of the NCD would appear to preclude the coverage decision from adapting to recognize such changes in evidence-based care. The non-coverage portion of the NCD, therefore, should be modified such that it does not categorically exclude scientific advances from being translated into updates in coverage.

Next-generation sequencing occurs in cancer in a variety of contexts. Testing may be for a panel of somatic mutations in tumor samples, as is described in this NCD, or it may be in the context of germline mutations, and the technology can even be used for testing single genes. We would like to clarify that our assumption is that this NCD is limited to NGS panel testing in tumor samples, and our comments are in that context. We do not believe it is appropriate to apply the proposed NCD to germline testing, single gene testing, or other diseases. If CMS intends the scope of this NCD to apply more broadly, we recommend clarification and request additional opportunities to comment on such an expanded scope of policy.

In summary, we fully support the coverage of NGS cancer panel tests that have been FDA-approved as a companion diagnostic. We support the coverage of non-FDA approved NGS panels as part of NCI clinical trials, and we appreciate the provisional coverage of FDA-approved, but non-companion diagnostic, tests that will provide important reimbursement while additional data is collected on these tests. We encourage care in developing CED registry requirements to carefully balance assurance that needed data is collected while avoiding any unnecessary requirements. To ensure there is no potential disruption to patient access to NGS panel testing, any coverage for NGS panel tests under current CMS policy should be continued during a transitional period. Lastly, any finalized non-coverage decisions should not preclude patients from benefiting from advancing science that improves validated and medically appropriate genetic cancer testing.

Thank you for the opportunity to provide comments on this important issue for cancer patients. If you have any questions, please do not hesitate to contact myself or Mark Fleury (mark.fleury@cancer.org).

Sincerely,

Christopher W. Hansen
President
American Cancer Society Cancer Action Network

1- Merlo, L. M. F., Pepper, J. W., Reid, B. J., & Maley, C. C. (2006). Cancer as an evolutionary and ecological process. Nature Reviews Cancer, 6(12), 924–935. https://doi.org/10.1038/nrc2013

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I would like to raise my concern about the recently proposed national coverage determination from CMS regarding NGS testing in oncology.

Precision laboratories are fundamental to precision oncology and are an important part of patient care; it is critical that these tests be performed according to quality standards in a variety of settings and centers, and that they be able to contribute to ongoing advances as well.

The recently proposed national coverage determination from CMS limiting coverage to only one (or even 2) laboratories is, simply put, bad for patient care. Amongst my concerns are the following:

Patients depend on these tests being readily available in order to get diagnosed and treated! The large gene panel that was approved, and proposed to be covered by this NCD, will not be suitable for many samples, many types of cancer, and certainly not small biopsies or aspirates—so patient access will be hindered. Sending the representative tumor block may negate performance of other studies needed for appropriate patient care. Uncertain reimbursement for local laboratories will preclude performance of these critical studies at many centers, leaving patients and clinicians to await results from a remote laboratory not likely to be able to handle the testing volumes, or susceptible to any potential workflow disruptions.

Quality will be lessened:
Academic labs have established NGS as the current standard of care and have worked with professional societies to establish the quality standards that guide this field. The commercial vendor who worked with the FDA and CMS to obtain clearance did not develop the methods or quality systems utilized (which are in use in clinical laboratories across the country) but did have the financial resources to accomplish this approval. Few academic and community hospital labs will be able to pursue this approval in this era of cost containment, particularly if reimbursement for these services is further obstructed. Furthermore, there is no evidence that FDA’s newly established Breakthrough Device Program will lead to improved testing quality. In fact, it may be argued that the collective comparisons currently made between labs through the College of American Pathologists and other proficiency testing programs more broadly raise quality, particularly when coupled with adherence to laboratory performance standards for NGS.

Education will be obstructed:
The robust academic discussions that are so much a part of modern management of oncology patients, and the local training of our pathology residents, pathology and oncology fellows, and other colleagues, will lessen with the reduction of these important procedures to a send-out commodity. Findings are discussed at tumor boards which include an integrated team of professionals. Tumor boards are also valuable opportunities for physicians, and especially residents and fellows, to experience and learn the impact of these new technologies on the patients they care for. As precision oncology continues to advance, we must be sure that the next generation of oncologists, pathologists and other health care professionals are fully fluent in utilization of these approaches

Innovation will be hampered: Advances in the field made by local and academic laboratories will be hindered as institutions seek to trim costs and unreimbursed services.

Clinical Care may be hampered:
Removing the knowledgeable local/academic pathologist will lessen the impact of NGS interpretation at the local or tumor board level, and patient care may suffer as a result. NGS oncology testing at academic centers and other labs is standard of care, for making basic diagnoses and to help manage patients on standard-of-care approved medications. We are doing basic clinical service in our labs.

In addition the coverage determination will produce a monopoly and jeopardizes the solvency of hundreds of NGS labs at academic centers and beyond by incentivizing dismantling of existing laboratories. Monopolization hurts access.

Thank you.

Bruce Brockstein, M.D.
Division Head, Hematology/Oncology
Department of Medicine
NorthShore University HealthSystem
Kellogg–Scanlon Chair of Oncology
Director, Kellogg Cancer Center
Clinical Professor of Medicine
University of Chicago Pritzker School of Medicine

___________________

2650 Ridge Av, Evanston, IL 60201
847-570-2515 fax- 847-570-2336
bbrockstein@northshore.org

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January 17, 2018

Seema Verma, Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Hubert H. Humphrey Building
200 Independence Avenue, SW
Washington, DC 20201

Re: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

Dear Ms. Verma:

On behalf of Sema4, thank you for the opportunity to submit comments on the National Coverage Analysis’ (NCA) proposed decision memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N). A Mount Sinai Health System venture based in Stamford, Conn., Sema4 is enabling physicians and consumers to more seamlessly engage the digital universe of health data, from genome test results and clinical records to wearable sensor metrics and more. The company currently offers advanced genome-based diagnostics for reproductive health and oncology and is building predictive models of complex disease. Our clinical assays utilize NGS technology and we request significant clarifications in the draft NCA and recommend that the agency not finalize it in its current form.

Scope of the NCA:

First, we are deeply concerned about the scope of the proposed decision memo. Foundation Medicine participated in the Food and Drug Administration (FDA) and Centers for Medicare and Medicaid Services’ (CMS) Parallel Review program that streamlines the approval and coverage processes for breakthrough products. We applaud the recent approval of the FoundationOne CDx (F1CDx) test and the agency’s quick action to propose coverage to this test. Unfortunately, the scope of the proposed decision memo is beyond the F1CDx test and instead creates new policy for a technology platform that will have dramatic effects on Medicare beneficiaries’ current access to the NGS-based tests that in many instances are considered the standard of care.

Further, the broad scope of the non-coverage section would effectively eliminate Medicare beneficiaries’ access to already available NGS-based tests, many with practice guidelines supporting their use and positive local coverage determinations. While we understand that CMS intended to propose a coverage pathway through which other indications could be covered if sufficient evidence has been generated, the proposed national coverage determination, as written, would supersede local coverage determinations for genes included on solid tumor panels and eliminate coverage for tests that have already been successfully integrated into the clinical setting. As an example, the MolDX Program has determined that testing for EGFR, KRAS, and BRAF, and Noridian has determined that ROS1 among other genes, meets Medicare’s criteria for a covered service.

Moreover, the language in the non-coverage section is so vague that it’s reasonable to conclude that the non-coverage policy applies to all laboratory developed tests and FDA reviewed tests that do not fall under the CED. Further, it appears to apply to NGS-based tests used in all indications beyond cancer such as hereditary risk, infectious disease, and others.

We ask the agency to clarify why it has chosen to have the national coverage analysis focuses on a genomic technology platform instead of the clinical utility of the information provided by the F1CDx test and its implication for treatment and patient care. We also respectfully request that the final national coverage determination be narrowed in scope to only apply to the F1CDx test and at the most, to other NGS-based tests performed on tumors with treatment indications that have been approved by the FDA or a designated third party reviewer. We also strongly recommend that the agency remove the non-coverage section and not include it in the final decision memo.

Impact on NYSDOH Reviewed Tests:

In November 2017, with the clearance of Memorial Sloan Kettering Cancer Center’s IMPACT test, the FDA also announced its approval of the New York State Department of Health (NYSDOH) as a third party reviewer. Laboratories located in New York are required to submit applications to the NYSDOH for approval prior to providing the test to patients clinically. Now as part of that approval process, laboratories have the option to request that the NYSDOH also review their test for 510(k) clearance and if successful, request that the FDA subsequently grant clearance. Through this new pathway for verifying the analytical and clinical validity of a test, the FDA has acknowledged the rigorous review provided by the NYSDOH to determine that tests are safe and effective, and thus not experimental or investigational, per FDA regulations. This alternative pathway to achieve FDA clearance is a great opportunity to laboratories in New York and to those who wish to seek approval by NYSDOH.

Yet, Memorial Sloan Kettering’s test and any other tests using NYSDOH as a third party reviewer for 510(k) clearance would not be able to also achieve coverage without further evidence development under the proposed decision memo simply because they used an alternative review pathway. While the memo contains a section proposing coverage with evidence development (CED) applicable to these test, the criteria is unrealistic and unnecessarily restrictive. Most NGS-based tests, even ones that are FDA cleared or approved, are offered clinically and not as part of a clinical trial as they are not experimental. Additionally, even within a trial, most laboratory medical professionals are not involved in the patient’s care throughout their lifetime. Hence, unlike treating physicians, they are unable to measure metrics such as overall survival, objective response rate, and other health outcomes required by the CED. Furthermore, most laboratories would not have the resources to create and maintain a registry housing this information. We recommend that CMS policy accurately reflect recent changes to federal regulatory policy including NYSDOH as a third party reviewer and provide coverage for tests meeting these premarket review standards without requiring CED. If the agency insists on proceeding with CED, then we strongly urge you to modify the criteria to acknowledge current regulatory standards, clinical practice guidelines, and approaches to care. Furthermore, CMS should clarify at what point sufficient evidence has been collected to warrant coverage.

Thank you again for the opportunity to provide these comments and in advance for your thoughtful consideration of our concerns. Already widely used clinically, NGS-based testing enables patients the ability to engage in precision medicine, tailor their care, and improve their health. The proposed decision memo would create unnecessary barriers to access these lifesaving tests and fails to reflect both the current standard of care and the quality of the premarket review conducted by federal and state agencies. In summary, we strongly urge CMS to narrow the final national coverage determination to focus on the F1CDx test, to modify the CED section, and remove the non-coverage section.

Sincerely,

Eric Schadt, PhD
Dean for Precision Medicine at the Icahn School of Medicine at Mount Sinai
Founder and CEO, Sema4

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To Whom it May Concern:

I am an academic medical oncologist, focusing largely on the treatment of lung cancers. While thoracic oncology has led the way in terms of incorporation of NGS testing, I feel the proposed approval has significant limitations. First, it broadly applies NGS to tumors without established targets. In this role, it goes a bit "too far". Next, it limits approved testing to once per patient. This is a huge problem for patients receiving targeted therapies (the very group intended to benefit from this approval). As has already been shown with the approval of osimertinib for EGFR mutant NSCLC, repeated genomic interrogation is critical to guide therapy in the setting of resistance to TKI's. That repeat testing, whether liquid or tissue based, has a profound impact on patient outcomes. While we have only proven this with EGFR in NSCLC so far, the writing is on the wall for ALK and ROS1 modified tumors receiving TKI as well. This is the future of targeted cancer therapy, and to only approve a single test is short sighted.

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I am a medical oncologist and researcher at Emory University. In addition to regularly seeing patients with metastatic cancer, I also conduct research into new therapeutic and diagnostic technologies. I am concerned that elements of the referenced draft NCD are too restrictive and might inadvertently reduce access of Medicare patients to high quality cancer care.

I am thinking specifically of the way the NCD treats comprehensive liquid biopsies. I have used the liquid biopsies test in my clinical practice. When I have treated patients based on these results, I have seen patients respond to therapy just as they do when my test results come from tissue-based NGS testing. Comprehensive liquid biopsy has become an important step in my diagnostic workup for many patients, especially for those who do not have a recent tissue sample available or for whom a repeat invasive biopsy would be too risky.

Without access to this important technology many of my patients would not have access to targeted therapies, which provide better outcomes with fewer side effects compared to standard chemotherapy.

Please consider revising the proposed NCD to include a solution for NGS-based liquid biopsies.

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Centers for Medicare & Medicaid Services
Department of Health and Human Services
7500 Security Boulevard
Baltimore, MD 21244-8013
SENT ELECTRONICALLY TO: at press@cms.hhs.gov

We are writing to comment on the Proposed Decision Memorandum for Next Generation Sequencing for Medicare Beneficiaries with Advanced Cancer (CAG-00450N), issued by the Centers for Medicare and Medicaid Services (CMS) on November 30th, 2017.

The Society for Immunotherapy of Cancer (SITC) is a professional membership organization established in 1985 to advance the science and application of cancer immunotherapy. Through emphasis on high-caliber scientific meetings, dedication to education, outreach activities, standards, value and guideline setting, as well as a commitment to collaborations with domestic and international organizations, government and regulatory agencies and patient advocacy groups, SITC brings together all aspects of the cancer immunology and immunotherapy community to ultimately to improve cancer patient outcomes.
The field of cancer immunotherapy is creating a revolution in cancer treatment options. The field is rapidly changing with five recently FDA approved classes of agents, which treat 30 different cancer indications, with many new trials in process.

In the field of cancer immunotherapy, there are still many unknowns: why some patients have durable complete responses, while others have no response; why some patients experience minor or no side effects, while others have severe adverse effects; which combination drugs will provide the best treatment options for patients, and the list of unanswered questions continue. With so many questions, we must remain open-minded, flexible and responsive to adapt how we design trials and treat patients.

We applaud both the Federal Drug Administration (FDA) and CMS for their use of new policies of parallel review and break through device program to allow access to promising new technologies. Being responsive and utilizing all of the mechanisms available to accelerate advances to patients is laudable.
We are hopeful that there will be a long term strategy for continued rapid review and reimbursement coverage of new diagnostic assays. We would also strongly encourage reimbursement coverage for laboratory developed assays developed in CLIA-certified and CAP-accredited molecular genetics laboratories. We believe empowering academic medical centers throughout the country to be innovative and responsive during this time of accelerated discovery is vital. Given the dynamic nature of gene expression in cancer cells, we believe that some patients that have initial disease progression may require more than one NGS test and that clinical decision making should be left to the treating physician.

In the future, we would encourage an initial “call for comments” period prior to issuing a Proposed Decision Memorandum. Offering a period time to assemble the wisdom of external experts and key stakeholders to provide input to CMS regarding a significant policy like this is an important process in change management. We would also suggest that the accelerated implementation timeline of this new policy appears unnecessarily rushed, which may negatively impact the very outcome we are all trying to achieve, which is access to important testing to provide truly precision medicine.

We appreciate the opportunity to respectfully submit our comments for consideration and offer our society’s leadership in future considerations impacting the field of cancer immunotherapy.

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[PHI Redacted]

I tell you this because I want to comment on the National Coverage Analysis entitled ‘Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer’. Cancer patients all over the country are benefitting from new knowledge in the genomic causes and drivers of cancer, as evidenced by increased access to personalized therapeutics and care based on the genetic makeup of cancer. We are grateful for advances in diagnostic technologies, such as next generation sequencing, as it is one tool to obtain a more comprehensive genetic understanding of cancer. This technology is of particular relevance to lung cancer patients as it typically requires less tissue sample than separate sequencing of multiple genes. I thank CMS for recognizing the value of precision diagnostics in the care of cancer patients by proposing coverage for FoundationOne CDx (F1CDx).

Overall I support a positive coverage determination for the product reviewed in the Parallel Review program, F1CDx, HOWEVER I have serious concerns about the broad scope of the proposed NCD. The proposed policy would limit cancer patients to 1 test per lifetime, which is not in line with the realities of personalized medicine based therapy for cancer patients. This is because unfortunately the cancer finds a way around our drugs and often sub-mutates, which means we now need another test to find out which sub-mutation is making the cancer progress. Some patients may have 3-4 of these tests during their treatment.

Also, the new policy will eliminate coverage for other NGS tests for advanced cancer patients enrolled in Medicare. These tests are currently being used to deliver high-quality, advanced cancer care across the country, including at virtually all major cancer centers and academic institutions. I support CMS’ proposal to cover the F1CDx test but URGE CMS not to finalize the rest of the policy as it will result in several unintended negative consequences to cancer patients by erasing important medical advances and existing local coverage policies already in place.

Thank you for your consideration of my comments.

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January, 16, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Re: NCD CAG-00450N

Dear Ms. Syrek Jensen,

Thank you for providing this chance for the public to comment on the proposed NCD covering tissue-based NGS testing. This type of testing has truly become part of the standard of care for me at the University of San Francisco Helen Diller Comprehensive Cancer Center.

I have several concerns based on the currently proposed decision memo. First among these is the requirement that patients “have not previously been tested using the same NGS test”. This requirement overlooks one of the most challenging and clinically active areas for cancers with targetable alterations. When lung cancer patients are started on targeted therapy for EGFR, ALK, ROS1, BRAF, MET exon14 skipping mutation, NTRK, or RET alterations (and many others in development), the cancer will ultimately become resistant to the treatment due to evolution of the cancer cells from the selective pressure of treatment. The mechanisms of resistance are varied and sometimes not detectable but we rely heavily on the use of NSG based testing of either tissue or plasma to help identify the mechanism of resistance after disease progression on targeted therapy. In EGFR mutated lung cancers treated with targeted therapy ~50% of patients develop a mutation (T790M) that is treatable with a currently FDA approved drug (osimertinib). However, based on the current memo, if a patient already had their tumor tested by NGS to find the EGFR mutation (which is how it is done) they would not be covered for any additional tests to identify the T790M mutation when the cancer became resistant.

Additionally, the approval of a single diagnostic also risks the position the US has in the world as a leader for research. The coverage determination will create a monopoly and essentially a vacuum given that hundreds of academic molecular laboratories as well as competing tests will be rendered non-reimbursable. The value of these group of CLIA certified laboratories is provide motivation and competition to provide the best testing and also create niche testing to detect challenging alterations that a commercial entity may not be in a position to allocate resources for.

Finally, tissue-based NGS testing requires access to a timely tissue sample. This is not a luxury all my patients have at their disposal. For many patients, there is simply not enough tissue left for commercial NGS after the pathologist makes the initial diagnosis. It is in these situations where academic laboratories and competing companies may provide valuable testing options. Additionally, a patient may not be able to undergo a biopsy for a multitude of reasons. Others have samples archived from earlier in their treatment history, but those fail to provide an up-to-date picture of their tumor because, as mentioned, tumors evolve during treatment.

In cases like these, I often rely on comprehensive liquid biopsies in which we draw blood and send it to a well-validated lab for sequencing. Unfortunately, the draft NCD appears to exclude NGS-based liquid biopsies from coverage. This limitation on access may create substandard care for patients who need access to comprehensive genotyping, access that CMS seems interested in making available.

Thank you for considering these comments

Caroline McCoach MD, PhD
Assistant Professor
Thoracic Medical Oncology
UCSF Helen Diller Comprehensive Cancer Center

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Thank you for the opportunity to comment on the CMS decision.

Natera is a leader in innovative genetic testing with businesses focused on reproductive health and oncology. Our CLIA-certified and CAP-accredited laboratory in California has processed over 1 million cell-free DNA tests over the past five years. We have a nascent business in oncology, which we believe will help save many lives among people battling cancer, and which may be affected by the new National Coverage Determination.

In response to your request for comments, we have three discussion points:

1. Narrow the scope to “Comprehensive Genomic Profile Testing,” not “Next-Generation Sequencing”

It is important to narrow the scope of tests to which this Determination will apply. The current proposed decision, released by CMS on December 17, 2017, refers broadly to “Next-Generation Sequencing tests for Advanced Cancer Patients.” This can be misinterpreted to apply to any test using NGS technology, even those with intended uses that may be different from the FoundationOne CDx test, which performs Comprehensive Genomic Profiling. The formal request from Foundation Medicine, dated November 17, 2017 and signed by CMO Vince Miller, specifically asks for a decision on “Comprehensive Genomic Profile testing,” not “Next-Generation Sequencing.”

There are other applications of NGS in cancer that have been described in peer-reviewed literature, such as detecting residual disease and monitoring for recurrence and therapy response.(ref. 1,2,3) This is very different from Comprehensive Genomic Profiling panels which detect therapeutically relevant base substitutions, indels, CNAs, and rearrangements. Additionally, applications such as genome/exome sequencing for heritable disorders and cancer recurrence monitoring should not be subject to this NCD.

Therefore, CMS should revise the policy in “Decision Summary Section A: Coverage” by modifying “Next Generation Sequencing (NGS)” to “Comprehensive Genomic Profile Testing using Next Generation Sequencing (NGS).”

2. Provide flexibility for coverage through Local Coverage Determinations (LCDs)

Our second comment is regarding the broad language around non-coverage. The memorandum states “CMS proposes non-coverage of NGS as a diagnostic laboratory test when patients do not have the above-noted indications for cancer or when the test does not meet the above-noted criteria.” In addition to limiting coverage for clinically valuable applications of NGS, there is no guidance on whether or not Local Coverage Determinations can provide coverage for testing when there is non-coverage at the national level.

CMS must also clarify the role of MACs when NCDs and LCDs conflict with one another, with a bias towards maintaining coverage through LCDs when conflicts exist. Tests currently covered through an LCD should have their coverage preserved, and local MACs should retain authority to cover additional indications or test types beyond those specifically covered under this NCD.

Therefore, we propose the following:
A. Positive LCD should be upheld when the NCD does not cover
B. Positive NCD should be upheld when the LCD does not cover

This will preserve local flexibility and allow smaller labs to introduce innovative, impactful applications that increase access to high quality care.

3. Loosen requirements for CED

Our third comment is regarding Coverage with Evidence Development (CED). We believe that 510k-approved comprehensive genomic profiling tests should be covered under this NCD without the burden of participating in a prospectively-planned registry or an NIH-NCI National Clinical Trial Network trial. We also believe that laboratory-developed tests (LDTs) should be covered under this NCD, if they show substantial concordance with FDA-approved predicates in peer-reviewed studies.

Furthermore, the burden of implementing RECIST criteria may be unsustainable for small laboratories. This may restrict patient access to new innovations.

Thank you for the opportunity to comment on the NCD. Please feel free to contact me with questions.

Kind Regards,
Solomon Moshkevich
Senior VP Product & Strategy
Natera, inc.
solomon@natera.com

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We at Baylor College of Medicine are very concerned about the “Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N). The proposed regulation is anti-competitive and would adversely affect innovation, patient care, and implementation of personalized medicine. As such, it would dramatically hinder the goals espoused by the 21st Century Cures Act. This act, passed with bipartisan support of Congress, aims to bring state of the art research developments to patients in the context of personalize medicine.

This proposal would institute a new regulatory oversight system that is essentially incompatible with participation by academic medical center laboratories in personalized oncology care. This will be detrimental to patient access to timely genetic testing and coordination of care, and produce devastating long-term effects on our national genetic testing infrastructure and molecu-lar diagnostics community through market destabilization of this burgeoning field of personalized medicine in oncology. This proposal will destabilize the majority of the personalized cancer care now taking place at academic centers nationwide. These centers are the engine of innovation and advanced diagnosis and treatments espoused by the 21st Century Cures Act.

If this proposal is not substantially modified, the result would be the shut-down of nearly all academic medical center genomic testing services, which serve as focal points for standard-of-care diagnostics and organizing centers for personalized medicine programs and research.
It would lead to the centralization of all cancer genomic testing into one or a few commercial laboratories, with resulting reduced patient access and severely limit diagnostics innovation and development, with repercussions affecting patient care and clinical trials across our entire national University hospital system.

Thus, for the purposes of this proposed National Coverage Determination, we strongly urge CMS to rely, for the time being, on established CLIA statute with regard to laboratory quality, while the national discussion that is currently underway regarding the optimal regulation of LDPs continues between FDA, CMS, congress and professional societies.

Next generation sequencing (NGS) platforms as part of standard-of-care practice laboratory-developed protocols (LDPs) for performing genetic analyses of our patients’ tumor samples. These tests are used to make basic cancer diagnoses and provide critical information used for personalized therapy decisions for all manner of cancer treatments, including standard chemotherapy, targeted therapy and the latest approved immunotherapies important in the routine delivery of cancer care at our institutions, and they are depended upon by patients (including Medicare beneficiaries) and oncologists. Our nation’s network of Academic University hospital NGS diagnostic laboratories is valuable, critical, and worthy of protection. Academic centers are critical links in our national cancer care infrastructure, they share techniques and methodologies, we participate in cross-site proficiency testing and publish details of our test methodologies and data analysis systems in the peer-reviewed literature.

The CLIA statutes were written to expressly allow non-FDA LDPs because of the key realization that clinical laboratories often need to adapt to changing science, including the need to provide tests for novel biomarkers as the need arises. The need for this flexibility is crucial for innovation. FDA approval of an LDP appears to require substantial investment and clinical trial data, requiring multiple years for certification of a single test. This is a bar that is only attainable by large companies aiming to market services nationally, not for small academic laboratories
For academic laboratories, following Foundation Medicine’s footsteps through this FDA process for all of our tests (current and future) is simply an impossibility. FDA approved tests cannot be modified or improved by their very definition, meaning any assay approved would become ‘locked in time’ and unadaptable to quality or scientific needs.

Because of these reasons, not only will the proposed regulations stifle innovation, it will directly hurt patient care and access to state of the art technologies that can save lives.

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January 17, 2018

Ms. Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, Maryland  21244

Dear Ms.Jensen:

We are writing to comment on the Proposed Decision Memorandum for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N), issued by Centers for Medicare & Medicaid Services (CMS) on November 30, 2017.  The Mount Sinai Health System (MSHS) is an integrated health care network in New York committed to providing distinguished care, conducting transformative research, and advancing biomedical education. We strongly feel and share the same concerns as other stakeholders that if the Proposed Decision is finalized such an action will limit the Medicare beneficiary to life saving cancer care.

MSHS believes our patients will gain greater access to cancer care by the action taken by CMS in granting a proposed National Coverage Determination (NCD) to Foundation Medicine’s comprehensive genomic profile (F1CDx).  However, we respectfully disagree with CMS using this specific proposed NCD as a basis to broaden and apply such coverage decisions to an entire class of NGS genomic profile testing.  We also believe the non-coverage statement should be removed from the proposed NCD as it is both too broad in scope, will limit access to innovative testing, and diminish the role of the physician in the management of the Medicare beneficiary with metastatic and recurrent cancer. 

Additionally, MSHS rejects the assertion implied in the Proposed Decision that only laboratory tests that are cleared or approved by the FDA can provide actionable information to a physician who is determining the best course of treatment for a patient.  MSHS has developed and performed hundreds of thousands of laboratory developed tests (LDTs) at the highest level of quality and with approval by the New York State Department of Health (NYSDOH).  Subsequently, our clinicians are able to provide our patients with cutting edge state of the art cancer care in a timely manner, allowing for rapid and accurate clinical responses to very complex diseases.  This ability to respond rapidly to clinical needs would be greatly impaired and even halted in some cases if LDTs were required, for reimbursement purposes, to undergo lengthy premarket FDA clearance or approval.

Lastly, with regard to process, although we appreciate that CMS extended the comment period until January 17^th, we remain concerned that to finalize non-coverage provisions with significant changes within a short period of only 90 days is unprecedented.  We encourage the agency to convene stakeholders to discuss national coverage policy for diagnostics, including LDTs, that are not FDA cleared or approved but validated by external third parties such as NYSDOH.

Thank you for your time and consideration.  We look forward to working with you on this most important issue. 

Sincerely,

Carlos Cordon-Cardo, MD, PhD
Professor and Chairman
Department of Pathology
Professor, Department of Genetics and Genomic Sciences
Professor, Department of Oncological Sciences
Icahn School of Medicine at Mount Sinai
Professor and Director, Department of Pathology
Mount Sinai Health System
carlos.cordon-cardo@mssm.edu

Ramon Parsons, MD, PhD
Icahn Scholar
Ward-Coleman Chair in Cancer Research
Director, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Director, Mount Sinai Cancer, Mount Sinai Health System
Professor and Chairman, Department of Oncological Sciences
ramon.parsons@mssm.edu

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Subj: Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

Dear Sir/Madam:

The American Association for Clinical Chemistry (AACC) appreciates the opportunity to comment on the Centers for Medicare and Medicaid Services (CMS) proposed national coverage determination (NCD) for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer.  Our association has serious concerns regarding the scope of this document and its potentially adverse effects on scientific innovation and patient access to care. 

AACC is a global scientific and medical professional organization dedicated to clinical laboratory science and its application to healthcare.  AACC brings together more than 50,000 clinical laboratory professionals, physicians, research scientists, and business leaders from around the world focused on clinical chemistry, molecular diagnostics, mass spectrometry, translational medicine, lab management, and other areas of progressing laboratory science.  Since 1948, AACC has worked to advance the common interests of the field, providing programs that advance scientific collaboration, knowledge, expertise, and innovation.

In November 2017, the Food and Drug Administration (FDA) approved an NGS-based test submitted by Foundation Medicine (Foundation One CDx, F1CDx) that provides information on a variety of genetic mutations that may be helpful in clinically managing patients with cancer.  CMS, as part of its parallel review program with the FDA, drafted a national coverage policy to expedite Medicare reimbursement for this diagnostic test and, therefore, patient access to the test.  Although AACC strongly supports this parallel approach, we are concerned that CMS’ draft NCD makes policy recommendations that go far beyond the F1CDx test.  Our comments follow:

Proposed NCD Is Not Consistent with Past NCDs
The draft NCD determines coverage based on the methodology employed by the laboratory.  AACC opposes this new approach.  Differing methodologies can be employed to obtain accurate, useful test data.  CMS coverage policy for NGS-based tests should be based on the specific characteristics of the test, such as whether the test identifies the appropriate gene mutations, not the method used by the laboratory to obtain the information. 

Proposed Draft Would Supersede Local Coverage Determinations
AACC is also concerned how this NCD may affect patient access to care.  Many NGS-based tests have been approved by Medicare Administrative Contractors (MACs) at the local level based on evidence-based guidelines and input from the healthcare community.  This proposed NCD, if implemented, could invalidate those local coverage determinations that are already in place and serving their local communities.  Many patients could be forced to pay for these tests on their own or decline the testing because of Medicare non-coverage. 

Proposed NCD Interferes in Ongoing Policy Discussions Pertaining to LDT Oversight
Most NGS-based tests are laboratory developed tests (LDTs) subject to the Clinical Laboratory Improvement Amendments (CLIA) regulations.  The CMS NCD would interfere with current federal regulatory policy by essentially barring clinical laboratories from performing these NGS tests, since they would not be reimbursed.  Further, it sets a precedent that FDA clearance or approval could serve as the basis for whether a test is reimbursed by Medicare.  Congress is currently reviewing the appropriate level of federal oversight for LDTs.  CMS should not make any payment decisions that interfere with this ongoing legislative review. 

Proposed NCD Would Hinder Innovation and Patient Access to Testing
AACC is alarmed that this NCD, if it moves forward unaltered, may have a chilling effect on future scientific advancements and patient access to critical testing.  Most clinical laboratories performing tests using NGS technology do not have the resources to seek FDA approval or clearance for the tests they perform or participate in NIH-NCI clinical trials.  Academic medical centers, which are at the forefront of cancer research, will be particularly harmed by this proposal.  Many of these testing facilities could be forced to stop developing and offering NGS-based tests, thus stifling innovation and reducing patient access to care. 

Proposed NCD Requirements Would Limit Provision of Patient Care
Further, some of the coverage requirements outlined in the NCD are not feasible.  For example, the document states that laboratories performing an approved NGS-based test for a non-specified (i.e., rare) cancer and/or cancer therapeutic must be part of a registry or NIH-NCI clinical trial.  Laboratories, however, do not have access to the data required by registries, such as: patient survival; progression free survival; objective response rate; and patient reported outcomes.  Therefore, laboratories that don’t become part of a registry would be unable to perform this type of testing.  AACC is also concerned that the current NCD does not have the flexibility for laboratories to provide novel applications of NGS in oncology, such as the use of cell-free DNA, and it excludes the routine use of NGS technology for patients with rare cancers.  The NCD is basically setting up a process, where few laboratories will be able to perform this testing.

We look forward to working with you on this issue.  If you have any questions, please email Vince Stine, PhD, AACC’s Director of Government Affairs, at vstine@aacc.org.

Sincerely,

/s/
Dennis J. Dietzen, PhD, DABCC, FAACC
President, AACC

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January 17, 2018

Ms. Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mail Stop #S3-02-01
7500 Security Boulevard
Baltimore, Maryland 21244

Submitted electronically

Dear Ms. Jensen,

Baylor Scott & White Health (BSWH) appreciates the opportunity to comment on the CMS Proposed Decision Memo entitled “Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N).” Many patients rely on NGS tests provided by CLIA/CAP certified labs in their vicinity and at their local hospitals, such as BSWH, and the lack of Medicare coverage of these tests could hinder access to potentially life-saving information for our late-stage cancer patients, as well as prenatal and inherited diseases cases. Though CMS' proposal would benefit NGS tests with FDA-approved CDx indications, few tests hold this distinction because of the resources and time required to meet the agency's regulatory requirements. The proposal would lock out LDTs that have been the backbone of patient access to NGS testing.

BSWH is the largest not-for-profit health care system in Texas with 48 hospitals, 9,600 affiliated physicians, 48,000 employees and the Scott & White Health Plan. BSWH has over 5,300 hospital beds and 5.8 million patient encounters annually. BSWH has in house laboratories that support complex testing in cancer and prenatal and postnatal care, as well as thousands of routine lab tests. BSWH is a major transplant center, performing over 6,000 successful solid organs, bone and marrow transplants. The complex structure of the integrative model required to provide excellent care to transplant, cancer, prenatal, and postnatal patients requires the use of sophisticated laboratory tests.

While we appreciate the desire for standardization for testing and payment of testing for Medicare patients, and the effort to fast track FDA approval of this category of critically important tests, there is an infrastructure already in place to regulate laboratories and laboratory developed tests as well as recent ICD 10 codes that could be used to process payment for these tests. It is the professional interpretation of the tests that needs standardized, not the tests themselves. Practitioners need the ability to choose which lab to use for which tests. This proposal should be narrowed in scope and more time should be taken to consider the impact it would have on patient care.

Limiting coverage for these patients for diagnostic laboratory tests to those tests approved or cleared by the U.S. Food and Drug Administration (FDA) could: 1) impede innovation and increase the use of older or outdated technology; 2) result in Medicare beneficiaries receiving lower quality diagnostic testing; 3) drive institutions to seek FDA approval for diagnostic tests when no such approval is now required and a national discussion about regulation of these tests is actively ongoing, and 4) drive testing into a small number of commercial labs despite much of the research to improve patient care being performed in academic labs. A great deal of NGS testing takes place in the oncology space and is considered standard of care by specialty oncologists. Driving this testing to a single vendor or small group of vendors is similar to limiting a patient’s access to brand name drugs only and no generic drug alternatives.

Academic medical centers and teaching hospitals provide innovative and cutting edge treatments for patients, and proven and precision diagnostic tests give providers information on which to make healthcare decisions. When providers have access to more advanced diagnostic tools, treatment decisions may be more effective and result in better outcomes with fewer delays caused by inaccurate or imprecise diagnoses. For example, in a recent case involving an oncology specimen, we needed a test to confirm a suspected diagnosis. There was no commercial lab available so we performed the test in house. Even if there had been a commercial lab available, it is unlikely it would have FDA approval as this case was rare. It is important to note that technology in this space is rapidly evolving and changing. Tests often are proven to have very little clinical utility in as short time as a year and very often the FDA approval process is just not equipped to keep up with the pace of change. These changes are however, most often initiated and validated at major academic centers.

BSWH shares CMS’ goals of ensuring that the diagnostic tests used to determine the course of treatment for all patients, including Medicare beneficiaries, are being deployed with confidence as to their clinical and analytic validity. CMS has long looked to FDA imprimatur as the method for allowing Medicare coverage. However, at a time of rapidly improving diagnostic testing that is necessary for personalized care, allowing only for FDA approval as a prerequisite to Medicare payment may be harmful to Medicare patients and limit innovation. By adding the significant hurdle of FDA approval to getting coverage for NGS-developed tests, CMS will create disincentives for creating and improving these tests for cancer patients. This Proposed NCD could also limit the use of these diagnostic tests to those institutions or companies that have chosen to seek FDA approval. Also, if FDA is not prepared to process these requests, a backlog could also hinder access to testing and care.

BSWH is concerned that this Proposed NCD could result in Medicare beneficiaries receiving less effective or advanced diagnostic tests, which could mean that they receive less than optimal treatment. Acquiring FDA approval of a single diagnostic test as a medical device is an expensive and lengthy process. Because FDA approval is not currently required for these tests, a decision to continue using the tests but not seek FDA approval could restrict the availability of these tests to those patients who are not covered by Medicare, due to a lack of reimbursement. This would result in more limited access to these diagnostic tools by Medicare beneficiaries and would create an economic obstacle to equitable care.

The breadth of the Proposed NCD has also led to concerns at academic institutions about the impact on laboratory-developed tests (LDTs) developed using NGS technologies and offered by clinical labs at academic health centers. LDTs are not currently regulated by the FDA, although the labs which develop the tests are subject to regulation and inspection through the Clinical Laboratory Improvement Amendments (CLIA) overseen by CMS. Over the past several years, the debate about the FDA’s role in the regulation of LDTs, and what role CMS has or should have through CLIA, has played out across the agencies and is now in Congress. This discussion is relevant to the Proposed NCD, as it has raised questions about when FDA approval should be required, and through what mechanism such approval should be considered and granted. The suitability of the FDA’s medical device regulations for reviewing LDTs was called into question after the FDA released draft guidance in October 2014 on its proposed oversight of LDTs and in vitro diagnostic (IVD) tests using the existing device regulations. In January 2017, more than two years after the draft guidance was released and in the final days of the outgoing administration, the FDA announced that it would not be issuing final guidance on the regulation of LDTs and instead released a discussion paper synthesizing the FDA’s response to over 300 sets of comments to the draft guidance and setting forth its proposal for significant modifications that could be made to a future version of the agency’s efforts.

BSWH has concerns about the proposed CED requirement that LDTs without FDA approval or clearance must be part of an NCI trial. Given that only around four percent of cancer patients eligible to partake in clinical trials actually participate, the requirement might be a significant roadblock to patient access.

While there are several NCI-sponsored trials involving NGS platforms, the majority of cancer patients receiving treatment in the community setting may not have access to such trials, and even if they do, may not ultimately make it onto the study. While patients are eager to partake in these new types of precision oncology trials, not everyone gets the chance.

We agree with others that CMS should include billing guidance, and recommend the consideration of CPT codes 81450, 81445, and 81455 to be utilized when seeking payment for covered NGS services.

Although we share CMS’ desire to advance equitable and predictable coverage for the entire class of NGS tests, this proposed NCD pushes institutions to seek FDA approval for diagnostic tests when the current pathway to FDA approval for LDTs using NGS is unclear, especially following the FDA’s stalled 2014 draft guidance and 2017 white paper.

If the final national coverage decision is not delayed for further engagement with stakeholders, CMS should consider listing additional indicators of clinical and/or analytic validity that could be the basis for coverage. FDA approval could be included as one option for demonstrating the usefulness of a diagnostic test, but to require FDA approval for every covered test developed with NGS technology (or other technology) undermines the promise of better diagnostic tools.

Again, we appreciate the opportunity to comment. Please do not hesitate to contact me with any questions.

Sincerely,

Kristi Sherrill Hoyl
Chief Policy and Community Officer

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January 17, 2018

To the Centers for Medicare & Medicaid Services:

Re: Proposed Decision Memorandum on Next Generation Sequencing (“NGS”) for Medicare Beneficiaries with Advanced Cancer

We represent the community ALK Positive, a group of more than 800 survivors and caregivers of individuals with advanced anaplastic lymphoma kinase (“ALK”) positive Non-Small Cell Lung Cancer (“NSCLC”). ALK translocations in NSCLC are estimated to affect approximately 5% of NSCLC patients, and almost all of ALK positive cancer diagnoses are found at advanced stages, most frequently stage IV. The importance of testing for ALK, for all oncogenic mutational drivers of lung cancers is critical: finding the ALK translocation will directly impact a patient’s treatment course and his or her survival. Only a fraction of NSCLC patients are provided genomic testing at diagnosis, and we applaud the Proposed Decision Memorandum’s (“the Proposal”) coverage of NGS for Medicare beneficiaries. We believe this testing will result in more people learning that their cancer is driven by a mutation/translocation, which will inevitably result in more effective, sustained treatments.

ALK positive patients currently have access to four Food and Drug Administration (“FDA”) approved tyrosine kinase inhibitors (“TKIs”) (Crizotinib, Ceritinib, Alectinib, and Brigatinib, with two other medications in Phase III clinical trials Ensartinib and Lorlatinib). While there are differences, these TKIs effectively keep the cancer at bay for a time, ranging from several months to sometimes years in some patients, with far fewer side effects than traditional treatments.

Due to drug resistance, the TKI inhibitor will inevitably fail, and, patients then move onto another TKI. Approximately 50% of ALK positive patients’ cancers will develop a sub-mutation, and those mutations often vary from patient to patient. Research has shown that certain second and third generation TKIs can treat certain sub-mutations very effectively. Other TKIs may be known to be completely ineffective against a particular ALK sub-mutation. The only way to find out which sub-mutation has developed, however, is a subsequent NGS test. Yet the Proposal only pays for one NGS test.

CMS is asking Medicare patients and their doctors to play darts blindfolded by failing to fund testing for these sub-mutations on a second, or a third NGS test, after each TKI medication has failed. This is unnecessary, dangerous to the patients, and financially wasteful. Precision medicine requires precision testing.

This guessing game is unnecessary because assays, either through FoundationOne, academic institutions, or others, currently exist that can identify sub-mutations, which can accurately guide a doctor’s prescribed next course of treatment. It is dangerous because subjecting a patient to a treatment that likely won’t work will inevitably worsen his or her condition, if not hasten their death. Please make no mistake: the failure to do subsequent NGS tests can and will lead to the premature deaths of patients. Finally, the suggestion to test only once is financially wasteful; it will cause doctors to prescribe medication costing approximately $15,000 a month and might not work when a test could determine a medication’s effectiveness for a fraction of the price. In other words, by failing to allow for subsequent NGS testing, the Proposal is “penny wise but pound foolish.”

We are also concerned about the Proposal’s lack of testing options for which CMS proposes to pay. While FoundationOne has been very beneficial to our members, so have many other NGS tests by both commercial and academic providers. Problematically, many of the members of our group have provided tissue samples to more than one provider, and obtained differing results. A doctor and a patient should make the decision as to where to send biopsy samples, factoring in the type of sample, suspected type of mutation, etc., without having to worry if CMS is going to pay for it.

We are also troubled by the conditional manner in which CMS proposes to pay for a test. If a patient tests negative for a useful biomarker, or tests positive for a biomarker that does not yet have an FDA approved companion diagnostic, all patients who wish CMS to cover their NGS test must be prepared to enter a patient registry, enroll in a clinical trial, or pay for the test themselves.

Any of these conditions place unacceptable burdens on patients. A patient should not have to waive his or her privacy rights in order to get a genomic test. Yet this is exactly what the Proposal demands. Privacy is important to patients. Cancer patients are subjected to a seemingly endless barrage of invasive procedures as part of their treatment. Many patients feel the only thing they can control is their own privacy. Patients should not be forced to give that up due to a patient registry enrollment requirement, in order to get access to potentially life-saving genomic testing. Further, it is not at all clear to what end the patient registry or registries will be used. While ALK Positives can and do support the rational collection of data so as to spur medical advancements, there are inadequate safeguards in place here to preserve patient privacy, and in no event should a registry be compulsory.

While the goal of increasing clinical trial participation is commendable, forcing patients to enter a clinical trial in order to have access to NGS testing is not appropriate. Clinical trial sites for patients are often few and far between. It is not uncommon for our members to travel many hundreds, if not thousands of miles, for clinical trial appointments. There is a substantial time commitment to most clinical trials and the transportation costs are rarely, if ever, reimbursed. Frankly, most Americans cannot afford the time and expense to participate in a clinical trial. There are many advantages to clinical trials, but there are many potentially serious drawbacks as well. Simply put, CMS should not require patients to subject themselves to experimental treatments in order to have access to a potentially life-saving test. The Proposal erodes the historic and, crucially, voluntary nature of clinical trial enrollment. Encouraging participation in clinical trials is critically important, but this is not the mechanism by which to do it.

ALK Positive members applaud the proposed coverage of NGS testing. However, we find three significant flaws in the Proposal that must be corrected and we respectfully request the following changes to the Proposal:

Thank you for your consideration.

ALK Positive

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January 15, 2018

Via Electronic Submission:

Tamara Syrek Jensen, JD
Director, Coverage & Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mailstop S3-02-01
7500 Security Blvd
Baltimore MD 21244

Dear Ms. Syrek Jensen:

Bayer Corporation ("Bayer") appreciates the opportunity to submit comments pertaining to the Centers for Medicare & Medicaid Services ("CMS") proposed National Coverage Analysis (NCA) for Next Generation Sequencing (NGS) as a diagnostic laboratory test for Medicare Beneficiaries with Advanced Cancer (CAG-00450N).

Bayer has more than 12,000 employees across the United States and is a global life science company with more than 150 years of experience researching and developing new pharmaceuticals and medical devices. We focus our efforts where we can have the most beneficial impact on the lives of those who depend on our innovative products. Our mission is to discover and manufacture products that will improve human health worldwide by diagnosing, preventing and treating diseases.

On the basis of our experience, we wish to focus our comments on the following elements of the NCA.

I. Parallel Review and Coverage Process
Bayer applauds CMS for executing parallel review for coverage of the Foundation Medicine lnstitute's NGS test while the FDA conducted its own review for approval of the test itself. The Foundation Medicine test development and reviews for its FDA approval and Medicare coverage were undertaken in a swift and efficient manner. In order to continue to keep in step with technologic advances, Bayer recommends that CMS consider establishing a comparable expedited coverage reviews (similar to the FDA's Accelerated Review) for breakthrough methods of testing for other types of cancer and illnesses where science is advancing at a rapid rate.

Bayer is dedicated to the safety and wellbeing of its patients and would not suggest premature approval of new forms of genetic testing. However, it is imperative that patients have access to innovative, reliable quality testing with adequate reimbursement as soon as is practicable. In order to ensure access for patients during these times, it is important for CMS to continue to take a leadership position by providing scientifically sound accelerated approval pathways for coverage to support breakthrough or fast-tracked testing and treatment for patients. CMS should, however, seek to further streamline its evaluation processes and coverage developments for new tests to match the availability of new and innovative tests in the market. Accordingly, Bayer strongly supports the parallel review process as a way to bridge the gap between product availability and coverage, especially in cases where a more efficient process leads to more effective patient access and treatment within a reasonable time period.

II. Scope of Proposed Coverage Determination
We commend CMS for advancing coverage of NGS through the National Coverage Determination (NCO) process. NGS is a critical technology designed to identify patient-specific disease characteristics and to more appropriately treat patients with advanced cancer. Bayer recognizes the critical need for advanced diagnostics to identify and properly treat a variety of cancer types, and believes it is imperative that patients receive the appropriate testing to specifically target genetic types of cancer for which there are available treatments.

However, Bayer is concerned that the NCA in its current form may restrict access to important testing as new targets are identified and new treatments are approved for use. Bayer recommends a rapid and transparent approval process for newly identified tumor targets and treatments including those in other indications and in other therapeutic areas. Because this NCA is extremely specific and limited to solid tumor gene profiling for Medicare beneficiaries with advanced, recurrent, or metastatic cancer at a single time point, it does not apply to other areas where NGS technology may be applied. Such approaches may include initial diagnostic assessment, tracking diseases longitudinally, or where companion designation of a test is not plausible. Therefore, CMS should clarify that the scope of this national coverage determination is tailored to a specific use of NGS technology, and that the NCO would not apply to all NGS uses. CMS should make it clear that future uses for NGS would be subject to coverage through an appropriate future NCO. Alternately, CMS could consider a more generalized NCO around the technology and allow for Local Coverage Determinations (LCD) guidance in specific instances.

Ill. Minimizing Disruption of Existing Local Coverage
In addition, it is Bayer's observation that the NCA does not yet outline a method to extend coverage to tests that are already covered locally under LCD published by the Medicare Administrative Contractors (MAC). Articles within LCDs exist in many regions to define billing and coding guidelines for NGS testing. Because NCDs supersede LCDs, including a clear transition plan in the NCO to adopt local decisions and not interrupt currently covered testing/treatment models would remove any potential barriers to access and interruptions in patient care. Bayer recommends a method to transition or "grandfather'' coverage for these existing tests in order to ensure coverage for patients who are under the care of oncologists within these jurisdictions.

IV. Coverage With Evidence Requirement (CED)
Utilization of CED allows for evidence generation while providing access and coverage for innovative technologies without implementing broad coverage policies. CMS has successfully employed CED in the past for imaging, transplants, device use, and oncology purposes. We urge CMS to continue to work with researchers, providers and other stakeholders to ensure the process does not further delay access to care, maintains a low administrative burden, and does not discourage participation by certain entities.

Regarding the CED requirements, we also recommend that CMS consider including available and appropriate retrospective data in the registry. In rare tumor types, large numbers of cases would take a very long time to accrue and the timing could undermine the objective for rapid identification and treatment.

Bayer appreciates the opportunity to comment on the proposed NCA and looks forward to working with CMS on efforts to improve access to quality, affordable healthcare.

Sincerely,

Raymond F. Kerins Jr.
Senior Vice President,
Head of Communications,
Government Relations & Policy
Bayer U.S. LLC

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To Whom It May Concern,

I would like to congratulate the FDA and CMS for recent decisions regarding Next Generation Sequencing. As a full time medical oncologist, I have found that NGS has provided my patients with advanced disease the ability to access biomarker driven FDA approved therapies as well as clinical trials. I do hope that the CED registry will have a low burden for patients and their treatment team.

Best Regards,
Sandeep Kodityal, MD
Assistant Professor of Hematology-Oncology, Baylor College of Medicine

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17 January 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Ms. Jensen -

Thank you for the opportunity to comment on the draft national coverage determination (NCD) CAG-00450N related to the FoundationOne CDx (F1CDx) test.

I am a physician and practicing molecular pathologist in the Department of Laboratory Medicine at the University of Washington, and I am board certified in anatomic, clinical, and molecular pathology. My clinical responsibilities entail both the acquisition and selection of appropriate tissues for clinical testing and the interpretation of data from laboratory-developed procedures used in the clinical care of patients. I oversee the procurement and qualification of formalin-fixed paraffin-embedded (FFPE) tissues for use in testing for somatic mutations or other findings that are related to the diagnosis, prognosis, and selection of treatments for patients with cancer that are treated at the University of Washington Medical Center, Seattle Children’s Hospital, the Seattle Cancer Care Alliance, and across the Pacific Northwest region. I am extensively involved in the training of medical residents and fellows, both in didactic and practical settings. I have been involved in the design, validation, deployment, support, and interpretation of clinical moleculartechnique- based procedures, both FDA approved/cleared and laboratory developed, for almost 20 years.

I applaud Centers for Medicare & Medicaid Services (CMS) for recognizing that broad profiling of mutations in solid tumors is a medically necessary activity that is reimbursable by CMS for Medicare patients with advanced cancers. At the same time, I am very concerned that the draft FoundationOne CDx (F1CDx) national coverage determination (NCD) would establish unnecessary and harmful restrictions on the practice of the pathology and laboratory medicine and has a high likelihood of causing harm to patients through elimination of currently available laboratory procedures. As educator who trains the next generation of physicians regarding the performance of precision medicine, I have concerns that the NCD will limit the ability of academic medical centers (AMCs) to properly train the practitioners who will be tasked with generating and using the findings of laboratory tests to treat their patients. Finally, a large share of the innovations in laboratory medicine and pathology using next generation sequencing (NGS) have originated from academic-based clinical practices, where physicians developing and utilizing laboratory techniques for clinical use are able to improve upon techniques and publish the findings for other professionals to use.

Proposal for non-coverage based on the underlying technology platform is inappropriate
The draft NCD includes language to explicitly prohibit CMS from reimbursing for laboratory procedures that use next generation sequencing (NGS), a generalpurpose technology platform that happens to be employed in the F1CDx test. Many of the techniques, approaches, and quality-control metrics that constitute the F1CDx were developed in the public sector, often by providers at AMCs, and are not unique to the F1CDx test. There are currently hundreds of laboratory developed procedures (LDPs) that employ NGS technology that are currently reimbursed by CMS, either under analyte specific Current Procedural Terminology (CPT) codes or local coverage determinations (LCDs) that have been deployed by Medicare Administrative Contractors (MACs). The clinical tests currently using NGS evaluate a wide scope of genetic diseases, from relatively common germline conditions, germline conditions related to cancers, somatic overgrowth syndromes, infectious disease, and oncology applications. The vast majority of these tests are not cleared or approved by the FDA due to the incredible expense of FDA evaluation, the need for many tests to be adaptable to changing clinical and scientific needs, and the fact that laboratory procedures are regulated under the CMS-administered clinical laboratory improvement amendments of 1988 (CLIA). It is conceivable that prohibition on CMS reimbursement for NGS-based tests that is stipulated in this draft NCD would apply to many of these currently-available LDPs, likely limiting access to critical tests for Medicare patients. For some tests, there may be alternatives to NGS-based tests, but many other technological approaches are more expensive, less comprehensive, and require longer to arrive at the most relevant results. Increased Medicare spending, decreased testing breadth, and increased time-to-result for patients and physicians is not consistent with the practice of pathology and laboratory medicine or the spirit of constant quality improvement that CMS has embraced in other areas.

It is inappropriate to equate the F1CDx test with a general-purpose technique that is used in a diversity of clinical applications. Prohibiting Medicare reimbursement based on a core underlying technology is inappropriate, will result in decreased patient access to important diagnostic methods, and should not be included in a NCD that was prompted by a single test, designed for a single narrow application. Testing that is currently reimbursed by CMS should continue to be reimbursed, and existing programs, such as LCDs, should be available to future LDPs that utilize NGS technology.

Proposed Coverage with Evidence Pathway is Restrictive and Inappropriate for Well-Studied Biomarkers
Although an alternative pathway to CMS reimbursement is included in the draft NCD, it requires that the laboratory procedure be cleared or approved by the FDA and mandates patient participation in outcomes registries. While this alternative reimbursement pathway may sound reasonable when taken at face value, even a superficial interrogation of the requirements suggests that very few academic laboratories will have the ability to meet the stipulated requirements. This coverage with evidence development (CED) model requires that the assay used is FDA approved or cleared, while most NGS-based test are LDPs. As detailed elsewhere the expense and limitations imposed by FDA review are not appropriate for LDPs performed at AMCs. Many of the data elements that are stipulated in the CED model of the draft NCD would require multiple physician visits, imaging studies, and other assessments, all of which could cost tens of thousands of dollars. Many of the analytes that are currently evaluated using NGS techniques have already been established to be clinically meaningful. As such, it is unlikely that any institution or funding agency would provide resources to demonstrate clinical utility for a biomarker when it has already been demonstrated. Any coverage with evidence model should reflect the relevant scientific and medical features that are pertinent to laboratory testing. One reasonable approach might be an analyte-specific approach where laboratories demonstrate adequate analytical performance and maintain performance with mandated proficiency testing. Rather than recapitulate studies that have shown clinical benefit, data sharing of unique variants identified in clinical samples may be more useful to practitioners and patients.

If a coverage-with-evidence model is deployed, a more reasonable set of parameters tailored to the testing methodology should be employed in the setting of wellestablished biomarkers.

The majority of residents and fellows who train in pathology, laboratory medicine, molecular genetic pathology, and oncology are trained at AMCs. Once in practice, pathologists are responsible for properly selecting the most appropriate solid tissues that are used in the testing covered by the draft NCD and a component of their training includes being informed custodians of patient tissues for current and future diagnostic and ancillary uses. In many AMC programs, trainees are educated in the limitations and strengths of NGS techniques through first-hand experiences in clinical services using these methods for patient care. This experiential model of physician training is the foundation of our medical training system and allows trainees to provide critical patient services while learning the necessary practices that will be essential to their independent practice. If AMCs are unable to be reimbursed for clinical NGS testing of patients in their systems due to the implementation of this NCD, the ability or properly train these physicians will be severely impaired because the clinical substrate for medical practice will not be available to them. It is critical that the physicians responsible for the collection, selection, maintenance, and integration of these results have access to the data generated through clinical NGS procedures so that their comprehension of the salient factors will allow them to provide appropriate and cost-effective management of very limited resources.

In addition to education of most pathology residents and fellows taking place at AMCs, most oncology fellows are trained at academic medical centers as well. Pathologists and laboratory medicine physicians often educate trainees outside of their official scope of responsibility, including oncology trainees. Through our daily interactions, didactic lectures, and tumor board presentations, oncology trainees are educated on the utility, limitations, nuances, and strengths of NGS-based tests performed in our laboratories. If we are not able to perform NGS-based laboratory procedures for our patients, our ability to provide expert consultation and training will be dramatically diminished. Similarly, education does not end at the time of graduation. Pathologists and laboratory medicine providers are constantly interacting with our clinical and oncology peers regarding the proper use and interpretation of NGS-based laboratory results. Limiting the ability of expert practitioners to be reimbursed for their work with Medicare patients will decrease the opportunities for ongoing and interactive education related to patients that are being cared for at our institutions.

Finally, the majority of Medial Laboratory Scientists (MLS) training occurs in AMCs. These highly trained professionals are responsible for staffing the majority of highcomplexity hospital and outpatient laboratories in the United States. These training programs are critical because they provide not only the technical skills needed in modern clinical laboratories, but also provide the context of the clinical environment, including the important roles that regulation, quality control, and continuous quality improvement play in generating accurate and reliable results. Many of the MLS programs have closed across the country in the past several decades, and the average age of the current workforce is nearing retirement agei. Thus, it is critical that the future MLS staff that will perform these advance NGS assays have access to rigorous academic instruction, both at the classwork and practical levels, such that they can be well trained for the laboratories that will need these staff.

Reimbursement for NGS-based laboratory procedures should be retained at AMCs responsible for all levels of medical education.

The prohibition on CMS reimbursement for NGS-based methods threatens to limit the innovation that is inherent in AMCs that perform this type of testing. In order to innovate in the clinical space, physicians who are involved in this aspect of patient case need to observe the limitations and difficulties that are occurring in order to conceive of ways to change their practice and add value. For example, our laboratory noted that there were features present in the sequencing data of patients who were undergoing sequencing of their colorectal or endometrial cancers that happened to mismatch repair deficient. This led our faculty and residents to develop the first method for determining microsatellite instability status from NGS data^1,2.

That method was published and made freely available to the entire scientific and medical community, which is unlike the behavior seen in many private entities. The culture of continuous quality improvement and innovation in testing methods is at the core of pathology and laboratory medicine, but such innovation often springs from the questions and limitations that are observed in the current testing methods. Consolidating solid-tumor oncology testing in a single laboratory combined with the prohibition on reimbursement for a whole class of technology, that is key to this draft NCD, will decrease opportunities for innovative approaches in laboratory testing.

Reimbursement for NGS-based laboratory procedures should be retained at AMCs to allow for continued innovation in laboratory methods.

Tension between LDPs and FDA-approved/cleared products
Central to the draft NCD and the problems related to a prohibition on reimbursement of a class of laboratory tests is the fact that the vast majority of AMC-based NGS-based laboratory procedures are LDPs and have not been submitted to the FDA for clearance and approval. Laboratories are currently regulated under CLIA, and LDPs are regulated under that program. There is extensive oversight of LDPs regulatory bodies and qualified directors, and requirements to constantly evaluate method performance using structured programs, such as proficiency testing and quality control systems. Systematic evaluation of laboratory methods, including NGS-based assays, show excellent concordance of analytical results^3,4, demonstrating the power of the current regulatory structures. The continuous quality improvements (CQI) model that is used in AMCs that use LDPs, combined with rigorous technical and medical evaluation are a valid alternative to FDA regulation that has been accepted by CMS and medical practitioners for decades.

In addition to having a rigorous oversight process in place, most academic laboratories do not have the financial or administrative resources to apply to submitting individual LDPs for FDA review. Currently, the FDA considers laboratory procedures, developed and performed by licensed medical practitioners, to be equivalent to medical devices, such as pacemakers or joint replacement products. The process of obtaining FDA approval for LDPs that would qualify as companion diagnostic tests have been estimated to cost millions of dollars, with medical devices in this FDA category estimated to cost, on average, $94 million in 2010ⁱⁱ. Dedicating this level of funding to a single laboratory test out of a menu of thousands is not typically available to practitioners in AMCs, which are tasked with servicing a huge variety of patient conditions. Dedicating resources to FDA-approval activities is not reimbursable and would divert scarce, often Medicare-derived, resources from other laboratory activities, which impact patient care. Given the current state where LDPs are demonstrated to be at least equivalent to FDA-cleared/approved products, there is limited rationale for increasing the cost of demonstrating the current state of excellent correlation.

As medical practitioners at the forefront of medicine, AMC professionals are constantly improving and developing laboratory methods to better serve the needs of the patients they are responsible for. Such continuous improvement is not readily accommodated into the current FDA evaluation model, and test methods that have been altered are currently required to go through re-evaluation by the FDA. Given that the FDA-approval process is often measured in years, the practical effect of this requirement is that tests that are known to be out-of-date are NOT updated to reflect the current scientific and medical knowledge because to do so is not financially viable. For examples, the first HIV-1 RNA viral load test was approved in 1999, and within a short period of time was recognized to have limitations in detecting less common, but clinically significant subtypes. Despite this knowledge, an updated assay from the same manufacturer was not approved by the FDA until 2007ⁱⁱⁱ. Such delays are not acceptable in current clinical practice, which is a primary reason for medical professionals practicing in a rapidly-changing clinical landscape to develop analytically valid, but clinically nimble LDPs.

There has been tension between FDA, CMS, and medical practitioners for decades over the role of FDA and CMS in the regulation of medical practice using LDPs that are not manufactured and distributed by large commercial companies. Although the FDA released a draft guidance proposing to end the multi-decade period of regulatory oversight discretion in 2014^iv, the FDA ceased those plans in early 2017. In a 2017 white paper ^v, the FDA indicated that congressional legislation was the preferred vehicle for resolving the matter. The call for legislation as a vehicle for resolving the disagreements have been echoed by others, including senior administrative leaders, such as the current FDA commissioner^vi. There are currently several proposals in circulation, with at least one in legislative language, that propose to address the actual and perceived limitations in the current regulatory paradigm for LDPs. The spirit of this NCD, requiring FDA clearance/approval as a condition for reimbursement for tests that uses a specific, general-purpose technology, circumvents the legislative process and the stated desires of numerous stakeholders.

CMS should delay finalization of this draft NCD until the legislative branch of government can address the regulatory questions related to laboratory procedures that are currently classified as LDPs and how CMS and FDA should regulate those procedures.

1. The finalization of the F1DCx NCD should be delayed until the central issue of regulation of LDPs is resolved by congress.
2. If the draft NCD must be finalized before congress can develop legislation:
   1. The prohibition on reimbursement for non-FDA cleared/approved NGS-based tests must be removed
   2. NGS-based laboratory procedures that are currently reimbursed should continue to be reimbursed
   3. Future NGS-based laboratory procedures that are required to be assessed under LCD programs should continue to be eligible for consideration.
   4. Medical education and method innovation are critical to the practice of precision medicine. NGS-based tests performed at AMCs should be reimbursed for the value they add to the health system.
   5. Any coverage with evidence model should reflect the salient aspects of laboratory medicine. Well-studied biomarkers do not require additional clinical studies and extensive survival and response criteria should not be included.

Thank you for your consideration.

Eric Konnick, M.D., M.S., FCAP
Assistant Professor
Associate Director - Genetics and Solid Tumor Laboratory
Department of Laboratory Medicine
University of Washington

References and endnotes:

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Ms. Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mail Stop #S3-02-01
7500 Security Boulevard
Baltimore, Maryland 21244
Submitted electronically

RE: Comments on Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

Dear Ms. Jensen,

Mayo Clinic respectfully submits comments on the proposed decision memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N). As a provider of Next Generation Sequencing (NGS) clinical testing to patients across the United States, we want to take this opportunity to comment on the proposed NCD requested.

Mayo Clinic is a not-for-profit health care system dedicated to medical care, research, and education. With more than 3,600 physicians and 60,000 employees, Mayo Clinic demonstrates a relentless and unwavering commitment to excellence which has spawned a rich history of health care innovation. Each year, more than one million people from all 50 states and 140 countries come to Mayo Clinic to receive the highest quality care primarily in Rochester, Minnesota, but also in facilities in Arizona and Florida. In addition, Mayo Clinic Health System, a family of clinics, hospitals and health care facilities, serve rural and small communities in Iowa, Minnesota, Wisconsin, and Georgia.

The Mayo Clinic Department of Laboratory Medicine and Pathology (DLMP) in Rochester MN is one of the largest and most sophisticated clinical laboratory and pathology departments in the world. The department offers a unique perspective to the LDT issue as it provides support for a large and sophisticated tertiary care network through Mayo Clinic but also offers laboratory and pathology services through Mayo Medical Laboratories (MML), a global reference laboratory operating within the Mayo DLMP. Backed by the knowledge and expertise of more than 160 pathologists and scientists and over 3,000 allied health staff in a wide range of professional roles, the der,artment r,erforms over 25 million tests annually across the continuum of patient care ranging from patient bedside to esoteric laboratory and pathology services.

Mayo Medical Laboratories provides reference laboratory testing for more than 4,000 medical facilities around the world. Our mission through MML is to support the local delivery of laboratory services by providing support to build and expand laboratory testing locally and to offer Mayo's clinical laboratory and pathology expertise and consultative services that all facilitate communitybased health care.

Mayo Clinic supports Foundation Medicine's original request for an NCD for comprehensive genomic profile testing for the management of cancer in patients with solid tumors that are metastatic, including Stage IV and recurrent tumors, with FoundationOne CDEx™ (FlCDx). However, the draft NCD proposes a coverage policy that has implications beyond the FlCDx test. Specifically, the proposed NCD limits coverage only to FDA approved NGS tests with companion diagnostic indications and imposes very narrow criteria for coverage with evidence development, and makes a policy of non-coverage for NGS tests that do not meet the specific criteria listed in the NCD. The FlCDx test has clinical utility for certain indications, but it is not the only clinically acceptable test for patients with advanced cancer, nor is it the only test that has been demonstrated to be high quality and offered with regulatory oversight under CLIA or CAP.

The Proposed NCD has a far broader reach than the scope of the request and of the evidence CMS cites in Section VII of the Proposed NCD. The evidence CMS cites to address health outcomes in Medicare beneficiaries focuses almost exclusively on tumor-based multigene panels, yet we understand that the scope of non-coverage in the Proposed NCD would reach any test using NGS technology that does not meet certain criteria. Until and unless CMS reviews evidence relevant to other kinds of laboratory tests using NGS technology, it is inappropriate for the agency to issue an NCD that extends beyond tumor-based somatic multigene NGS oncology panels. CMS should change the title and scope of the NCD accordingly.

NGS is a technology and is not a diagnostic test. Performing DNA and/or RNA sequencing is relatively straight forward and NGS or other molecular technologies for sequence analysis are performed by CLIA certified clinical laboratories every day across the country. Molecular testing using NGS technology performed in CLIA laboratories adhere to evidence-based guidelines developed by professional societies, including AMP, CAP, ASCO, ASH, WHO and NCCN. The draft policy evidence has in many instances, been the foundation for laboratory developed and clinically-validated procedures using NGS technology for cancer mutation detection.

NGS is simply a sequencing technology rather than a diagnostic test. NGS technology can be used to perform virtually any genetic test across all areas of oncology diagnostics, and over the next few years most oncology testing will likely migrate onto these platforms. Thus by proposing this NCD based on a single technology rather than on a particular analyte, CPT code or test, CMS is in effect proposing that the future of every single CPT code across all of molecular oncology diagnostics should be governed by this NCD, which rather than being focused on a particular test in effect creates a novel and redundant regulatory oversight system.

By focusing on NGS technology, the proposed NCD runs counter to established coverage determinations which are based on the clinical utility of a proven effective biomarker, independent oftest methodology, and whether a test has received regulatory approval for marketing and labeling.

As a leading academic and medical institution, Mayo Clinic has Clinical Laboratories Improvement Amendment (CLIA) certified laboratories providing valid laboratory developed NGS-based tests. The proposed NCD would supersede existing Local Coverage Decisions (LCDs) for most of the tests and limit a Medicare beneficiaries' access to testing.

The proposed NCD's requirement of achieving FDA approval for coverage is inconsistent with the FDA's position on enforcement discretion for laboratory developed tests (LDTs), including its 2016 announcement that it does not intend to finalize the draft guidance establishing a framework to regulate LDTs. The proposed NCD requirement of FDA approval establishes a regulatory bar that is impractical for most laboratories to reach, including academic medical centers and cancer programs. Implementation of this policy would restrict Medicare beneficiaries' access to care, slow down areas of rapidly advancing science and be a barrier to advancing medical practice in a rapidly evolving landscape. Furthermore, current NGS tests for advanced cancer patients are currently being used to deliver high-quality advanced cancer care across the country. The proposed policy would cease reimbursement for testing that has proven beneficial and may cause many laboratories, which are unable to sustain providing testing without reimbursement, to use other laboratories which will delay needed care.

We are extremely concerned that the NCD, by tying all future reimbursement for our NGS based tests to FDA approval, creates a novel and extremely burdensome additional laboratory oversight regime that is not consistent with current legislation and which is incompatible with the continued practice of personalized oncology care and laboratory medicine at a local level.

LDTs must go through rigorous validation procedures and meet several criteria before results can be used for decisions regarding patient care. Several governmental and non-governmental entities regulate and guide the development and validation of this group of tests. These groups include CLIA, State requirements, and laboratory accreditation programs.

CLIA includes extensive requirements for laboratories to verify or establish a test's analytical performance characteristics before offering it and reporting patient results based on the test. CLIA regulations require laboratories that use LDTs, that modify FDA-cleared or -approved tests, or that use a test system for which the manufacturer did not provide performance specifications to establish the following performance characteristics before reporting patient test results: accuracy, precision, analytical sensitivity, analytical specificity to include interfering substances, reportable range of test results for the test system, reference intervals (normal values), and any other performance characteristic required for test performance¹. CLIA regulations also require a laboratory director to ensure that test methodologies have the capability of providing the quality of results required for patient care, which is the case only when they are clinical relevant for the patient populations being tested (i.e., are clinically valid).² Clinical validity is also ensured by CAP-accreditation, whose goals include ensuring that tests are analytically and clinically valid, that there is patient safety and patient access to testing, and that there is innovation and improvement of LDTs.³ Currently, approximately 8,000 laboratories are CAP-accredited.⁴

Precision oncology is a medical practice that occurs at the local level, at the patient's bedside and in interactions between local healthcare professionals including molecular pathologists. The flexibility to triage urgent patient samples, to discuss in depth the findings at local tumor boards with multidisciplinary teams, and to participate in quality improvement initiatives specific to institutions will be lost if testing is effectively centralized to certain laboratories with the resources to obtain FDA approval.

Many Medicare beneficiaries rely on NGS tests provided by CLIA/CAP certified labs in their vicinity and at their local hospitals. The lack of Medicare coverage of these tests could hinder access to potentially life-saving information for late-stage cancer patients. Furthermore, studies show that there is a high degree of accuracy and comparable performance of both LDTs and FDACDs in regards to oncology analytes. However, more significantly, the same study shows that the majority oflaboratories using FDA-CDs have modified the scope of their assay to allow for more clinical practice variety, rendering them LDTs. The findings support both the excellent and equivalent performance of both LDTs and FDA-CDs in clinical diagnostic testing⁵.

In many cases, LDTs yield better and more up-to-date results than FDA-approved kits. A recent peer-reviewed study published in the journal Molecular Diagnosis & Therapy assessed mutations detected in EGFR, KRAS, and BRAF genes using an LDT that combines NGS with confirmation by Sanger sequencing, and compared it with mutations that could be detected by FDA-cleared test kits. The study found that significantly more mutations in these genes are detected when the LDT combining NGS and Sanger sequencing was used than when FDA-cleared kits were used. The study's authors stated that rapid advances in analyzing molecular abnormalities make it difficult for FDA-approved test kits to keep pace and remain the standard in patient care and oftentimes, FDAapproved tests become outdated quickly.⁶ Another study, published in JAMA Oncology in December 2017, compared performance ofLDTs and FDA-approved assays for EGFR, KRAS, and BRAF testing. The study included 6,897 College of American Pathologist (CAP) proficiency testing responses and found 97 percent accuracy across both FDA-approved assays and LDTs. Authors also noted that more than 60 percent of study participants using FDA-approved assays modified the approved assays to broaden clinical practice, rendering them LDTs.⁷

Many academic medical centers, such as Mayo Clinic, are at the forefront of cancer diagnosis, treatment and care. Moreover, these same institutions have led the development of novel NGSbased clinical assays that are used in the diagnosis, therapy and care of their patients. If CMS permits reimbursement only for NGS panels that are FDA-approved, many of the NGS assays performed in this country by academic medical center laboratories will not be available, despite careful documentation of analytic and clinical validity. If these labs are not reimbursed for the high quality and innovative work that they do, then these same innovative laboratories will not only stop performing these important assays, but they will also lose the incentive to develop new assays based on new and emerging genetic discoveries in cancer diagnosis and cancer care. When top laboratories cannot provide these studies or develop novel tests based on new discoveries, then the ability of clinicians to provide care for their patients will be significantly - and negatively - affected. For example, validated custom gene panels for a small number of genes known to be associated with outcomes in a particular tumor may not be available in a timely fashion, even though they are both valid and less costly.

The proposed Coverage with Evidence Development unnecessarily restricts Medicare beneficiary access to valuable testing. While the Proposed NCD appears to allow for Coverage with Evidence Development (CED) of certain LDTs using NGS technology that are provided to patients as diagnostic tests within NIH-NCI National Clinical Trial Network clinical trials and that are registered in the NIH Genetic Testing Registry, this provision is unnecessarily restrictive. For laboratories, this CED is unworkable and inappropriate as proposed. Many laboratories do not have the resources to participate in NIH-NCI clinical trials. And laboratories often times do not have access to data that is required by a registry, such as overall survival, progression-free survival, objective response rate, and patient-reported outcomes. Thus, for many laboratories, the "choice" to use CED for an LDT using NGS technology, in lieu of FDA-approval or-clearance, is not a real choice.

1. Any CMS decision needs to consider first the needs of the patient. Any decision that limits access to highest quality, innovative care should be reconsidered.
2. We support Foundation Medicine's request for coverage of FoundationOne CDx™, but we do not believe that CMS should finalize the Proposed NCD as drafted.
3. The proposed non-coverage of testing beyond the original request would significantly impact Medicare beneficiaries' access to cutting-edge tests using NGS technology for cancer and other indications - especially those tests that are LDTs which are scientifically valid, medically necessary, and effective in the treatment of beneficiaries' illness, condition or disease.
4. CMS should recognize the high quality ofNGS cancer laboratory testing that is currently provided by high-quality clinical laboratories in academic medical centers and other laboratories.
5. CMS should limit this NCD so that it applies only to FDA-approved assays and not to any other NGS-based test.
6. Both this and future NCDs should focus on individual analytes or CPT codes rather than on NGS technology.
7. CMS should leave the local coverage determination process intact for all other assays, thereby allowing a mechanism for coverage of clinically and analytically valid assays performed across the country. This will appropriately reward companies/entities that choose to punme FDA approval while not penalizing laboratories engaged in high quality ciuc as demonstrated by other measures of clinical and analytic validity.
8. As noted in the proposed NCD, regulation requires that diagnostic tests be ordered by the physician who is treating the beneficiary.⁸ However, we remind CMS of the surgical and cytopathology exception allowing pathologists to order additional testing to provide a complete and accurate diagnosis to the treating provider whom will utilize the results of the tests in the treatment of the beneficiary.⁹
9. CMS should engage the relevant stakeholders including academic medical centers, as well as FDA, and Congress to identify paths forward that assure appropriate reimbursement for testing that has met determinants of analytical and clinical validity, recognizing that the mechanism of establishing these determinants and the mechanism to enforce them is ambiguous and may be established legislatively.

Respectfully,

/s/
William G. Morice, II, M.D., Ph.D
Chair, Department of Laboratory Medicine and Pathology
President, Mayo Collaborative Services, LLC
Professor of Laboratory Medicine and Pathology
Mayo Clinic

/s/
Marie E. Brown
Associate Administrator, Department of Laboratory Medicine and Pathology
Senior Vice President, Mayo Collaborative Services, LLC
Mayo Clinic

/s/
Curtis A. Hanson. M.D.
Professor of Laboratory Medicine and Pathology
Chief Medical Officer, Mayo Medical Laboratories
Mayo Clinic

CC: Sara Luther

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January 17, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Department of Health and Human Services
7500 Security Boulevard
Baltimore, MD 21244

Dear Ms. Jensen,

On behalf of the 30 million Americans with one of the approximately 7,000 known rare diseases, the National Organization for Rare Disorders (NORD) would like to thank the Centers for Medicare and Medicaid Services (CMS) for the opportunity to provide comments on the proposed National Coverage Determination (NCD) entitled “Proposed Decision Memorandum on Next Generation Sequencing (NGS) for Medicare beneficiaries with Advanced Cancer”.

NORD is a unique federation of voluntary health organizations dedicated to helping people with rare "orphan" diseases and assisting the organizations that serve them. NORD is committed to the identification, treatment, and cure of rare disorders through programs of education, advocacy, research, and patient services.

Next Generation Sequencing (NGS) represents one of the most promising methods for diagnosing individuals with rare, genetic disorders. For many, if not most, rare diseases, NGS is the only reliable method for diagnosis. The advent of NGS technology has brought hope to millions of Americans with rare diseases still waiting for an accurate diagnosis. On average, individuals with a rare disease wait seven to ten years to obtain an accurate diagnosis, leaving many individuals with chronic conditions still waiting for a diagnosis. There are millions of patients in the U.S. who are still undiagnosed, and NGS may be their only hope.

As the voice of the rare disease patient community, we have two concerns with the NCD as proposed. First, we are alarmed that the proposal could potentially severely limit access to NGS based tests for our patients by creating an arbitrarily narrow eligibility for FDA cleared or approved NGS based tests. We anticipate this narrow eligibility for coverage could severely impede the development and access to these critical diagnostics.

In addition, this NCD sets an explicit policy of non-coverage for NGS based tests that did not receive FDA approval or clearance. This is incredibly problematic for several reasons.

The regulation of NGS, particularly lab-developed NGS, is still evolving. Over the last several years, various regulatory schemes have been proposed by the FDA, members of Congress, and outside stakeholders, yet none of them have been promulgated nor implemented by FDA. A very careful regulatory balance must be established in order to ensure lab-developed NGS tests are valid and reliable, while also not stifling innovative labs across the country from developing such tests. None of these proposals as of yet have successfully found the equilibrium.

Since this balance has yet to be established, it makes little sense to us to finalize an NCD that relies on an essentially nonexistent regulatory scheme. Declining coverage for all NGS based tests that have not received FDA approval would result in a vast number of innovative diagnostics for Medicare beneficiaries with rare diseases going uncovered.

We ask CMS to consider the millions of Americans with a rare disease still searching for a diagnosis as it considers finalizing of this National Coverage Determination.

NORD thanks CMS for the opportunity to comment, and we look forward to working with CMS on ensuring that rare disease patients receive timely diagnoses and appropriate care. For questions regarding NORD or the above comments, please contact me at pmelmeyer@rarediseases.org or 202-545-3828.

Sincerely,

/s/
Paul Melmeyer
Director of Federal Policy

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January 17, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Dear Ms. Jensen,

The American Society of Hematology (ASH) is pleased to offer comments on the proposed decision memorandum on Next Generation Sequencing for Medicare Beneficiaries with Advanced Cancer. The proposal was issued in conjunction with the Food and Drug Administration (FDA)’s approval of the FoundationOne CDx (F1CDx). The test was reviewed as part of FDA and the Center for Medicare & Medicaid Services’ (CMS) Parallel Review Program, where the FDA approval process and the CMS evaluation for coverage occur concurrently.

ASH represents over 17,000 clinicians and scientists worldwide who are committed to the study and treatment of blood and blood-related diseases. These disorders encompass malignant hematologic disorders, such as leukemia, lymphoma, and multiple myeloma, as well as non-malignant conditions, such as sickle cell anemia, thalassemia, bone marrow failure, venous thromboembolism, and hemophilia. In addition, hematologists were pioneers in demonstrating the potential of treating various hematologic diseases through bone marrow transplantation, and continue to be innovators in the fields of gene and cellular therapy, regenerative medicine, and transfusion medicine. ASH membership is comprised of basic, translational, and clinical scientists, as well as physicians who provide care to patients in diverse settings including teaching and community hospitals, as well as private practice.

ASH commends CMS for recognizing the value of precision oncology diagnostics in the care of cancer patients and proposing to cover F1CDx. However, we have significant concerns about the broad scope of the policy and recommend that it be narrowed such that CMS provide coverage for F1CDx but remove the non-coverage portion of the policy. Removing the non-coverage portion of the policy will allow coverage determinations to continue to be made at the local level for other NGS-based hematology and oncology testing, including local decisions related to testing for blood cancers such as lymphoma, multiple myeloma, and leukemia. If this policy is finalized as currently drafted, it will disrupt care for the patients our members treat because none of the NGS-based tests currently recognized as the standard of care in this patient population would meet the coverage requirements in this proposed policy.

As drafted, the policy defines all current and future uses of NGS-based testing in oncology as not medically reasonable and necessary unless the test is FDA-approved or meets strict coverage with evidence development (CED) requirements. This draft is a non-coverage determination for many clinically valid and medically necessary testing services for extremely vulnerable patient populations, including those with hematological malignancies. NGS-based testing has become a well-established part of delivering targeted therapies to the patients treated by ASH members. The coverage changes in this policy will disrupt the delivery of appropriate care, potentially resulting in negative health outcomes.

This proposal outlines a coverage policy for the following advanced cancers: lung, melanoma, breast, ovarian, and colon. CED would be available for NGS-based testing for all other advanced cancers, but this testing would not be covered for cancers that are not considered advanced. All currently used NGS-based tests for advanced leukemia and lymphoma would require CED, denying Medicare beneficiaries access to this testing until CED trials could be designed and implemented. This would be an unreasonable disruption in patient care that is currently delivered in accordance with established clinical guidelines such as those approved by the National Comprehensive Cancer Network and others.

ASH appreciates the agency’s proposal to provide national coverage for NGS-based testing for Medicare beneficiaries with advanced cancers; however, the draft policy as written does not reflect the complex reality of receiving FDA-approval or meeting the CED requirements. Both options may be cost-prohibitive for the majority of laboratories, including academic medical centers, performing clinically useful and valid tests. If an institution would like to pursue CED, they most likely will have to establish the appropriate infrastructure that is not already place.

As CMS considers changes to the scope of this policy, ASH would like to highlight the following language included in the proposal:

NGS-based testing is currently available to test for non-malignant or pre-malignant hematological disorders that must not be disrupted. Given ASH’s concerns about the scope and impact of this policy on NGS-based oncology testing, the Society wishes to remind CMS that any attempt to expand the scope of this policy beyond oncology contradicts the wording of the policy referenced above.

Furthermore, NGS is a technology, not a diagnostic test. By focusing this proposed policy on a specific technology without connecting it to a specific biomarker or Current Procedural Terminology (CPT) code, this policy runs counter to established practices to determine coverage which has evaluated clinical usefulness independent of test methodology. The proposal overrides established and carefully reviewed local coverage policies that provide coverage for the tests that help identify targeted therapies for our patients based on specific biomarkers and CPT codes. For example, National Government Services (a local Medicare carrier) provides coverage for gene panel testing in leukemia under code 81450 (5-50 genes, hematopoietic gene panels) in L36926: Genomic Sequence Analysis Panels in the Treatment of Acute Myelogenous Leukemia (AML). We anticipate that providers will revert back to using sequential single gene testing if this policy is finalized without significant changes because of their favorable coverage status. However, NGS-based tests provide results more quickly, are less expensive, provide greater genetic coverage and yield more actionable results with less tissue. ASH urges CMS to consider these factors when developing a National Coverage Determination that will not be revised regularly.

Thank you for this opportunity to provide comments on the proposed decision memorandum on NGS for Medicare beneficiaries with advanced cancer. ASH supports a final policy that covers the F1CDx, but we urge CMS to re-evaluate the non-coverage portion and allow coverage for NGS-based testing for cancer to continue to be made at the local level. This will ensure our patients retain access to the NGS-based testing shown to be clinically useful and referral to genetic counseling that guide treatment. We look forward to working with the agency to improve this policy. If you have any questions or require further clarification, please contact Suzanne Leous, ASH Chief Policy Officer at sleous@hematology.org or 202-292-0258.

Sincerely,

/s/
Alexis Thompson, MD
President

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January 17, 2018   

Submitted Electronically

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, Maryland 21244

Re:   Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

Dear Ms. Jensen:

Greater New York Hospital Association (GNYHA) appreciates the opportunity to submit comments on the Centers for Medicare & Medicaid Services’ (CMS) Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer, which CMS put forward on November 30, 2017. GNYHA represents the interests of 150 hospitals and health systems throughout New York, New Jersey, and Connecticut, many of which are major academic medical centers that devote significant efforts to developing and delivering high-quality, innovative care. They are thus very interested in any proposals that might create unnecessary barriers to the services they provide, particularly in the area of precision medicine that benefits so many patients each and every day and that they hope will continue to be available to do so in the future.

Deferring a Position on Non-Coverage Criteria to Afford Time to Study

GNYHA’s position is straightforward. We appreciate CMS’s efforts to approve Foundation Medicine, Inc.’s comprehensive genomic profiling test and do not intend to disturb that approval. Indeed, we believe CMS’s approval of Foundation Medicine’s test recognizes the importance of such tests.

However, we strongly urge CMS to defer taking action on its proposed position of non-coverage for NGS tests that do not meet the criteria listed in its Proposed Decision Memo. As CMS has heard from many commenters, its proposed coverage (non-coverage) criteria are unnecessarily restrictive and exacting, and in some cases are not understood by the community that would have to apply them. The result is that the proposed criteria will unnecessarily stifle the very innovation that presumably led CMS to approve Foundation Medicine’s application for coverage in the first place.

We thus most respectfully but strongly request CMS to defer taking a position on non-coverage criteria to allow CMS to develop a broader understanding of pathways for approval and coverage without undermining the nation’s important pursuit of precision medicine with respect to cancer care.

Specific Concerns Regarding Coverage Criteria

GNYHA outlines below some of the proposed criteria it believes are unnecessarily restrictive and offers to discuss them in more detail with CMS through meetings or other opportunities for explanation and discussion. For this purpose, GNYHA proposes to include representatives of its members who can best outline the steps they take in developing and ensuring the quality, efficacy, and utility of the tests they currently perform.

FDA Approval Requirement—Two of CMS’s three proposed coverage options would require the subject tests to be approved by the Food and Drug Administration (FDA). GNYHA believes that FDA approval should not be required, particularly when there is no current requirement for FDA approval of laboratory-developed tests when academic medical centers are caring for their own patients.

We recognize that the FDA had previously issued proposed guidance that would have begun a process for FDA approval of many such tests. However, that process was ultimately deferred, given the strong concerns raised by academic medical centers and others about its potential negative impact on innovation, precision medicine, and overall patient care. Indeed, prior to the FDA’s deferral of its proposed guidance, GNYHA hosted a meeting with the then-FDA Commissioner and many of GNYHA members’ chairs and chiefs of laboratories, precision medicine, and molecular diagnostics to explain the quality, safety, and other efforts they undertake in developing and administering tests and the burdens FDA approval would bring.

CMS’s proposed decision memo correctly points out that the FDA’s accreditation of third-party reviewers may reduce the burden of FDA approval in the future. GNYHA is therefore pleased that the FDA recently announced that it has accredited New York State’s Wadsworth Center as a third-party reviewer. However, CMS’s requirements are more exacting than merely obtaining such third-party review and approval. As proposed, CMS’s initial “Coverage” category (its first of three categories) would require that the test be an FDA-approved companion diagnostic. GNYHA understands that the FDA does not delegate such approvals to its third-party reviewers.

In addition, regardless of whether a test must be approved as a companion diagnostic, the FDA currently must act upon a third-party reviewer’s recommendation in order for the test to be considered “FDA approved,” which adds an additional layer of process to the FDA-approval requirement. As indicated, GNYHA is exceptionally pleased that New York State’s Wadsworth Center is now accredited as a third-party reviewer, but Wadsworth’s approval and recommendation of a test is not the entire process that would be required by CMS’s proposed decision memo.

GNYHA therefore recommends that FDA approval not be required for coverage purposes, particularly for laboratory-developed tests performed with respect to a center’s own patients. Separately, however, tests that have been approved by a third-party reviewer such as New York State’s Wadsworth Center should be deemed to meet any eventual criteria for coverage.

Coverage with Evidence Development—Two of CMS’s three coverage options would require evidence development, a process CMS calls “coverage with evidence development” (CED). GNYHA appreciates that CMS proposes to make those options available, but the first of those options requires the test to be FDA approved (which GNYHA has already discussed above), and the second requires the test to be made available within an NIH-NCI National Clinical Trial Network clinical trial.

GNYHA members have raised concerns about the exacting nature of the overall CED requirements and the restrictiveness of NIH-NCI National Clinical Trial Network clinical trials. In part, members are not certain what the basic CED requirements under the first CED option (which requires FDA approval) might entail. Separately, our members are very concerned that the two pathways would exclude many investigator-initiated trials and industry-sponsored trials, which are apparently commonly used (and accepted) mechanisms for evidence determination.

GNYHA therefore recommends that, to the extent that CMS might require coverage with evidence development in the future, it do so only after reviewing the types of evidence development being undertaken today, particularly in academic medical centers, and expanding the categories of evidence development it would find acceptable.

Defining the Scope of the Coverage Decision—GNYHA members have inquired about the precise scope of the proposed coverage decision. We urge that the scope of any position about non-coverage, which we believe should be deferred, should be as narrow as possible given the importance of the issues raised.

Preserving Local Coverage Decisions—GNYHA understands there are local coverage decisions that have served providers and patients (and CMS) quite well.  We therefore urge that any future national coverage (or non-coverage) decisions preserve any favorable local coverage decisions.

Preserving Local, Patient-Specific Practice of Medicine—Among the concerns raised by GNYHA members about CMS’s proposed non-coverage position is the concern that testing would become unnecessarily centralized in certain laboratories. They view such centralization as undermining the role molecular pathologists and others in academic medical centers play in the care of cancer patients as they participate in tumor board meetings to discuss treatment options, engage in quality improvement initiatives, and triage the most urgent samples within a center. The fear is that the centralization of testing would undermine these efforts and, in the process, undermine precision patient care. We urge that centralization of testing not be permitted except when essential and that local, individualized patient care be encouraged.

Ensuring Access, Quality, Safety, and Efficacy

In summary, GNYHA strongly urges CMS to defer its position on coverage/non-coverage to ensure that it does not unnecessarily burden or undermine access to innovative, precision medicine.

In the meantime, GNYHA assures CMS that its members undertake significant efforts to ensure the quality, safety, and efficacy of the care they deliver and the tests they develop and administer, whether they are laboratory-developed tests in general or NGS tests in particular. Indeed, our members subject such tests to exacting quality, safety, and efficacy processes and studies, all aimed at improving patient outcomes. Their laboratories are regulated and inspected under the Federal Clinical Laboratory Improvement Amendments, a role that is delegated to New York State but is ultimately overseen by CMS. In New York State in particular, all laboratory-developed tests used in laboratories permitted by New York State must be reviewed and approved by the State’s Wadsworth Center under its Clinical Laboratory Evaluation Program, a process that has been in place for many years. Finally, as academic medical centers, our members are committed to ensuring the quality, safety, and efficacy of the care they deliver.

We thank CMS for the opportunity to comment. GNYHA offers to arrange a meeting among CMS and its members, for it is they who can best explain their concerns and processes, and we invite CMS to tour member laboratories and centers.  We believe such activities will help inform CMS’s deliberations and demonstrate additional pathways for approval and coverage.

Very truly yours,

/s/
Susan C. Waltman
Executive Vice President for Legal, Regulatory, and Professional Affairs and General Counsel

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Ms. Tamara Syrek-Jensen
Director, Coverage & Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard Baltimore, MD 21244

On behalf of Inivata, Inc., I sincerely appreciate the opportunity to comment on the Centers for Medicare & Medicaid Services’ (CMS) draft proposed National Coverage Decision of Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N). While we agree with the progressive decision to advance Comprehensive Genomic Profiling (CGP) of cancer patients and support for an essential technology platform (NGS), we believe several areas of concern need to be highlighted and would also like to propose alternative pathways for consideration.

First and foremost, patient welfare should be the highest priority. Ensuring continued access to qualified, well-validated diagnostic testing, intended to aid decision making based on individual patients and their circumstances in the real-world experience, must be considered with the implementation of this unprecedented NCD. Those patients that may be negatively impacted by this proposal must be considered. For instance, in lung cancer, the difficulties of accessing sufficient quantity and quality of tissue via invasive biopsy may leave as many as 50% of patients without a CGP result needed to properly inform a treatment decision. For this reason, current National Cancer Care Network Guidelines recommend the use of liquid-biopsy based CGP when tissue CGP fails or is not feasible. There are no currently available FDA Approved/Cleared liquid-based CGP assays therefore the proposed non-coverage language in the NCD would eliminate this option for approximately half of all Medicare Beneficiaries with lung cancer.

Additionally, the current proposal may result in the following limitations:

• decreased patient access to targeted therapies that require a test result for on-label use
• delayed CGP test results or failed samples due to limited number of provider(s) capable of offering CGP NGS tissue testing
• restricting current coverage to single sample type (FFPE tissue) with no alternative should tissue testing fail
• unintended hindrance of innovation and technology development in cancer care
• requirement for FDA reviews that, in the past, have been time-consuming, expensive, and would likely inhibit many laboratory organizations from developing new and innovative tests
• the clinical trial route for reimbursement is constrained by patient availability, location, qualification, and willingness to participate in a trial, resulting in potential delay to product introduction(s) and patient access to needed test results.

The proposed memo indicates non-coverage for NGS assays if the test does not meet the criteria listed in the NCD and considers FDA approval as the only method to ensure analytical and clinical validity [Refer to page 76: “3. For tests that have not been shown to be analytical and clinically valid (not FDA approved or cleared), and are not part of CED we propose non-coverage.”] Currently established methods for demonstrating analytical and clinical validity have been excluded as coverage determinants despite broad industry awareness, precedent, and clearly defined requirements (such as the Palmetto GBA’s MolDX program).

With these thoughts in mind, we offer the following for your consideration:
Establish a “grandfather clause” for any LDTs that were submitted prior to the NCD that are designed, manufactured, and used in a CLIA certified lab to continue with the current route to reimbursement (including a possible approach to LDT oversight via review by a Medicare Administrative Contractor(s) such as the MolDX program). The goals of such organizations are also to ensure analytical, clinical validation/utility of a test. A phased-in approach of regulating future test submissions would facilitate a balance between patient protection with continued access and innovation and could be accomplished during a three-year period.

FDA provided an example phased-in approach to continue patient access to testing and includes a pathway to eventual FDA approval/clearance and CMS reimbursement. As indicated in the “Discussion Paper on Laboratory Developed Tests (LDTs) - January 13, 2017,” a possible phased approach includes:

• Exempting LDTs already on the market from all FDA oversight except for adverse event and malfunction reporting (“grandfathering”)
• Providing additional time before FDA would begin actively overseeing certain regulatory requirements; and
• LDTs could be phased in over 4 years
• Year One: Serious adverse event and malfunction reporting for all LDTs except: traditional LDTs, LDTs intended solely for public health surveillance, certain stem cell/tissue/organ transplantation LDTs, and LDTs intended solely for forensic use.
• Year Two: Premarket review for new/modified LDTs with the same intended use as an IVD approved under a PMA (i.e., tests that have already been identified as high risk by FDA).
• Year Three: Premarket review for new/modified LDTs with the same intended use as a Class II device type subject to 510(k) clearance (i.e., tests that have already been identified as moderate risk by FDA).
• Year Four: Premarket review for new/modified LDTs that do not fall into the above categories.

“To ensure patient access to existing tests is not disrupted, those tests that are introduced between the effective date of such framework and their phase-in date could continue to be offered for clinical use during the period of premarket review. Because FDA Quality System requirements would likely be a new activity for laboratories, and to help foster innovation, such tests would also have an additional two years before having to meet quality system requirements, as described below. In addition, because tests could be offered for clinical use prior to FDA’s readiness to review them, registration and listing would occur at the time an LDT receives marketing authorization. In addition, coverage of such tests should remain while the test is under review by the agency.”

In addition, the proposed decision memo asked the following direct questions and the Inivata response is included for your review.

CMS Directed Questions

1. Should the proposed NCD be expanded or narrowed by clinical conditions, test methodology to measure the same clinical biomarker, or clinical scenarios?

If so, please provide supporting documentation, including peer-reviewed evidence, and a detailed analysis in support of your view.
The NCD should be expanded to include additional test methodologies and/or new indications of initial tests approved through the NCD to allow for different scenarios, such as, patients that are at high-risk or unable to undergo tissue biopsy. It should also provide for the patient in instances where there is insufficient tissue from a biopsy for NGS testing and reflex testing should be allowed. With the current coverage, patients have no other alternative for testing and would fail to benefit from targeted therapy.

2. How do laboratories assess analytical and clinical validity? Based on laboratory experience, how long does it take to compile data demonstrating analytical and clinical validity, such as what would be submitted to the FDA or the New York State Department of Health? What are the variables that affect the duration of this time?

Currently, there is a wide array of methodologies to assess analytical and clinical validity and this varies depending on the type of laboratory, the type of test, the sample matrix and the availability of samples to cover the various limits of the assay. For some sample types, contrived samples are used to conduct performance testing to ensure availability of samples across the range of testing.

It takes a significant amount of time to compile data which includes developing, under a quality system, multiple lots of reagents for testing and having access to available samples that test the limits of the assay from the correct intended population. Included in this is the cost associated with expensive technology and high-complex testing personnel to ensure valid results. Rarer alterations with a frequency of 1-2% (ALK, ROS) or even rarer (< 1%) present exceptional challenges and significantly increase the sample collection timeline and overall costs.

In addition, concordance testing ensures equivalence to an established method, however, does not account for situations where the system under study performance is better than the approved method.

Thus, the time frame for realization of organized and significant data collection, testing, analysis, formal submission and time to review and approve an assay would far exceed a year, in practicality, more than 2 years. Any clinical utility data requirements in addition to analytical validity and clinical validity would likely add significantly to the development timeline as patient outcomes are often required to demonstrate clinical utility.

3. Would the approach(es) used currently in laboratories be similar to the approach used in this proposed NCD for the FDA to analytically and clinically validate a diagnostic laboratory test? Are there other possible approaches? If so, please provide supporting documentation, with peer-reviewed evidence, and a detailed analysis in support of the approach, including the number of tests using such an approach.

We agree that a standardized, external review of an individual LDT is warranted beyond the laboratory certification by CLIA, particularly for highly complex tests such as those based on NGS technology. Third-party reviewers, such as NY State and MolDX or others, can provide a means for academic institutions and commercial laboratories to allow assay access to the market and enable diversity in testing solutions as an adjunct to review by FDA as would be required under the draft NCD. The third-party review process fosters innovation and growth at a time when new developments in testing technology are rapidly emerging.

4. How do laboratories assess clinical utility? With regard to the proposed NCD, what would be examples of circumstances in which coverage would be adequately addressed by a local Medicare Administrative Contractor (MAC) including the ability to identify clinical utility of specific tests?

The local Medicare Administrative Contractor (MAC) can be used for assessing the analytical and clinical validity of the test combined with a post-approval/coverage registry for collection of the most pertinent clinical variables, which would be dependent on the intended use of the test. This data could be submitted to the MAC and CMS to determine real-world utility and continued coverage of the test in lieu of the proposed NCD option requiring CED.

Unfortunately, the current NCD proposal outlining CED is overly onerous and will potentially lead to a dearth of new diagnostic development. The requirements for full outcome studies is not feasible for most diagnostic companies due to the inadequate payoff for conducting them. Such outcome studies can be afforded by therapeutics developers as the commercial revenues compensate for them. For diagnostic companies offering a one-off test, the commercial returns are not commensurate with such clinical development programs, and abbreviated forms of CU studies are required.

In summary, we believe the above pathways help to ensure patients have continued access to convenient and beneficial testing, while providing a staged pathway to a more well-defined process for validating testing and establishing reimbursement.

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Thank you for allowing me to comment on this important policy. I work as a Molecular Genetics Pathology Fellow at the University of Texas Southwestern Medical Center.

We recently brought on a new NGS assay for patients with advanced cancer (many of whom are Medicare beneficiaries based on their age). This assay was created with the highest levels of technical talent from the basic science research field. We also were able to expand a basic panel to a large one that will capture >1000 genes. This could lead to new discoveries that will affect patients in the future. This innovation would not be possible if the NCD is accepted as written. Instead, testing would be monopolized by a single company, Foundation One, which from our experience does not report all of the relevant cancer mutations that may be found in a patient. Further, they cannot comment on any mutations that could be related to a genetic risk for cancer. This means family members would not receive important cancer screening. Our ability to innovate has allowed us to perform multiple level of care for patients and this is directly related to the flexibility allowed in the current system. If this NCD is adopted, it will hurt patient care.

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Dear Centers for Medicare and Medicaid Services,

We applaud the effort made by the Centers for Medicare and Medicaid (CMS) to provide coverage of next generation sequencing (NGS) tests for cancer patients via the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N). We understand the need to prevent patients being harmed by and money being wasted on inaccurate testing, and we are glad to see CMS attempt to create a pathway for coverage with evidence development (CED) for laboratory developed test (LDTs).

Coverage of NGS testing for cancer patients is a huge need. Lung cancer is at the forefront of precision medicine. Oncologists rely on molecular or NGS testing to identify biomarkers that enable FDA-approved treatments such as targeted therapies for four driver oncogenes (EGFR, ALK, ROS1 and BRAF) as well as PD-1 blockade immunotherapies. Since lung cancer patients often have tumor tissue collected via fine needle biopsies, tissue is precious. NGS panels are better able than individual molecular tests to provide results on many biomarkers using the available tissue.

However, the lung cancer advocacy organizations whose names appear below have significant concerns about this proposed decision memo (PDM). As written, the PDM’s broad scope risks limiting cancer patient access to clinically and scientifically validated NGS tests.

Below are our concerns regarding this PDM.

1. Providing coverage of a given NGS test only once in a patient’s lifetime does not reflect the realities of cancer treatment. This limitation ignores the fact that a patient might need more than one NGS test in the course of treatment because:
   1. A tumor sample or other specimen might not provide adequate cancer cells for accurate NGS results. Retesting on a new specimen may be required to get clinically actionable results.
   2. Patients who have multiple simultaneous tumors might need more than one tissue sample tested with the same NGS test.
   3. Research continues to find new treatment targets. A patient who tested negative for all biomarkers in 2015 may test positive for a biomarker in 2018 using the same test.
   4. Cancer evolves. A patient might need to have the same NGS test in the future to determine appropriate subsequent treatment options if they develop resistance to a therapy, or develop new mutations over time. For instance, some EGFR+ T790M NSCLC patients on osmertinib have seen their cancer lose its EGFR mutation and develop a BRAF mutation. The Foundation One CDx test is an approved companion diagnostic for both mutations.
   5. Patients can develop more than one type of cancer in their lifetime.


2. The CED places undue requirements and financial burdens for CMS coverage on cancer centers and small laboratories that have LDTs with established analytical and clinical validity.

   Many patients rely on academic cancer centers (e.g., National Comprehensive Cancer Network facilities) to diagnose and treat difficult cancer cases. Each of these centers use many LDTs with established analytical and clinical validity. To have CMS coverage of these LDTs, the PDM would require these centers and small laboratories to (i) arrange to have each LDT either cleared by the FDA or approved as an in vitro diagnostic, and (ii) create a registry or a clinical trial for each LDT. These burdens could result in those tests being withdrawn from the market, which means patients might lose access to essential resources. In that event, only patients who could afford to pay out-of-pocket would be able to access many of these validated tests.

   1. The PDM requires LDTs to submit to time consuming, labor intensive, and prohibitively expensive processes in order to obtain CMS coverage. The procedural and financial burdens imposed by this PDM may make facilities that provide validated LDTs unable to compete with FDA approved (and therefore CMS-covered) tests. In this event, the marketplace would contract, testing prices would go up due to reduced competition, and patients would have fewer testing choices suitable for their type of cancer.
   2. Subjecting validated LDTs to additional evaluations in order to acquire FDA approval is not an unbiased, evidence-based criterion for coverage. The PDM covers only tests that are cleared or approved by the FDA, yet the FDA has not published guidelines for validating NGS-based tests. Requiring validated LDTs to undergo additional evaluation in order to obtain FDA clearance may provide an advantage to those agencies with deep pockets, but it provides no scientific or clinical advantage for patients.
   3. A validated LDT at an academic cancer center might actually be more appropriate or clinically valid for a patient’s cancer than any commercially-developed FDA-approved test. For some cancers with known oncogene drivers and FDA-approved treatments, a validated LDT may be the only useful test available. Patients who have those cancers should be able to have NGS testing covered by CMS. For example, many ROS1 non-small cell lung cancer (NSCLC) patients were diagnosed by LDTs and successfully treated with an FDA-approved treatment (crizotinib) before June 2017; however, ROS1 NSCLC did not have an FDA-approved ROS1 companion diagnostic until June 2017 (Oncomine™ Dx Target Test). Also, for those cancers that develop resistance on targeted therapies, LDTs are often the only tests capable of the deep sequencing necessary to identify resistance mutations.
   4. A test that has established validity should not be withheld from patients while it goes through the process to be cleared or approved by the FDA—a process which can take years with the existing infrastructure. Cancer research is evolving rapidly, and academic cancer centers are constantly developing and improving LDTs that have established analytical and clinical validity in order to offer the best treatment options to their patients. The existing FDA approval infrastructure is insufficient to process the number of current NGS LDTs in a timely manner.


3. Many oncogene-driven cancers have small populations that would be unable to support all the clinical trials required to validate LDTs under the CED.
   These cancers barely have enough patients to power two or three simultaneous Phase 1 clinical trials, much less clinical trials for every prospective LDT that desires CMS coverage. For example, about 207,000 new NSCLC cases were predicted for 2017. A recent paper found only 60% of NSCLC patients are getting tested for known driving oncogenes. The oncogene ROS1 occurs in about 1% of tested NSCLC patients. Typically 3% of cancer patients enroll in clinical trials. This means about 37 new ROS1 patients enrolled in clinical trials 2017—barely enough to power even a few phase 1 clinical trials.


4. The CED registry requirement does not ensure that useful information will be generated for a given test or biomarker.
   To ensure their LDTs are eligible for coverage, each institution would be incentivized to create a patient registry (at no small technical and administrative expense) for each LDT, and for each biomarker in an LDT. The cost of these registries would likely be factored into the cost of the test. In addition, the PDM includes no provisions to ensure these registries will be useful. The number of resulting registries would ensure few if any registries would have statistically valid samples for any biomarker. Unless some common bioinformatics infrastructure is used by each registry, and/or a central registry or federated database system is created to access all the fragmented registries, the data for small populations would be trapped in silos. This is not beneficial for patients or the advancement of scientific knowledge.


5. The PDM must ensure that patients will know BEFORE TAKING THE TEST whether they will be responsible for the cost of the test, and whether they will be required to join a registry and/or clinical trial.
   We assume the PDMs intention is that an NGS test which includes an FDA-approved companion diagnostic for a given cancer site is covered for ANY patient who has that cancer. We also assume that patients who have such a cancer will not be subject to requirements of the CED. However, the wording of the PDM does not state either of these points clearly.

Given the significant concerns listed above, we would prefer this PDM address ONLY the Foundation One CDx test, instead of addressing all NGS testing for cancer. This will give everyone more time to consider the best generic approach to Coverage with Evidence Development as well as coverage for LDTs already proven in successful patient care.

Thank you for the opportunity to present our concerns about the PDM. We hope you find our concerns compelling, and will consider revising the PDM to address them.

Sincerely,

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On February 14 [PHI Redacted] will celebrate 5 years of relatively normal life with Stage 4 Non-Small Cell Lung Cancer driven by an ALK genetic rearrangement. While he is not near Medicare age I believe that CMS determinations affect his well-being, and the proposal to cover the Foundation One test is welcome news. However, the broad scope of the proposed policy should be reconsidered, particularly the lifetime limit of one NGS test per patient and the monopoly it grants to Foundation Medicine. As to the lifetime limit, ALK patients have 3 or 4 (depending on whose interpretation you accept) generations of highly effective tyrosine kinase inhibitors, and there are choices to be made even within the generations. [PHI Redacted] is on his second inhibitor and has already had 2 NGS tests. There are at least 4 TKIs ahead of him but if he can’t be tested for them his doctors are consigned to an expensive game of trial and error. There’s not much use in personalized research and development if the appropriate target can’t be identified. As to the monopoly granted to Foundation Medicine, I believe it will stifle innovation and unduly retard what has been outstanding progress in diagnosis and treatment. In summary, I am fully in support of the proposed policy except to the extent of the lifetime limit and sole provider. Thank you for the opportunity to speak.

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Dear Sir/Madam,

Thank you for your hard work in this extremely challenging and fast-paced field that remains critical for understanding the mechanisms behind each patient’s tumor (and, especially in the population you reference, their immune contexture). Prior to starting Fellowship in Pediatric Hematology-Oncology (effective July 2018), I have participated both in the engineering development of NGS tests and their clinical implementation through Molecular Tumor Board (including FoundationOne across adult and pediatric patients). I understand the spirit of the CMS policy as a first step in creating trust across stakeholders to help us find common ground where everyone (patients, providers, payers, NGS test developers) is in agreement.

In academic medicine, oncologists have important collaborative relationships with other pathologists, radiologists, radiation-oncologists, numerous other consulting services; these relationships enhance the quality of the care we provide to our patients. Academic centers must retain the ability to continue using their cutting-edge medical and scientific acumen (and training programs!) to translate new discoveries into clinical care. This has been laudable at MSKCC indeed yet similarly rigorous and common at numerous institutions country-wide. I have seen numerous examples where an academic assay has outperformed (and provided better patient care) than a FDA-approved assay. Discordances exist for numerous reasons beyond just test design. If major restrictions or a high financial bar is placed on LDTs to provide testing, many very high quality academic labs will be less equally-able to offer these tests as currently-approved workflows.

Expansion to Pediatric Patients:
Children with cancer should be afforded access to tests for which they have no developmental or societal ability to afford themselves. To me, this is an ethical appeal. Besides their age, children are a particularly vulnerable patient population in this schema since the (relatively miniscule) addressable market they comprise might not be enough of a market to justify the R&D investment for a company to build or modify an assay to the extent of the hurdles proposed in this draft policy.

Expansion to Earlier Stages of Cancer:
As ~80-90% of cancer deaths are caused by their metastases, the utility of NGS will be most clinically and economically impactful if utilized earlier in treatment decisions. The Proposed NCD overlooks Stage III non-resectable cancers from NGS coverage. In general, Stage III cancers have invaded into adjacent tissues, whereas Stage IV includes patients in whom cancer has metastasized to other organs. In many cases, the clinical decisions for systemic targeted therapy (or chemotherapy) are the same across Stage III and IV tumors.

Contemporary Sample Considerations:
The latest available tumor sample should be utilized for informing targeted therapy selection or discontinuation since tumors evolve over time. Perhaps physicians may have a simple means to indicate the need for repeat testing and such cases can be tracked in their own registry for clinical and economic analyses. Contemporary sample utilization will be ever more important in designing the right types of combination therapy clinical trials in checkpoint blockade settings given temporal considerations in immunotherapy.

Analyte Considerations:
Existing molecular diagnostic tests measure DNA, RNA, and protein. NGS is powerful technology whose specimen workflow (both hardware and software) must account for numerous pre-analytical and analytical factors and their contextual interpretation will be increasingly valuable (simultaneous PD-L1 expression and TMB considerations), fusion measurements (more cost effective through RNA-seq), and the breadth of genomic content required for calling TMB concordantly across different workflows.

Academic Exception:
Numerous comments from academicians confirm that FDA approval is extremely expensive and time-consuming. The proposed noncoverage of LDTs portends a risk to the critical aspect of translational medicine that bridges the gaps between scientific discoveries and their fit-for-purpose clinical implementation. Pathway 2b excludes investigator-initiated trials and industry sponsored trials, both commonly used mechanisms for evidence determination. There should be flexibility with academic testing to encourage the further development of NGS testing such as:

1. reduced barriers for CED compliance
2. ability to perform tests if the turnaround time is clinically meaningful for patients as compared to existing (commercial) alternatives that have economic incentives and workflow practicalities to batch samples
3. a unique path for equivalence demonstration to existing assays
4. CED registry design flexibility - that both supports meaningful clinical utility analyses and accounts for real-world constraints and limitations of clinical practice. Because of variable patient follow up with clinicians, it is unrealistic that academic laboratories will successfully collect outcomes and survival data for 100% of patients tested. Moreover, Medicare beneficiaries outside the catchment areas of comprehensive cancer centers (such as in rural areas) deserve to have access to this important testing and the registry requirements should not preclude access
5. meaningful incentives for EHRs, IT platforms, and imaging modalities to solve gaps in means for evidence determination (as was pointed out by FLATIRON regarding RWE utility) – registries will vary in their clinical resolution, design, scope, populations and additional data streams provide valuable clinical and health economics context

One potential solution for academic LDTs to demonstrate clinical equivalence could be quarterly concordance testing on contrived specimens (to resolve concerns re tumor heterogeneity) that is free unless the lab’s result is discordant from the majority or some established (approved) standard. Another solution could be differential reimbursement (IVDs vs. LDTs) since LDTs may not meet the same gold standard of FDA-approved IVD tests but, based on objective performance measures (test analytic validity and clinical validity of the gene-drug association), they provide patients with a much-needed option and quicker access to the latest advances in science, while an equivalent IVD test is developed. There have been multiple cases where IVD tests have lagged by one year or more after oncology drug approvals (such as MSI – which is notably pan-cancer and more on that later, KRAS, ROS1 etc.) meaning the test could be used only as an LDT in an academic or NCI trial.

A tiered coverage and reimbursement model allows Medicare beneficiaries to benefit from both LDT and IVD testing approaches, gather valuable registry data on static as well as evolving LDTs, and reward IVD tests with a premium reimbursement given the underlying development costs (which ought also to remain transparent so we can begin quantifying this financial concerns and means for democratizing outcomes data measurement).

Guidance for Non-Oncology Applications:
Numerous NGS assays are developed for infectious disease, autoimmune, neurologic, and heritable conditions that will similarly rely on robust evidence generation and clinical uptake. Perhaps exome or genome-breadth panels, performed as part of a research setting, may also have additional guidance to reflect the intent that clinically reasonable testing merits payer reimbursement that must be understandably limited for research activities. While I support CMS’s goal to establish predictable and transparent coverage policy for NGS diagnostic testing in oncology, the proposed decision framework is not readily applicable beyond the context of solid tumor gene profiling for companion based treatment.

Consideration for repeat testing especially as it will inevitably pertain to ctDNA PCR and NGS diagnostics:
Repeat testing especially necessary for ctDNA - at this time, no plasma-based NGS tests are approved by the FDA and the proposed language could significantly limit patient access to testing through liquid biopsy when sufficient tissue is not available. Beyond the EGFR PCR example approved by FDA, additional circulating variants will be key for measurement in residual disease quantitation and resistance detection contexts that strongly inform clinical management and patient counseling.

Economic Impact:
An economic impact study of this NCD should be performed to assure everyone that the result will not have significant negative impact on healthcare spending and/or access. An objective and quantifiable metric for policy reversal or modification should be considered if evidence accumulates to substantiate that vulnerable covered populations or institutions/practices do not have equal access to testing as those patients treated at MSKCC or profiled by Foundation Medicine. We must recognize and (somehow) trend the implications of this decision on private payer reimbursements for NGS testing in oncology since there is no process on the private payer side that is consistent across payers which creates a significant bottleneck in delivering high quality patient care in a timely fashion. While transparency of parallel review gives sense of optimism in sense of diagnostic opportunities, there remains a need to clarify how physicians can order the best tests for their patients and not constantly worry about the administrative process and potential lack of insurance coverage. Further, patients and physicians shouldn’t have to wait for commercial entities decide whether or not it is worth their time and money to adapt their existing offerings to include the latest translational findings.

It is my hope that this process will additionally include steps to drastically simplify the administrative process and to bring these much-needed tests to our patients as early in the disease process as possible.

Thank you again for the opportunity to comment and contribute. Please let me know if I may further support your efforts in any aspect of policy development around CAG-00450N.

Vali Barsan, MD
UCSD Department of Pediatrics
San Diego, California

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I am a patient advocate with a family member who has stage IV lung cancer. Through genomic testing my family member was able to identify ALK+ biomarker and get targeted therapy that is significantly extending their quality of life and overall survival duration.

Thank you for the opportunity to provide comment on the National Coverage Analysis entitled ‘Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer’. We are grateful for advances in diagnostic technologies, such as next generation sequencing, as it is one tool to obtain a more comprehensive genetic understanding of cancer. This technology is of particular relevance to lung cancer patients as it typically requires less tissue sample than separate sequencing of multiple genes. I thank CMS for recognizing the value of precision diagnostics in the care of cancer patients by proposing coverage for FoundationOne CDx (F1CDx). I support a positive coverage determination for the product reviewed in the Parallel Review program, F1CDx, however I have serious concerns about the broad scope of the proposed NCD. The proposed policy would limit cancer patients to 1 test per lifetime, which is not in line with the realities of personalized medicine based therapy for cancer patients. Mutations develop resistance to targeted therapy and follow up testing is essential for deciding next lines of treatment. Also, the new policy will eliminate coverage for other NGS tests for advanced cancer patients enrolled in Medicare. These tests are currently being used to deliver high-quality, advanced cancer care across the country, including at virtually all major cancer centers and academic institutions. I support CMS’ proposal to cover the F1CDx test but urge CMS not to finalize the rest of the policy as it will result in several unintended negative consequences to cancer patients by erasing important medical advances and existing local coverage policies already in place.

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January 16, 2018

Ms. Seema Verma
Administrator
Centers for Medicare & Medicaid Services
U.S. Department of Health and Human Services
Hubert H. Humphrey Building, Room 445–G
200 Independence Avenue, SW
Washington, DC 20201

Re: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

Dear Administrator Verma:

Memorial Sloan Kettering Cancer Center (MSKCC) appreciates the opportunity to comment on the proposed decision memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer. MSKCC is a National Cancer Institute-designated comprehensive cancer center providing more than 23,000 inpatient admissions and more than 600,000 outpatient visits annually. MSKCC developed and administers the MSK-IMPACT™ test, which recently received FDA clearance as an in vitro diagnostic test that uses NGS for rapid identification of mutations in 468 cancer-related genes, including those associated with FDA-approved therapies, as well as other molecular changes in the genomic makeup of a person’s tumor. MSKCC welcomes CMS’s initiative to establish a national coverage determination (NCD) to ensure appropriate access to this service for all Medicare beneficiaries.

NGS is the most sensitive, efficient, and cost-effective method of laboratory testing to identify genetic alterations in patients’ cancer. A national coverage policy for NGS for Medicare beneficiaries with advanced cancer would help to ensure access to a critical, clinically useful service for these beneficiaries, and would help to remedy the unequal access to coverage that has been created by the existing patchwork of local coverage determinations (LCDs). The policy should encourage broader use of NGS so patients can receive the best test to detect clinically validated alterations and enable the development of registries that will teach us about the clinical utility of other alterations. The current proposal is an important first step, but it should be modified to better reflect the clinical utility of the NGS tests covered by the policy and to clarify certain requirements in order to ensure that it does not delay or even impair the achievement of these goals.

First, coverage without evidence development (Level 1 coverage) should not be limited to tests that specifically obtained companion diagnostic approval from FDA; other NGS tests cleared or approved by FDA, but without a companion diagnostic indication (including MSK-IMPACT™), analyze the same biomarkers and provide clinically useful information to healthcare professionals to aid in the management of a beneficiary’s cancer treatment, including the information necessary to determine whether an FDA-approved therapy targeting a specific genetic mutation is appropriate. Additionally, a primary concern is that the proposed approach would establish variations in coverage of testing for genetic mutations based on the type of technology employed, i.e., NGS versus non-NGS tests, rather than based on the value and nature of the results provided to healthcare professionals. These variations could result in suboptimal patient care by, for example, effectively encouraging the serial performance of single analyte companion diagnostic tests, a scenario associated with longer overall laboratory testing times and resulting delays in care, reduced testing sensitivity, frequent exhaustion of the small biopsies typically obtained from patients with advanced stage cancers (requiring additional biopsies to obtain complete results), and overall higher charges generated by the use of multiple individual companion diagnostic tests. For these reasons, Level 1 coverage of NGS tests should be established for the provision of an FDA approved or cleared test that has been shown to reliably identify genetic mutations for which there are specific FDA-approved therapies, independent of individual companion diagnostic approvals.

As is the case with FDA-approved companion diagnostics, MSK-IMPACT™ reliably identifies the presence of somatic mutations in beneficiaries with advanced cancers for which mutation-targeting therapies are approved, including non-small cell lung cancer, melanoma, colorectal cancer, and ovarian cancer. Based on submission of extensive evidence, the FDA specifically cleared MSK-IMPACT™ to facilitate the clinical interpretation of detected mutations, including of cancer mutations with evidence of clinical significance, such as EGFR, KRAS, BRAF, BRCA1/2 (somatic), as well as microsatellite instability, each of which is targeted by specific FDA-approved therapies. In issuing de novo authorization for MSK-IMPACT, FDA explained that, “Its ability to detect genetic mutations (analytical performance) was evaluated for precision, accuracy and limit of detection. Results indicated that the assay is highly accurate (greater than 99 percent) and capable of detecting a mutation at a frequency of approximately 5 percent (range of 2-5 percent).”

While its FDA clearance is not conclusive or prescriptive for labeled use of any specific therapeutic product, the MSK-IMPACT™ test offers significant clinical value to aid qualified healthcare professionals in managing beneficiary care, including but not limited to the determination by the healthcare professional of the appropriateness of a particular FDA-approved therapy targeting a specific genetic mutation as identified by the assay. In order for the FDA to authorize MSK-IMPACT™, documentation was submitted relating to the types and levels of evidence used to classify a mutation as a cancer mutation with evidence of clinical significance versus a mutation with potential clinical significance. For mutations characterized as clinically significant, a description of the data associated with such mutations, such as clinical evidence presented in professional guidelines (e.g., NCCN guidelines) must also be submitted.

Moreover, we have published our extensive validation studies demonstrating the excellent reliability of MSK-IMPACT™ in detecting specific genetic alterations targeted by specific FDA-approved therapies, including point mutations and indels (e.g., in EGFR, KRAS, BRAF in PMID: 25801821), HER2/ERBB2 gene amplification (PMID: 28027945), and microsatellite instability (http://ascopubs.org/doi/abs/10.1200/PO.17.00084). The performance characteristics and effectiveness of MSK-IMPACT™ have also been published, across all cancers (PMID: 28481359), and in specific cancer types, such as, for instance, colorectal cancer (PMID: 29316426) and lung adenocarcinoma (PMID: 28336552); the latter paper also included a detailed analysis of clinical benefit from FDA-approved and investigational therapies selected based on the results of the MSK-IMPACT™ NGS test.

In addition, by requiring companion diagnostic approval for coverage of NGS tests but not for tests using other technologies in the same patient population – an unprecedented approach that is difficult to rationalize, MSKCC is concerned that the proposed Medicare coverage policy could promote suboptimal patient care. As the proposed policy does not encompass laboratory developed tests (LDTs) that utilize older analytic technologies, the most highly sensitive, tissue-efficient, state-of-the-art assays currently available (i.e., NGS assays) that test for precisely the same biomarkers would be eligible only for coverage with evidence development (CED). In particular, MSKCC is concerned that the proposed NCD could unintentionally incentivize the development and delivery of single analyte /single mutation companion diagnostics in place of multiplex assays in a way that could be detrimental to patient care. As an example, such an approach could require invasive and potentially risky biopsies to collect additional tumor material to allow for multiple reimbursable single analyte tests to be performed, if more sensitive and tissue-efficient multiplexed tests are not covered. Of further concern, for instance, some patients may fail to receive potentially curative therapies, such as pembrolizumab, because insufficient material was available for both MSI testing and single analyte tumor genetic analysis.

Finally, requiring FDA approval as a companion in vitro diagnostic for Level 1 coverage would limit access to NGS testing for Medicare beneficiaries with advanced cancer due to the significant resources necessary for and costs associated with obtaining premarket approval. Further, the absence of Level 1 coverage for FDA cleared NGS tests would largely remove the incentive for more laboratories to pursue FDA clearance using the 510(k) pathway announced in November 2017.

For the reasons above, CMS’s final coverage determination should recognize the clinical utility of FDA-cleared NGS panels, and the coverage policy outlined at A.2. of the proposed NCD should be amended to read as follows:

MSKCC strongly supports the proposal to establish CED for NGS testing for beneficiaries with advanced cancer types, but only those for which no therapies targeting specific genetic mutations have received FDA approval. In this patient population, NGS testing may identify a genetic mutation for which a clinical trial of an investigational therapeutic agent targeting that mutation is underway, enabling enrollment. This type of testing is critical to the advancement of precision medicine and to ensuring that beneficiaries for whom no FDA-approved therapies are available have the opportunity to explore additional treatment options within the context of FDA-authorized clinical trials. Given the crucial role of NGS testing in advancing precision oncology, MSKCC also urges CMS to expand CED under category 2.a. to include New York State Department of Health-approved tests (or tests approved by other third party reviewers to be designated by the FDA in the future) that have not yet been submitted for FDA approval or clearance.

We are also concerned that the proposed criteria and requirements for registries mandated by the CED mechanism are unclear. Specifically, the criteria do not specify whether the diagnostic laboratory must participate in a specific national NIH Genetic Testing Registry, whether CMS intends to establish a national registry, or whether individual, site-specific registries could qualify. Regardless, MSKCC urges CMS to identify or develop a national registry. The establishment of individual, site-specific laboratory registries would be suboptimal, as it would likely result in registries utilizing differing definitions, formats, and data fields, making direct comparisons of outcomes and national analyses of data more difficult. Use of individual site-specific registries would also impose a greater administrative and financial burden on hospitals and laboratories, which would require the participation of oncologists, molecular pathologists, data analysts, and others to design and implement the registries.

In addition, the proposed NCD does not specify whether the CED requirements are time-limited or what criteria or endpoints need to be met to move from CED to full coverage. If the proposed decision is altered to allow coverage of both FDA-approved and -cleared tests for beneficiaries with advanced cancer types for which there is an FDA-approved therapy, a logical transition point from CED to Level 1 coverage would be when a therapy receives FDA-approval for a specific mutational cancer subtype. The NCD should specify what data or outcomes will qualify a test subject to CED for elevation to Level 1 coverage.

For NGS tumor profiling panels that are not FDA-cleared or -approved, the proposed requirement that the diagnostic laboratory test using NGS is provided to beneficiaries within an NIH-NCI National Clinical Trial Network clinical trial is also problematic. In general, NGS testing is rarely provided as part of a clinical trial. Instead, NGS testing is performed in order to identify clinical trials that may offer possible further therapeutic options for beneficiaries who have exhausted conventional therapies. Furthermore, many therapeutic trials are run outside of the NIH-NCI National Clinical Trial Network clinical trials program, and access to such industry-sponsored or institutional trials remains vital for the care of advanced cancer patients and to optimally assess the utility of the therapy and the validity of the genomic biomarkers being used as trial entry criteria. Therefore, if CED for these tests is limited to instances in which they are provided within an NIH-NCI National Clinical Trial Network clinical trial, CED for non-FDA cleared or -approved tests would be extremely limited.

Certain NGS tests are currently reimbursed under LCDs issued by Medicare contractors. A number of local Medicare Administrative Contractors (MACs) have issued LCDs that offer coverage on the basis of the ability to identify specific somatic genetic mutations. For example, National Government Services has issued an LCD providing coverage for a targeted genomic sequence analysis panel of 5 to 50 genes in certain beneficiaries with advanced non-small cell lung cancer. To ensure that there is a sufficient time period for sponsors to qualify for the new criteria for coverage, and to avoid disruptions of services for beneficiaries who are currently eligible for coverage of these tests, the NCD should include an appropriate transition period during which tests covered under an LCD would continue to be covered under the current terms of the applicable LCD.

Although coding and payment are not germane to this coverage policy, MSKCC urges CMS to take steps to clarify how it will operationalize coding and payment for these tests. First, as CMS is aware, the Protecting Access to Medicare Act (PAMA) established a new category of tests known as “Advanced Diagnostic Laboratory Tests” (ADLTs). An ADLT is defined as: “a clinical diagnostic laboratory test covered under this part that is offered and furnished only by a single laboratory and not sold for use by a laboratory other than the original developing laboratory (or a successor owner) and meets one of the following criteria:

Rather than being reimbursed under the weighted median reported private payer rate methodology used for most clinical laboratory tests, new ALDTs will be reimbursed on the basis of actual list price for an initial period and then priced according the weighted median private payer rate or using crosswalking or gapfilling processes.

MSKCC anticipates that MSK-IMPACT and other NGS tumor profiling tests that may receive FDA clearance will be classified as ADLTs. However, the process for applying for ADLT designation and the assignment of a unique HCPCS code remains unclear, despite the PAMA provisions relating to payment for laboratory tests taking effect on January 1, 2018. To ensure beneficiary access to these tests, CMS should issue further guidance to facilitate coding and payment.

In summary, we applaud the proposed establishment of a national coverage policy for NGS for Medicare beneficiaries with advanced cancer. However, we strongly urge CMS to:

• Revise the coverage policy to better reflect the clinical utility of FDA cleared NGS panels. Coverage without evidence development (Level 1 coverage) should be available to all FDA approved or cleared tests that identify mutations targeted by FDA approved therapies; coverage should not be tied to companion diagnostic approval.
• In the absence of an existing national registry, MSKCC encourages CMS to develop or identify a national registry that can be used to meet the CED registry requirements.
• Recognize the critical role that all types of NGS tests play in determining patient eligibility for various types of clinical trials in advancing precision oncology.

If we can be a resource on this issue as you move forward, please do not hesitate to contact us.

Sincerely,

Marc Ladanyi, M.D.
Chief, Molecular Diagnostics Service
David S. Klimstra, M.D.
Chair, Department of Pathology

cc: Tamara Syrek Jensen, JD, Director, Coverage and Analysis Group
Demetrios Kouzoukas, JD, Principal Deputy Administrator & Director of the Center for Medicare

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We, the undersigned, are all physicians and/or certified directors or members of the leadership of molecular diagnostics laboratories at a group of academic medical centers nationwide. We write in concern about the “Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)”, and thank CMS for the opportunity to provide our comments. While it is reassuring to see that CMS agrees that oncology testing using NGS platforms merits reimbursement, by tying all future reimbursement for any NGS assay to FDA approval, the proposal would circumvent existing regulatory oversight with mandates that are essentially incompatible with the continued practice of laboratory medicine in personalized oncology care at academic centers. This will be detrimental to patient access to timely genetic testing and coordination of care, and produce devastating long-term effects on our national genetic testing infrastructure and molecular diagnostics community through market destabilization of this burgeoning field of personalized medicine in oncology. Our academic centers are critical links in our national cancer care infrastructure, and this proposed National Coverage Determination (NCD) will have a magnified impact on academic center laboratories, thus we are writing to provide our viewpoint in the hope that it will assist this ongoing discussion. If there is one point that we would like to convey most strongly, it is that we believe our nation’s network of Academic University hospital NGS diagnostic laboratories provide high-quality and heavily-regulated services that are valuable, critical, and worthy of Medicare reimbursement. Each person named below is signing this letter as an individual, and does not represent the position of each institution, which may be submitted separately.

Academic medical center diagnostic molecular laboratories exist at the very intersection of oncology patient care, translational research, and medical training and education. We are physicians and laboratorians who work extremely hard to provide the highest quality and most up-to-date diagnostics for our patients to help manage their care. We help our institutions to support and channel desperate patients into clinical trials and we help to facilitate basic translational cancer research, all while working to train the next generation of oncologists, pathologists, laboratorians and physicians centered in personalized medicine. The testing procedures that we oversee have become a key focal point in the routine delivery of cancer care at our institutions, and they are depended upon by patients (including Medicare beneficiaries) and oncologists. We are not profit-driven and are devoted to sharing and cooperation. We share techniques and methodologies, we participate in cross-site proficiency testing, we publish details of our test methodologies and data analysis systems in the peer-reviewed literature, and we are committed to sharing the genomic findings that we learn about cancer to support improved diagnostics and biomarker development and improve our communal understanding of cancer genetics. As members of academic laboratory leadership, we are extremely concerned that the NCD, by tying all future reimbursement for our NGS based tests to FDA approval, creates a novel and extremely burdensome additional laboratory oversight regime that is not consistent with current legislation and which is incompatible with the continued practice of personalized oncology care and laboratory medicine at a local level.

CMS may not have a full perspective of the degree to which we as University hospital laboratories participate in standard-of-care clinical practice using NGS technology. We do not believe that it is CMS’ intent via this proposal to destabilize the majority of the personalized cancer care now taking place at academic centers nationwide, thereby endangering patient access to testing. However, it is our belief that this would be exactly the outcome were this coverage determination to take effect as written in draft form. Collectively, we are certain that if this proposal is not substantially modified, the determination would produce severe barriers to routine diagnostic testing at academic sites, resulting in centralization of cancer genomic testing into one or a few commercial laboratories, with the unintended consequences of reduced patient access, back-log, and price increases. The net effect will be to severely limit diagnostics innovation and development, with repercussions affecting routine clinical diagnostics, clinical trials and translational studies across our entire national University hospital system.

While some modernization of LDP oversight may ultimately be beneficial, from our perspective the labs that require such oversight are generally commercial start-up laboratories with proprietary test systems and significant financial incentives to compress validation timelines and deliver a return on investment. Typical commercial start-ups have few tests and potentially high volume, whereas academic centers typically have many tests and lower volume. Thus, by placing enormous demands on laboratories on a per-test basis, this proposal places an unfairly disproportionate burden on academic laboratories. As academic laboratorians, we are not opposed to the idea of expanded oversight, but we would ask that such a system respects 1) the difference between hospital labs that primarily test their own patients vs. labs that sell services nationwide (with respect to financial resources and reach of impact), 2) the need for continuous test improvement/evolution including incorporation of new biomarkers as the science progresses, and 3) the special nature of our academic medical centers as routine care providers, rapid responders to emerging clinical needs, scientific innovators and supporters of translational research and clinical trials. We do not believe the FDA approval process in its current form fulfills any of these criteria.

As a brief background: NGS is simply a sequencing technology rather than a diagnostic test. NGS instruments are just one of the many genetic analyzers that we use in our laboratories on a daily basis, and are separated from other instruments only by their versatility and favorable cost profile. NGS technology can be used to perform virtually any genetic test across all areas of oncology diagnostics, and over the next few years most oncology testing will likely migrate onto these platforms. Thus by proposing this NCD based on a single technology rather than on a particular analyte, CPT code or test, CMS is in effect proposing that the future of every single CPT code across all of molecular oncology diagnostics should be governed by this NCD, which rather than being focused on a particular test in effect creates a novel and redundant regulatory oversight system. We arrive at this conclusion because NGS adoption by oncology diagnostics laboratories is accelerating, and it is clear that most future applications in genomic diagnostics will depend on NGS technology.

At the heart of this NCD seems to be the implicit assertion that all of the LDPs in use by academic molecular diagnostics labs lack clinical validity unless deemed to be clinically valid by the FDA. CMS asserts that NGS oncology panels are valuable for many cancer patients and deserving of reimbursement, but only when FDA approved, and if not FDA approved are reimbursable as part of efforts intended to show clinical validity only through ongoing patient outcome assessments. This determination that LDPs lack clinical significance in the absence of FDA approval is not consistent with established science and published literature1-41, clinical laboratory medical practice, or with either existing federal and state laboratory oversight structures. The Clinical Laboratory Improvement Amendments (CLIA), overseen by CMS, permits non-FDA approved diagnostic laboratory tests to be created and clinically validated in-house by medical professionals, thus Congress explicitly created a non-FDA framework for establishing clinical validity which has been considered acceptable for local and national Medicare coverage determinations for the past three decades. If CMS is concerned that the current CLIA-centric paradigm for assurances of clinical and analytic validity are not sufficient, we urge CMS to explore other approaches for such assurances. One available approach is embracing proposals to modernize and expand the scope of CLIA, which has the advantage of allowing CMS to flexibly deem 3rd parties to enforce quality standards.

If a lab aims to implement a test for an entirely new biomarker that has not been previously studied, then it may be scientifically and medically appropriate to ask for clinical efficacy data. Otherwise, according to the CLIA regulations (Subpart K, Sec 493.1253: Standard: Establishment and verification of performance standards (b)(2)), in-house developed tests should require technical validity assessments, not independent clinical outcome data. An NGS oncology profiling panel is simply a combined group of such standard single analyte tests. For clinically established biomarkers, technical equivalency is the proper hurdle to ask laboratories to meet for clinical validity. Requiring clinical efficacy data for each laboratory test for the same well-studied genetic analyte is simply too burdensome and represents an enormous departure from our historical federal oversight structure through CMS. NGS panels are now the de facto standard-of-care in tumor genetic analysis due to the cost/breadth profile of the technology and the growing lists of companion diagnostic biomarkers requiring assessment for individual tumors. For example, for lung cancer it is simply not feasible to test via an antiquated piecemeal approach for each of the required FDA-approved targets in EGFR (4 exons), BRAF (1 exon), ALK (fusion), ROS1 (fusion), as well as microsatellite instability (MSI), while also covering the many additional targets recommended by the National Comprehensive Cancer Network (NCCN) for possible targeted clinical trial recruitment, a primary focus of academic medical centers. Single-analyte testing also does not meet the expectations of patients and their oncologists, who wish to pursue broader profiling in an effort to identify all possible potentially targetable alterations and other key clinical trial-related biomarkers. Very frequently there is not enough specimen to allow for that approach, and few oncologists would permit precious samples to be handled in that way. What CMS is now proposing is to allow laboratories to ONLY continue to be reimbursed for testing standard-of-care biomarkers if they adopt multiple suboptimal, non-comprehensive test systems (i.e., multiple single-analyte systems) that are not compatible with modern clinical service. This is not in keeping with good financial or clinical practice, and leaves laboratories with no viable options.

The available evidence supports the conclusion that LDP quality is very high nationwide42-43. The CLIA statutes were written to expressly allow non-FDA LDPs because of the key realization that clinical laboratories often need to adapt to changing science, including the need to provide tests for novel biomarkers as the need arises. The need for this flexibility is not just a talking point, it is a constant daily feature of the practice of laboratory medicine, and nowhere is that more evident than in our field of molecular diagnostics, particularly in the academic laboratory setting. It is for this reason that we are extremely concerned to see CMS propose to de facto enforce a regulatory schema that directly conflicts with CLIA statutes and is not compatible with the practice of adaptable laboratory medicine for which we are trained. Furthermore, this de facto enforcement is expressly against the stated priorities of FDA Commissioner Gottlieb, who has indicated that oversight of LDPs should be addressed at the level of Congress.

National coverage policies should be compatible with existing and evolving clinical service needs. Regarding off-the-shelf options for NGS panel testing, the only existing FDA approved NGS in vitro diagnostic for cancer (OncoMine) is approved for only a small number of targets (inadequate for many tumor types) on a sequencing platform that many laboratories do not own. For this reason, among many others, laboratories have pursued LDP development. However, direct FDA approval of an LDP appears to require substantial investment, clinical data and potentially other criteria such as manufacturing controls, alterations to vendor practices, and implementation of medical-device requirements which would be out of the reach of nearly all academic facilities. It is likely that full approval is only attainable by large companies aiming to market services nationally, not for academic laboratories that test primarily their own patient population. To our knowledge, Foundation Medicine took over two years to become certified, and probably spent several millions of dollars in the process (including laboratory, clinical trial and regulatory submission costs). Most academic medical centers already perform more than one NGS LDP, making this problem even more intractable if each separate NGS assay would need to undergo this process. For academic laboratories, following Foundation Medicine’s footsteps through this FDA process for all of our tests (current and future) is simply not possible.

Furthermore, it is important to note that FDA has not established clear guidance on what would be required to achieve approval for NGS-based testing. FDA has held numerous workshops and published white papers and guidances exploring potential regulatory paradigms, but has also proposed a substantial list of questions that remain to be answered in identifying paths forward. Additionally, the most recent standards guidance from FDA about this topic is specifically geared towards questions of using this platform for germline testing, and does not address tumor testing.

Even if we could somehow achieve FDA approval, we would still find ourselves in an impossible position because FDA approval of tests is not compatible with the clinical practice of quality improvement. Our diagnostics clinical training and our daily activity as physicians is focused on constantly assessing and improving test systems so they function optimally, and working to evolve test methodologies so they can evaluate the newest biomarkers as they arise. FDA approved tests cannot be modified or improved by their very definition, meaning any assay approved would become ‘locked in time’ and unadaptable to quality or scientific needs. Adopting this philosophy for all NGS laboratory testing has enormous implications for the future of cancer diagnostics and treatment, particularly as most traditional tests are now being migrated towards NGS platforms for reasons of quality and efficiency.

Other than full FDA approval, another option for laboratories under this proposal is to work towards attaining class II cleared status. This also requires substantial effort and costs, but per this proposal only a full class III FDA approval will merit reimbursement. There is no information available to laboratories about a direct FDA pathway for class II clearance, and no LDP has ever undergone this process. FDA oversight via New York State (NYS) Dept. of Health (DOH) regulation is possible, as NYSDOH was recently approved as a 3rd party reviewer for the FDA. Memorial Sloan Kettering Cancer Center (MSKCC) recently underwent this process for their IMPACT NGS panel. Clearance has some limited benefit under “Part 2: Coverage with Evidence Development (CED)” as discussed below. But it is worth delving into this New York State pathway briefly to highlight the difficulty of following in MSK’s footsteps even to attain the level of clearance.

The current wait time even for initial inspection by NYS DOH for an out-of-state laboratory is approximately one year. Once a laboratory is inspected, the process of NYS LDP approval takes roughly 1.5 years (NYS offers early provisional approval but this is not recognized by FDA). Only at the time of NYS approval (after 2.5 years) would a laboratory be eligible to apply to the FDA through this pathway. Typical FDA approvals take one to two additional year(s). Thus we could expect this NYS pathway to take at least 3 to years until a single test is FDA cleared. And even at that point we still would not qualify for Medicare reimbursement under this proposal despite performing high quality testing as determined by successful bi-annual proficiency testing as mandated by CMS/CLIA and enforced by multiple mechanisms, including CLIA deemed entities such as CAP. To ask laboratories to pursue 3-4 years of additional regulatory burden on top of our existing CMS/CLIA oversight, only to reach a level of FDA approval that is still not compatible with reimbursement, is excessively onerous and contradicts best practices in patient care.

The last option for academic laboratories is to pursue “Part 2: Coverage with Evidence Determination”. We have a fundamental objection to the philosophical basis of this section of the proposal, which operates on the assumption that our NGS LDPs are experimental in nature and lack clinical validity. The majority of the tumors we analyze via NGS assays are interrogated for biomarkers already documented in peer reviewed and published studies to be clinically valuable and are tested daily for standard-of-care practice via rigorously controlled systems in accordance with federal law and professionally certified oversight.

Regarding the language of the CED, what is proposed here is extremely rigid. Assuming laboratories will have difficulty meeting FDA clearance for one or multiple NGS assays (which we note above would take laboratories more than 3 years via NYSDOH, the only mechanism provided), most laboratories will fall under part 2b. Under this part, laboratories can only qualify for reimbursement if they participate in an NCI National Clinical Trials Network (NCTN) trial. These trials are few in number and mostly unavailable to participation by academic laboratories, with steep barriers to creation of additional trials. NCTN trials that are open to academic laboratories (including the MATCH trial) are likely to permit participation by only a limited set of laboratories, and may cover only certain subsets of patients while requiring implementation of a burdensome research consenting pipeline for all tested patients. And after NCTN trials close, laboratories will be left with no options to pursue coverage under this paradigm. The CED notes among 13 different trial requirements that trials have to show a benefit of the sequencing-related intervention and should also be non-duplicative. Because so many biomarkers are standard-of-care today, even if new NCTN trials could be created, the stand-alone assessment of the testing would not be feasible, because the testing we perform is now routine and it will not be ethical to withhold standard testing from patients in order to assess the impact of the testing. Furthermore, the CED requirements with regard to registries are unduly onerous. Although part of academic medical centers, our laboratories are not directly connected to the clinical trials programs or registries within our institutions, thus laboratories will not know which specimens received are associated with enrolled clinical trial status or have patient consent to participate. Overall, the CED proposal essentially represents an absolute barrier to participation by most laboratories, and provides no mechanism for laboratories to graduate from CED to full coverage.

We are encouraged by CMS’ recognition of the clinical value of precision oncology diagnostics, but we hope for modifications to this NCD that are more harmonized with existing CLIA statutes and which are compatible with patient care needs and the continued practice of oncology personalized medicine at academic medical centers. We would ask that CMS consider the following:

Any of the below listed signers would be happy to meet in person and discuss possible alternatives to the proposed coverage determination, and contact information is listed by each name. As academic laboratory professionals, we remain as devoted as ever to providing the highest quality testing possible for our patients. We simply wish to have realistic options that are compatible with our clinical practice in personalized oncology, such that we can continue to care for our patients and support their evolving needs.

Sincerely (in alphabetical order),

References:

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[PHI Redacted]

Thank you for the opportunity to provide comment on the National Coverage Analysis entitled ‘Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer’. Cancer patients all over the country are benefitting from new knowledge in the genomic causes and drivers of cancer, as evidenced by increased access to personalized therapeutics and care based on the genetic makeup of cancer. We are grateful for advances in diagnostic technologies, such as next generation sequencing, as it is one tool to obtain a more comprehensive genetic understanding of cancer. This technology is of particular relevance to lung cancer patients as it typically requires less tissue sample than separate sequencing of multiple genes. I thank CMS for recognizing the value of precision diagnostics in the care of cancer patients by proposing coverage for FoundationOne CDx (F1CDx). I support a positive coverage determination for the product reviewed in the Parallel Review program, F1CDx, however I have serious concerns about the broad scope of the proposed NCD. The proposed policy would limit cancer patients to 1 test per lifetime, which is not in line with the realities of personalized medicine based therapy for cancer patients. Also, the new policy will eliminate coverage for other NGS tests for advanced cancer patients enrolled in Medicare. These tests are currently being used to deliver high-quality, advanced cancer care across the country, including at virtually all major cancer centers and academic institutions. I support CMS’ proposal to cover the F1CDx test but urge CMS not to finalize the rest of the policy as it will result in several unintended negative consequences to cancer patients by erasing important medical advances and existing local coverage policies already in place.

Thanks
Anthony C. Mitchell

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January 17, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed Decision Memorandum on Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG #00450N)

Dear Ms. Jensen,

As a practicing molecular pathologist with significant research and clinical expertise in the molecular pathology of cancer, I would like to offer my comments on this over-reaching coverage policy. In summary, this proposed coverage policy is unnecessarily restrictive. At a time when most academic centers, leading cancer institutions, and essential community cancer centers have Clinical Laboratories Improvement Amendment (CLIA) certified laboratories providing validated laboratory developed gene panels using NGS technology, this policy, if finalized would supersede existing local coverage policies for most of those tests and limit Medicare beneficiaries’ access to a single laboratory and single test, which would be quite deleterious to patient care. This policy concentrates testing to a single entity and only for cancers with an FDA approved companion diagnostic indication (lung, melanoma, breast, colon, ovarian and colon cancers) and will eliminate coverage or impose severely restrictive coverage with evidence (CED) requirements for all other tests utilizing NGS technology for all advanced cancer patients enrolled in Medicare. These tests are currently being used to deliver high-quality, advanced cancer care across the country as part of standard of care in oncology diagnostics. While I agree that the F1CDx test has clinical utility for certain indications, it is absolutely not the only clinically validated test for patients with advanced cancer, nor is it the only test that has been demonstrated to be high quality by peer review and offered through existing regulatory oversight, e.g., the CLIA and CAP laboratory inspection processes. This policy as proposed would have a severe negative impact on extremely vulnerable Medicare beneficiaries by eliminating coverage for clinically valid and medically necessary testing services currently being used to deliver high quality cancer care across the country, including at virtually all major cancer centers and academic institutions.

I strongly recommend that CMS narrow this policy so that is applies ONLY to the F1CDx assay, and not to any other NGS-based test. Coverage for these other clinically- and analytically- validated NGS-based tests should continue to be regulated, as per long-standing CMS precedent, by existing local coverage determinations (LCDs) administered by local Medicare Beneficiary Administrators.

I welcome the opportunity to discuss with you the current state of molecular diagnostic testing, including NGS technology, to inform this and other future coverage policies.

Laboratories already provide high quality and heavily regulated cancer biomarker testing services

In addition to being specific to a particular technology rather than a diagnostic test or CPT code, the preliminary NCA disregards another responsibility of CMS; overseeing laboratory and laboratory developed testing procedures (LDPs). Clear legal guidelines for CMS’ oversight of LDPs exist currently and allow laboratories to pursue both FDA and non-FDA laboratory service pathways. Inexplicably, in this NCA, CMS is proposing an overly broad, method-specific, universal non-coverage policy because of the assessment of a different government office (FDA), which Congress has stated should not be overseeing the medical practices of laboratory physicians. Such a policy would represent a grave inconsistency that would serve to harm providers and patients alike.

As per long-standing policy, CMS should consider providing local MAC adjudicated coverage for NGS-based tests that are used in CLIA accredited laboratories with appropriate analytical and clinical validation. Numerous evidence-based guidelines written by expert professional medical societies have been published in the last few years to clearly establish the clinical utility of high quality NGS-based services for specific clinical indications, , with additional evidence based guidelines currently in development (Jennings, L et al) (Li, M et al) (Roy, S et al). In all of these guidelines, the clinical utility of a diagnostic test is assessed independently of the testing methodology and, within specific clinical contexts, includes any actionable information that can guide disease diagnosis, prognosis, monitoring, or therapy. (Joseph L, Cankovic M, Caughron S, Chandra P et al). Evidence-based guidelines from the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH), Association of Molecular Pathology (AMP), CAP, and World Health Organization (WHO) support the clinical utility of molecular alterations in various diseases (see Appendix B). Such alterations can also be detected by non-NGS technologies, so coverage policies should not be restricted to a specific method, but rather to the genetic alteration(s)/ cancer type / targeted therapy combination that together defines clinical relevance. Coverage policies for laboratory tests that utilize NGS-based methods need to be aligned with these evidence-based best clinical practices for optimal, cost-efficient patient care.

It is critical that CMS cover laboratory tests that specifically direct patient care and are deemed effective by the treating physician (and his/her consensus professional colleagues). Often, lab testing sought by a treating clinician is outside of the scope of FDA-approved indications, which is, by definition, the practice of medicine. Based on the numerous professional society guidelines referenced, many NGS-based laboratory tests, including F1CDx, meet this bar. The results from these tests are used in conjunction with other clinical and laboratory information to inform clinical decisions, such as diagnosis, prognosis, disease monitoring, and often (targeted) therapy. Many per-review articles in high-impact journals confirm the utility of these tests in clinical cancer care. CMS coverage policy for Medicare beneficiaries should not exclude entire categories of testing that use a common methodology, i.e., those that use NGS, when such testing is performed in CLIA accredited laboratories and adheres to evidence-based guidelines developed by leading subject matter experts and endorsed by medicine’s preeminent professional societies, including AMP, CAP, ASCO, ASH, WHO, and NCCN.

Impact of the FDA Approval Requirement

The NCA presents differing proposals for coverage based on whether a test is FDA-approved versus FDA-cleared. As part of a 510(k) premarketing submission, it is demonstrated to FDA that the IVD to be marketed is accurate and reliable. The policy also fails to acknowledge that there are other proven, time-tested federal government oversight entities responsible for verifying the accuracy and reliability of laboratory developed testing procedures (LDPs). Requiring FDA approval as a condition for coverage is inconsistent with the FDA’s position on enforcement discretion for LDPs, including its 2016 announcement that it does not intend to finalize the draft guidance establishing a framework to regulate LDPs. The vast majority of LDPs utilizing NGS-based technologies offered today are already stringently regulated by CLIA. These diagnostics are considered part of the practice of medicine when they are developed and validated by healthcare professionals for use in their own laboratories (Kaul K et al).

Every laboratory performing clinical testing is, by federal mandate, CLIA-certified. The stringent policies of the CLIA statute continuously assure high-quality laboratory performance standards and each test’s accuracy and reliability over the entire lifetime of a test. As part of this certification, CLIA (or a federally-deemed partner) conducts laboratory inspections, and additionally, those performing high-complexity tests must, under CLIA, undergo regular proficiency testing. Many laboratories obtain CLIA certification through accreditation by CMS-approved accrediting agencies, such the College of American Pathologists (CAP) or the Joint Committee on Hospital Accreditation. The standards of these accreditation programs must meet or exceed those of the CLIA regulations. These programs often go well beyond CLIA including more stringent requirements for proficiency testing, as well as documentation of clinical validity.

FDA review mandates that once a test is approved, no changes can be made to it. This freezes a test in time, and does not allow laboratories to modify their tests in light of new scientific understanding. The process of updating testing is exceedingly common, as new information is constantly being identified that can improve the test’s analytical and/or clinical performance characteristics. A recent comparison of LDPs versus FDA approved assays for BRAF, EGFR, and KRAS molecular testsin 6,897 blinded proficiency testing responses showed that LDPs and FDA reviewed companion diagnostics both performed well, with both test types exceeding 97% accuracy for all three cancer mutations. This study also found that more than 60 % of participants using an FDA reviewed companion diagnostic test reportedly modified the assay to allow for a greater breadth of sample types, minimum tumor content, and instrumentation (Kim, A et al). This comprehensive study confirms that the most up to date test offered by labs is often not the FDA approved or cleared test. As a result, this NCA may be promoting coverage of an inferior test. An unintended consequence of this proposed NCA would be to incentivize laboratories to shift away from NGS-based testing, despite its wide deployment nation-wide, and move backwards to one-at-a-time gene testing (or other inferior non-NGS multiplex methods), which is contrary to the best interest of patients.

Further, the cost and time to obtaining FDA review, which is not necessary to establish the clinical and analytical validity of a LDP, is prohibitive for most laboratories and would result in them no longer offering the test which also reduces patient access to lifesaving diagnostics.

Sincerely,

Richard D. Press, MD, PhD
Professor, Director of Molecular Pathology
Dept. of Pathology & Knight Cancer Institute
Oregon Health & Science University
3181 SW Sam Jackson Pk Rd, L113
Portland, OR 97201
503-494-2317
FAX 503-494-2025
pressr@ohsu.edu

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Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Re: CAG-00450N

Dear Ms. Syrek Jensen,

On behalf of Illumina, a leading developer and manufacturer of next generation sequencing (NGS) tools for both research and clinical use, we appreciate the opportunity to provide comments on the proposed National Coverage Determination (NCD) for NGS for Medicare beneficiaries with advanced cancer.

First, we would like to commend the Centers for Medicare & Medicaid Services (CMS) and the U.S. Food and Drug Administration (FDA) for their efforts and leadership in completing the parallel review process for the FoundationOne CDx (F1CDx) test. We strongly support the CMS decision to provide immediate national coverage for Medicare beneficiaries for F1CDx as well as other FDA-approved CDx tests that use NGS technology, including the Illumina Praxis™ Extended RAS Panel.

While we are fully supportive of immediate coverage for F1CDx, we would like to share comments on several other components of the draft NCD, which have implications beyond F1CDx. First, we are very concerned about how the other components of the draft NCD will impact patient access to rapid, accurate, and well validated NGS-based clinical diagnostic testing in advanced cancer. Second, we would like to comment on the evidentiary standards CMS has applied for NGS-based assays vs assays using other technologies. We respectfully request that CMS finalize the NCD for F1CDx and other FDA-approved CDx assays, while the other elements of the NCD should be delayed until further public comment and feedback from the health care community, academic thought leaders, and professional organizations can be incorporated. Illumina fully supports high standards and quality frameworks for diagnostic testing. We believe that the interests of patient access, high-quality patient care, high standards for diagnostic assay validation, and evidence-based medicine can be balanced in a final coverage determination for NGS-based assays in advanced cancer.

1. Patient Access Considerations

2. CMS position on NGS-based assays vs assays based on other technologies

Thank you for the opportunity to comment on this draft NCD. Furthermore, we welcome the opportunity to work with CMS in helping to establish and evaluate NGS-based applications for Medicare patients.

Sincerely,

Ammar Qadan
Vice President, Global Market Access
Clinical Genomics
Illumina, Inc.

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I write this letter to express grave concern over the recently drafted memo by CMS, which outlines proposed changes for clinical laboratories: Next Generation Sequencing (NGS) for Medicare Beneficiaries (CAG-00450N).

As the Laboratory Director of a CLIA-certified and CAP-accredited reference lab focused on NGS’s integration into the Precision Medicine movement in oncology, I see the proposed guidelines as being stifling on several, intertwining levels, particularly:

• innovation
• patient and physician access to the best available tests

Innovation
This proposal significantly restrains a laboratory’s ability to innovate and develop, improve and produce the best NGS tests for cancer patients. Our profession is an ever-evolving field of knowledge and discovery, both from a technical and biological standpoint. Because the proposal would significantly and, in my professional view, unnecessarily increase the time and expense of testing, it would halt a lab’s ability to be fluid and change, and ultimately hurt the sole aspect for existing: helping cancer patients through the most advanced testing.

This proposal also restricts testing to those deep-pocketed laboratories who have the financial means to support the technical and operational structure the additional testing would demand. These labs will ultimately be offering outdated tests as the additional requirements would increase the time and cost of validating and submitting test improvement, which would limit the frequency of test revision. In a field where the knowledge of the genome and its impact on treatment decisions changes weekly, such delays could be deadly by limiting access to the most current information that could bear on a patient’s case. Again, the harm falls on patients, as they will be the recipients of outdated test content and technology, thus potentially missing the most accurate treatment options.

Patient Access
By limiting reimbursement to Stage IV patients, the guidelines would exclude Stage I-III cancer patients. This policy would dictate that a clinician is limited in choice of what test they can order (versus what test is best for their patient), handcuffing them to a very small number of labs/tests. This limitation would especially matter in cases of rare and childhood cancers, where there are often few, if any, good conventional treatment options even in the early stages of the disease, and where NGS testing shows some of the strongest promise for providing precision care to individual patients.

I know I do not stand alone in my perspective and worry, and hope that my and my colleagues voices are heard, and our concerns heeded.

Sincerely,

Janine LoBello, D.O., F.C.A.P
Laboratory Director
Ashion Analytics

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January 16, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Dear Director Jensen:

On behalf of the Coalition for 21st Century Medicine (C21), we appreciate the opportunity to submit comments on the Proposed Decision Memorandum for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N). C21 comprises many of the world’s most innovative diagnostic technology companies, clinical laboratories, physicians, venture capital companies, and patient advocacy groups. C21 strongly supports the Centers for Medicare & Medicaid Services’ (CMS’) proposal to provide uniform national coverage for solid tumor tissue-based somatic multi-gene oncology sequencing panels using an NGS platform when performed with a Food and Drug Administration (FDA) approved companion diagnostic indication for beneficiaries with advanced cancer.

C21’s mission is to improve the quality of healthcare by encouraging research, development, and commercialization of innovative diagnostic technologies that will personalize patient care, improve patient outcomes, and substantially reduce healthcare costs. Likewise, C21 shares the common goal of CMS and FDA of expediting and facilitating coverage of precision diagnostics through mechanisms such as parallel review. In our comments, we respond to the specific questions that the agency included in the Proposed Decision Memorandum, and include certain recommendations for the agency to consider in developing the Final NCD. In particular, we recommend that the agency provide a 24-month transition period to allow other laboratories sufficient time to pursue this new pathway, and focus the National Coverage Determination (NCD) only on solid tumor tissue-based somatic multi-gene oncology sequencing panels using NGS.

The recommendations in this letter are provided by C21 as part of our general mission to develop and make available novel diagnostics that improve patient health. Individual C21 members may submit independent responses and/or comments. The decision of any C21 member to submit independent comments should not be viewed as reflecting a disagreement or an endorsement by such member of the recommendations expressed in this letter, unless expressly stated by such individual member.

C21 agrees with the agency’s coverage policy in Section A of the Proposed Decision to provide national coverage for those solid tumor tissue-based somatic multi-gene oncology sequencing panels that use an NGS platform and have received FDA premarket approval. We share CMS’ view that the use of these tests as FDA-approved companion diagnostics to guide treatment of patients with advanced cancer is “reasonable and necessary for the diagnosis or treatment of illness or injury” under Section 1862(a)(1)(A) of the Act. FDA’s approval of a diagnostic test establishes the test’s analytical and clinical validity. The reference to the use of the companion diagnostic in the FDA intended use labeling for an approved therapeutic product establishes clear clinical utility for the diagnostic. As noted in the Proposed Decision Memorandum, the agency’s evidence review indicates that health outcomes data support the clinical utility of solid tumor tissue-based somatic multi-gene oncology sequencing panels that are performed on an NGS platform when used as an FDA-approved companion diagnostic to provide FDA-approved test results to the treating physician. CMS bases this conclusion on the fact that these tests assist the patient and their oncologist to make “a more informed decision on selecting treatments with demonstrated evidence of efficacy.”

Although FDA-approved precision tests for companion diagnostic indications have generally been covered through Local Coverage Determinations (LCD) by the MACs, we believe that national uniformity in coverage of solid tumor tissue-based somatic multi-gene oncology sequencing panels that use an NGS platform and are FDA-approved as companion diagnostics promotes administrative simplicity for oncologists, hospitals, and laboratories, and furthers patient access to well-informed cancer treatment. If finalized, the Proposed Decision would provide specific coverage for multi-biomarker tests that serve as companion diagnostics for multiple FDA-approved treatments, and would remove the potential inconsistency in coverage policy between contractors.

Finally, we recommend that where a new gene or variant is approved as a companion diagnostic and this gene or variant is included in an FDA-approved panel with coverage under the Proposed Decision, but the gene or variant is not an approved indication for use for the already-covered panel, the newly-approved gene or variant will immediately be covered as an indication for the already-covered panel. For example, consider an FDA-approved panel that includes BRAF and KRAS, its initial FDA approval has a companion claim only for the BRAF, and the FDAapproval is subsequently expanded to include a companion claim for KRAS as well. Under such circumstances coverage should be expanded from BRAF to both BRAF and KRAS immediately upon the approval of the companion claim for KRAS. We believe this approach would prevent unnecessary hurdles to patient access to precision diagnostics and therapies.

The Proposed Decision Memorandum refers generally to tests for advanced cancer that use NGS. C21 believes that it is important for the agency to take into account that NGS is not a discrete category of tests with common characteristics but instead is a technology platform to analyze genes upon which a clinical laboratory test may be developed and performed. An NGS technology platform (of which there are varieties) can be used to analyze different kinds of genes on varying sample types to answer a wide range of clinical questions, including those beyond cancer.

Because NGS is not a type of test but rather a type of technology platform upon which a clinical laboratory test may be developed, it is imperative that the Final NCD title and scope are further refined to align with other NCDs by specifying a class of clinical laboratory tests subject to the decision’s scope. In reviewing past NCDs, it is evident that CMS decisions have focused on a class of technology or a type of procedure that fits within a benefit category—not on a technology platform. NGS on its own does not fit within a benefit category; it only fits a benefit category as a clinical laboratory test.

In order to ensure consistency in NCDs and reduce confusion, C21 believes that the Final NCD should only apply to solid tumor tissue-based somatic multi-gene oncology sequencing panels that use an NGS platform. Based on our analysis of the FDA and CMS regulatory review in advance of FDA approval and the Proposed Decision Memorandum, our understanding is that the agencies only reviewed data and clinical literature with respect to solid tumor tissue testing through multi-gene sequencing panels. This view is supported by the fact that the Foundation Medicine, ThermoFisher, Memorial Sloan Kettering Cancer Center and Illumina tests that CMS proposes to cover (either outright or through CED) are all analyses of solid tumor tissue through multi-gene sequencing panels. Additionally, Foundation Medicine’s November 17, 2017 Formal Request for NCD requested coverage only for management of cancer patients with solid tumors, and the “Evidence” section of the Proposed Decision Memorandum is limited to clinical literature on tissue-based testing.

CMS should make clear in the Final Decision Memorandum that the NCD will not apply to liquid-based tests (e.g., blood samples), tests for hematopoietic cancers, tests for germline mutations, or single-gene tests, even when these categories of tests are performed on an NGS platform. At present there are no FDA-cleared or approved liquid-based multi-gene sequencing panel tests for oncology that use an NGS platform (and only one single-gene liquidbased test has been FDA-approved), so the impact of making the Final NCD applicable to liquidbased tests would effectively be national non-coverage for all assays using a liquid sample. This would be problematic as liquid-based tests are becoming important in precision diagnostics when tissue samples are unavailable.

As with liquid-based tests, at present there are no FDA-cleared or approved tests using an NGS platform for hematopoietic cancers, or for multi-gene panels for germline mutations. In addition, given that the Proposed Decision Memorandum dealt almost exclusively with multi-gene panels, C21 believes that the Final NCD should not address single-gene analyses, which present issues distinct from larger panels. For these reasons, we believe that coverage of classes of tests that use the an NGS platform other than solid tumor tissue-based somatic multi-gene oncology sequencing panels should not be subject to a national coverage policy at this time.

C21 supports new and flexible approaches to coverage for precision diagnostics. We recommend the following changes to the CED option in the Proposed Decision to mitigate the risk of coverage delays or undue financial burdens for laboratories that wish to pursue CED and providers who participate in CED studies.

Under the Proposed Decision Memorandum, FDA cleared or approved tests without a companion diagnostic indication and LDTs that fall within the scope of the NCD would only be covered by Medicare in the context of a CED study. In finalizing this CED option, it is critical that CMS ensure that the process does not create coverage gaps for certain tests as a result of the transition from local coverage to CED. As the agency is aware, in some cases designing and receiving approval for a CED study can be a lengthy process. We are concerned that if the agency finalizes an NCD under which certain tests are only covered through the CED pathway, gaps in coverage could result from a lag in time as laboratories develop registries, seek approval for CED studies from CMS, secure Institutional Review Board (IRB) approvals as needed, and work with clinical practices to implement these studies.

To avoid these issues, we recommend that the agency establish a list of criteria that a study must meet to be eligible for CED, and make coverage under CED effective upon the laboratory’s certification of compliance with these criteria. Such criteria could overlap with the required CED criteria that the agency has developed to implement section 1862(a)(1)(E) of the Act, such as IRB approval and informed consent.¹ Other criteria could include enrollment of a clinical site or investigator and certification that the test will only be submitted for reimbursement for a patient with an indication for which testing is intended as denoted by ICD-10 diagnosis codes.

Additionally, it will be important for the requirements of CED to be economically feasible. Designing and implementing CED studies can be lengthy and financially burdensome both to laboratories and participating clinicians, and less burdensome study designs than those currently contemplated in the Proposed Decision Memorandum may be adequate to demonstrate clinical utility depending on the test. For instance, we are concerned that requiring objective response rate monitoring consistent with the Response Evaluation Criteria in Solid Tumors (RECIST) definitions could make CED highly burdensome for clinicians and financially prohibitive for many laboratories because obtaining such data would require testing and reporting that are not typically included in clinical practice. As the CED pathway proposed in section B.2.a of the Proposed Decision is likely to include a broad swath of tests that use an NGS platform, CMS should give laboratories flexibility to independently design and execute studies influenced by test-specific characteristics, such as intended use of the test and patient population, while maintaining high standards of scientific rigor.

We also believe that the agency can take affirmative steps to promote rigorous CED studies that are within the capabilities of laboratories. In particular, C21 encourages CMS to leverage the resources at its disposal to assist sponsors in optimizing their CED studies. For example, we look forward to working with the agency to improve the availability of Medicare claims data to ensure that investigators in CED studies have access to the most relevant data in a timely manner.

C21 also recommends that the agency expand the CED pathway proposed under Section B.2.a of the Proposed Decision to include LDTs with sufficient evidence of analytical and clinical validity. Under Section B.2.b of the Proposed Decision, LDTs in this class can only be covered through CED when provided within an NIH-NCI National Clinical Trial Network (NCTN) clinical trial. These trials, however, provide only a narrow avenue to coverage given that only 4- 5% of patients with cancer enroll in clinical trials and even then, only a subset of this 4-5% fall within NCTN trials. We are concerned that LDTs that fall within the scope of the Proposed Decision, some of which are currently covered by local MACs as having provided evidence that these tests are reasonable and necessary, could be effectively non-covered as a result of being restricted to NCTN trials given the small number of eligible Medicare beneficiaries in these trials.

C21 agrees with the agency that any coverage policy must “ensure that the NGS test is a validated, reliable test”. As CMS notes in the Proposed Decision Memorandum, the FDA has announced the accreditation of the New York State Department of Health (NYSDOH) as a thirdparty reviewer of in vitro diagnostics, including tests similar to the MSK-IMPACT test. This will enable laboratories with NYSDOH-approved tumor-based somatic multi-gene oncology sequencing panel profiling tests that use an NGS platform and otherwise fall within the scope of the NCD to request that their NYSDOH application, review materials, and recommendation forwarded to FDA for possible 510(k) clearance in lieu of filing a full 510(k) application. Based on FDA’s position, we believe that LDTs that have been approved by the NYSDOH have demonstrated sufficient analytical and clinical validity to be covered outside of NCTN clinical trials. We encourage the agency to cover these NYSDOH-approved LDTs under CED on the same basis as FDA-cleared or approved non-companion diagnostics under section B.2.a of the Proposed Decision.

Finally, C21 agrees with the agency’s expectation “that the studies conducted under a CED NCD will produce evidence that will lead to revisions to Medicare coverage policies.”² We wish to confirm that the agency will remain committed to ensuring that CED is a temporary step for tests rather than a permanent state. To that end, we encourage CMS to indicate in the Final Decision Memorandum the circumstances under which, and the process by which, it will establish full coverage of a test that has been covered under CED pursuant to the Final NCD.

For instance, we recommend clarifying that coverage under Section A of the Proposed Decision will be effective for new tests upon their approval as companion diagnostics by the FDA. This would be analogous to CMS’ existing policy for Transcatheter Aortic Valve Replacement (TAVR), under which TAVR moves from more rigorous CED requirements to less rigorous registry-based requirements when the use for which it is furnished becomes listed as an FDAapproved indication.³ C21 encourages the agency to work with FDA to develop an automatic process by which notice of FDA approval of a companion diagnostic indication can be communicated in a timely manner to both CMS and the MACs to effectuate prompt coverage. Such communication should be publicly available to ensure that physicians have the most up-todate information to inform diagnostic and treatment decisions for their patients.

Finally, C21 believes that implementation of the NCD should take into account the abbreviated nature of this NCD process. We agree that CMS should implement the coverage portions of the NCD (Section A of the Proposed Decision) by February 28. However, a transition period to the CED and non-coverage sections of the NCD (Sections B and C of the Proposed Decision) should be created during which existing Medicare local coverage policies would remain in effect. In particular, we would note that the normal timeline for CMS to complete an NCD is 9 to 12 months with two public comment periods.⁴ This NCD will become effective within only 90 days with just one public comment period. Though we agree that this expedited timeline is appropriate with respect to the Section A of the NCD, we believe that the agency must guard against detrimental consequences of implementing the other Sections so quickly.

Given the substantial impact that the CED and non-coverage portions of this NCD are likely to have on beneficiary access to solid tumor tissue-based somatic multi-gene oncology sequencing panels that use an NGS platform, this abbreviated timetable is not sufficient to achieve the orderly implementation of the new policy. From the perspective of test developers, 90 days is not a sufficient amount of time to prepare for, seek, and obtain the FDA approval or clearance that would be required for most of the coverage under the Proposed Decision. It will be particularly challenging to educate health care practitioners, patients, and caregivers in the oncology space about the new coverage rules in such a short time period. Establishing a transition period for the new CED and non-coverage provisions will mitigate these difficulties by giving stakeholders time to understand the new coverage landscape and providing laboratories the time to design CED studies and/or seek the requisite regulatory approvals.

A transition period would also be in accordance with historic agency practice. In the past, CMS and FDA have used transition periods to promote the orderly implementation of new regulatory requirements with a potentially significant impact. For instance, in FDA’s 2014 Draft Guidance on regulatory oversight of LDTs,⁵ FDA proposed that premarket review of even the highest risk devices would not begin until 12 months after finalization of the Guidance, and that phased-in enforcement of premarket regulatory requirements for lower-risk Class II devices would not be completed until 9 years after the Guidance was finalized.

For the implementation of new coverage requirements obligating solid tumor tissue-based somatic multi-gene oncology sequencing panels that use an NGS platform to receive, at the very least, NYSDOH approval and expedited FDA clearance to be covered under CED, C21 recommends that the applicable transition period be tied to the timeline for those two regulatory processes. Based upon our experiences, we understand that it frequently takes approximately 12 months for NYSDOH to complete its review of high complexity tests, like comprehensive genomic profiles using an NGS platform for patients with advanced cancers. To that timeline must be added the need for a laboratory to have a pre-submission meeting with the FDA to determine what FDA will require for clearance or approval (typically 75+ days from submission of the pre-submission application). In addition, time must be allotted for FDA to review the application for clearance following NYSDOH’s review (30 days). Given these time frames, and the possibility of unavoidable delays as more laboratories make use of this regulatory process, we believe a 24-month timeline is the minimum reasonable to accommodate the requirements to obtain FDA clearance or approval. Therefore, to further the goal of smooth implementation of the NCD, to ensure continued beneficiary access to lifesaving technologies, and to reflect the length of the regulatory process necessary for FDA and/or NYSDOH approval, we encourage the agency to consider a 24-month transition period in implementing the CED and noncoverage provisions at Sections B and C of the Proposed Decision.

More specifically, CMS can use its authority under Section 1862(a)(1)(E) of the Act (which provides authority for CED) to allow for coverage of tests not meeting the reasonable and necessary standard of Section 1862(a)(1)(A) under the Final NCD during such transition period. This means that tests which would otherwise not be eligible for coverage under the Final NCD could be covered through a transitional period CED established per specifications of the Final NCD while those tests seek compliance with the other provisions of the Final NCD. For example, if a test is undergoing NYSDOH review and then FDA clearance based upon such, but approval by NYSDOH and FDA clearance has not been obtained by February 28, 2018, such a test could be eligible for coverage during the transition period subject to its providing certain required data elements for a transitional period CED as set forth in the Final NCD. We believe that this approach would be a permissible one for CMS and would allow for a more manageable transition to the CED and non-coverage portions of the NCD.

C21 appreciates CMS’ efforts to establish national coverage policy for certain FDA-approved companion diagnostics for advanced cancer that use an NGS technology platform, and agrees with the agency’s decision to cover these tests.

Thank you for considering our specific comments and recommendation for a 24 month transition period following the implementation of the NCD. Please contact me at hmurphy@c21cm.org should you have any questions or if we can provide you with further information.

Sincerely,

/s/
Hannah Murphy
Executive Director
The Coalition for 21st Century Medicine

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Thank you for the opportunity to offer our thoughts on this issue. The promise of personalized medicine has led to a proliferation of large NGS panels that offer tumor mutation profiling, such as the F1CDX™. These panels are intuitively attractive to use in clinical care because they can screen for numerous mutations within many genes quickly, and may lead to greater efficiency in the disease work-up. It is also possible that some of these “bundled” gene tests may be more cost effective than direct sequencing. However, this testing provides information on genetic variants that are of unclear clinical significance for a given disease, or for which no targeted treatments are available. Identification of variants for which the clinical management is uncertain may lead to unnecessary follow-up testing, treatments, and procedures, all of which have their own inherent risks.

The impact of test results related to non-indicated mutations and variants of uncertain significance must be well-defined and account for the possibility that the information may cause harm by leading to additional unnecessary interventions that would not otherwise be considered based on the patient’s clinical presentation. Unfortunately, such concerns have not been sufficiently addressed in studies of F1CDX™ and other non-specific NGS cancer panels. In addition, this NCD is likely to undermine the development and use of more tailored laboratory-developed panels. Therefore, we do not support this NCD in its current form.

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Friends of Cancer Research (Friends) appreciates the opportunity to comment on the CMS “Proposed Decision Memo for Next Generation Sequencing for Medicare Beneficiaries with Advanced Cancer”. Next Generation Sequencing (NGS) is a very powerful technology platform for detection of multiple genetic alterations and has the potential to provide significant benefits to patients. The proposed coverage for NGS-based diagnostics is a step in the right direction that can positively impact patients and help support evidence generation to promote high-quality test development. To promote optimal implementation of this coverage decision, Friends offers several considerations as CMS finalizes its guidance for NGS Medicare coverage.

While there are many diagnostic techniques used in oncology, including immunohistochemistry, in situ hybridization, and polymerase chain reaction, NGS provides the most comprehensive genetic analysis of an individual’s cancer because it enables collection of the entire cell genome and detection of multiple genetic alterations simultaneously. This information can elucidate clinically actionable mutations in cancers to help guide patients and physicians as they develop a treatment strategy.

The FoundationOne CDx companion diagnostic, developed by Foundation Medicine, Inc., received FDA approval as a breakthrough device and is participating in the Parallel Review Program. The FDA-CMS Parallel Review Program was begun in 2010 to better align the timing of FDA approval with CMS coverage determinations through collaboration for faster patient access. The “Proposed Decision Memo for Next Generation Sequencing for Medicare Beneficiaries with Advanced Cancer” is a product of the parallel review of FoundationOne CDx, but extends to other FDA approved tests using NGS recognizing the need to develop a national coverage decision (NCD) for NGS tests.

CMS has proposed a NCD for NGS tests intended to inform treatment decisions for patients with recurrent, metastatic, or advanced stage IV cancer who have not been previously tested using the same NGS test and intend to seek further cancer treatment. NGS tests which are FDA-approved companion in vitro diagnostics will qualify for coverage provided that the test is used in a cancer with an FDA-approved companion diagnostic indication. For example, a NGS test approved for the detection of the EML4-ALK fusion gene in lung cancer would be covered for that indication only and not for detection of other genes not in the initial FDA approval. Coverage is also dependent upon the test providing an FDA-approved report of test results to the treating physician that specifies the FDA-indicated treatment options for the patient’s cancer based upon the results of the test and be used in treatment selection. We interpret this test result requirement to mean that the test results must be provided with interpretation of result in an FDA-approved format and not that coverage is dependent upon the biomarker status of the patient as determined by the test. We believe this test result requirement to be an appropriate component of the NCD provided this interpretation is correct. Only NGS tests which meet these requirements and are used for the described population will be covered under the proposed NCD. The NCD specifically identifies FDA-approved companion diagnostics for coverage, referencing the Premarket Approval (PMA) pathway which the FDA utilizes to review Class III devices or Class I/II devices with no existing predicate device. The specific terminology used suggests that FDA-cleared NGS tests, those which utilized the 510(k) pathway for Class II devices based upon substantial equivalence to a predicate device, would not be covered under this proposed NCD. However, an additional provision is outlined in which FDA-approved or cleared NGS tests can receive coverage with evidence development (CED) provided there is adherence to certain provisions.

To qualify for CED, a test must be an FDA cleared or approved in vitro diagnostic, provide a report of results to the treating physician for use in management of the patient’s cancer, and be registered in the NIH Genetic Testing Registry (GTR). The patient receiving the test and the laboratory providing the NGS test must both be enrolled in a registry collecting data to track overall survival, progression free survival, objective response rate, and patient-reported outcomes of symptomatic toxicity in clinical trials. The registry must be able to identify the patient’s cancer type, stage, and extent of invasion and metastasis, and have an analysis to address all CED questions patient outcomes compared to clinical validation of the companion diagnostic and how clinical characteristics of registry patients affect clinical endpoints. The proposed NCD does not specify the intended use for this data collection, the timeframe for data evaluation, or the level of evidence collection required for a final coverage determination. Finally, for those NGS tests that are not FDA-approved or cleared, CED is only available if the test provides a report to a treating physician to aid in management of a patient’s care, is registered in the GTR, and is provided for patients as a diagnostic test within an NIH-NCI National Clinical Trial Network clinical trial. NGS tests that are developed to be similar to an FDA approved test by an individual laboratory for use only by that laboratory, often referred to as laboratory developed tests (LDTs), would not qualify for coverage under the requirements of this category unless the sponsor undertook the additional steps to receive FDA-clearance or approval. It is important to note that, while the decision memo acknowledges the many techniques currently utilized in the diagnosis and genetic analysis of cancer, this NCD will stipulate coverage requirements for NGS only and will not alter coverage for tests using other laboratory diagnostic techniques.

NGS is a powerful laboratory approach which represents a new gold standard for genetic diagnosis of cancer. Friends applauds CMS for its recognition of the importance of this transformative technology within the cancer community through its proposal of a NCD. However, to ensure optimal benefit of these tests, patients and providers must have assurance of the accuracy of diagnostic results and confidence in the treatment decisions based on these results. This NCD provides an opportunity to ensure that patients receive high-quality diagnostic testing that provides accurate information to guide treatment selection. We suggest the following points for consideration as CMS finalizes the NCD for NGS tests.

• Emerging Data on New Targets. CMS should consider expanding coverage requirements of NGS tests beyond only FDA-approved companion in vitro diagnostics for FDA-approved companion diagnostic indications in cancer. NGS technology makes these test platforms highly amenable to modifications that improve and expand upon current capabilities but for which requiring subsequent PMA could be unnecessary and even pose an excessive burden on patients to participate in clinical trials. For example, a FDA-approved NGS companion diagnostic test may seek to expand its FDA-approved indication for a target already included on its platform once it became clinically actionable. Under the proposed NCD, that diagnostic test, which had already been demonstrated to meet analytic standards for that target as part of its approval, would not receive coverage without submitting to additional FDA review and approval, which may include additional clinical trials or other, redundant requirements. We recognize that the NCD does provide an alternative pathway for CED in which FDA-cleared or FDA-approved tests that had been modified could be covered while collecting additional data. This path is designed to build evidence for coverage development through an expanded evidence base, but the registry requirements for CED may place additional financial or personnel burden on diagnostic manufacturers and clinical laboratories, which could dis-incentivize innovation. CMS should consider how CED could serve as a model to streamline evidence collection that supports both approvals or modifications to tests, and CMS coverage through registries and real-world data. CED could also help establish a framework to investigate rare genetic alterations through a registry or real-world application. Processes should be developed through which pre-specified modifications⁽¹⁾ could be agreed upon between sponsors and regulatory authorities that include how the use of registry data could support the approval of modifications based on this post-market evidence. For instance, a test developer could develop a pre-specification plan that is agreed upon by the regulatory agency that establishes a protocol and performance metrics that would need to be met to support the modification. Because of the agreed upon pre-specification plan, the modification would not require additional regulatory review. This would avoid unnecessary duplication of efforts and facilitate the development of high quality information.


• Pathway for Ongoing Data Collection. The proposed NCD requires participation of diagnostic test sponsors and patients in a registry for evidence collection to qualify for CED. The collection of post-market data can often provide valuable information that would not otherwise be feasible in a clinical trial, which appears to be the intent of the registry participation and data collection requirement. However, since neither a timeframe nor endpoint for evidence collection and evaluation, including level and quality of evidence required, is specified in the framework, it is unclear how the data collected under CED would contribute to informing future coverage decisions. The absence of this stipulation suggests that the additional registry requirements would exist indefinitely or until the diagnostic sponsor applied for and received FDA approval for the new indication. For many platform modifications, including those that facilitate use in a new indication or patient population, obtaining FDA approval through the PMA process for a new indication of an approved test may be unnecessary, particularly when it is possible to collect sufficient evidence through CED. CMS should consider a mechanism, in partnership with the FDA, that would allow the evaluation of the data collected in the registry and, provided there is sufficient evidence to support use in an additional indication or expanded patient population, approve the new indication for coverage without need for further evidence collection.


• Demonstration of Analytical and Clinical Validity. Academic centers are the most common developers of LDTs and often serve to drive innovation in diagnostic tests. Friends is concerned that, under the proposed NCD, academic centers would be subject to unnecessary requirements that could stifle innovation. Specifically, under this proposal, LDTs would become eligible for coverage only as either an FDA-approved diagnostic after approval of a PMA or for CED after receiving 510(k) clearance. While we appreciate this general approach to encouraging FDA review of analytical and clinical validity of all NGS diagnostic tests, we believe that the requirement of a PMA for coverage of an LDT is not only unnecessary, considering the existence of the 510(k) pathway, but that a clinical study to validate clinical utility for every LDT would pose an undue burden on patients participating in clinical trials. Additional clinical trials or evidence collection are unnecessary for coverage of diagnostic tests certified as analytically and clinically concordant to FDA-approved or cleared tests. Further, another potential unintended consequence of requiring FDA-clearance with CED would be the significant financial and personnel burden placed on clinical laboratories to conduct registries that often are not seeking to benefit financially from sale of the NGS platform. Instead, CMS should consider a mechanism for coverage, not CED, of LDTs based upon comparison to FDA-approved or cleared companion NGS diagnostic tests. CMS has indicated interest in a similar mechanism and referenced newly established regulatory framework at the FDA which would enable a third-party review, namely via New York State Department of Health, to be used for 510(k) clearance. This pathway would indeed streamline the clearance process for LDTs and facilitate faster patient access, however, as proposed, would still only qualify the 510(k) cleared LDT for CED. An alternative approach could be for CMS, in collaboration with FDA, to require minimal analytical performance standards as the baseline for NGS tests and develop acceptable processes for use of clinical samples or adequate reference material that could be used to infer clinical performance.¹ This approach may need to be reserved for well-characterized biomarkers and would be limited by the availability of sufficient reference material. This would reduce the potential variability between NGS tests for well-characterized biomarkers and provide additional incentives to develop high quality reference material. Those NGS tests which meet the minimum analytical performance standards could then be certified as eligible for coverage under the NGS NCD.


• Stipulations for Clinical Trial Sponsors. Regarding the requirement of clinical trial participation, CED is proposed to include NGS tests being used as a diagnostic test within an NIH-NCI NCTN clinical trials only. NGS tests are used to identify patients for both publicly and privately funded trials. Excluding coverage for LDTs in non-NCTN could impact patient access to clinical trials. CMS should consider extending the CED to clinical trials that adhere to the standards of the CED of scientific integrity and relevance to the Medicare population beyond those within the NCTN to include trials conducted by non-governmental entities and public-private research partnerships. CMS should also examine ways to evaluate whether coverage determination under this proposed NCD interferes with patient access to clinical trials and access to appropriate therapies, more generally.


• Coverage for Early Stage Cancers. CMS has proposed coverage of NGS for patients with recurrent, metastatic, or advanced stage IV cancer based upon an extensive review of clinical outcomes in clinical trials for NGS tests. Friends is concerned that isolating coverage to these patients will restrict access of patients with early stage or an initial diagnosis to NGS tests. As noted in the CMS proposal on page 66 of the NCD, there is some evidence that the composition of genetic alterations in recurrent and advanced stage IV cancers may have accumulated in response to initial radiation or chemotherapy.^(2),(3) This may hinder a patient’s ability to receive the targeted treatment most appropriate to the genetic makeup of the individual’s cancer. CMS should consider expanding coverage of NGS for initial diagnosis in addition to recurrent, metastatic, and advanced stage IV cancers to ensure all patients receive the most efficacious treatment.


• Endpoints for Registry Data Collection. The CMS proposal stipulates that CED is dependent upon participation in a prospective registry tracking the following metrics: overall survival (OS), progression free survival (PFS), and objective response rate (ORR) consistent with response evaluation criteria in solid tumors (RECIST). Indeed, OS is the optimal measurement for successful therapy in oncology and PFS and ORR are also valuable indicators of effective treatment, but there are other important metrics that should be considered as well. Specifically, the FDA considers surrogate endpoints, appropriate for the indication and disease setting, in its review for accelerated approval. CMS should consider alternative metrics, including surrogate endpoints, in its review of coverage decisions as well. Additionally, the quality of data collected regarding the inclusion of OS, PFS, and ORR can vary and measures consistent with RECIST may not provide practical information since few physicians use such criteria in routine practice. CMS should consider other endpoints that better reflect the real-world experience with cancer drugs and data collection, such as treatment failure or time to next treatment documented with the reason a new treatment was selected (e.g., toxicity or progression).⁽⁴⁾ In addition, CMS should identify registries that laboratories and practices could participate in that meet the CED requirements as an alternative to establishing an independent registry for each laboratory or institution.


• Collection of Patient-Reported Outcomes. An additional stipulation for an NGS test to be CED requires that “patient-reported outcomes using measurement development to evaluate symptomatic toxicity in patients on cancer clinical trials” be tracked in the registry. Patient-reported outcomes (PROs), which have been investigated primarily in clinical trials and, even in the setting of well controlled trials, can be difficult to collect and interpret. This is, in part, due to a lack of guidelines and standardized methods for collection. This requirement raises questions regarding what will be collected and how the registry data will be utilized. Further, it is likely that barriers or impediments unique to PRO collection in a registry will be encountered. While Friends is very supportive of collecting quality of life data that is important to patients, CMS should consider outlining what types of PRO data would be most valuable when evaluating the collected data to ensure it is meaningful.


• NCD Phase-in Period. Once finalized, the NCD will supersede local coverage decisions regarding NGS tests, some of which include coverage of some LDTs. Clarification is needed regarding the time periods for implementation of the NCD proposed by CMS as this could negatively impact clinical laboratories utilizing LDTs. It would be preferred for CMS to outline a phase-in period for which the NCD would gradually replace local coverage determinations with allowances for clinical laboratories to gather supporting evidence sufficient to transition under the NCD. CMS should also consider evaluating whether LDT data submitted for local coverage determination could suffice for their inclusion in the NCD.

While Friends is supportive of the intent of this proposal, we believe there are several areas that could benefit from additional clarity. When finalizing this document, CMS should ultimately ensure that patients are receiving high-quality NGS tests and that access is not compromised.

(1) Friends-Alexandria Blueprint Forum Whitepaper. Charting the Course for Precision Medicine: Adopting Consensus Analytical Standards and Streamlining Approval Pathways for Post-Market Modifications for NGS Tests in Oncology. https://www.focr.org/sites/default/files/pdf/Friends_Alexandria%20White%20Paper_Final.pdf (Accessed Dec. 20, 2017)

(2) Meric-Bernstam F, Brusco L, Shaw K, et al. Feasibility of large-scale genomic testing to facilitate enrollment onto genomically matched clinical trials. J Clin Oncol. 2015;33(25):2753-2762.

(3) Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol., 2017; 18(1):75-87. doi: 10.1016/S1470-2045(16)30559-9. PMID: 27908594.

(4) Friends-Alexandria Blueprint Forum Whitepaper. Blueprint for Breakthrough: Exploring the Utility of Real World Evidence. https://www.focr.org/sites/default/files/pdf/RWE%20-%20Project%20PRE-MEETING%20DRAFT.pdf (Accessed Dec. 20, 2017)

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Comments on CMS’s Proposed NCD for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer

As director of the Hollings Cancer Center at the Medical University of South Carolina, I appreciate the opportunity to comment on the proposed decision memo on Next Generation Sequencing for Medicare beneficiaries with advanced cancer. The concerns we outline below also include the perspectives of Dr. Steven Carroll, professor and chair of MUSC’s Department of Pathology and Laboratory Medicine.

The CMS has proposed a NCD issued in conjunction with the FDA approval of a FoundationOne CDx (F1CDx) NGS test as in vitro diagnostic. However, the draft NCD proposes a coverage policy that has implications that reach far beyond the F1CDx test. Specifically, the proposed NCD limits coverage only to FDA approved NGS tests with companion diagnostic indications, imposes very narrow criteria for coverage with evidence development, and makes explicit a policy of non-coverage for NGS tests if the test does not meet the criteria listed in the proposed NCD.

At present, most academic centers and leading cancer institutions have Clinical Laboratories Improvement Amendment (CLIA) certified laboratories that provide validated laboratory developed NGS tests. The proposed NCD would supersede existing local coverage policies for most of those tests and will limit Medicare beneficiaries’ access to a single test from a single commercial laboratory (i.e., it will establish a monopoly solely designed to benefit FoundationOne). Consequently, this proposed coverage policy is unnecessarily restrictive. The F1CDx test is absolutely not the only clinically acceptable test for patients with advanced cancer. The F1CDx test is also not the only test that has been demonstrated to be of high quality by peer review and or that is offered with existing regulatory oversight through the CLIA and CAP laboratory inspection and accreditation processes.

Precision oncology is a medical practice that occurs at a local level and involves interactions between local healthcare professionals including molecular pathologists. Our flexibility for triaging urgent patient samples, to discuss in depth the findings at local tumor boards with a multidisciplinary team, and to participate in quality improvement initiatives specific to institutions will all be lost if testing is effectively centralized to one laboratory as proposed by the NCD. Also, the opportunity to ensure that the next generation of oncologists, pathologists and other healthcare professionals fully understand the utility of these tests in clinical practice will be diminished.

The overly restrictive nature of the draft NCD will curb innovation. As this is an area where science is advancing rapidly, good coverage policy must be able to adapt to advances in understanding of the science and clinical applications. Because NCDs are difficult to modify, in such an area of rapidly advancing science, this NCD will be a barrier to advancing medical practice.

The NCD requirement of achieving FDA approval for coverage is also inconsistent with the FDA’s position on enforcement discretion for laboratory developed testing procedures (LDPs). In 2016, the FDA announced that it does not intend to finalize the draft guidance establishing a framework to regulate LDPs. Rather, the NCD requirement of FDA approval for coverage establishes the FDA as determining the regulatory bar for acceptable clinical tests and thereby the practice of medicine. FDA approval is impractical or impossible for most clinical laboratories to reach, including those in many leading academic medical centers and cancer programs. Laboratories cannot sustain clinical services without reimbursement and, therefore, could not offer NGS tests to patients with advanced cancer.

NGS is a technology, not a diagnostic test. This NCD is not tied either to a specific biomarker or specific CPT code. This approach is inconsistent with established coverage determinations, which are based on the clinical utility of a proven effective biomarker, independent of test methodology and whether a test has received regulatory approval for marketing and labeling. If finalized, it will disrupt existing local coverage policies for more targeted panels and specific CPT codes.

If there’s any way we can answer any questions or be a further resource, please feel free to contact us.

Sincerely,

Gustavo W. Leone, PhD
Director, Hollings Cancer Center

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January 16, 2018

Seema Verma
Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
200 Independence Ave, S.W.
Washington, DC 20201

RE: Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

Dear Administrator Verma:

The American Society of Clinical Oncology (ASCO) is pleased to offer these comments in response to the proposed decision memo regarding a National Coverage Determination (NCD) titled Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer. ASCO is the national organization representing over 42,000 physicians and other healthcare professionals specializing in cancer treatment, diagnosis, and prevention. ASCO members are also dedicated to conducting research that leads to improved patient outcomes, and we are committed to ensuring that evidence-based practices for prevention, diagnosis, and treatment of cancer are available to all Americans, including Medicare enrollees.

ASCO commends CMS’s clear intent to ensure consistency in the reimbursement and performance of Next Generation Sequencing (NGS) diagnostics used in the care of Medicare beneficiaries with advanced cancers. Sophisticated, biomarker-targeted therapies are being increasingly administered to such patients based on abnormalities identified in NGS tests. ASCO supports holding such high-risk tests to a high regulatory standard in order to ensure that physicians and patients have reliable information for clinical decision-making and to advance our understanding of precision medicine.

ASCO also strongly supports provisions to ensure ongoing coverage with evidence development (CED) of other use cases of NGS tests, including when used in clinical trials and with prospective clinical registries. CED programs serve the dual purpose of enabling patient access to emerging NGS tests while also collecting data on how these tests are used to inform clinical decision-making and their impact on patient outcomes. More broadly, these CED provisions could also serve to further advance the field of cancer research through more explicit annotation of test characteristics and performance that will be essential to accurately characterize emerging connections between biomarker targets, associated therapies, and patient outcomes.

ASCO believes that the NCD could be improved by addressing specific concerns and points of clarification, as outlined below.

CMS should ensure this NCD does not disrupt the coverage and delivery of cancer care. Requirements for CED should be broadened to include NGS tests performed in laboratories that are both CLIA-certified and accredited by the College of American Pathologists (CAP) or other molecular laboratory accreditation organizations with deemed status from CMS. Existing local coverage determinations (LCDs) for NGS tests should also remain in effect.

The NCD as written currently restricts CED, outside of a clinical trial, to FDA-approved or -cleared NGS tests. While ASCO supports increased oversight of NGS tests directing cancer therapy, a more flexible framework is critical to the clinical research enterprise and to support the rapid development of necessary evidence on the clinical utility of NGS tests. Requirements for CED should be broadened in order for NGS tests to develop the data to justify full coverage as well as FDA clearance. NGS tests used in the clinical research setting are often rapidly improved upon at their respective institutions based on emerging data. To that end, the scope of CED defined under B(2)(a) of the draft decision memo should be expanded to include any NGS tests performed in laboratories that are both CLIA-certified and accredited by organizations with deemed status from CMS. Such additional accreditation is recognized as an improvement over existing CLIA requirements for laboratory testing used in patient care, and ensures that NGS tests used in a clinical setting are of high quality and analytical validity.

Additionally, without a defined timeline for implementation, it is not clear how quickly a sufficient number of NGS tests could be brought into compliance with the NCD, as written. Patients and oncology care specialists already frequently rely on NGS tests performed at their hospital or affiliated lab (institutional or commercial) to identify treatment options and determine eligibility for clinical trials. Oncologists are often able to take advantage of reviewing and analyzing the information directly with expert pathologists who are performing these tests, something of high value given the complexity of their interpretation in many cases. Some of these NGS tests are currently approved for coverage at the LCD level, and would fall outside the scope of the proposed NCD. Rather than issue a national non-coverage determination, ASCO would urge CMS to allow these LCDs to remain in place to prevent any disruptions in coverage and delivery of cancer care.

CMS should carefully consider the impact of proposed non-coverage language, including non-coverage of repeat NGS testing.

Proposed non-coverage of repeat NGS testing is problematic – particularly if the medical and clinical context are not taken into consideration. As written, the NCD language that the “patient has not been previously tested using the same NGS test” is ambiguous and could preclude coverage of medically appropriate re-testing and therefore coverage and access to treatment. ASCO clinical practice guidelines generally counsel clinicians and patients that repeat testing is not required for most patients, but some specific clinical circumstances clearly warrant repeat tests. For example, a previously tested primary tumor sample could differ genetically from a new metastatic lesion. In addition, the genomic features of a tumor may change in response to a therapy, and additional testing may be required to determine a course of therapy after non-curative treatment or recurrence. In many cases repeating the “same” NGS test is preferred so that changes in the tumor genomic profile over time can be more readily identified. If different tests are used it may be more difficult to determine if a newly detected alteration was present previously or not.

The decision to re-test and treat in these scenarios should be based on scientific evidence and clinical judgement, without impediments due to coverage or reimbursement policies. Additional clarification on what constitutes re-testing a patient sample with “the same NGS test” would help avoid such impediments. Whether this would only apply to a single NGS test used repeatedly, or also to similar tests of the same analytes or to updated versions of the original test including additional analytes, is not clear.

Similarly, the concluding non-coverage clause of the NCD for all other NGS testing highlights the need for careful consideration of the issues outlined above. CMS could accomplish its goal of facilitating consistent reimbursement and appropriate use of NGS tests to direct patient care solely through the incentives outlined in the NCD. Inclusion of the non-coverage clause could potentially introduce unnecessary impediments to access to medically necessary testing and treatment.

CMS should further clarify and refine several requirements related to CED. Screening NGS tests used to qualify patients for trial participation should be broadly covered. The scope of eligible trials should not be narrowed beyond existing CMS policy for qualifying clinical trials. CED requirements should not substantially restrict access to medically appropriate testing and treatment.

While ASCO appreciates and supports the inclusion of CED for NGS tests used in clinical trials, the requirements for such coverage should be clarified and refined. Section B(2)(b) of the draft decision memo appears to permit inclusion of NGS tests beyond those that are an “FDA cleared or approved in vitro diagnostic,” so long as the other requirements of B(2)(b) are met. However, we would appreciate greater clarity on this point, particularly the intent of the word “within” a qualifying clinical trial. Specifically, ASCO interprets this section to mean that qualifying clinical trials would have coverage of NGS tests that are required to qualify a patient for the clinical trial –whether the test is offered “within” the trial or required by the trial- even if they are not FDA cleared or approved in vitro diagnostics. ASCO supports broad interpretation of the language.

CMS’s intent also appears to broadly cover the use of screening NGS tests to facilitate enrollment onto therapeutic clinical trials. However, coverage of tests used to screen patients for a trial, but who do not ultimately enroll, is not explicitly mentioned. As above, ASCO would urge that all such tests be included for CED, in order to facilitate trial enrollment and remove the potential for unexpected costs for patients. It is also not clear whether the CED requirements would only apply to future trials, or what the expectations are for existing trials whose protocols may not meet the proposed requirements.

ASCO also appreciates CMS’s proposed requirements to ensure the scientific rigor of prospective registries and clinical trials eligible for CED. However, we believe that CED for NGS tests should be inclusive enough to permit broad participation, without abandoning existing standards of scientific rigor. As written, many of the requirements in subsection B(2) of the decision summary could significantly restrict CED eligibility and, by extension, severely constrain our ability to learn about the usefulness of NGS in different clinical circumstances. For example, restricting the scope of CED-eligible trials to only National Clinical Trial Network studies, as in subsection B(2)(b)(i), is overly narrow and would exclude many other high quality, rigorously reviewed clinical trials from participation in CED, including commercially-sponsored trials conducted under IND as well as IND or IND-exempt trials conducted by not-for-profit research institutions and foundations.

Additionally, the list of data collection requirements for CED in subsection B(2), while well-intentioned, presents another significant obstacle to qualification for CED under this NCD. Such requirements will have a negative impact on access to testing and treatment, particularly for oncologists practicing in the community. For example, requirements for collection of objective response rate through use of the Response Evaluation Criteria in Solid Tumors (RECIST) will largely preclude participation outside of academic medical centers or research-focused institutions. RECIST can be a valuable tool within clinical trials, but is overly burdensome in the context of prospective registries that could instead rely on documentation of response by the treating oncologist.

The additional requirements listed in section B(2)(c) are duplicative and unnecessary. As was the case with a 2006 draft decision memo (CAG-00071R2) proposing additional standards for the qualification process for clinical trials under Medicare, we believe current policy remains sufficient to ensure the scientific integrity of clinical research, including CED. The 2007 NCD on clinical trials reflects this consensus view that a broad definition of qualifying study designs should support robust clinical research programs. For these reasons, the 2007 standards for clinical research should be referenced as necessary for the CED portions of the NGS NCD, in place of the current list of requirements in subsection B(2)(c).

CMS should work with the FDA to better outline the requirements of any NGS test submitted by an entity seeking FDA approval or clearance per the proposed NCD.

ASCO urges CMS to work with FDA to better outline the requirements of any NGS test submitted by an entity seeking FDA approval or clearance to secure coverage per the proposed NCD. Setting aside applying for a complete pre-market review by FDA, the regulatory pathway for demonstrating equivalence to an FDA-approved NGS diagnostic is not clear, and can require substantial time and resources to fulfil. The relationship between CMS’s requirements for CED; FDA’s existing framework for biomarker validation in NGS tests; and the role of third-party approvers to expedite approval decisions warrants further clarification.

ASCO interprets this NCD as an attempt by CMS to broaden and standardize coverage of NGS somatic genomic testing and ensure that non-covered testing is done in a research context where we can increase our knowledge of this rapidly expanding field. While we generally support this goal, we have significant concerns that the proposed NCD might constrain research on potentially useful tests due to excessively burdensome data collection requirements and thereby limit patient access to all but a few NGS tests that have received FDA clearance. We hope that our comments will inform thoughtful improvements to the draft NCD to ensure medically appropriate access to these tests and associated therapies. Thank you for your willingness to consider our comment on the proposed decision memo. Please contact Sybil Green at Sybil.Green@asco.org with any questions.

Sincerely,

Bruce E. Johnson, MD, FASCO
President, American Society of Clinical Oncology

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Like many academic laboratories, we offer lab-developed procedures for somatic variant detection, classification and clinical reporting. We are regulated under CLIA and although it is not FDA approved or cleared, the FDA has determined that such approval or clearance is not necessary.
The results of clinical testing at our laboratory are just as valid as those performed elsewhere. Moreover, by performing such testing in-house, we can continually improve testing to meet changing needs (e.g. new targets), offer consultation to clinicians, educate and train the next generation of clinicians and laboratory professionals.
But maybe you've heard this from others so I'll leave you with one more thought—the current cancer panels were built for adult tumors. they are not intended nor appropriate for pediatric tumors. Even if someone comes out with a pediatric panel that gets FDA clearance, there will always be a subset for whom the latest test is less optimal.

this proposal will negatively affect patient care as well as the education and training of the next generation.

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My names is Merita Carroll and I am a [PHI Redacted] patient advocate with, and founder of ALK Positive, a support group for ALK-positive lung cancer patients (https://www.alkpositive.org/).

[PHI Redacted]

[PHI Redacted]

This can and will never happen under this new policy. I cannot believe Medicare is in the business of delivering a death blow to their patients. Please reconsider your position in this matter.

Thank you for the opportunity to provide comment on the National Coverage Analysis entitled ‘Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer’. Cancer patients all over the country are benefitting from new knowledge in the genomic causes and drivers of cancer, as evidenced by increased access to personalized therapeutics and care based on the genetic makeup of cancer. We are grateful for advances in diagnostic technologies, such as next generation sequencing, as it is one tool to obtain a more comprehensive genetic understanding of cancer. This technology is of particular relevance to lung cancer patients as it typically requires less tissue sample than separate sequencing of multiple genes. I thank CMS for recognizing the value of precision diagnostics in the care of cancer patients by proposing coverage for FoundationOne CDx (F1CDx). I support a positive coverage determination for the product reviewed in the Parallel Review program, F1CDx, however I have serious concerns about the broad scope of the proposed NCD. The proposed policy would limit cancer patients to 1 test per lifetime, which is not in line with the realities of personalized medicine based therapy for cancer patients. Also, the new policy will eliminate coverage for other NGS tests for advanced cancer patients enrolled in Medicare. These tests are currently being used to deliver high-quality, advanced cancer care across the country, including at virtually all major cancer centers and academic institutions. I support CMS’ proposal to cover the F1CDx test but urge CMS not to finalize the rest of the policy as it will result in several unintended negative consequences to cancer patients by erasing important medical advances and existing local coverage policies already in place.

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As a provider seeing a large volume of patients with advanced malignancies, I have the chance to experience, on a daily basis, the power of targeted therapies for patients with alterations that have been revealed by molecular profiling. From ALK, to ROS1, to TRK, finding these alterations leads to more effective and better tolerated therapies that otherwise would not be considered for these patients.

Patients benefit not just in quantity of life, but in quality of life and the ability to continue to spend time with family, continue to work, and continue to live a meaningful life.

Please consider the benefit to patients as you make your decision!

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January 17th, 2018

To: Centers for Medicare and Medicaid Services and Food and Drug Administration

To Whom It May Concern:

Fight Colorectal Cancer (Fight CRC), with input from members of our Medical Advisory Board, appreciates the opportunity to publicly comment on the proposed decision guideline for next generation sequencing (NGS) for Medicare beneficiaries with advanced cancer.

Fight Colorectal Cancer (Fight CRC) is the United States’ leading advocacy-focused colorectal cancer nonprofit. We envision victory over colon and rectal cancers. We serve as a resource for advocates, policymakers and medical professionals. Additionally, we lead efforts to increase and improve research of colorectal cancer at all stages and throughout the cancer continuum.

This proposed decision is a monumental step towards access to healthcare coverage for a large portion of the US population. Prior to the decision by the FDA and CMS, the process to receive NGS tests was fraught with difficulties such as access to testing, complex filing systems between patients and hospital systems, which often resulted in patients absorbing the costs. The quality and access of testing was variable and often not available to patients outside of academic medical settings. This decision allows for more routine, quality testing for Medicare beneficiaries, and as a leader in patient advocacy, we strongly support opportunities to increase access to healthcare.

As treatment decisions are often guided by diagnostic tests, the accuracy of the tests is as important as the efficacy of the treatment. To that end, we support the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N), with some comments and requests for clarification.

In the current Memo, patients with metastatic colorectal cancer will have coverage per the following guidelines:

We would appreciate a clarification on the following item and also wish to express our concerns:

“Patient has not been previously tested using the same NGS test”

This statement implies that a patient tested with one NGS test would not be able to be tested with the same test, but it’s not clear whether the patient would be able to be tested with a different test. This lack of clarity is concerning. In addition, there are growing data that suggests that primary tumors and metastatic disease have very different genetic profiles, and thus if a patient had initial testing, repeat testing of metastatic disease may be appropriate. Furthermore, for metastatic disease patients, overtime tumor genetic profiles change and it may be appropriate to repeat NGS testing for patients to guide future treatment decisions. Therefore, additional tests may be very appropriate, if not under Coverage then under Coverage with Evidence Development (CED).

Cancer patients, including CRC patients, often receive a combination of routine care or through a clinical trial. Consider this situation: a colorectal cancer patient received a covered NGS test shortly after diagnosis as part of routine care. Two years later, the patient is considering a clinical trial which requires a current NGS test as part of the entry criteria, and one of the CED NGS tests is an option. Would this patient be able to receive a second NGS test as part of the clinical trials?

We suggest that the issue of >1 test on the same patient be re-examined with these comments in mind.

A growing number of companion diagnostics being developed for specific drugs. This topic was discussed in a 2015 FDA-AACR-ASCO workshop (http://blog.aacr.org/fda-aacr-asco-workshop-complexities-in-personalized-medicine-harmonizing-companion-diagnostics/) where the number of PD/PD1 drugs and companion diagnostics was used as an example. Please consider the situation where an anti-PD and companion diagnostic is approved for patients with metastatic colorectal cancer. Our assumption is that the covered NGS tests will include some version of the companion diagnostic; however, it may not be as specific as the companion diagnostic.

Specific Questions:
Will patients have access to both the covered NGS test and the companion diagnostic?
Will physicians assume that the test on the covered NGS test is the same as the companion diagnostic?
This issue is complex and probably beyond the scope of this Memo; however, we believe that it’s critical to consider the actual patient – physician interaction as the number of look-alike drugs / diagnostics increases.

In addition, we have heard concerns from many of our academic researchers regarding the impact this Coverage decision may have on academic pathology labs and patient impact. We acknowledge their concerns, as we believe that patients are best served when both academic and corporate research thrive. If this decision leads to the closing of pathology labs, especially at research centers, we are concerned this may create a limitation in quality and access to some patients.

Regarding the Memo and the discussion of CED, we strongly support the requirement that the tests be covered if data is gathered. This data will help assess the actual clinical validity of the NGS tests. We appreciate the partnership of CMS with the NCI NCTN network trials, because CED of these tests will help these critical trials accrue more patients over the age of 65.

In the process of reviewing this issue with our Medical Advisory Board, collection of registry data was noted as a potential laborious step for physicians; particularly physicians who don’t routinely participate in research. We suggest the entities supporting this initiative might work with practitioners to examine novel ways to populate the registries – for example, by automating extraction of information from the electronic health records. Similarly, there are concerns about the patient-reported outcomes data requirement. Unfortunately, there is a growing demand on clinicians in terms of utilizing electronic medical records, which can become costly and timely. While collecting data is a necessary step, it is crucial to find an efficient way to do so. The administrative and data gathering time, is reducing the amount of time clinicians truly can dedicate to the art of medicine and one-on-one time with patients.

A specific consideration, is as it’s common for newly-approved drugs to enter registry trials, as a way to evaluate their impact in a more real-world setting (Genentech has a history of such registries). Perhaps there are lessons learned in the drug world which could be applied to the device world and this is a discrete example.

Based on our experience with the patient community and leading experts guiding care, the above comments encapsulate the most pressing concerns which reflect the perspective of colorectal cancer patients. By in large, we feel this coverage announcement provides further opportunities to improve these types of tests, ultimately keeping the patient’s best interest in mind.

We support the proposed decision memo and understand it is an important next step for expanding coverage for Medicare beneficiaries with Advanced Cancer. Ultimately, we hope that our comments on the proposed guideline will lead to better diagnostics and treatment options for patients.

Thank you for allowing an opportunity to comment and taking into consideration our comments and concerns.

Sincerely,

Anjee Davis, MPPA
President
Fight Colorectal Cancer

Fight Colorectal Cancer believes in fully disclosing all potential conflicts of interest. As an organization, we have received sponsorships and/or educational grants from companies who have an interest in novel screening methods for colorectal cancer, including: Foundation One, Caris, Genomic Health, and Quest. It is important to note however that none of these companies or additional sponsors have influenced the following comments.

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Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244
Re: NCD CAG-00450N

ArcherDX, Inc (ArcherDX) appreciates the opportunity to respectfully submit the following comments in response to the “Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer” National Coverage Analysis (NCD).

ArcherDX applauds insurers, including CMS, in recognizing the clinical importance of NGS testing in advanced stage cancer patients. Furthermore, we recognize and appreciate the need for oversight as applied to the quality of testing performed for patients suffering from cancer. Like many others, however, we believe the policy as drafted will have a negative impact on patient care.

As written, we believe that this guidance will establish a new qualification standard for coverage decisions. Current Clinical Laboratory Improvement Amendments of 1988 (CLIA) guidelines outline the requirements for testing to support diagnosis, treatment and management of medical conditions including laboratory developed tests (LDTs). As is currently practiced, the CLIA statutes establish the requirements for analytical validity of laboratory tests and set the standard for CLIA certified laboratories and current laboratory practice. The Institute of Medicine (IOM) report referenced in the Proposed Decision Memo concludes that the path forward to ensure adequate validation of clinical testing is the current CLIA certification statutes. Moreover, these regulations are employed for several complex tests that are reimbursed by Medicare, such as OncotypeDx for breast cancer, Veristrat for lung cancer, and several tests for inherited genetic diseases. We believe that requiring FDA clearance for oncology related NGS testing alters the current standards for LDT implementation in clinical laboratories, and as such, creates unequal standards for reimbursement applied to laboratory testing.

Additionally, we believe the requirement that oncology related NGS testing be FDA cleared before reimbursed by Medicare will unintentionally limit access to NGS for patients. At least some of the FDA cleared technologies are offered as a service and not distributed kits. This could create a near-monopoly provider scenario where Medicare patients would be forced to use one of a few possible vendors for NGS testing. This issue is heightened as hundreds of molecular laboratories across the US provide clinically validated NGS services under CLIA. These may range in scope from small, tumor specific gene DNA panels to tumor agnostic expanded comprehensive genomic profiling (CGP). The proposed NCD would force samples to be sent to only a few sites adding time, cost, and restricting testing access.

The requirement for FDA cleared tests may also stifle innovation and promote tests that are not in the best interest of patients. While we ourselves are in the process of pursing FDA approval for an NGS-based CDx, we understand the notion that a single test will be insufficient for all types and indications of cancer. History teaches us that the preceding molecular technologies to NGS matured under a much more broad development path than the one that is proposed here, including reimbursement for LDTs prior to FDA approval. Contrary to the stance in this draft coverage proposal, we believe FDA’s recent accreditation of the New York State Department of Health (NYSDOH) as a third party reviewer for in vitro diagnostics will not fundamentally alter the approval requirements.

Of particular concern is the assumption that all clinical assay technologies utilized in NGS testing are equally sufficient for all types of cancer driver mutations. This may result in technologies with poor clinical sensitivity increasing the cost of health care overall with false negative results. While available, non-cleared technologies would be preferred due to their ability to detect the relevant mutation. In addition, alternate test methods offer other advantages such as discerning false positive, PCR errors, relevant gene fusion translocations, or have lower input requirements. Coverage solely for the proposed tests will have a negative impact on NGS capabilities in the clinic. Driving technology usage through payment criteria and ignoring the potential of missing a diagnosis is not in the patient’s best interest. Additionally, as new variants are discovered in genes with approved assays, these variants would require FDA submission and approval prior to availability for testing and reimbursement under this proposal. Forcing labs to utilize often-outdated FDA IVD testing kits run counter to both scientific and clinical advances. By doing so, we feel this NCD as currently written puts unnecessary restrictions in place for labs attempting to provide the best patient care per their scientific and clinical judgment.

Finally, the proposed restriction within this NCD is for a one-time coverage of late stage cancers only. The cancers specifically outlined in this coverage policy are aggressive and their genomics evolve based on therapeutic pressures. While a majority of tumors seen for genomic testing do include non-small cell lung cancer (NSCLC), melanoma, breast and colorectal cancer, and ovarian, there are many others such as sarcomas, glioblastomas (GBM) and hematologic malignancies for which NGS testing is not only vital from a therapeutic care perspective, but also from a differential diagnostic and prognostic perspective. As such, we believe it should be up to the treating physician to exercise his or her clinical judgment whether and when to perform NGS-based analysis. This proposed NCD puts these Medicare patients and their treating physicians in a precarious position where information is desperately needed and sought, but testing will not be reimbursed.

As an NGS industry partner, we will always support our Molecular Laboratory colleagues. We feel strongly that patients and their providers have the right to the most advanced and cost-effective NGS testing solutions available that maximize therapeutic value. This proposed NCD as currently written seems to run counter to industry progress and creates perception of industry-influenced monopolies. We feel this particular NCD should be focused specifically on coverage of comprehensive genomic profile testing with F1CDx and Oncomine Dx Tests initiated by Foundation Medicine and not to determine whether or not all diagnostic laboratory tests using NGS may be covered nationally under the Medicare program.

We appreciate your considerations of these comments and look forward to your response.

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Title: Laboratory Manager
Organization: UMass Memorial Medical Center, Diagnostic Molecular Oncology Lab
Date: 1/16/2018

As a laboratory manager in molecular diagnostics, I have concerns about the negative impact I foresee with the CMS proposed national coverage determination (NCD) for next generation sequencing. I have had the privilege to be heavily involved with our in-house NGS implementation, which has proven to be a powerful tool for Oncologists, Pathologists, and Faculty. Due to the location of our lab, we do not have direct patient interaction, however, this doesn’t hinder our daily communication with treating oncologists who often have anxious patients awaiting their NGS results. We have the fortunate ability and bandwidth to alter our workflow to expedite patient results, and to have results available for presentation at tumor board. This flexibility, and quality care, may become impossible due to the influx of volume with only one or two labs doing the testing, especially if hospital labs dissolve due to the NCD requirements.

I sense cancer patients and their Oncologists have ample red tape to process, which is why I advocate for an in-house NGS resource especially for difficult cases, limited samples, and expedition of results. Many academic institutions around the country provide swift, high quality NGS results with LDTs and might be constrained by the pitfalls that can inherently occur when a monopoly is suddenly formed. I fear this may come to fruition if the NCD is allowed to proceed with the terms proposed. An institution’s ability to maintain control of samples collected on-site, as well as, using a disciplinary team to decide on NGS and ancillary testing, is often pivotal in providing Medicare patients with quality care. With reimbursement rates slowly shrinking and the strict CMS requirements listed out in the NCD, unknowing Medicare patients will be the individuals suffering the consequences.

Think about your health and that of your loved ones, and ask yourself, how quickly do you want a diagnosis and review of treatment options? Would you want a family member, friend, co-worker, neighbor, or just a familiar face to have the unnecessary burden of waiting for one or two testing facilities countrywide to process and complete testing in a timely manner on their specimen? I think the answers to these questions are evident and warrant a careful review of the proposed NCD which will have unfavorable outcomes for Medicare patients. Fighting cancer is a hard enough battle without blocking avenues for rapid, accurate NGS testing, which hospitals and academic centers currently provide. Passing the new proposed NCD guidelines would be a travesty that many cancer patients may not overcome.

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January 17, 2018

Ms. Seema Verma
Administrator
Centers for Medicare & Medicaid Services
Hubert H. Humphrey Building
200 Independence Avenue, S.W., Room 445-G
Washington, DC 20201

BY ELECTRONIC DELIVERY

Re: CAG-00450N – Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer

Dear Ms. Verma:

Dartmouth-Hitchcock Health is pleased to submit comments on the Centers for Medicare & Medicaid Services’ (CMS) Proposed Decision Memo for Next Generation Sequencing for Medicare Beneficiaries with Advanced Cancer. As the Director of the Laboratory for Clinical Genomics and Advanced Technology at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, I am specifically concerned about the CMS proposal and its impact to our patients which could result in longer wait times to receive life-saving therapy as well as higher medical costs.

Dartmouth-Hitchcock Health is a nonprofit academic health system that services a population of 1.9 million in northern New England. Our largest hospital, Mary Hitchcock Memorial Hospital, is a CMS designated Sole Community Hospital and serves as the safety net hospital for New Hampshire and southern Vermont, treating some of the region’s most vulnerable patients. Despite decreasing reimbursement rates, Dartmouth-Hitchcock Health continues to treat all patients with the highest quality of care possible.

Our health system also includes the Norris Cotton Cancer Center, one of only 49 National Cancer Institute designated comprehensive cancer centers in the United States. The Norris Cotton Cancer Center coordinates all cancer care at the Dartmouth-Hitchcock Medical Center, serving more than 32,000 patients annually with a full range of treatment options. With 17 interdisciplinary oncology programs, we strive to bring care as close to home as possible, working with patients’ personal physicians and local specialists to make appropriate therapy available throughout our region. The Cancer Center also has about 250 active research projects supported by more than $68 million in grants each year from federal and other sources.

The Laboratory for Clinical Genomics and Advanced Technology at Dartmouth-Hitchcock is a full service clinical molecular diagnostics laboratory that offers testing for genetic diseases, infectious diseases, hematologic diseases, oncology and pharmacogenomics. Using a variety of molecular biology techniques, including the polymerase chain reaction (PCR), microarrays and next generation sequencing (NGS), we are able to provide state-of-the-art diagnostic testing to an underserved population that would otherwise not have access to this testing. We are the only laboratory in New Hampshire performing many of these tests.

I appreciate that in this proposed National Coverage Determination CMS is recognizing the value of precision oncology diagnostics in the care of cancer patients. However, I am concerned by the narrow scope of the proposal.

Our laboratory meets the highest standards of quality, accuracy and consistency and is accredited by the College of American Pathologists (CAP) and has Clinical Laboratories Improvement Act (CLIA) certification. We currently utilize the NGS assays to help better manage our patients. The tests include all of the actionable mutations recommended in clinical guidelines as well as additional genes. Performing the testing for just a few of the clinically actionable genes as required under the CMS proposal would cost three to four times more than doing a single NGS assay.

In addition to the added costs that would result under the CMS proposal, I am very concerned with the workflow issues that would arise. We currently turn around test results to our oncologist within 10 days of receipt of sample and these results are incorporated into their management decision-making algorithms and timelines for treatment. Requiring prior authorization or the use of specific laboratories would significantly impact patient care and ultimately result in patients not receiving potentially life-saving therapy in a timely manner.

Thank you for consideration of these comments. Please contact me at 603-650-5498 or gregory.j.tsongalis@hitchcock.org with any questions.

Sincerely,

Gregory Tsongalis, PhD, HCLD, CC
Professor of Pathology
Director, Laboratory for Clinical Genomics and Advanced Technology (CGAT)
Department of Pathology and Laboratory Medicine
Dartmouth Hitchcock Medical Center
The Audrey and Theodor Geisel School of Medicine at Dartmouth-Hitchcock

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Dear CMS,

I am Dr. Jeffrey Gagan, MD, PhD, Molecular Genetic Pathology Fellow at Harvard Medical School. Thank you for the opportunity to provide comments on the proposed NCD for NGS assays in advance cancer patients.

During my relatively brief time in medical training, I have already witnessed several large paradigm shifts in how we approach DNA sequencing in oncology. While I agree that the traditional framework of an LDT may not be sufficient to regulate the clinical use of NGS assays, neither is the attempt to approve specific assays a productive way forward.

Regulation needs to focus on the association of a detected analyte and clinical response, not the test itself. Then comparability studies can be performed to make sure new assays perform as well as previously approved ones based on detection of an analyte, not patient outcomes. The current proposed guidelines assumes that NGS is a much more static and mature technology than it currently is.

Second is the Catch 22 of reimbursement. Substantially more data are needed to evaluate clinical utility of NGS testing, but data collection on that scale is impeded by uncertain reimbursement policies. There needs to be a central repository of information that can track associations of detected DNA variants, administered medications and clinical outcomes, with the default being covered diagnostics until the data shows otherwise. Denying molecular diagnostics to patients is akin to undoing much of the progress of oncology over the past decade. The price of targeted therapy can be so high that proper diagnostics will quickly pay for themselves when viewed at the level of the entire medical system. Funneling all testing through a select group of labs that cannot easily alter their assays is not a good way to stay on top of the continual progress being made.

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January 16, 2018

The Honorable Scott Gottlieb, MD
Commissioner
Food and Drug Administration
10903 New Hampshire Avenue, Room 2217
Silver Spring, MD 20993

Ms. Seema Verma
Administrator
Centers for Medicare and Medicaid Services
200 Independence Avenue, SW
Washington, DC 20201

Dear Commissioner Gottlieb and Administrator Verma:

As a patient founded, patient driven and patient led organization the Bonnie J. Addario Lung Cancer Foundation applauds the effort made by the Centers for Medicare and Medicaid (CMS) and Food and Drug Administration (FDA) to ensure approval and coverage of next generation sequencing (NGS) tests for patients. Through our work, and that of our sister foundation the Addario Lung Cancer Medical Institute, we have been at the fore front of promoting, testing, and validating the clinical utility of such tests and have seen first-hand the benefit to patients.

Our foundation is devoted to the rights and aspirations of lung cancer patients, many of whom suffer needlessly and pass away because of the difficulty in identifying the most effective therapy for their particular disease. Science has shown us that each tumor can vary at the molecular level and that two lung cancers, for example, can be different. Genomic tests that can show how a person’s DNA is altered will mean that a patient can receive personalized treatment options that are best for him or her.

Patients need access to this kind of comprehensive genomic testing so that their physicians can match them most quickly and efficiently to the best therapy. While not every patient has a treatment option, NGS testing will arm physicians and give patients their best chance for survival and quality of life. We are excited that your agencies recognize the importance of making these tests safe, affordable and available to every lung cancer patient.

However, as a patient organization, we do have concerns about the draft recommendations as written, much of which has been iterated by other organizations and expressed by the patients themselves, specifically:

• The proposed coverage limit of one NGS test in a patient’s lifetime does not reflect the realities of cancer treatment.
• The NCD places unfair procedural and financial burdens on some patients. Since no one can predict test results in advance, patients will not know these burdens until after they receive test results.
• The NCD places undue requirements and financial burdens on academic cancer centers that have laboratory developed tests (LDTs) with established analytical and clinical validity.
• Small laboratories that are not backed by deep pockets would be subjected to burdens similar to academic cancer centers, and may be forced to withdraw products from the market.
• Many oncogene-driven cancers have small populations that would be unable to support the several simultaneous clinical trials required to validate LDTs.
• 80% of cancer patients are treated in a community setting and the undue requirements within the NCD may limit utilization.
• The decision linking NCD-level coverage to FDA clearance and approval of NGS testing may limit access to comprehensive liquid biopsies. While tissue genotyping is a powerful tool for physicians, there are limitations with the tissue biopsy paradigm. Tissue is unavailable in 20-50% of NSCLC patients, and repeat biopsies can cause harm.

Based on these concerns, we believe it is in the best interest of lung cancer patients to decouple the approval and coverage of the Foundation Medicine F1CDx test, and three in vitro companion diagnostics, from the broader NCD on NGS testing. This will allow for additional dialog and to build a plan that addresses the above concerns. More importantly, this will allow time to develop a standard pathway for all to follow to ensure that patients receive the right test at the right time to guide their care. Thank you for the opportunity to submit comments.

Sincerely,

/s/
Bonnie J. Addario
Bonnie J. Addario Lung Cancer Foundation

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January 12, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

RE: Proposed Decision Memorandum for National Coverage Analysis (NCA) for Next Generation Sequencing (NOS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

Dear Ms. Jensen:

The National Comprehensive Cancer Network® (NCCN®) is pleased to comment on the Proposed Decision Memorandum for National Coverage Analysis (NCA) for Next Generation Sequencing (NOS) for Medicare Beneficiaries with Advanced Cancer, as it relates to NCCN's mission of improving the quality, effectiveness, and efficiency of cancer care so that patients can live better lives.

As an alliance of 27 leading academic cancer centers in the United States that treat hundreds of thousands of cancer patients annually, NCCN is a developer of authoritative information regarding cancer prevention, screening, diagnosis, treahnent, and supportive care that is widely used by clinical professionals. NCCN Clinical Practice Guidelines in Oncology® (NCCN Guidelines®) are the recognized standard for clinical policy in cancer care and are the most thoroughly and frequently updated clinical practice guidelines available in any area of medicine. Since 2008, CMS has recognized the NCCN Drugs & Biologics Compendium (NCCN Compendium®) as a mandated reference for establishment of coverage policy and coverage decisions regarding the use of drugs and biologics in cancer care. The NCCN Guidelines® and their derivatives help ensure access to appropriate care, clinical decision-making, and assessment of quality improvement initiatives. Our guidelines and compendia products are utilized by public and private insurers alike representing more than 75% of covered lives in the United States, and our drug compendia specifically is authorized under Medicare.

NCCN thanks CMS for referencing our Guidelines in the Proposed Decision Memorandum's Discussion of Evidence. As our Guidelines are the most frequently updated clinical practice guidelines available in any area of medicine and innovation is occurring rapidly, we encourage CMS to continue to use NCCN as a resource for coverage determinations.

NCCN believes that the principles articulated in the proposed decision are a good first step toward the advancement of personalized medicine in oncology. However, NCCN does have concerns that the current requirements for Coverage with Evidence Development, as currently outlined in the proposed policy, may create unnecessarily onerous barriers for providers and restrict patient access to high-quality cancer care. Additionally, NCCN seeks further clarification on how the proposed decision would affect existing local coverage determinations (LCD) for NOS-based tests, and potential access implications for necessary diagnostic coverage for these Medicare cancer beneficiaries. NCCN urges CMS to strike any provisions that would eliminate coverage under current LCD' s and rendered in adherence to evidence-based guidelines in order to preserve patient access.

While implementation may present challenges, we believe that these can be overcome with good faith efforts on all sides, working toward improving the lives of Medicare beneficiaries who carry the burden of advanced cancer. NCCN member institutions are at the forefront of cancer diagnosis, treatment, and supportive care and lead the way in conducting ground-breaking research and advancing scientific innovations that are the basis of improved cancer care. These innovations include many in the complex molecular diagnostic space, and all of our member institutions have been leaders in establishing the principles of NOS somatic mutation analysis to guide therapeutic decisions. A strong collaboration with NCCN and our network of Member Institutions will be critical to ensuring a smooth transition under the proposed policy. We would welcome the opportunity to bring our expertise, as well as the expertise of our Member Institutions, to the table in what we anticipate would be collaborative ongoing discussions with CMS and other stakeholders.

Because this is a parallel review decision that stratifies Medicare coverage conditions by FDA regulatory status, we encourage CMS to work with FDA to ensure an efficient, predictable, and transparent implementation. While we recognize that CMS and FDA are separate agencies with distinct authorities under their statutes, recent FDA regulatory actions have also generated questions about the implementation of the eventual NCD. In particular, FDA recognition ofNYSDOH (New York State Department of Health) review and approval of NOS based tests may lead to uncertainty about the path to regulatory clearance for some tests. NCCN feels it is imperative that a path be defined so that our member institution and other high-quality laboratories might be included as participants in the Coverage with Evidence Development (CED) component of the NCD.

A recent commentary by Eisenberg and Varmus (Science December 1, 2017) summarizes the challenges of developing persuasive evidence for broad genomic tests in oncology, and recommends that stakeholders, including federal agencies, collaborate in a CED paradigm. While we are aware of various existing small registries in oncology, none currently exist that can capture the data elements articulated in the proposed NCD. If as a consequence of this proposed NCD multiple competing registries are developed, we believe that siloed data collection could limit our ability to draw the strongest conclusions across the total body of evidence. NCCN has robust experience producing evidence-based recommendations within guidelines that could be used across multiple registries to streamline and organize data. Given our longstanding experience in cancer treatment and in critical review of data, analysis, and dissemination we fully appreciate the challenge.

A new paradigm may be needed to achieve rapid scalability and broad participation. We believe that this could be more readily achieved with collaborative input from stakeholders and program funding support from additional federal agencies such as NIH, NCI, AHRQ, and other relevant agencies.

CMS in recent national coverage decisions has placed emphasis on shared decision making, a concept that incorporates patients' values and priorities in discussions about treatment decisions. This principle is especially relevant in cancer treatment and is supported when patients can more fully understand the anticipated personal impact of a treatment choice, guided by appropriate biomarker testing. Ultimately, their own choices and the treatment recommendations of their physicians should be informed by well-studied tests to maximize the likelihood of benefit and minimize the likelihood of unintended harms.

NCCN again appreciates the opportunity to comment on CMS' Proposed Decision Memorandum NCA for NGS for Medicare beneficiaries with advanced cancer. We would welcome the opportunity to discuss our comments further look forward to working together to ensure access to high quality, high value care for patients with cancer. Thank you for your time and consideration of our comments today.

Sincerely,

/s/
Robert W. Carlson, MD
Chief Executive Officer
National Comprehensive Cancer Network
carlson@nccn.org 215.690.0300

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January 16, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244
Submitted via email: tamara.syrekjensen@cms.hhs.gov and CAGinquiries@cms.hhs.gov.

Dear Ms. Jensen,

PathGroup is pleased to provide comments to the proposed draft National Coverage Determination (NCD) for next generation sequencing in Advanced Cancer (CAG-00450N).  We are glad to see that CMS has taken initial steps to allow for the provision of valuable molecular and genomic testing for patients with cancer and are soliciting public input.

PathGroup is one of the largest privately owned laboratory testing service providers in the United States.  We have over 85 pathologists and PhDs with expertise spanning every subspecialty of pathology including molecular pathology and genomic medicine.  Our physicians and scientists are active members of the College of American Pathologists (CAP), the Association of Molecular Pathology (AMP) and the American College of Medical Genetics and Genomics (ACMG).  Our vast experience in provisioning laboratory services spans multiple states, more than 60 hospitals, hundreds of outpatient practices, and thousands of physicians.  Please find below a summary of our comments and recommendations as it pertains to the questions posed by CMS.

High quality next generation sequencing tests for cancer patients are readily available today in CLIA accredited laboratories across the country, which adhere to evidence based guidelines and best clinical practices.

Next generation sequencing is a promising laboratory technique that allows for cost efficient interrogation of genomic aberrations in cancer tissue (1).  This technique is widely utilized today by more than 100 CLIA-validated clinical diagnostic laboratories during the laboratory work-up of various cancers (2).  Results of next generation sequencing are used in conjunction with other laboratory tests to inform clinical decisions such as diagnosis, prognosis, and/or therapy (2-4).  

In the setting of hematologic malignancies, use of next generation sequencing has become routine practice (3).  Although morphologic examination by light microscopy remains an integral part of initial histopathologic assessment for hematolymphoid neoplasms, a variety of laboratory techniques are now utilized to optimize diagnostic information in the appropriate clinical context.  These techniques include, but are not limited to next generation sequencing, immunohistochemistry, flow cytometry, cytogenetics, fluorescent in situ hybridization (FISH), DNA microarray, and/or single analyte polymerase chain reaction (PCR).  Information rendered from these technologies are critical for the molecular sub-classification of the genetically defined diseases according to evidence- based, standard of care guidelines that are outlined in recent publications (4-5)  and the most recent World Health Organization Classification of hematolymphoid neoplasms (6)

The WHO manuscript is an authoritative text book that provides an international standard for oncologists and pathologists and references more than 4,500 peer reviewed publications.  In addition to providing critically necessary molecular diagnostic classification, this textbook additionally details how genomic information rendered from various laboratory technologies can help establish clonality, provide prognostic risk stratification to optimize therapeutic selection, and can be used in monitoring patient's response to therapy.  Diagnostic criteria, pathological features, and associated genetic alterations are delineated in a strictly disease oriented manner (6). 

Similar evidence based guidelines have also been published across a variety of solid cancers.  For example, the practice of surgical neuropathology increasingly relies on molecular genetic methods to aid in diagnostic molecular classification, prognostic risk stratification, and predicting response to therapy.  The diagnostic workup of diffuse gliomas, medulloblastomas, low-grade circumscribed gliomas, as well as other diseases now routinely incorporates the results of genomic studies such as next generation sequencing (7).  Recognition of the clinical utility of genomic aberrations, such as IDH1 and IDH2 mutations in glioma (8-9), has led to their integration into the consensus, evidence based WHO diagnostic criterial of CNS Neoplasms (10). This evidence-based textbook references more than 2,500 publications, sets the diagnostic standard of care across a wide range of CNS neoplasms, and is utilized by physicians who are involved in diagnosis and management of CNS tumors (10).

As you can appreciate, molecular techniques are integral to the practice of pathology and laboratory medicine and include a variety of testing modalities to detect clinically meaningful changes in DNA, RNA, and protein.  Next generation sequencing is just one of the many laboratory testing modalities that are vital to inform diagnosis, prognosis, and/or therapy.

Over the past 2 years, AMP has published 3 evidence-based guidelines and standards to ensure the delivery of high quality next generation sequencing services, bioinformatics-driven technical and clinical interpretation, and clinical report generation (11-13).  These evidence-based guidelines cover the entire gamut of next generation sequencing workflow and outline steps to assure the delivery of high-quality next generation sequencing services across a wide range of academic and community practices, including this country’s premier and widely respected institutions.  In short, these 3 evidence-based guidelines are a framework for standard of care and best molecular pathology practices for next generation sequencing in the oncology setting. Over 300 peer-reviewed references are incorporated collectively in these 3 evidence based guidelines.  Under CLIA regulation, these high-quality services have been rigorously validated and are currently being rendered to Medicare beneficiaries across the country.

As of 2016, next generation sequencing in cancer is a laboratory service that was offered in more than 100 clinical and molecular diagnostic pathology laboratories across the country, according to data from CAP proficiency testing (14).  According to recent CAP data, this number exceeds 200 today. 

NCD limitations to only FDA approved next generation sequencing tests will, therefore, severely restrict local patient access to clinically useful, high-quality next generation sequencing tests that are currently available in molecular pathology laboratories across the country.  More than 200 CLIA-regulated laboratories will be impacted by this NCD. The impact will include Medicare beneficiaries that may have already received medically appropriate next generation sequencing analysis of cancers and are now experiencing additional tumors or therapy related malignancies. These patients will experience a decreased level of medical care under the coverage decision.

Laboratory developed tests (LDTs) versus FDA approved tests

When compared to FDA approved tests, well validated molecular pathology assays available in CAP/CLIA laboratories are generally of equally high quality with regard to analytical performance (15).  For a detailed review on how CLIA-regulated laboratory testing ensures accurate, reliable, and reproducible testing, we urge you to review a recent publication (16).  A key and critical advantage of CLIA-validated molecular pathology assays is that they can be continuously modified to meet the constantly evolving landscape of clinical utility spanning diagnostic molecular classification, prognostic risk stratification, and/or therapeutic prediction across the full range of solid tumors and hematologic malignancies.  This is a significant challenge for FDA approved tests, which are locked down for a significant period of time and cannot be altered to keep up with the quickly evolving developments in cancer genomics. 

Limiting coverage to FDA-approved tests only will drastically impede innovation, significantly reduce local patient access to life saving laboratory services and lead to increased costs incurred by Medicare.  As written, the draft NCD allows the FDA to dictate how medicine is practiced which is outside of the scope of authority of the FDA and against the recent intentions of Congress. 

CPT codes are already in place for next generations sequencing services.  CMS should, therefore, evaluate the clinical utility of NGS agnostic as to whether the test is an IVD or an LDT.  Doing so is within the statutory responsibility of CMS.

Oncology-based next generation sequencing assays are most commonly billed through 3 CPT codes that are specific to genomic sequencing:

1. 81445 (Targeted genomic sequence analysis panel, solid organ neoplasm, DNA analysis, and RNA analysis when performed, 5-50 genes (e.g., ALK, BRAF, CDKN2A, EGFR, ERBB2, KIT, KRAS, NRAS, MET, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed)
2. 81450 (Targeted genomic sequence analysis panel, hematolymphoid neoplasm or disorder, DNA analysis, and RNA analysis when performed, 5-50 genes (e.g., BRAF, CEBPA, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, KRAS, KIT, MLL, NRAS, NPM1, NOTCH1), interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed)
3. 81455 (Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm, DNA analysis, and RNA analysis when performed, 51 or greater genes (e.g., ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MLL, NPM1, NRAS, MET, NOTCH1, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed

It is also important to note that laboratory analysis of genomic aberrations involving a single gene at a time can be performed utilizing a variety of techniques (i.e. IDH1, IDH2, EGFR, BRAF, KRAS, or NRAS).  These techniques include but are not limited to single analyte PCR, Sanger Sequencing, and next generation sequencing.  In many instances, the CPT codes used by laboratories to bill for these services is agnostic to the technology utilized to perform the analysis.  Next generation sequencing technology is, therefore, also being utilized by laboratories, including ours, when assessing for genomic aberrations in 1-4 genes.

Utilization of next generation sequencing services need to be aligned with evidence-based best clinical practices and cost-efficient patient care.  Simply performing a comprehensive (and expensive) genomic profiling assay on all stage IV cancers would lead to increased healthcare spend, particularly given that many clinical questions can routinely be addressed with single analyte gene testing and/or genomic sequencing of 50 genes or less.

For example, in the setting of metastatic colon cancer, a clinician may need results of molecular testing to determine whether a patient is eligible for expensive monoclonal anti-EGFR therapy.  This question can cost-effectively be answered by testing the tumor for mutations in KRAS and NRAS, which is in line with evidence based guidelines (17).  Detection of these molecular aberrations can be accomplished either through single analyte molecular testing or through a targeted NGS panel (CPT code 81445) that is focused on detecting molecular aberrations important in colorectal cancer.  Based on CLFS 2018 Medicare payment rates, the cost for either testing strategy would be less than $700 compared to $2900 (or greater) for a more comprehensive genomic profiling panel.

Pathologists and molecular professionals have demonstrated clinical expertise in test utilization, which has led to cost-effective patient care (18). Multi-disciplinary institutional efforts to include test utilization committees and diagnostic management teams will be critical to ensure value based delivery of personalized patient care, particularly given the growing interest in molecular and genomic testing in hospitals across the country.

Please find below a summary of our comments to the solicited questions along with our recommendations.

1.  Should the proposed NCD be expanded or narrowed by clinical conditions, test methodology to measure the same clinical biomarker, or clinical scenarios?  If so, please provide supporting documentation, including peer-reviewed evidence, and a detailed analysis in support of your view.

National Medicare coverage of next generation sequencing in cancer would be a very significant advancement for patient care.  However, it is important to ensure that this promising clinical service is responsibly utilized according to best practices and evidence based guideline recommendations so as to optimize cost-efficient and high-quality patient care. 

Eliminating reimbursement for CLIA-regulated tests that do not meet the stringent requirements detailed in this NCD would severely restrict local patient access to high-quality next generation sequencing services that are currently provided by more than 200 academic and community-based molecular pathology laboratories across the country. 

In addition to our laboratory, examples of other institutions include Harvard, Stanford, Mayo Clinic, Johns Hopkins, MD Anderson, Emory, University of Chicago, Columbia, and Yale amongst others. Most of these institutions, including ours, will be forced to discontinue offering these valuable medical services to the patients and communities we serve.

We respectfully ask CMS to consider the following requests:

Allow continued coverage of high-quality next generation sequencing services (CPT codes 81445, 81450, and 81455) performed in CLIA accredited laboratories that adhere to evidence based guidelines, per existing LCD processes.  Please find below examples of clinical indications where the utilization of next generation sequencing technologies are supported by society guidelines, existing LCDs and/or FDA drug approvals:

Advanced pediatric and adult solid tumors that are unresectable or metastatic where utilization of checkpoint inhibitors, such as Keytruda (Pembrolizomab), is being considered

Keytruda is FDA approved for unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) (19).  Of note, the FDA label for Keytruda does NOT require an FDA-approved test to detect evidence of microsatellite instability.   Keytruda is indicated in solid tumors with defective mismatch repair function that have progressed following prior treatment and who have no satisfactory alternative treatment options, or colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.  Tumor mutational burden (TMB) is a quickly emerging biomarker with therapeutic utility across a variety of tumor types and is associated with an increased likelihood of response to checkpoint inhibition with anti-PD-1/PD-L1 agents (20). Next generation sequencing techniques can be used to detect both MSI and TMB (20-22).

Myeloid disorders and acute leukemia

NCCN guidelines recommend molecular testing in the context of myeloid disorders such as myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), and acute leukemia (23-26) The clinical utility of identifying somatic mutations in myeloid neoplasms is reviewed here (27).  An evidence-based guideline by ASH and CAP which recommends molecular testing in acute leukemia (28).  There is currently no single FDA-approved test that covers all of the genomic aberrations that are vital to the diagnostic, prognostic, and therapeutic management of myeloid disorders and acute leukemia.

In the setting of myeloid disorders, next generation sequencing has demonstrated clinical utility in being able to inform diagnosis, prognosis, and/or therapy.  In greater than 80% of cases of myeloid disorders, molecular abnormalities can be detected which support a diagnosis in clinically suspicious cases.  The use of next generation sequencing technology, as opposed to sequential single gene analysis decreases the time to establish a diagnosis, which, in turn, enhances the delivery of the appropriate therapy.  Certain molecular aberrations are a diagnostic requirement that are set forth in the most recent WHO classification of hematologic malignancies (6).  Detecting a BCR/ABL fusion helps to define a diagnostic molecular category of chronic myelogenous disorders or acute myeloid leukemia.  CSF3R mutation is a diagnostic requirement necessary to establish a diagnosis of chronic neutrophilic leukemia. RUNX1 mutation is associated with a specific molecular subtype of acute leukemia (required for diagnostic classification).  RUNX1 mutated acute leukemia is also associated with a dismal outcome particularly in patients undergoing bone marrow transplant.

Molecular alterations can also be utilized to inform prognostic risk classification in myeloid disorders and acute leukemia.  According to NCCN guidelines and other publications (5,23-26), certain mutations  (i.e. TP53, ASXL1, RUNX1, IDH2, IDH1, DNMT3A mutations) are associated with high-risk disease characterized by increased likelihood of failure to standard therapies, increased risk of relapse, and increased risk of disease progression to acute leukemia.  The greater the number of mutations, the greater the risk of disease progression.  Some mutations predict for a dismal outcome in patients who undergo bone marrow transplant (30-33).  Collectively, these studies demonstrate that integration of molecular profiling results into the work up of myeloid disorders improves the prognostic risk stratification, which, in turn, better guides therapeutic decision making. For a detailed review article, please refer the latest publication published the American Society of Hematology which delineates the clinical utility of molecular alterations in the setting of MDS (34).   Other publications show improved prognostic risk stratification in patients with AML who undergo molecular profiling, which in turn, enhances therapeutic decision making.  (35) 

Once a diagnosis of myeloid disorder or acute leukemia is established, the appropriate therapy can be implemented and customized according to the molecular aberrations associated with prognosis and also based on the diagnostic context.  These include FDA approved chemotherapies and/or bone marrow transplant in high risk patients (34, 36-37) Bone marrow transplant, according to evidence based guidelines from the American Society of Blood and Bone Marrow Transplantation, is considered a valuable therapeutic option in high risk myeloid disorders and acute leukemia (38). There are also FDA approved therapies that are directed against specific molecular aberrations in acute leukemia.  Midostaurin is currently FDA approved for acute myeloid leukemia with FLT3 mutation and Enasidenib has been FDA approved for acute leukemia with IDH2 mutation (39-40).

Metastatic non-small cell carcinoma

NCCN guidelines (41) indicate the clinical utility of next generation sequencing services to guide therapeutic decision making.  According to NCCN guidelines, “Broad molecular profiling is a key component of the improvement of care of NSCLC patients.”  Next generation sequencing is one of the technologies that are indicated to detect clinically useful molecular abnormalities. Certain mutations in genes such as EGFR, BRAF, ALK, and ROS1 are associated with increased likelihood of response to FDA-approved therapies that specifically target the perturbed molecular pathways of these alterations.  Many LCDs have been finalized across the country that address molecular profiling (including but not limited to next generation sequencing) in the setting of NSCLC.

Other tumors

Other cancers for which next generation sequencing is supported by NCCN guidelines includes CNS tumors, indeterminate thyroid lesions, metastatic melanoma, non-Hodgkin  lymphomas, and advanced ovarian cancer.  We urge you to review pertinent NCCN guidelines (https://www.nccn.org/) and LCDs that are in draft or final form.

2.  How do laboratories assess analytical and clinical validity?  Based on laboratory experience, how long does it take to compile data demonstrating analytical and clinical validity, such as what would be submitted to the FDA or the New York State Department of Health? What are the variables that affect the duration of this time?

According to CLIA, Sec. 493.1253,“Establishment of performance specifications. Each laboratory that modifies an FDA-cleared or approved test system, or introduces a test system not subject to FDA clearance or approval (including methods developed in-house and standardized methods such as text book procedures, Gram stain, or potassium hydroxide preparations), or uses a test system in which performance specifications are not provided by the manufacturer must, before reporting patient test results, establish for each test system the performance specifications for the following performance characteristics, as applicable:     (i) Accuracy.     (ii) Precision.    (iii) Analytical sensitivity. (iv) Analytical specificity to include interfering substances. (v) Reportable range of test results for the test system. (vi) Reference intervals (normal values).     (vii) Any other performance characteristic required for test performance.”

In other words, CLIA has clearly defined guidelines which are utilized by laboratories to validate and provision high quality laboratory services.  These guidelines would most certainly extend to next generation sequencing services.  As indicated earlier, evidence based guidelines (11-13) have been established to ensure high quality next generation sequencing services are available in CLIA regulated laboratories.  Collectively, these guidelines reference more than 300 peer reviewed publications, span the entire next generation sequencing workflow and cover all aspects of analytical and clinical validity.

It would take most laboratories at least greater than 3 years to compile data that would be required for FDA or New York State Department of Health approval.  The duration of this time would be impacted by certain factors including the level of regulatory burden, data requirements, and necessary financial resources. 

Furthermore, the NCD as currently proposed only provides clear reimbursement policy for FDA-approved assays (e.g. Pre-Market Approval). Only a few large, well-funded corporations in the United States have the necessary resources to comply with FDA regulations and data requirements, including prospective clinical trials, for Pre-Market Approval. The “average” laboratory, including nearly all academic laboratories, do not have the resources to comply with FDA Pre-Market Approval regulations.

This NCD also proposes significant regulatory hurdles for FDA-cleared assays (e.g. 510K clearance) in the form of Coverage with Evidence Development trials. A slightly larger group of entities have the resources to achieve FDA 510K clearance. However, very few laboratories and academic medical centers have the resources to comply with the Coverage with Evidence Determination studies, which purportedly would include significant patient monitoring studies outside of the normal course of medical care. The ability to recruit patients into clinical trials remains a significant issue across the American medical community.”

These efforts are further hindered by the recent and future climate of severe reimbursement pressure on the laboratory industry, which produces valuable information that drives more than 2/3 of clinical decision making and accounts for less than 3% of total health care spend. 

3.  Would the approach(es) used currently in laboratories be similar to the approach used in this proposed NCD for the FDA to analytically and clinically validate a diagnostic laboratory test?  Are there other possible approaches?  If so, please provide supporting documentation, with peer-reviewed evidence, and a detailed analysis in support of the approach, including the number of tests using such an approach. 

The FDA has not finalized pathways to approval of NGS based assays.  The fact that less than a handful of organizations have successfully done so indicates the extraordinary effort in the face of insufficient guidance.  At this time, the FDA is still considering how it would approach the regulation of NGS based assays, and has opened a door through NYS as an approved 3^rd party.  Unless and until the FDA creates clear criteria for approval of a next generation sequencing based assay, this is an unfair and inappropriately high bar to achieve for the vast majority of molecular pathology laboratories across the country.

4.  How do laboratories assess clinical utility?  With regard to the proposed NCD, what would be examples of circumstances in which coverage would be adequately addressed by a local Medicare Administrative Contractor (MAC) including the ability to identify clinical utility of specific tests?

In a manuscript published in 2016, AMP has set important standards for how clinical utility is defined and how clinical utility should be assessed (42).

Key recommendations from this publication include utilizing a modified ACCE model, that incorporates aspects of clinical utility beyond drug selection; adopting patient-centered definitions of clinical utility that encompass diagnosis, prognosis, and/or therapy prediction; recognizing that clinical utility for molecular pathology is context dependent; supporting multiple modalities of evidence generation, including appropriate alternatives to randomized clinical trials; recognizing the critical role of appropriately trained and board certified molecular professionals; and supporting professional organization driven practice guidelines.

We strongly recommend that FDA, CMS, and local MACs adopt a similar definition of clinical utility that is in the best interest of patient care. Importantly, the above definition of clinical utility is most optimally aligned with evidence based best practices and medical society guidelines.  We would like to refer you to a recent NCCN presentation that describes the multiple facets of clinical utility (43). 

With regard to local MACs, this NCD, will supersede and supplant any local coverage determinations (LCDs) such as those from Palmetto-MolDx, Noridian, Novitas, etc.  Considerable efforts have been made by local MACs to evaluate clinical utility and issue coverage of next generation sequencing for various clinical indications. For example, currently, Palmetto’s LCD (L36143) for comprehensive genomic profiling in advanced non-small cell carcinoma includes coverage for next generation sequencing utilizing appropriate NGS CPT codes 81445 and 81455.  Palmetto’s LCD (L36044) for non-BCR/ABL myeloid disorders includes coverage for NGS CPT codes 81450 and 81455 in myeloid disorders. 

An unforeseen impact will be inadvertent and severely reduced local patient access to next generation sequencing, unless the NCD is appropriately revised to be aligned with existing LCDs pertaining to next generation sequencing that are already in place for CPT codes such as 81450, 81445, and 81455. 

5.  How can the information in this proposed NCD be clearly communicated to health care practitioners, patients, and their care-givers in addition to our existing communications through listservs, coverage updates, and outreach and education materials?

We encourage regular and continued engagement with AMP in addition to other organizations including CAP, ASCO, ASCP.  PathGroup will be more than happy to serve as a resource for CMS on this and other pertinent topics related to molecular pathology testing and Precision Medicine.

We sincerely appreciate the opportunity to comment on this NCD and would like to remain a resource for you in the future.  We hope that you find these comments helpful in your final decisions.  The field of pathology is evolving rapidly to integrate exciting discoveries in cancer genomics.  We leave you with a fitting quote taken from a recent editorial publication in a recent issue of CAP’s official publication, Archives of Pathology: (44):

“The only constant in pathology is change.”

Thank you.

Respectfully,

Pranil K. Chandra, DO, FCAP, FASCP
Vice President and Chief Medical Officer
Genomic and Clinical Pathology Services

PathGroup
601 Grassmere Park, Suite 5
Nashville, TN 37211
phone: 615-234-6610
cell:  615-927-7270
fax:  615-263-9606

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January 16, 2018

Ms. Tamara Syrek-Jensen
Director, Coverage & Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

Dear Director Syrek-Jensen:

On behalf of the Cancer Support Community (CSC), an international nonprofit organization that provides support, education, and hope to cancer patients, survivors, and their loved ones, we appreciate the opportunity to provide comments on the Centers for Medicare & Medicaid Services' (CMS) Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N).

As the largest direct provider of social and emotional support services for people impacted by cancer, and the largest nonprofit employer of psychosocial oncology professionals in the United States, CSC has a unique understanding of the cancer patient experience. Each year, CSC serves more than one million people affected by cancer through its network of over 40 licensed affiliates, more than 120 satellite locations, and a dynamic online community of individuals receiving social support services. overall, we deliver more than $40 million in free, personalized services each year to individuals and families affected by cancer nationwide and internationally. The patients and families we serve each day are optimistic and excited about the proven benefits of targeted therapies, companion diagnostics, and next generation sequencing, and we ask that CMS work diligently to ensure that any proposed coverage decisions do not restrict or reduce access to such technologies.

CSC is pleased that CMS acknowledges the importance of NGS in delivering personalized medicine for cancer patients. We appreciate CMS' attempt to initiate a regulatory pathway for technologies that are used to identify targeted, personalized treatments for patients with advanced cancer, however, we want to ensure that the final decision memo is developed with a comprehensive understanding of any potential, unintended impacts on patient access to such technology.

CSC regards this proposed decision memo as a first step in a complicated process with promise to provide coverage and access to technologies that will make personalized medicine the standard of care for all individuals diagnosed with cancer. That being said, we would like to raise the following issues for CMS to address when finalizing the National Coverage Decision (NCD).

Can CMS confirm that once the proposed NCD goes into effect that there will coverage of these NGS tests? If not, we believe there needs to be more stakeholder input into the scope and details of the NCD. CSC encourages CMS to hold a stakeholder meeting on the topic of patient access to NGS technologies. The meeting should provide an opportunity for a diverse group of stakeholders to address the impact of this NCD to include:

• The lifetime limit of one NGS test per patient should be eliminated given the quickly evolving nature of cancer and cancer treatments.
• The capacity of the FDA to review forthcoming NGS applications in a timely manner to ensure that patients will not suffer from gaps in coverage.
• The scope of the NCD should outline if certain NGS tests will be excluded and if this could lead to gaps in patient access.

CSC thanks CMS for the opportunity to provide comments on this proposed decision memo and we offer our network of patients, our Research and Training Institute, and our Cancer Policy Institute as resources to better understand the impact of this NCD on patient access to NGS tests. CSC supports the coverage of NGS technologies but would like to ensure that the proposed NCD does not risk or eliminate coverage of the many proven, effective tests that are currently used in practice across the country. CSC stands ready to serve as a resource to CMS as we work together to ensure that patients have affordable access to the newest technologies available to identify targeted cancer treatments. Please reach out to me at efranklin@cancersupportcommunity.org for more information.

Sincerely,

/s/
Elizabeth Franklin, LGSW, A CSW
Executive Director, Cancer Policy Institute
Cancer Support Community

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Cleveland Clinic (CC) is a not-for-profit, integrated healthcare system dedicated to patient care, teaching, and research. Our health system is comprised of a main campus, 10 community hospitals, and 21 family health centers with over 3,500 salaried physicians and scientists. Last year, our system had more than seven million patient visits and over 220,000 hospital admissions. We appreciate the dedication of the Agency staff on behalf of the Medicare Program and the work they devote to its administration. We believe it is important for hospitals to share information with the Centers for Medicare and Medicaid Services (CMS) so the Agency has a better appreciation of the challenges and practicalities faced by health care providers regarding proposed changes which effect patient care. The following are the comments of Cleveland Clinic in regard to the Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N) proposed decision memo.

Cleveland Clinic is supportive of and encouraged by the cooperation between the Food and Drug Administration and CMS in considering the FoundationOne CDx (F1CDx) test through its parallel review program. Further, Cleveland Clinic supports immediate coverage for the F1CDx test as specified in the proposal.

However, Cleveland Clinic has concerns that the proposed National Coverage Determination (NCD) is overreaching in that it extends beyond the F1CDx test and has the potential to significantly limit patient access to clinical testing services that are currently rendered according to accepted, evidence-based standards and are subject to local coverage determinations (LCDs). In particular, the NCD as written extrapolates a very narrowly-defined set of payable criteria, appropriate for the F1CDx test, and applies those criteria to determine the medical necessity and clinical utility of an entire methodology for all laboratory tests involving NGS. As currently written, the proposal appears that rather than expanding options for testing and care of patients, this NCD proposal will exclude entire categories of testing for which NGS is currently employed and used to assist in the treatment of patients.

First and foremost, NGS is not a diagnostic test per se for which a NCD can reasonably be promulgated, rather it is laboratory technique which may be used to interrogate one or more commonly, a group of analytes, for example, multiple mutations in one or more genes. Whether the analysis of the analyte(s) is medically necessary is determined by the medical needs of the individual patient, as determined by his or her physician. The medically reasonable and necessary application will vary by patient condition, and for which established usage will continue to evolve, potentially quite rapidly, over time. With regard to detecting acquired mutations in specific cancer genes, the NGS technique is often used in “gene panel” tests that simultaneously sequence multiple “actionable” genes that can be the target of precision medicine drugs of direct therapeutic use or be of diagnostic relevance to the subtyping of malignancies and are currently employed in numerous accredited clinical laboratories. NGS facilitates the simultaneous sequencing of multiple genes of relevance to a cancer subtype in a single, efficient and cost-effective assay. Thus, the use of NGS in the clinical laboratory extends far beyond F1CDx test and the proposal as written will limit the use of the NGS technology outside of the narrow indications for coverage as specified in the proposal and limit the application of NGS technology to personalized medicine.

Accredited clinical laboratories have the option of performing gene analysis using NGS technology subject to the Local Coverage Determination (LCD) process. The quality standards of clinical laboratories are governed by CLIA ’88. Limiting the coverage of use of the NGS technique to the strict criteria proposed in the NCD would likely have the unintended effect of limiting coverage for NGS panels for patients who would benefit from the use of the technology.

We have significant concerns that the requirement to submit patient information to a registry is not only impractical, but may be in violation of HIPAA requirements for treatment of protected health information.

In summary, while Cleveland Clinic supports the coverage of the F1CDx test for Foundation Medicine as specified in the proposal, Cleveland Clinic recommends strongly that the proposal should be restricted to determining the coverage of the FoundationOne F1CDx test only.

Thank you for conducting a thoughtful process that allows us to provide input on such important issues and for your consideration of this information. Should you need any further information, please don’t hesitate to contact me.

Sincerely,
Robert Wyllie, M.D
Chief Medical Operating Officer
Medical Operations
Cleveland Clinic

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Among the key roles of the FDA is “… advancing the public health by helping to speed innovations that make medicines more effective, safer, and more affordable and by helping the public get the accurate, science-based information they need to use medicines and foods to maintain and improve their health (FDA Mission Statement, 2017).

Many of my colleagues have already pointed out the negative effects of this regulation on innovation, patient care, and medical costs.

I would like to add to the conversation a personal anecdote based on my face-to-face dealings with FDA personnel. I participated in the 2016 AACR Think Tank on Genomics in Clinical Medicine in Washington, DC. At this meeting, I discussed with representatives of the FDA their set of proposed Regulatory Guidelines for NGS-based LDTs. Going through the guidelines, item-by-item, I demonstrated that they overlapped significantly with existing CAP guidelines and CLIA regulations and in no way would improve upon the reliability of testing compared with the current LDT regulations. I don’t believe that anyone in the room (except for Michael PellinI, CEO of Foundation Medicine) supported the FDA’s proposal to regulate LDTs. The response of representatives of the FDA and CMS to the confusion about the superimposition of their rules on the existing regulatory framework was that academic laboratories don’t need to comply with the FDA regulations if they don’t want to. They just won’t get reimbursed for testing under CMS.

The FDA has gotten extremely negative feedback from numerous individuals and professional societies, as well as Congress, but nevertheless rolled out this NCD. I have to wonder whom they are representing and what their goals are in the context of their mission statement with which I began this public comment. The effect of this NCD, if enacted, will be to limit reimbursement for NGS testing in patients with advanced cancer to a few private companies that can afford to meet FDA regulations. These companies do not support the most up-to-date and insightful patient care, development of new, cutting-edge methodology, or establishment of public databases that drive medicine and science forward.

I have to compare the likely effects of this NCD to allowing Myriad Genetics to hold a patent that monopolized BRCA1 and BRCA2 testing. The FDA should be aware that as soon as the BRCA patent was invalidated, the floodgates were opened for improved hereditary cancer testing, and the price of testing plummeted as much as 10 fold with no reduction in quality. I urge the FDA to rethink how this policy aligns with their mission.

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To The CMS Coverage Determination Panel:

Thank you for the opportunity to comment on the document "Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)".

I write to you from a clinical services laboratory within an academic medical center, where we practice CLIA-licensed, CAP-certified, clinical standard-of-care oncology testing using next generation sequencing (NGS) as a basic clinical service. This standard-of-care testing includes basic diagnostic testing, using next-generation sequencing (NGS)-based tests that assist in diagnosis and treatment decisions regarding standard-of-care, approved medications. We have developed, rigorously validated and verified the performance of these tests within our lab (LDT) in accordance with CLIA'88 and the more-stringent and NGS-specific CAP guidelines. CLIA'88 specifically allows licensed and certified laboratories to develop in-house tests for patient care.

Our clinicians are clamoring for state-of-the-art diagnostic cancer testing to be available quickly, locally, and affordably. The cancer diagnosis and treatment landscape is rapidly evolving, and the ability of experienced clinical laboratories to quickly and accurately develop and validate (LDT) clinical tests for the latest proven biomarkers provides a critical mechanism for this testing to be widely available.

Our patients rely on these tests being readily available and affordable. The assays are critical for rapid diagnosis and for precise targeted care using state-of-the-art, clinically approved treatment.

The Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N) is unreasonably restrictive. FDA clearance or approval for clinical tests is extremely difficult, expensive and time-consuming to achieve. Furthermore, standard-of care testing and treatment do not fit within the scope of the “coverage with evidence development” approval route.

Academic clinical laboratories generally operate on very narrow margins, and lack of reimbursement for vital NGS-based LDTs will undoubtedly damage the foundation of these services, effectively denying this testing and the resulting precision cancer treatment to most patients, due to:

• an effective monopoly on NGS-based diagnosis
• delays in testing and return of results
• delays in directed care, leading to reduced efficacy of treatment
• loss of services from academic clinical service laboratories due to loss of reimbursement
• reduced patient access to NGS-based testing
• loss of "precision" treatment opportunities
• increased patient morbidity and mortality
• reduced training opportunities for tomorrow's laboratory medicine practitioners

In summary, the proposed memo, if finalized, could be disastrous not only for patients, but for laboratory medicine and ultimately healthcare in general. Please rescind this proposed coverage decision.
Sincerely,

Ruthann B. Pfau, PhD, FACMG
Clinical Laboratory Director
Institute for Genomic Medicine

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January 12, 2018

Tamara Syrek Jensen, J.D.
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Blvd
Baltimore MD 21244

Dear Ms. Jensen:

Background:
In association with the approval of the Foundation One Companion Dx under parallel review, CMS issued a National Coverage Analysis for the use of NGS-based tests in patients with advanced cancer. The proposed National Coverage Determination would exclude affirmative coverage for an NGS-based test unless the test is an approved FDA companion diagnostic. Coverage for other NGS-based tests would be forced under Coverage with Evidence Development (CED), but only if such tests are approved or cleared by FDA. The NCD would prohibit coverage for laboratory developed tests used on patients with cancer, and could potentially apply to indications for use outside of cancer diagnoses.

Intentions:
In a meeting with CMS, we learned that – counter to initial conceptions by stakeholders that this decision might be limited to only multi-gene, NGS-based, tumor-profiling tests – the coverage decision would impact any NGS test regardless of the number of genes analyzed, or the type of cancer/tumor addressed by the diagnostic test. In fact, CMS left open that the proposed NCD would foreclose coverage for NGS-based tests with indications unrelated to cancer.

Underlying issues being addressed:
The proposed NCD’s requirement for FDA approval or clearance for coverage appears to be based on the desire to demonstrate analytical and clinical validity of the test for coverage, which CMS views as being met by FDA approval/clearance. Although the inquiry into the clinical utility of the test would be left to CMS, the agency expressed a willingness to consider other benchmarks or methods for an assurance of analytical and clinical validity of the test. We agree with the need to assure analytical and clinical validity while acknowledging that more than one approach to meet this goal is necessary.

Impact on patient access to care:
Many academic medical centers are at the forefront of cancer diagnosis, treatment and care. Moreover, these same institutions have led the development of novel NGS-based clinical assays that are used in the diagnosis, therapy and care of their patients. If CMS permits reimbursement only for NGS panels that are FDA-approved, many of the NGS assays performed in this country by academic medical center laboratories will not be available, despite careful documentation of analytic and clinical validity. If these labs are not reimbursed for the high quality and innovative work that they do, then these same innovative laboratories will not only stop performing these important assays, but they will also lose the incentive to develop new assays based on new and emerging genetic discoveries in cancer diagnosis and cancer care. When top laboratories cannot provide these studies or develop novel tests based on new discoveries, then the ability of clinicians to provide care for their patients will be significantly – and negatively – affected. For examples, validated custom gene panels for a small number of genes known to be associated with outcomes in a particular tumor may not be available in a timely fashion, even though they both valid and less costly.

Requests to CMS:

1. Any CMS decision needs to consider first the needs of the patient. Any decision that limits access to highest quality, innovative care should be reconsidered.
2. We support Foundation Medicine’s initial request for coverage for the Foundation One CDx, but CMS should broaden the pathways by which NGS testing can be validated for coverage decisions.
3. CMS also needs to recognize the high quality of NGS cancer laboratory testing that is provided by high-quality clinical laboratories in academic medical centers and other laboratories.
4. It is imperative to engage experts from laboratories at academic medical centers and other high quality laboratories in order to develop clear standards for analytic and clinical validity, leading to clear pathways for coverage approval for NGS tests.
5. CMS also needs to define the desired benchmarks for analytical and clinical validity sufficient for coverage.

Sincerely,

/s/
Jan C. Buckner, MD
Chair, Department of Oncology
Betty J. Foust, M.D., and Parents’ Professor
Chair, Enterprise Mayo Clinic Cancer Center
Mayo Clinic
Rochester, MN

jcb/djd

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To Whom it May Concern:

[PHI Redacted]

It has come to my attention that CMS is thankfully recognizing the value of precision diagnostics in the care of cancer patients by proposing coverage for FoundationOne CDx (F1CDx). I am in favor of a positive coverage determination for the product reviewed in the Parallel Review program, F1CDx. I am, however, disappointed to learn that under a new policy some cancer patients will be limited to only one (1) test per lifetime and that medicare patients may not have access to other important testing. I respectfully submit that only one test is not enough given that the personalized medicine that cancer patients need is so greatly facilitated by these tests.

At bottom, I support CMS’ proposal to cover the F1CDx test but respectfully request that the CMS not finalize the rest of the policy as it will likely result in negative consequences to cancer patients by depriving them of crucial medical advances and may be a step background for some cancer victims.

Thank you very much for your consideration of this request. Please let me know if you would like any further information from me.

Sincerely,

Jennifer Cosgrove

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Thank you for the opportunity to comment on the NGS coverage for Medicare beneficiaries. NGS is a critical tool in the personalized management of cancer; however, I am concerned that your proposal only covers one NGS test per lifetime.

Cancer patients typically require re-testing upon disease progression, and this often occurs multiple times as the cancer continues to mutate. And as new targets for treatment become available in the cancer field, additional opportunities open up for re-testing and more personalized therapies. The leading cancer hospitals and centers around the U.S. use NGS as a critical tool in the management of patient care and guiding treatment decisions. Limiting a patient to one NGS test per lifetime would significantly curtail current state of the art practice, and significantly worsen patient outcomes!

In addition, NGS testing (even multiple times) is cost-effective compared to the high potential cost of giving a patient the wrong drug.

I speak from personal experience, as a patient-advocate with a targetable mutation. (More information would be PHI). Our community is very concerned about the limit of one NGS test per lifetime. I ask that you reconsider this aspect of the proposal. Thank you for your consideration.

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January 14, 2018

Ms. Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
U.S. Department of Health and Human Services
7500 Security Boulevard
Baltimore, MD 21244

Dear Ms. Jensen,

I am writing to you regarding CAG-00450N on behalf of myself, an academic molecular pathologist and medical director of a CLIA-certified, CAP-accredited molecular diagnostics laboratory that serves a large midwestern academic hospital, with an NCI-designated cancer center, and rural outreach clinics. I appreciate CMS’s support for the use of NGS in the clinical setting of oncology and I agree that it is worthy of reimbursement. However, I have significant concerns regarding the proposed limitation of this reimbursement to only FDA-approved NGS assays in oncology, and for cancers with a specific FDA-approved companion diagnostic for FDA-approved therapies. I have briefly outlined my reasons below.

1) FDA-approved In Vitro Diagnostics in Oncology, using NGS testing, are very limited in both their coverage of various cancers and in their accessibility to academic and community hospital molecular diagnostic testing laboratories to perform. A couple of these tests must be performed by specific reference laboratories (FoundationONE CDx and MSK IMPACT), which can’t possibly handle all of the testing that is required to identify potential targeted therapies for all advanced oncology patients in the United States, even if treating these patients in the “on label” setting. In the case of the FoundationONE CDx, Illumina’s Extended RAS Panel, and Thermofishers’s Oncomine Dx Target Test, the number of cancers are very limited in scope for testing and therefore, many patients will be denied testing that could identify important targets for therapy.

2) Oncologists often use these multi-gene tests for off-label purposes in oncology under the scope of the practice of medicine. The practice of medicine cannot be regulated by the FDA. Again, if this testing is highly limited in its reimbursement, patients with rarer cancers or with rarer mutations in certain cancers that still may benefit from targeted therapies can’t be identified to be treated under an oncologist’s practice of medicine. Many trials are ongoing to see if NGS testing in oncology is useful in treatment with targeted therapy (NCI-MATCH and ASCO TAPUR) and I would encourage that CMS await these trial results before further pursuing any reimbursement decisions.

3) Clinical molecular diagnostics laboratories undergo significant regulation and inspections by CMS-deemed entities, such as The College of American Pathologists. Our laboratory has validated two large NGS panel assays, and each validation took over a year of testing to verify and validate all specific CLIA requirements of laboratory validation. For each assay, we went over and above all requirements and do continual monitoring of our assays for accuracy, precision, etc. Via many reports from our local oncologists, our testing has helped many patients respond to both on and off label drugs, verifying that our testing is accurate and clinically validated.

4) It is extremely important that oncologists understand the testing at their respective institutions, or from their reference laboratory and have easily accessible contact with the laboratory directors who oversee the testing. I am on the phone constantly with my oncologists at my institution discussing our testing results. If this testing will only be reimbursed if performed by large reference laboratories, they will lose that accessibility. I often get calls from oncologists about reference testing reports and since I am not performing the testing, I can only give them so much insight. Cancer is a very unique disease for each patient and every patient has significant differences in their clinical presentations and clinical needs. We discuss these at various tumor boards at our institution, including molecular tumor boards. If oncologists are forced to send their testing to only a few laboratories that offer FDA-approved tests, due to reimbursement limitations, they will lose this personal accessibility to pathologists and laboratory personnel performing the testing, and clinical discussion, which is so important in the practice of medicine in any field. Additionally, it is difficult to get outside reference results into the medical record so they are easily viewable by oncologists, which increases their time to assist patients. Finally, the turnaround times for their patient results will increase, with only a few laboratories performing this testing. For some of these advanced cancer patients, they don’t have much time and need to get started on a therapy, whether it be a targeted therapy or a chemotherapy that would be started if no target were identified.

I appreciate your time reading my above concerns and greatly appreciate CMS’s consideration of reimbursement of oncology-based NGS testing. Thank you for the opportunity to comment. We all want what is best for oncology patients. I am happy to address any further questions you may have.

Sincerely,

Allison M. Cushman-Vokoun, MD, PhD, FCAP
Academic Molecular Pathologist and Medical Director, Academic Molecular Diagnostics Laboratory
Omaha, NE
402-659-8630

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Tamara Syrek Jensen, JD
Director, Coverage & Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop S3-02-01
7500 Security Boulevard
Baltimore, MD 21244–1850

Re: CAG-00450N (NGS for Medicare Beneficiaries with Advanced Cancer)

Dear Ms. Syrek Jensen:

I am writing to you as an academic molecular pathologist and concerned citizen regarding the draft NCD for Next Generation Sequencing (NGS) in oncology. I am writing as an individual and my statements represent my personal position and do not represent the position of the University of Colorado. I thank CMS for recognizing the importance of molecular testing, particularly for assessing multiple analytes simultaneously as enabled by NGS, in the care and management of cancer patients. I also appreciate the quality concerns which this draft NCD attempts to address; however, I feel that the current draft could lead to many downstream problems.

For the past several years, testing by multi-analyte approaches, such as achieved by NGS technologies, for cancer patients has become standard of care, despite the lack of an FDA-approved test. This testing was performed in CLIA-certified academic medical and commercial clinical laboratories and has become integrated into guidelines from many professional societies including ASCO, ASH, and NCCN. This testing has provided valuable information to guide treatment for thousands of cancer patients. By requiring FDA-approved testing for reimbursement, CMS risks reducing access to this type of testing due to potential bottlenecks at approved labs and the risk of monopoly-related price increases, with downstream consequences for patients.

In addition, precision medicine often changes rapidly with new medical discoveries. By requiring FDA approval for payment, CMS adds a lengthy and expensive regulatory hurdle to the incorporation of new biomarkers into clinical care. This is not to say that new markers should be adopted without careful consideration and clinical validation; however, CLIA accreditation requires extensive validation to offer a clinical test and local coverage determinations are the most flexible approach to determine the clinical value and payment determinations for new analytes. Furthermore, many labs focus their testing on well-established biomarkers, which are incorporated into standard of care testing. By instituting FDA oversight, this process would be significantly delayed and stifle innovation and patient access, including for Medicare beneficiaries.

In summary, I appreciate the recognition of the importance of NGS testing in oncology; however, I urge CMS to reconsider the requirement for FDA approval for coverage. I believe that CLIA provides effective technical oversight and local coverage determinations can fill the role of evaluating evidence to determine coverage rates.

Respectfully,
Mark D. Ewalt, MD
Section Director, Hematologic Malignancies, Colorado Molecular Correlates Laboratory
Assistant Professor of Pathology
University of Colorado

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o whom it may concern;

[PHI Redacted]

Thank you for the opportunity to provide comment on the National Coverage Analysis entitled Next Generation Sequencing (Cancer patients all over the country are benefitting from new knowledge in the genomic causes and drivers of cancer, as evidenced by increased access to personalized therapeutics and care based on the genetic makeup of cancer. I am so grateful for advances in diagnostic technologies, such as NGS as it is one tool to obtain a more comprehensive molecular understanding of cancer. This technology is of particular relevance to lung cancer patients as it typically requires less tissue sample than separate sequencing of multiple genes. I thank CMS for recognizing the value of precision diagnostics in the care of cancer patients by proposing coverage for FoundationOne CDx (F1CDx). I support a positive coverage determination for the product reviewed in the Parallel Review program, F1CDx, however I have serious concerns about the broad scope of the proposed NCD The proposed policy would limit cancer patients to only one test per lifetime, which is not in line with the realities of personalized medicine–based therapy for cancer patients. Only being allowed one test could have cost [PHI Redacted] physically and could have cost [PHI Redacted] life. IAlso, the new policy will eliminate coverage for other NGS tests for advanced cancer patients enrolled in Medicare. These tests are currently used to deliver high quality advanced cancer care across the country—including at virtually all major cancer centers and academic institutions. NGS should be a standard of care in oncology. I support the proposal by CMS to cover the F1CDx test, but I urge CMS not to finalize the rest of the policy, as it will result in several unintended negative consequences to cancer patients by erasing important medical advances and existing local coverage policies already in place.

Sincerely,
Gina Hollenbeck

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This draft LCD clearly reflects the efforts of a single commercial genomics laboratory, working with CMS, to limit access to NGS testing for business reasons.

As someone who has worked at a high level both in commercial laboratories and academic genomics laboratories for many years, I know that when purely commercial considerations alone drive policy, patients are harmed.

A large number of operational factors, financial constraints and access issues affect whether patients can obtain essential NGS cancer diagnostic services. In general, a larger number of high-quality providers operating in various settings and with various business models leads to the best availability of testing and the needed flexibility for the range of health care systems.

In my current institution, we often see cases where Foundation Medicine cancels testing because samples do not meet their sample requirements whereas our in-house NGS assays, custom-designed for small volume samples, deliver highly accurate and actionable results.

Similarly, reporting formats for the large commercial providers, optimized for marketing appeal, often do not fit the needs of clinicians. Additionally, the lack of genomic correlations with histomorphological features and other laboratory testing hinders the needed integration of NGS data and can lead to profound mis-interpretations that lead to confusion that can harm patients and delay care.

In all of our genomics laboratories, large NGS panels have a role but are often very expensive, overhyped, more cumbersome assays that would be better replaced with focused, faster, more inexpensive NGS panels. This is especially true when doing sequential monitoring of genomic changes for assessing treatment response. The marketing practices of Foundation Medicine and other commercial labs also tend to bypass hospital review committees and CMS-driven cost utilization programs and add significant cost and lack of coordination to oncology care.

Finally, although there are many in commercial laboratories who are completely dedicated to delivering high-quality care, the main drivers of these laboratories have been (and will always be) marketing considerations. It is in the nature of a commercial enterprise.

This draft LCD clearly reflects those commercial priorities above all and does not put patient care and access front and center.

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My name is Kathryn Hall, and I am a Molecular Technologist at Colorado Molecular Correlates (CMOCO) at the University of Colorado Anschutz Medical Campus.

Thank you for the opportunity to provide you with feedback regarding your proposed National Coverage Determination.

CMOCO is a molecular diagnostics laboratory in the field of Precision Medicine, and our emphasis is primarily in solid tumor cancer samples (although we expanding into germline and heme-based assays). My role is working with Next Generation Sequencing-based assays, specifically assays that look for mutations, insertions, and deletions, and assays that search for gene fusions in DNA and TNA (total nucleic acid) samples that have been extracted from FFPE blocks and from DiffQuick slides. I perform these assays in a clinical capacity, and I assist in the research and development of upgraded chemistry for these tests. I perform both the wetbench and the data analysis side of these NGS assays. I have been on the NGS team at CMOCO for nearly 3 years.

Our laboratory is certified by CAP and participates in regular CAP testing as well as our own internal QC testing. We have internal Quality Management program and metrics to verify that the work we do consistently maintains a high standard. In the past year, we’ve performed over 1200 NGS tests (gene fusion testing and mutation testing) on nearly 700 patient samples. We are constantly developing new assays and updating old assays to take advantage of new advances in assay chemistry and new technologies in molecular biology that improve sensitivity and increase our target regions to cover more recently identified cancer-treatment-related genes.

As a molecular technologist who works directly with NGS-based precision cancer medicine assays , I am concerned with some of the ideas proposed in this NCD. The two main aspects that concern me relate to the requirement for the approval of only FDA-approved NGS assays, and the proposed cap of 1 NGS diagnostic test covered for the patient’s entire lifespan.

The requirement that any assays be FDA-approved concerns me because the approval process is laborious and slow, and because the very nature of an FDA-approved test is that it’s very restrictive. Technology is rapidly advancing that allows assays to increase in sensitivity and scope, and with the current FDA approval process taking approximately two years, it is likely that even newer chemistry with greater improvements will be available by the time any test upgrade would make it through the approval process. For example one of our current assays, FusionPlex, was developed, extensively validated, and finally put into clinical use approximately a year ago. As of August of this year, newer chemistry has been available from the vendor that vastly improves our ability to detect gene fusion events, and that improves the quality of the data and thus our confidence in results – this will help us obtain answers from FFPE samples whose RNA is borderline in quality, patients who we might not be able to provide a confident answer regarding the presence or absence of gene fusion events in their tumors under the current version of the assay. We are currently in the process of validating this newer chemistry, but if we had to push this through a multi-year FDA approval process, there would be many patients who would have reduced access to high-quality of care because the improvement would not be available in time to make a difference to them.

The limitation of 1 NGS test per lifetime is inappropriate for cancer care. There are different kinds of NGS-based assays that identify different tumor markers – our laboratory has an NGS diagnostic test that uses DNA to check for mutations, insertions, and deletions, and a separate NGS diagnostic test that requires RNA input in order to analyze and identify gene-fusions in tumor samples. Furthermore, cancer tissues acquire mutations as time and treatment progress – an example of this is the EGFR T790M mutation. Tumors with EGFR exon19 deletions in patients treated with TKI drugs can acquire EGFR T790M mutations that then provide the tumor with resistance to the TKI drugs. A second round of NGS testing on a new biopsy of the tumor can uncover EGFR T790M mutations in patients on TKIs whose tumors have started to show resistance to the drug, and can detect these mutations at far lower variant frequencies than by Sanger sequencing. Additionally, cancer patients and cancer survivors can develop additional tumors beyond their first. Next Generation Sequencing is an important tool for determining whether these new tumors are the results of metastasis or whether they’re new cancers that are unrelated to the first – this can make a huge difference in how the new tumors should be treated and what the expected outcome is for the patient.

I sincerely hope you reconsider your position on these two matters. The NCD for Medicare acts as a blueprint for many other insurance companies across the nation, and thus affects nearly everyone in America. Cancer is not static, and neither is the technology to diagnose and treat it.

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Dear Colleagues,

The proposed national coverage determination concerning next generation sequencing is going to hurt patients and hurt medical care in the United States, and I sincerely hope the Centers for Medicare and Medicaid Services will eliminate further consideration of this plan.

My opinion is based on my expertise as a physician who specializes in laboratory testing, a medical director of a large clinical laboratory performing over 10 million tests per year, and a professor at a highly –regarded medical school and academic medical center. I would like to make it clear that I am an academic physician with a salary that is not dependent on volume of laboratory testing, so my concerns are not related to finances. Rather, I am concerned about the impact this policy will have on current clinical care and the impact it will have on the development of this area of medicine known as “precision” or “personalized” medicine that offers tremendous hope for the future.

While the field of laboratory testing has struggled with measuring one protein at a time or one gene at a time, next generation sequencing has created the ability to sequence many genes at the same time, and to distill the information in a way that can create a treatment plan for an individual patient, tailored to their specific genetic signatures. The testing has been standardized, national organizations that CMS has empowered to oversee the accreditation of laboratory testing have developed validation and performance standards, and these laboratory-developed tests are being widely used across the country, improving the lives of patients in every state in our nation. Studies have shown that these laboratory-developed tests, being used at major academic medical centers across the country, are as reliable as FDA-approved tests.

To limit these tools that are improving the lives of millions of patients across the country will reverse the very positive developments in health care, and will hurt millions of people. Today, physician working groups (often called multidisciplinary teams) can work together to make diagnoses, determine what testing is needed in caring for an individual patient, and can use next generation sequencing to evaluate a large number of genes at one time to determine the full range of options available to develop the best care plan for each patient.

The limitation of testing to FDA-approved tests would mean that all testing must be performed in a very narrow range of laboratories, destroying the advances we have made in personalized care, and creating a monopolistic testing strategy that will undermine the progress that has been made in this field. This will set the field back, eliminate the many benefits that have already been developed, and destroy the ability to pursue new approaches. And all of these setbacks will occur without improving the reliability of testing at all, since laboratory-developed tests developed in accordance with laboratory accreditation standards are as reliable as FDA-approved tests. At the same time, this plan will create an unchecked single-vendor (or very limited vendor) system in which errors will increase due to results that are never verified by other labs using other methods, or challenged by the multidisciplinary team most familiar with the patient and their response to therapy.

I urge the Centers for Medicare and Medicaid Services to discard this national coverage determination, and instead, to rely on the input of those with the highest levels of expertise, such as the national pathology organizations in this area, and those whom CMS has empowered to determine accreditation standards for laboratories. These are the organizations with the highest level of expertise and experience in overseeing both FDA-approved testing standards, and overseeing the standards for laboratory-developed testing. Laboratory accreditation standards in the United States has been consistently rigorous and reliable, and I hope you will rely on these highly-respected approaches to deal with next generation sequencing testing standards, rather than the proposed NCD.

Thank you for considering my concerns with this proposal.

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CLIA '88 laws allow laboratories to develop in-house tests for patient care. These laboratory-developed tests (LDTs) are widely used at academic center and community labs for standard patient care, including making diagnoses and helping manage patients on standard-of-care approved medications. This basic clinical service is currently being performed in labs across the country for cancer patients and often uses NGS technologies. As clinical labs, any LDT (including NGS based tests) undergoes validation and ongoing proficiency testing as required by CLIA. Cancer patients depend on these tests being readily available for timely diagnosis and treatment decisions.

This decision to cover only FDA approved NGS tests for advanced cancer patients will be detrimental to patient care, physician practice, and laboratories. FDA approval is difficult, expensive and time-consuming to get and is not compatible with a rapidly evolving landscape. With cancer care changing rapidly, LDTs are a critical mechanism by which patients can receive testing for the latest clinically relevant biomarkers. Limiting reimbursement will limit the treating physician’s ability to order the best test for their patient, especially if that test becomes outdated. FDA tests often require modifications to be more applicable to a particular patient (eg. specimen type) which can be done in the context of a local lab using either an LDT or modified FDA approved test but is not possible when using a large reference lab. Medicare patients who have unusual specimen types, such as body fluids or cerebrospinal fluid, will not have a local LDT option that is covered.

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CAG-00450N

I direct a clinical molecular pathology laboratory at the College of Medicine of the University of Florida in Gainesville, FL. The laboratory is CLIA- certified as required for any type of clinical laboratory work and we are using our own laboratory-developed tests to run NGS-based mutation profiling assays for the most frequent cancer types one can see in the associated UF teaching hospital and the surrounding Florida area.

I follow actively the development of NGS technology since its very beginnings and appreciate its role in precision medicine. It suffices to say that precision medicine in its current scope would be impossible without NGS. Based on this technology, hundreds, if not thousands of clinical laboratories in this country developed their own laboratory-developed tests for mutation detection in various types of cancer. They are all CLIA-certified and licensed to do such kind of testing. Foundation Medicine runs one of such laboratories and they went the extra step to have their test approved also by the FDA which helps them both with public recognition and billing. However, that FDA approval is not necessary for a CLIA lab to run a clinical test, if that said test was developed in that laboratory and fulfills CLIA guidelines. As a matter of fact, more than 95% of NGS-based clinical tests run in this country were not FDA approved, but they were all developed according to the CLIA guidelines. That these tests perform well can be seen from the published literature and also CAP proficiency testing results the molecular labs are taking part in.

I was therefore very disappointed seeing the CMS Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N) in which is requires that “the test is an FDA-approved companion in vitro diagnostic”. The wording of this proposed regulation is disturbing from several aspects. It is ignorant of the fact the CLIA, not the FDA regulates testing in clinical laboratories. It completely disregards the fact that the great majority of NGS-based tests in clinical use are non-FDA approved LDTs. It distorts the marketplace by an ill-advised government-initiated intervention to provide Foundation Medicine with a quasi-monopoly on NGS-based testing forcing providers to send samples to be tested to Foundation Medicine instead of using local CLIA-certified laboratories running their own laboratory-developed tests. I do not think that that was the original intent of the proposed regulation. But the authors of the CAG-00450N do not seem to understand that Foundation Medicine is not the only provider of NGS-based testing in the clinical arena. I ask you to remove the FDA wording form the proposal and expand the coverage to all CLIA- certified laboratories.

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The march of CMS to require FDA approval for NGS tests is foolish. The field moves too fast.

In this particular case, requiring FDA approval for molecular NGS testing will unnecessarily slow down the clinical application of advances in research and result in needless deaths. How long would it take to get FDA approval to include a new gene that could be a major, targetable driver for that particular cancer? The whole idea behind personalized medicine is to identify the specific genetic causes for the cancer and risks of specific treatments so that the patient can receive the most effective therapy with the least side effects.

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Tamara Syrek-Jensen, JD
Director, Coverage and Analysis Group

Joseph Chin, MD, MS
Deputy Director, Coverage and Analysis Group

Katherine B. Szarama, PhD
Lead Analyst
katherine.szarama@cms.hhs.gov

RE: CAG-00450N Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer

Dear Ms. Syrek-Jensen and Drs. Chin and Szarama:

We applaud this National Coverage Decision (NCD), it is well thought out and an elegant framework of coverage. The core principles of requiring independent validation of NGS, unification of NGS coverage policies across the nation, and the coverage with evidence development (CED) through prospective registries is a rational and sound method to introduce this important tool.

After both indirect and direct discussions with multiple stakeholders, including patients, oncology physicians and thought leaders, molecular pathologists, private payors, and former and present policy makers we would ask you to consider a few points that we believe are crucial to help this NCD be one of most important actions ever considered to advance cancer care.

Comment #1 Coverage with Evidence Development should be required in any scenario where any biomarker is reported to which there is no FDA-approved companion diagnostic and drug combination associated with this biomarker in the given disease state. This should be independent of whether a test is a “companion in vitro diagnostic,” a “in vitro diagnostic” or “a laboratory developed test.”

The draft NCD has several groups believing that with companion in vitro diagnostic approval a laboratory can report any companion diagnostic biomarker from any disease state without CED. This will likely lead to an increase in off-compendia use of drugs, a practice that requires CED to ascertain where there is and where there is not efficacy. The language should be clear that CED is required unless only the companion diagnostic genes in the given disease state are reported.

Comment #2: Registries should be approved by CMS and the sponsor should not be related to a commercial company (e.g. laboratory, pharma or informatics company). Each claim submitted to CMS should have the registry ID number on the claim.

Rationale:
Commercial groups such as laboratories, pharmaceutical companies, informatics/data companies (including for-profit subsidiaries or exclusive partners of non-profit organizations) each have an inherent conflict of interest of running their own registries. Conflicts include potential inducement of physicians to order tests, potential exclusive or preferential relationship with data sharing or clinical trial matching, potential decrease in patient protection due to financial motivation, and/or possible over-simplifying data collection necessary for showing clinical utility. Registry participation number should be provided on each claim to CMS to be able to verify compliance with CED requirements and this number should be able to be tied back to a specific patient by the registry. The requirement for CMS approval of registries has been standard in many other CED projects, and registry number on claims verifies registry participation of each patient covered under CED.

Comment #3 CMS should require that registries collect not only the result of NGS testing, but also detailed genomic information including instrument testing data, regions of DNA analyzed, raw genomic data, final variant calls and final report and compare these to clinical outcomes. This requirement should be applied to all labs (companion in vitro, in vitro or LDT).

Clinical Evidence and/or Rationale:
NGS and molecular medicine is unique from almost every other type of CED project that CMS has undertaken. In most CED projects the intervention under coverage is a reasonably static device (e.g. heart valves, PET scans), or a set procedure (e.g. allogeneic stem cell treatment or CPAP). NGS is dynamic and ever evolving. Although a laboratory may be able to show analytical validity (as demonstrated by sensitivity and specificity) in certain genes, there are multiple variables that can create substantial differences in testing even when two laboratories are using strict standards and following industry leading operating procedures. Reasons for these differences reside in the complexity of the component parts of these tests. These include sample prep methods and libraries, rapidly evolving instrumentation, fundamental difference in approaches to testing (hot-spot verses whole gene verses whole exome verses cell free DNA), different methods of analysis (coverage depth, read regions), informatic pipelines, manual curation of variant calls, comparison to germline reads and final reporting methods. The College of American Pathology has noted, “The NGS field continues to evolve at a rapid pace and this evolution reflects continuing improvements in NGS instrumentation, chemistries, and analytic tools and software” and readily admits that it is continuing to evolve its quality assurance efforts it each of these areas.³

The results of variation in testing methodology can lead to significant differences in reported biomarkers. For example, Boland showed marked differences in testing amongst three different NGS platforms4 when analyzing the same germline cell lines. Jones questions the need for sequencing matched germline specimens⁵, Head⁶ and vanDijk⁷ discuss the complexity and bias of library prep methods and Babayan shows marked differences in identifying known alterations based on actual prep methods when analyzed in different instrumentation⁸. Gray discusses difficulties of identifying copy number variation⁹. Burghel discusses problems with missing known alterations using methods that do not analyze certain regions of DNA (hot spot testing that does not cover certain genomic alterations found by other methods).¹⁰ Cornish identified the differences that can be seen when the same specimen is analyzed using different bioinformatics pipelines. ¹¹ In short, and especially in areas of low allele frequency and complex DNA alterations (insertions, deletions, duplications and copy number variation) reported differences, even in laboratories who have excellent and transparent validation can be substantial.¹²

CAP has recommended, “The overall goal of (a) quality program aims to ensure that testing is clinically relevant. This is particularly important for tests such as NGS, for which no comparative analytic result of greater sensitivity may exist. The appropriateness of test orders and analytic decisions must be grounded in medical science and evidence.”

Unless the detailed genomic data are collected as part of CED it will be near impossible to identify laboratory specific improvements or deficiencies that can only be found when deconstructing the testing into its discrete steps and comparing laboratories together. The added work on the laboratories to provide the necessary files is not onerous (they are already generating these files as part of the routine work of the laboratory).
Comment #4: CMS should require laboratories to participate in Quality Improvement Registries (QIR). This does not preclude a group from applying to CMS to have its own registry for collection purposes, but they should report detailed patient level genomic and outcome data into a CMS approved centralized QIR in a format that will allow comparison with other laboratories and allow not only determination of current utility, but improvement of quality of testing.

In 2010, under section 1115A of the Social Security Act (as added by section 3021 of the Affordable Care Act), Congress created the Medicare Innovation Center for various purposes, one of which is “evaluating results and advancing best practices.” On April 16, 2015, the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA), further emphasized the focus on quality through streamlining multiple quality programs under the Merit Based Payment System (MIPS).

AHRQ, through its description of Quality Improvement Registries (QIR)¹³ has highlighted the need for efforts that mesh data collection with quality improvement. QIRs unlike regular registries take collected data and use it to continuously improve care. As it is written, the draft NGS policy requires scientific outcomes reported at regular intervals, but does not require that the information that is being collected be compared to other laboratories or used in developing an improvement plan around the testing. The differences between a traditional registry and a QIR can be thought of as how data are collected and what questions can be answered with the data.

Evidence collection layers and data:

Scientific (traditionally captured in clinical trials or observational registries): Overall survival, progression free survival, response rate; in connection with the testing or compared to certain cohorts or clinical studies.

Science into Quality (QIR):

• Does NGS testing reduce the use of duplicated testing?
• How often does a physician treat a patient, with a known beneficial biomarker, with appropriate therapy?
• How does one laboratory’s NGS methods perform better or worse in similar cohorts?
• Are physicians treating variants of unknown significance (VUS) with targeted therapy?
• What is the appropriate clinical sensitivity and specificity of NGS testing?
  • Analytical sensitivity and specificity is different than clinical sensitivity and specificity. If a laboratory, when identifying EGFR+ NSCLC, has a 100% response rate to therapy then the testing is too specific (missing true positives) and is excluding patients that could have benefited from therapy. If only 20% of EGFR+ NSCLC patients respond to therapy then the test may be too sensitive (identifying false positives).
  • The only way to find the true clinical sensitivity and specificity is continuously improving that testing and finding an acceptable balance between the two.

  A centralized QIR, working with detailed genomic information, multiple laboratories and clinical outcomes can collect the data necessary to answer the quality questions as well as collecting the scientific outcomes required for CED. A centralized QIR could also work with other groups to enhance the data that is collected, (i.e. tying in claims data from CMS, staging data from SEER, additional clinical trials, etc.)

  A QIR can be identified to have the following characteristics:

  • Multi-stakeholder involvement in the planning, development and oversight
  • Independence from all groups
  • Ability to work with any group commercial or academic
  • Strict requirements to collect detailed NGS data in addition to clinical outcomes
  • Reporting of metrics separate from the clinical outcome data to allow improvement of patient care
  • A demonstrated ability to work CMS, FDA, laboratory community, and clinical community
  • Has been identified by an outside group as a quality data reporting organization

  CMS, on approving a QIR, may simplify other requirements for coverage by a laboratory to avoid duplication of work. For example, if a QIR is reviewing the analytical validation of a laboratory as part of the QIR enrollment AND this review is using methods and metrics accepted by FDA, and/or collecting the same information of the NIH Genetic Testing Registry, then coverage could be granted without an additional third party review, and NIH GTR enrollment could be removed (see comment #5).

  Comment #5: Coverage should be extended to any laboratory that participates in a CMS approved QIR that also reviews and updates the analytical validity of testing as part of its quality improvement plan. Labs that participate in these QIRs would not have to participate in the NCI Genetic Testing Registry.

  Clinical Evidence and/or Rationale:
  The only difference between an FDA approved “companion in vitro diagnostic”, a 510(k) cleared “in vitro diagnostic,” or NCI cancer center “laboratory developed test” is the analytical work done to show expected concordance with existing testing and the independent reviewing body. Although FDA companion diagnostic testing is considered the gold standard for testing it by no means should be considered the clinical gold standard. Literature is replete with the ever-evolving nature of companion diagnostics as new clinical outcome data are made available (HER2¹⁴ - latest update in 2013, BRAF¹⁵ - later addition of V600K, RAS – later addition of NRAS to KRAS). In most cases these advances occur in academic centers who are trying to improve upon the already FDA approved testing (laboratory developed tests) and then comparing it to clinical results. With NGS testing, many, if not all, of these academic centers have already done extensive validation work on their assays, and have been reviewed by a variety of groups, (CLIA, CAP, etc.) and are willing to provide any information necessary to show they are doing good work. New York State has over a year of backlog for testing review, and FDA approval takes longer, and additional 3rd Party Review bodies will take time to form and for FDA to clear. Without an alternative pathway to coverage it is likely that many patients that could receive testing will not be able to participate and many good laboratories because of review delays will be marginalized.

  Although analytical validity is crucial to arrive at the clinical utility of a test, it is the clinical results that will push the standards of analytical validity to continually improve. An independent registry that initially verifies a laboratories analytical validation using methods and metrics approved by FDA, continually shares outcome data in connection with testing metrics and then collectively work to identify any areas to improve, will advance more quickly than if multiple disparate groups are working separately. In addition, it is possible that by tying coverage to third parties review that move slower than the field is advancing will stifle the improvement of the quality of NGS testing. QIRs can solve this problem and simplify steps for coverage, and yet not sacrifice the initial quality of the testing. By allowing a QIR to do the initial analytical review, catalogue the findings and then as clinical outcomes are collect, allow the standards to evolve it will speed up the approval process for lab and will likely provide better utility data than if the only step to coverage is review by an outside entity.

  A QIR can also capture the essence of the testing better than the NCI Genetic Testing Registry by keeping a precise catalogue of the version of the testing connection with the outcomes and thereby providing better ability to analyze results.

  Although a QIR could consider becoming a 3rd Party Reviewer for FDA, it may have a conflict of interest due to molecular pathology leadership that work with labs being reimbursed by CMS. Furthermore, an QIR that is independent of laboratory approval bodies could advance the science better by allowing outside review by FDA or others who then can act as independent bodies to update approval criteria.

  Requirement for QIRs to allow CMS coverage and remove the requirement of registration with the NCI Genetic Testing Registry could be defined as:

  1. The laboratory is CLIA certified and has had their NGS testing reviewed by an outside group accepted by the QIR as an industry standard review body (i.e. New York State, CAP)
  2. The QIR has an independent body of molecular experts that reviews and publishes the validation of the NGS testing to make sure that it has been done correctly and meets the scientific standard necessary for participation in the registry. This scientific standard will at a minimum validate that the laboratory is able to correctly test for the companion diagnostics.
  3. The QIR will have its validation review metrics and quality improvement methods approved by FDA as meeting a reasonable scientific approach.
  4. QIR will work closely with FDA to continually review data and update metrics
  5. The QIR requires detail genomic data (as above) to be submitted and that this information will be transparently available (although de-identified by the registry) to allow analysis and review
  6. The QIR keeps track of versions of testing
  7. The QIR will work closely with CMS to act as an independent body to confirm compliance of laboratories with the CED policy

  Comment #6 RECIST criteria is onerous and will limit access to testing.

  The only routine use of RECIST criteria in clinical practice is in clinical trials. The time and effort to duplicate these tedious measurements will disproportionately affect patients in community and rural settings where physicians use a more subjective method of measuring disease response and who may not be able to implement a wholesale change in the way they practice medicine. Many targeted agents, when given to a patient with a responsive mutation, will show months-time to progression improvement and so a community based subjective response determination in connection with an objective time to progression measurement will likely give a reasonable surrogate for RECIST. Registries must use consistent methods of measuring outcomes (with strict definitions), but not be tied to the rigidity of RECIST.

  Comment #7 Patient Reported Outcomes (PROs) should be introduced later for simplicity and scalability.

  Development of patient reported outcomes are important, but adds to clinic work burden to educate patients and follow up on PROs. Rather than have clinics begin enrollment and operations with prospective registries AND have the added responsibility of introducing patient reported outcomes at the same time provides a substantial administrative burden. We would recommend that PRO be delayed at least one year after the opening of coverage to allow clinics to get accustomed and implement best practices for registry enrollment before the introduction of another element.

  Comment #8 Patients and laboratories in NCI-sponsored trials should not be treated differently than patients in non-NCI trials or patients treated off trial.

  As the draft policy currently is written, only patients that make it into an NCI-sponsored trial would have their testing covered. This is a very small number of patients (probably less than 0.1% of patients with cancer in the US). While, any patient who is an NCI-sponsored trial should be covered, CED should not be restricted to this small group of patients. There is a need for data points far beyond this small group of trials, and there is especially a need for data-points from community physicians, as well as academic centers and their associated NGS laboratories

  Conclusion:
  We strongly recommend that CMS move forward with the finalization of this NCD. We strongly agree with the need for standards, transparency and data collection.

  We recommend consideration in the following areas:

  1. CED for any test that reports any biomarker that is not a companion diagnostic biomarker in that given disease state
  2. Registries approved by CMS, non-commercial, and claims with registry ID
  3. Registries should collect detailed genomic data collect along with clinical outcomes by all labs
  4. Registries should be Quality Improvement Registries
  5. Coverage extended to any laboratory that participates in a CMS approved QIR
  6. RESIST criteria replaced with standardized real-world metrics
  7. Patient reported outcomes delayed for 1 year
  8. Patients and laboratories in NCI-sponsored trials should not be treated any differently

  Warmly,

  Razelle Kurzrock, MD
  Chief, Division of Hematology and Oncology,
  University of California San Diego (UCSD) School of Medicine,
  Senior Deputy Director,
  Director, Center for Personalized Cancer Therapy,
  Director, Clinical Trials Office,
  UCSD Moores Cancer Center
  San Diego, California

  Keith Flaherty, MD
  John Pfiefer, MD, PhD
  Dane Dickson, MD

  References:

  1. Ramalingam SS, Blais N, Mazieres J, et al. Randomized, Placebo-Controlled, Phase II Study of Veliparib in Combination with Carboplatin and Paclitaxel for Advanced/Metastatic Non-Small Cell Lung Cancer. Clin Cancer Res Off J Am Assoc Cancer Res 2017;23(8):1937–44.
  2. Teplinsky E, Muggia F. EGFR and HER2: is there a role in ovarian cancer? Transl Cancer Res 2015;4(1):107–17.
  3. Aziz N, Zhao Q, Bry L, et al. College of American Pathologists’ Laboratory Standards for Next-Generation Sequencing Clinical Tests. Arch Pathol Lab Med 2014;139(4):481–93.
  4. Boland JF, Chung CC, Roberson D, et al. The new sequencer on the block: comparison of Life Technology’s Proton sequencer to an Illumina HiSeq for whole-exome sequencing. Hum Genet 2013;132(10):1153–63.
  5. Jones S, Anagnostou V, Lytle K, et al. Personalized genomic analyses for cancer mutation discovery and interpretation. Sci Transl Med 2015;7(283):283ra53.
  6. Head SR, Komori HK, LaMere SA, et al. Library construction for next-generation sequencing: Overviews and challenges. BioTechniques 2014;56(2):61–passim.
  7. van Dijk EL, Jaszczyszyn Y, Thermes C. Library preparation methods for next-generation sequencing: tone own the bias. Exp Cell Res 2014;322(1):12–20.
  8. Babayan A, Alawi M, Gormley M, et al. Comparative study of whole genome amplification and next generation sequencing performance of single cancer cells. Oncotarget 2016;8(34):56066–80.
  9. Gray PN, Dunlop CLM, Elliott AM. Not All Next Generation Sequencing Diagnostics are Created Equal: Understanding the Nuances of Solid Tumor Assay Design for Somatic Mutation Detection. Cancers 2015;7(3):1313–32.
  10. Burghel GJ, Hurst CD, Watson CM, et al. Towards a Next-Generation Sequencing Diagnostic Service for Tumour Genotyping: A Comparison of Panels and Platforms. BioMed Res Int [Internet] 2015 [cited 2018 Jan 2];2015. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4553307/
  11. Cornish A, Guda C. A Comparison of Variant Calling Pipelines Using Genome in a Bottle as a Reference. BioMed Res Int [Internet] 2015 [cited 2018 Jan 2];2015. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619817/
  12. Dickson DJ, Pfeifer JD. Real-world data in the molecular era—finding the reality in the real world. Clin Pharmacol Ther 2016;99(2):186–97.
  13. Gliklich RE, Dreyer NA, Leavy MB. Quality Improvement Registries [Internet]. Agency for Healthcare Research and Quality (US); 2014 [cited 2017 Dec 30]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK208630/
  14. Wolff AC, Hammond MEH, Hicks DG, et al. Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol 2013;31(31):3997–4013.
  15. Ravnan MC, Matalka MS. Vemurafenib in patients with BRAF V600E mutation-positive advanced melanoma. Clin Ther 2012;34(7):1474–86.

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[PHI Redacted]

Thank you for the opportunity to provide comment on the National Coverage Analysis entitled ‘Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer’.

Cancer patients all over the country are benefiting from new knowledge in the genomic causes and drivers of cancer, as evidenced by increased access to personalized therapeutics and care based on the genetic makeup of cancer. We are grateful for advances in diagnostic technologies, such as next generation sequencing, as it is one tool to obtain a more comprehensive genetic understanding of cancer. This technology is of particular relevance to lung cancer patients as it typically requires less tissue sample than separate sequencing of multiple genes.

I thank CMS for recognizing the value of precision diagnostics in the care of cancer patients by proposing coverage for FoundationOne CDx (F1CDx). I support a positive coverage determination for the product reviewed in the Parallel Review program, F1CDx, however I have serious concerns about the broad scope of the proposed NCD. The proposed policy would limit cancer patients to 1 test per lifetime, which is not in line with the realities of personalized medicine based therapy for cancer patients.

Also, the new policy will eliminate coverage for other NGS tests for advanced cancer patients enrolled in Medicare. These tests are currently being used to deliver high-quality, advanced cancer care across the country, including at virtually all major cancer centers and academic institutions. I support the CMS proposal to cover the F1CDx test but urge CMS not to finalize the rest of the policy as it will result in several unintended negative consequences to cancer patients by erasing important medical advances and existing local coverage policies already in place.

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TO: Centers for Medicare & Medicaid Services

FROM: Roy A. Jensen, MD

RE: Proposed Decision Memo on Next Generation Sequencing for Medicare Beneficiaries with Advanced Cancer NCD (CAG-00450N)

My name is Roy Jensen, MD, director of The University of Kansas Cancer Center. I would like to thank the Centers for Medicare and Medicaid Services for the opportunity to comment on the Proposed Decision Memo on Next Generation Sequencing for Medicare Beneficiaries with advanced cancer.

The Clinical Molecular Oncology Laboratory (CMOL), a CLIA-certified and CAP-accredited molecular genetics laboratory founded in 2011 by Dr. Andrew K Godwin at the University of Kansas Medical Center, provides patients within KU’s clinical network access to standard of care practice incorporating various laboratory-developed next-generation sequencing based tests for solid tumors and hematologic malignancies. The CMOL developed their next-generation sequencing panels in close collaboration with numerous medical experts at KU across various disease specialties to meet the diagnostic and prognostic needs of their patients. To ensure we are maintaining the highest quality of patient care, the data our NGS panels provide are continuously monitored, in part, through routine tumor board meetings using the latest developments in the field. The introduction of our first next-generation sequencing targeted gene panel in 2016, a panel designed to target genes clinically relevant to acute myeloid leukemia (AML), provided our patients with unique and improved AML management through access to more comprehensive diagnostic and prognostic information, guidance to appropriate medications, and expanded clinical trial options. Where patient samples previously may have needed testing at multiple outside locations to cover all ordered testing, the CMOL’s development of NGS-based multiple gene panels has provided patients with the ability to cover their testing needs in one assay, reducing overall testing costs, minimizing collection of precious sample materials from patients, and providing multiple results simultaneously in a single comprehensive report. Our available testing has since expanded to include next-generation sequencing panels for solid tumors, including a panel for the detection of RNA-fusion products important in non-small cell lung cancer (NSCLC), and we plan to develop additional somatic testing panels, pharmacogenomic panels, hereditary testing panels and others.

Our ability to develop and deliver next-generation sequencing based panels has become a critical component of the appropriate clinical management of patients at KU, and represents the high standard of care on which patients have come to rely. Laboratory developed next-generation sequencing panels provide a critical mechanism by which we and other laboratories can stay on top of new biomarker discoveries on behalf of patients in the rapidly and continuously evolving field of genomically-driven personalized medicine.

The proposed NCD significantly jeopardizes re-imbursement of our current portfolio of genomic testing and is likely to curtail future development and innovation of such tests at nearly all academic medical centers. The last thing, which we need in this period of rapidly evolving technology and discovery are well-intended policies that will stifle innovation.

Thank you for your consideration. I would be happy to serve as a resource to CMS on this particular issue.

Sincerely,

Roy A. Jensen, MD
Director
The University of Kansas Cancer Center

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January 11, 2018

Tamara Syrek Jensen
Department of Laboratory Medicine & Pathology
Director, Coverage and Analysis Group
Center for Medicare & Medicaid Services
Mail stop# 53-02-01
7500 Security Boulevard
Baltimore, MD 21244

Dear Ms. Jensen-

My colleagues and I appreciate the open comment period to express our concerns with the Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N). We are strongly opposed to this National Coverage Determination (NCD)~ the scope of the draft is too broad and will have potentially disastrous consequences on the care of advanced cancer patients in the United States, as reviewed in detail below.

We are a group of academic physicians with subspecialty training and board certification in molecular genetic pathology (and other pathology discipl ines) at the University of Minnesota who direct a Molecular Diagnostics Laboratory (MDL) in conjunction with our nonprofit health system partner Fairview Heath Services. We are a NCI-designated cancer center with a health network including several major inpatient hospitals and numerous outpatient clinics serving patients across Minnesota. Our laboratory provides a diverse test menu for our clinicians and patients across the health system including NGS-based oncology testing. We perform approximately 1,000 NGS-based cancer tests per year (45% solid tumor, 55% leukemia). These Laboratory Developed Testing Procedures (LDPs) have been specifically designed to meet NCCN and FDA standard of care guide lines and we have validated their analytic performance to meet the high clinical quality standards of the Clinical Laboratory Improvement Amendments (CUA) and the College of American Pathologists (CAP). These tests provide a spectrum of (therapeutic) predictive, prognostic, and diagnostic information. We work in local, multidisciplinary teams with our clinical colleagues to optimize the entire workflow of patient care around these tests, including: flexible sample management that prioritizes testing on an individual basis, personalized result interpretation in the context of the patient's entire medical record, and quality improvement projects that ensure timely and effective return of test results.

The scope of the proposed NCD for Next Generation Sequencing for Medicare Beneficiaries with Advanced Cancer extends far beyond the considerations necessary for the joint CMS/FDA application from Foundation Medicine for the FlCDx test. Specifically, sections A2 and C set unacceptable precedents that narrowly limit coverage only to FDA-approved NGS-based cancer tests and expressly prohibit coverage for non-FDA approved tests respectively. This scope is excessive becaus'e: 1) it undermines the authority of existing, legally-defined entities that currently ensure the high quality of clinical lab testing, 2) it obfuscates existing local coverage detenninations (or the future development of such determinations) that support the practice of precision medicine with LDPs optimized for local patient needs, 3) it establishes a de facto, government-sanctioned monopoly for a commercial entity that will unquestionably stifle innovation in a rapidly evolving field of medicine, and 4) it represents an unprecedented attempt by the CMS to set a national coverage determination on a broad technology rather than a specific test for specified biomarker(s) in a specific disease.

The practice of precision medicine is an inherently local activity. It requires a holistic analysis of a patient's signs, symptoms, and test results. The best practice incorporation ofNGS-based cancer tests requires the interaction of local healthcare professionals, each bringing a different area of expertise_ to the patient's care. It requires knowledge of all diagnostic testing performed on the patient and an understanding of the intended care plan. The restrictive criteria ofthis NCD will unnecessarily limit (if not outright abolish) the ability of local hospital systems to implement in-house NGS-based oncology testing that best fits their patients' needs.

The practice of medicine with LDPs is already well established and regulated by CUA. NGSbased testing is widely utilized by CLIA-licensed clinical diagnostic laboratories across the country (doi: 10.5858/arpa.2016-0542-CP) and CUA-accredited LDPs are highly accurate and reproducible (doi.org/10.1177/2374289517708309 and doi: I 0.1001/jamaoncol.20 l 7.4021 ). Furthermore, the question of LDPs vs. FDA-approved in vitro diagnostics (IVD) has been recently and extensively evaluated; Congress effectively instructed the FDA not to alter its position on enforcement discretion for LDPs, maintaining the established avenues for regulation as set forth in CUA under the purview of CMS or deemed-status organizations such as CAP. With the current NCD, CMS is effectively inconsistent with its own policies to oversee the accurate delivery of clinical laboratory testing that adheres to evidence based guidelines. CMS should provide coverage for NGS-based tests that are validated and performed in CLIAaccredited laboratories which assess biomarker(s) that qualify patients for FDA-approved therapies.

Finally, the elimination of coverage for clinically necessary LDPs in oncology care runs a dire risk of suppressing the open accumulation of knowledge necessary to further vet and refine the clinical utility and technology development of genomics-driven cancer care. It also may unintentionally limit the accessibility of such testing for patients. In effect, the immediate instaHation of this NCD would create a national market accessible to only one commercial laboratory, at least for the short-term horizon. Most of the medical and scientific community in the United States could be shut out from the continued development of best clinical practices for genomics-informed oncology; at a minimum the intellectual freedom to operate separate from the commercial incentives of Foundation Medicine and Roche would be severely impacted. Further, this NCD may effectively abolish patients' access to local, high-quality NOS-based oncology tests and it will clearly incentivize referral to Foundation Medicine. It is unknown whether capacity for this volume increase exists and critical turnaround time of results may be delayed, leading to significant negative clinical impact for patients.

We strongly urge CMS to revise this draft National Coverage Determination, asking that you consider revising section A2 of the Decision Summary to allow for coverage of validated NGS testing in a CUA-accredited laboratory that meets any of the. criteria specified in sub-points a), b), or c). We further ask that you strike section C (noncoverage) from the final NCO and defer such determinations to local jurisdictions to allow for a more agile process that can better respond to the needs of local hospital systems for the best care of their patients.

Sincerely,

/s/
Andrew C. Nelson, M.D., Ph.D.

/s/
Sophia Yohe, M.D.

/s/
Michelle Dolan, M.D.

/s/
Leo T. Furcht, M.D.
Allen-Pardee Professor & Head
Dept. of Laboratory Medicine & Pathology

/s/
Bharat Thyagarajan, M.D., Ph.D.

/s/
Pawel Mroz, M.D., Ph.D.

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January 12, 2018

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Dear Ms. Jensen,

Thank you for the opportunity to comment on the draft national coverage determination (NCD) CAG-00450N related to the FoundationOne CDx (FlCDx) test.

UW Medicine provides high-complexity medical care for patients from Washington State and across the Pacific Northwest, including employing advanced diagnostic testing modalities. The current draft FlCDx NCD proposes unprecedented restrictions on patient access to clinical diagnostic procedures provided by academic teaching hospitals, such as two of the hospitals within UW Medicine. The draft FlCDx NCD also threatens to impair groundbreaking laboratory innovation and impact future patients through decreased quality of physician training.

Patients at UW Medicine and other academic health systems are routinely evaluated using laboratory tests that employ next generation sequencing (NOS), and tests using this technology have become standard of care in many conditions. The draft FlCDx NCD would prohibit Centers for Medicare & Medicaid Services (CMS) from reimbursing for these frequently used NOS laboratory procedures. Such restrictions on access could harm patients by preventing use of accurate and appropriate diagnostic methods in numerous clinical scenarios.

Properly trained physicians are critical to providing appropriate patient care in the era of precision medicine. The majority of physician education occurs at academic teaching hospitals, and the availability of NOS tests at these hospitals allows for careful and hands-on instruction of physician trainees. Appropriate training allows providers to be well versed in the appropriate use of N GS testing, which benefits current and future patients. If AMCs are unable to offer NOS laboratory tests, practicing physicians will have inadequate experience, which can result in risks to patients.

Limiting patient access to currently available NOS methods at teaching hospitals will impair future diagnostic innovations. Initiatives, such as the Brotman-Baty Institute for Precision Medicine (https:// newsroom. uw.ed u/ news/brotman-baty-institute-precision-medicine-launches-seattle) are designed to bring clinical experts and leading scientists together to rapidly transition important medical advances to the patient bedside. Limiting patient access to NOS at teaching hospitals will restrict the opportunities for improvements and advances in medical care.

UW Medicine recommends that CMS remove the prohibition on reimbursement for NOS procedures that is in the draft FlCDx NCD. Patient access to NOS methods developed and performed by teaching hospitals should be available for patient care and eligible for Medicare reimbursement.

Maintaining patient access to NOS methods developed at teaching hospitals will promote patient safety through.adequate physician training and allow deployment of future innovations. Promoting these activities will allow our leading teaching hospitals to continue to provide the best care for patients and their families, while advancing the field of precision medicine.

Thank you for your consideration,

/s/
Paul G. Ramsey, M.D.
CEO, UW Medicine
Executive Vice President for Medical Affairs and
Dean of the School of Medicine,
University of Washington

Geoffrey Baird, M.D., Ph.D.
Associate Professor and Interim Chair
Department of Laboratory Medicine
University of Washington

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January 12, 2018

BY US MAIL & EMAIL
Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop #S3-02-01
7500 Security Boulevard
Baltimore, Maryland 21244
Tamara.Syrekjensen@cms.hhs.gov

Re: Comment on Proposed CAG-00450N

Dear Ms. Jensen:

Please accept the following comments of OmniSeq, Inc. on the proposed decision memorandum for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-004SON) ("Proposed NCD"). OmniSeq, Inc. ("OmniSeq"), a subsidiary of Roswell Park Cancer Institute, is a CLIA and NYS CLEP licensed molecular diagnostic laboratory located in Buffalo, New York. OmniSeq and our parent corporation, Roswell Park Cancer Institute, have a direct stake in ensuring that laboratory testing using Next Generation Sequencing (NGS) technology is available when a Medicare beneficiary's physician has determined that it is medically necessary for treatment of the beneficiary. OmniSeq has had three NGS assays approved by NYS CLEP, and intends to submit two of those assays for review through the newly announced streamlined NYS CLEP /FDA clearance process.

We applaud that CMS and the FDA are taking an important step toward developing a common and defined pathway for medical policy for NGS testing for late stage cancer care. The Proposed NCD for NGS testing will correct current inconsistencies in NGS testing among the MACs' local coverage determinations. While we are certain there will be many detractors who are critical of this policy, CMS should not allow the finalization of this important coverage determination to be derailed.

We respectfully disagree with commenters who request that the Proposed NCD be limited in scope to providing coverage of FlCDx, asserting "onerous" Coverage with Evidence Development (CED) requirements should be omitted from the final policy. There are several competitor assays on the market that will be able to meet one of the three coverage scenarios set forth in the Proposed NCD, and both clinicians and Medicare beneficiaries deserve to choose from a variety of NGS assays that meet these high standards. Limiting the Proposed NCD to FlCDx coverage would effectually eliminate all existing NGS competitive assays from the marketplace and halt the innovation and growth of smaller laboratories working to improve cancer care through NGS assay development. The CED channel for coverage is an important part of the Proposed NCD.

OmniSeq agrees that CED dat~ will help assure equivalent clinical utility and ensure high quality across NGS assays. However, additional clarification in the CED coverage section is needed to ensure appropriate interpretation and implementation. OmniSeq urges CMS to require laboratories to take a representative approach to CED registry design that both supports meaningful clinical utility analyses and accounts for real-world constraints and limitations of clinical practice. Because patient follow up with clinicians is variable, it is unrealistic that independent laboratories will successfully collect outcomes and survival data for 100% of patients tested. Moreover, Medicare beneficiaries outside the catchm~nt areas of comprehensive cancer centers, i.e., rural areas, deserve to have access to this important testing and the registry requirements should not preclude their access to precision medicine.

Additionally, we ask that CMS give ample consideration to the cost associated with maintaining patient registries that include treatment response and survival. Supporting the review of imaging data to capture RECIST over time for large numbers of patients is very resource intensive and costly. It is imperative for CMS to take this burden to laboratories into account in setting reimbursement rates for assays meeting this stringent criteria for CED.

Finally, we note that the Proposed NCD omits Stage III non-resectable cancers from NGS coverage. In general, Stage III means that cancers have invaded deeply into adjacent tissues, whereas Stage IV includes patients in whom cancer has spread to other organs. In many cases, the clinical decisions for systemic targeted therapy ( or chemotherapy) are the same. These patients are appropriate for gene panel studies. We urge CMS to include Stage III non-resectable cancers in the definition of coverage, as patients with Stage III non-resectable cancers greatly benefit from NGS testing.

Thank you for considering OmniSeq's comments on the Proposed NCD.

Sincerely,

/s/
Margot Schoenborn

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Dear CMS representative,

We are writing to you from an independent molecular pathology laboratory operating in one of the more rural areas of the US, central and northern Maine regions. We serve 15 regional hospital clients and numerous outpatient facilities within the state.

The above ruling you are currently considering would limit next generation sequencing (NGS) to assays that have received FDA approval. That decision would limit this testing to few laboratories in the country, to which many patients from rural areas have no access, turnaround times are often unacceptably long, and/or the pricing is unaffordable.
As a result, many rural patients would be deprived of access to essential testing that provides them with novel treatment options and can qualify them to enter clinical trials.

NGS is not a single test; it is merely a method, utilized in many laboratory-developed tests (LDTs), which are rigorously monitored by CLIA, primarily via the College of American Pathologists (CAP), among other entities with deemed status by the Centers for Medicare and Medicaid Services. This oversight is performed via routine CAP inspections and continuous monitoring via CAP proficiency programs. Furthermore, clinical validation and routine clinical use has been well established through recommendations and guidance from joint commission studies representing the collaborative efforts from medical specialty governing bodies such as American College of Medical Genetics (ACMG), Association for Molecular Pathology (AMP),American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH), and the College of American Pathologists (CAP).

While not under the jurisdiction of the Food and Drug Administration (FDA), this oversight is rigorous, has been in place for decades and has represented the standard of care in laboratory medicine in the United States for a very long time.
The flexibility it provides to laboratories to develop LDTs has been essential for innovation and progress in the field, allowing patients in the most remote localities within the country access to cutting edge diagnostic testing.
LDTs have existed side by side with FDA-approved assays with which they have been routinely correlated as part of CAP proficiency testing and laboratory validation procedures.

In fact, the essentially “locked” nature of the FDA-approved assays inhibits modification once they are approved. Due to this inflexibility, many FDA-approved assays are rendered obsolete shortly after their approval, as they often fail to meet rapidly evolving standards of care. This is especially the case in the field of genomic testing. Therefore, in light of newer scientific discoveries and evolving standards of care (such as those established by the National Comprehensive Cancer Network (NCCN)), many of the currently approved assays fail to detect all of the abnormalities that have become standard of care since their approval. For example, the FDA-approved KRAS assay vastly fails to comply with the “Extended RAS testing” mandated as a standard of care for colon cancer patients by the NCCN. Similarly, the FDA-approved EGFR assay fails to detect the entire spectrum of mutations that could make patients with lung cancer eligible for EGFR inhibitor therapies. LDT assays provide laboratories with much greater flexibility to respond to the rapidly evolving science and establish testing for all that our patients and their oncologists need for modern treatment. The Association for Molecular Pathology has recently published a detailed article on this subject (Kaul KL et al. - The Case for Laboratory Developed Procedures; Quality and Positive Impact on Patient Care. Acad Pathol 2017;4:1-21).

Another limitation of many FDA-approved molecular tests is that they require more DNA and therefore larger biopsies which are difficult or impossible to safely obtain in many patients, especially in patients with advanced lung cancer where the size of the biopsies is usually very small. If separate FDA-approved tests have to be performed for each relevant target these small biopsies would be quickly exhausted and some critical tests could not be performed. In contrast, non-FDA approved NGS tests can use a single small biopsy to obtain all the relevant data, eliminating the need to subject the patient to costly and sometimes dangerous procedures to obtain larger biopsies.

Furthermore, sending out for FDA-approved assays, which is frequently required as these tests are often not available locally, invariably exceeds the acceptable turn-around time for patients who have the least time to spare due to the severity of their illness. In effect, these patients often remain deprived of such assays altogether, either due to lengthy time delays, lack of reimbursement for such out-of-network testing by their insurance carriers, or simply due to the high price tag these tests often are associated with. Local laboratories such as ours routinely offer generous discounts to local clients and rural patients. In addition, LDT testing is almost invariably less expensive than FDA-approved equivalents.

As a voice from rural laboratory services providers, we strongly encourage you to consider all the above issues in your decision NOT to limit NGS testing to FDA-approved assays only.

Thank you for your thorough consideration of this serious issue.

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Submitted via email to CAGinquiries@cms.hhs.gov

January 11, 2018

Department of Health and Human Services
Centers for Medicare & Medicaid Services
Department of Health and Human Services
P.O. Box 8013
Baltimore, MD 21244-1850

Dear Sir/Madam:

I am submitting these comments on behalf of the University of Vermont (UVM) Health Network, which welcomes the opportunity to comment on the proposed coverage decision for Next Generation Sequencing (NGS) for Medicare beneficiaries with advanced cancer that was released on November 30, 2017.

Background
The University of Vermont Health Network was formed in late 2011 with the objective of developing a highly-integrated regional network of health care providers focused on achieving the Triple Aim: improving the health of the populations we serve, enhancing patients' experience and outcomes, and reducing the per capita cost of care. The network includes six hospitals, three in Vermont (the University of Vermont Medical Center, Central Vermont Medical Center and Porter Medical Center) and three in New York (Champlain Valley Physicians Hospital, Elizabethtown Community Hospital and Alice Hyde Medical Center), and their employed providers, and serves a broad geographic region that stretches across Vermont and northern New York.

The Centers for Medicare and Medicaid Services made a bold pronouncement in January 2015: it set a goal of having 90% of traditional Medicare payments to quality or value by 2018. Vermont's leaders, policymakers and health care providers have embraced the challenge put forth by CMS. In October 2016, the State of Vermont entered into a unique six-year program, the All-Payer Accountable Care Organization Model Agreement (APM), with CMS that seeks to transform Vermont's payment and delivery systems by incentivizing a truly collaborative, integrated approach to health and health care by all parts of the care continuum. While the APM includes elements that are new to Vermont, it is really an evolution of decades' worth of efforts that have positioned the state to be a national leader in supporting a high-performing system focused on the health of the citizens we serve.

The UVM Health Network has fully embraced the concept of the APM and its focus on affordability, sustainability and predictability: affordability for those struggling to pay for health care today; sustainability to ensure that the high-value care system we have today can continue to serve Vermonters; and predictability for the providers - both individuals and organizations - dedicated to a healthy Vermont. Our commitment to the APM includes accepting financial risk for the patients we serve, starting with Medicaid beneficiaries in 2017 and expanding to include commercially-insured and Medicare populations this year.

Our success in transforming our current fee-for-service volume-driven system to a value-based system depends, however, on our ability to help the populations for whom we are accountable remain as healthy as possible, while stewarding our health care resources so as maximize their efficiency in treating people when they do need clinical care.

One of the investments the UVM Health Network has made in population health was the opening in January 2017 of a Genomic Medicine laboratory at the UVM Medical Center to expand the availability of advanced genomic testing for our patients. This laboratory performs targeted genomic sequencing for cancer patients in our Health Network and thereby generates clinically-relevant information that determines the course of cancer care as delivered locally by transdisciplinary cancer care teams. The service of the Genomic Medicine laboratory is delivered as a care pathway that is integrated into personalized care of a patient pre- and post-genomic analysis. Additionally, developing a Genomic Medicine laboratory within the Health Network is serving to increase genomic literacy at the point-ofcare and thereby facilitate informed use of this testing and the information it generates. It is this kind of "integrated" personalized medicine that is key to our vision of managing the health of the communities we serve.

The Proposed Decision Memo
The Food & Drug Administration (FDA) recently approved the FoundationOne CDx (F1CDx) NGS-based test as an in-vitro diagnostic. As part of the FDA's and CMS's Parallel Review Program, CMS then issued a proposed National Coverage Determination (NCD) relating to the F1CDx test.

While we are pleased that Medicare - whose payments policies are often adopted by commercial insurers - has in the proposed NCD recognized the value of precision oncology diagnostics in the care of cancer patients, the draft NCD has implications far beyond the F1CDx test. Specifically, the proposed NCD:

• limits coverage only to FDA-approved NGS tests with companion diagnostic indications;
• imposes very narrow criteria for coverage with evidence development; and
• makes explicit a policy of non-coverage for NGS tests if they do not meet the criteria listed in the NCD.

We have deep-rooted concerns over the scope and breadth of these proposed policies, especially the proposed exclusion of non-FDA-approved NGS-based tests from coverage. The negative impacts on care to our patients, and on the UVM Health Network's academic and research missions, could be extensive. If approved as written, it will likely limit access of our patients to NGS-based testing and reduce incentives to develop clinically-validated NGS assays in CAP-approved, CLIA-certified laboratories like ours. It could create a monopoly for NGS testing, which could reduce or eliminate academic innovation. The profession of molecular pathology may move from the hospital setting to industry. We envision this will severely limit precision cancer care as currently experienced and envisioned for patients and their care providers in our Health Network.

I am sure that the dedicated professionals who run our Genomics Medicine Program will be commenting directly to CMS on the proposed rule, and will be able to provide more detail about how the proposed NCD will impact their program and the patients and clinicians they serve. In the meantime, I appreciate the opportunity to make CMS aware of these larger potential negative impacts, which strike at the heart of the UVM Health Network's commitment to population health and value-based payments.

Very truly yours,

/s/
John R. Brumsted, MD
President and Chief Executive Officer

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My name is Frederick S. Nolte, PhD and I am a Professor of Pathology and Laboratory Medicine, Vice-chair for Laboratory Medicine, and Director of Molecular Pathology at the Medical University of South Carolina. Our clinical laboratories provide diagnostic services including NGS tests for patients with advanced cancer seen at our Hollings Cancer Center, a NCI designated cancer center. I am grateful to CMS for the opportunity to comment on the proposed NCD for NGS for Medicare Beneficiaries with Advanced Cancer.

I applaud CMS for their recognition of the value of precision oncology diagnostic tests in the care of patients with cancer as demonstrated by the proposed NCD issued in conjunction with the FDA approval of the FoundationOne CDx (F1CDx) NGS test as in vitro diagnostic. However, the draft NCD proposes a coverage policy that has implications far beyond the F1CDx test. Specifically, the proposed NCD limits coverage only to FDA approved NGS tests with companion diagnostic indications, imposes very narrow criteria for coverage with evidence development, and makes explicit a policy of non-coverage for NGS tests if the test does not meet the criteria listed in the proposed NCD.

At a time when most academic centers, leading cancer institutions, and essential community cancer centers have Clinical Laboratories Improvement Amendment (CLIA) certified laboratories providing validated laboratory developed NGS tests, the NCD as proposed would supersede existing local coverage policies for most of those tests and limit Medicare beneficiaries’ access to a single test from a single laboratory. I believe this proposed coverage policy is unnecessarily restrictive. I agree that the F1CDx test has clinical utility for certain indications, but it is absolutely not the only clinically acceptable test for patients with advanced cancer, nor is it the only test that has been demonstrated to be high quality by peer review and offered with existing regulatory oversight, e.g., the CLIA and CAP laboratory inspection and accreditation processes.

Precision oncology is a medical practice that occurs at the local level, at the patient’s bedside and in interactions between local healthcare professionals including molecular pathologists. The flexibility to triage urgent patient samples, to discuss in depth the findings at local tumor boards with a multidisciplinary team, and to participate in quality improvement initiatives specific to institutions will all be lost if testing is effectively centralized to one lab by the NCD as written. Also, the opportunity to ensure that the next generation of oncologists, pathologist and other healthcare professionals fully understand the utility of these tests in clinical practice will be diminished.

The overly restrictive nature of the draft NCD potentially curbs innovation. Especially in areas where the science is advancing rapidly, good coverage policy must be able to adapt to advances in understanding in the science and clinical applications. Because NCDs are difficult to modify, in areas of rapidly advancing science they can be a barrier to advancing medical practice.

The NCD requirement of achieving FDA approval for coverage is inconsistent with the FDA’s position on enforcement discretion for laboratory developed testing procedures (LDPs). In 2016 it announced that it does not intend to finalize the draft guidance establishing a framework to regulate LDPs. Rather, the NCD requirement of FDA approval for coverage establishes the FDA as determining the regulatory bar for acceptable clinical tests and thereby the practice of medicine. FDA approval is impractical or impossible for most clinical laboratories to reach, including those in many leading academic medical centers and cancer programs. Laboratories cannot sustain clinical services without reimbursement, and therefore could not offer NGS tests to patients with advanced cancer.

NGS, is a technology and is not a diagnostic test. The NCD focuses is not tied either to a specific biomarker or specific CPT code. This approach runs is inconsistent with established coverage determinations, which are based on the clinical utility of a proven effective biomarker, independent of test methodology and whether a test has received regulatory approval for marketing and labeling. If finalized, it will disrupt existing local coverage policies for more targeted panels and specific CPT codes.

Finally, the coverage with evidence development requirements within the proposed NCD are too narrow.

Thank you for your consideration of my comments.

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It is now widely accepted that for optimum evaluation and therapy for cancer, it is essential that physicians, other healthcare workers and patients need to know site of origin as well as molecular drivers of cancer. Without complete molecular characterization of every cancer seen in hospitals, physician's offices one can not design plan for treatment of that cancer patient.

Molecular testing is rapidely evolving and understandably there is concern about proliferation of tests without appropriate evaluation of analytical validity, clinical utility and clinical validity. I and my colleagues recognize this and are aware of many labs moving in the field without undertaking rigorous testing.

However, the current policy of CMS/Medicare about molecular testing is very restrictive and will lead to substandard care for larger number of patients particularly those being taken care of in community setting.
About 80-85 5 of patients are seen and cared for in comunity institutions. It is important that these patients also get state of art care. The current recommendations from CMS will be ineffective as the approved labs do not have the capacity to conduct that many tests in a timely fashion. Thus, many more labs need to be involved in testing. How?

One option is mandatory CLEA certification and perhaps regional inspection of labs to ensure that labs are meeting highest standard. Radiology and other specialities have adopted certification programs and these can be emulated also for pathology. This will allow timely and efficient and perhaps cost effective modern care for cancer patients. We urge you to reconsider the policy and hope that all our patients will receive state of art high quality care.
Thanks for your consideration.

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Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Re: NCD CAG-00450N

Dear Ms. Syrek Jensen,

We recently published a Policy Forum in Science encouraging more widespread insurance coverage, including coverage with evidence development (CED), for genomic testing of tumor DNA. [R Eisenberg & H Varmus (2017) Insurance Coverage for broad genomic tests in oncology. Science 358:133-34.] We therefore welcome the CMS Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N) issued on November 30, 2017 and are grateful for the opportunity to submit comments about it.

We see much to admire in the Proposed Decision Memo. We particularly commend CMS for proposing full coverage of FDA-approved, technically validated, NGS-based diagnostic tests for cancer patients. We admire the aspiration to issue a broad coverage determination that provides similar coverage for similar tests nationwide rather than a narrower decision limited to coverage of the F1CDx test, although we have concerns (detailed below) about whether the current proposal fulfills that aspiration. And we applaud the use of CED to support further clinical studies and to provide better data in patient registries to answer important questions about clinical utility of these tests in the Medicare population. We welcome these important steps towards broader coverage of NGS testing for the significant clinical benefits they offer to current and future Medicare patients, as well as for the promise they offer of improving the control of cancer more generally. We hope that this important step by CMS will inspire similar coverage decisions by private insurers.

As the Proposed Decision Memo recognizes, FDA has recently taken important steps towards streamlining the regulatory pathway for bringing new NGS tumor profiling tests to market. These steps include reclassifying such tests as “class II” devices. [FDA (Nov. 15, 2017) Reclassification Order DEN170058, available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/denovo.cfm?ID=DEN170058.] This allows these tests to be cleared through the less onerous premarket notification process, under section 510(k) of the Federal Food, Drug & Cosmetic Act, without having to go through the more elaborate premarket approval process necessary for approval of class III devices. FDA also accredited the New York State Department of Health (NYSDOH) as a third-party reviewer of such devices with authority to clear devices without the need for further FDA review, opening the door to similar arrangements with other reviewers. FDA’s classification of the MSK-IMPACT assay as a Class II device allows subsequent “next generation sequencing based tumor profiling tests” to take advantage of the 510(k) premarket notification process upon a showing of substantial equivalence to that predicate device. This classification reflects FDA’s determination “that class II (special) controls provide reasonable assurance of the safety and effectiveness of the device type.” [FDA (Nov. 15, 2017) letter from Reena Philip to Christina England, https://www.accessdata.fda.gov/cdrh_docs/pdf17/DEN170058.pdf, at p. 2.] These steps highlight a cost-effective and efficient pathway for regulatory clearance of similar devices in the future, while assuring physicians and patients that they meet FDA’s standards for safety and effectiveness. This is all good news for those who seek to bring advances in cancer research to patients with advanced cancers.

We are concerned, however, that the proposed CMS coverage policy could undermine the benefits of these important steps by FDA. In particular, we worry that the proposed policies will give future test developers an incentive to pursue the more costly and time-consuming route of FDA premarket approval of their tests as “companion diagnostics” in order to get the benefit of full CMS coverage. This is so because only “an FDA-approved companion in vitro diagnostic“ is immediately eligible for full coverage under part A of the proposed policy without the further requirements imposed on CED for “an FDA cleared or approved in vitro diagnostic” under part B of the Proposed Decision.

For a test that has merely been “cleared” for use as a “next generation sequencing based tumor profiling test,” like the MSK-IMPACT test, further requirements for CED include (i) registration of the test in the NIH Genetic Testing Registry; (ii) enrollment of the patient in a prospective registry designed to answer specified CED questions; (iii) “a written executable analysis plan to address the CED questions” with the registry and a plan to “make data available in a form and manner specified by CMS upon request;” and a registry that (iv) tracks certain information at baseline and (v) tracks further information after each intervention.

Such a registry would undoubtedly be a valuable resource for learning more about the significance of genetic data generated by the covered test and about effects of cancer therapies provided to patients with genetically diverse cancers, and that should be encouraged. But to require participation in such a registry as a condition for coverage adds to the costs and uncertainty facing test developers in deciding whether to pursue FDA clearance for a test for tumor profiling, rather than pursuing premarket approval for the same test as a companion diagnostic. By making it more lucrative to pursue the more burdensome premarket approval process at FDA, CMS may thus undermine the impact of recent efforts by FDA to streamline and accelerate review of NGS-based tumor DNA tests.

We recognize that FDA’s recent de novo classification decision covers “next generation sequencing based tumor profiling tests” and does not yet extend to companion diagnostics. But that was the only issue that FDA was called upon to decide in the context of the de novo request for classification of the MSK-IMPACT test. FDA has repeatedly recognized in guidance documents for industry and FDA staff that companion diagnostics might be classified as class II devices eligible for clearance without requiring premarket approval. As FDA explained in 2014,

FDA will apply a risk-based approach to determine the regulatory pathway for IVD companion diagnostic devices, as it does with all medical devices. This means that the regulatory pathway will depend on the level of risk to patients, based on the intended use of the IVD companion diagnostic device and the controls necessary to provide a reasonable assurance of safety and effectiveness. Thus, the level of risk together with available controls to mitigate risk will establish whether an IVD companion diagnostic device requires a premarket approval application (PMA) or a premarket notification submission (510(k)). [FDA (Aug. 6, 2014) In Vitro Companion Diagnostic Devices: Guidance for Industry and Food & Drug Administration Staff, at p. 10.]

FDA’s approach to device classification is flexible and permits change over time as initial concerns over safety and effectiveness for a new technology prove to be manageable with less burdensome regulatory controls. FDA explicitly anticipates this for in vitro companion diagnostics. Moreover, it has already expressed its satisfaction with the adequacy of “class II (special) controls” to ensure the safety and effectiveness of very similar NGS diagnostic tests for tumor profiling. Under these circumstances, we foresee future submissions to FDA seeking de novo classification of NGS tests for use as companion diagnostics, and we see no reason why CMS should make coverage of these products contingent on a more extensive regulatory approval process for these devices than FDA considers necessary.

A comparison between the MSK-IMPACT test (cleared as a tumor profiling test, and therefore eligible only for CED) and Foundation Medicine’s F1CDx test (approved as a companion diagnostic, and therefore eligible for full coverage) suggests that they differ more in the regulatory strategies pursued by their sponsors than in their technical features and clinical utility. Whether the test is called a “companion diagnostic” or a “tumor profiling” test, its clinical utility resides in its capacity to guide selection of appropriate care for cancer patients. Toward that end, the MSK-IMPACT test uses nearly identical methods to analyze the genes categorized as critical components of companion diagnostics in the F1CDx test. Both tests provide very similar or identical information about variants in very similar sets of genes, with similar implications for clinical care. The MSK-IMPACT test has some notable advantages, including more rigorous validation of the existence of somatic mutations because both tumor and germ line DNA are analyzed. Both tests have been used in tens of thousands of patients and validated by stringent criteria, such as those of the NYSDOH.

The different treatment of these similar tests is puzzling in light of CMS’s explicit choice in the Proposed Decision Memo to broaden the number of tests to be considered beyond the F1CDx test that is before CMS. The Proposed Memo states at p. 64:

Since our evidence question and analytic framework apply broadly to molecular diagnostic tests for advanced cancer we are considering the type of technology so that claims for similar tests will be covered in a similar manner nationwide under title XVIII.

As repeatedly stated in the Proposed Decision Memo, CMS seeks answers to the following question:

Is the evidence sufficient to conclude that next generation sequencing when used as a diagnostic test for patients with advanced cancer meaningfully improves health outcomes?

The Proposed Decision Memo answers this question with an unqualified “Yes” only for “FDA-approved companion diagnostics.” Other NGS diagnostic tests – including FDA cleared tumor profiling tests that provide similar information to physicians and patients who would use that information for the same purposes, and with the same degree of confidence that FDA considers the test to be safe and effective – do not qualify for full coverage under the Proposed Decision Memo. Instead, coverage of these tests is limited to CED for patients who agree to participate in further clinical studies and for service providers who comply with complex requirements. The result is to treat similar tests in a dissimilar manner depending on the regulatory pathway used to satisfy the FDA standards of safety and efficacy.

We recognize that allowing full coverage under part A to tests like MSK-IMPACT could reduce the use of CED under part B of the Proposed Decision, and thus slow the accumulation of data to guide further improvements in cancer care. We wholeheartedly support the use of CED as a mechanism to support further clinical studies in patients with advanced cancer, including observational studies conducted with well-curated patient registries. But the potential benefits of further research do not justify withholding coverage of diagnostic technologies with proven clinical utility. Moreover, use of CED to support a significant fraction of NGS testing would impose a significant administrative burden on test providers.

Rather than diverting patients and physicians who choose an FDA cleared or approved test other than F1CDx into CED, we suggest broadening the criteria for use of CED to test clinical utility beyond patients with “recurrent, metastatic, or advanced stage IV cancer” who have “not been previously tested” and “have decided to seek further cancer treatment.” These limitations omit the use of NGS-based tests in a number of situations in which it would be useful to assess their value, including: testing earlier in the disease process to decide about adjuvant therapies or to predict the course of the disease; repeated testing for appearance of mutations that confer therapeutic resistance; and testing of tumor DNA circulating in the blood (“liquid biopsy”), rather than DNA obtained through an invasive biopsy. We particularly welcome the availability of CED for diagnostic tests that have not yet been approved or cleared by FDA when used to identify candidates for participation in new clinical trials, although we would contend that a broader selection of trials, not just those conducted by NCI’s National Clinical Trials Network, should qualify for CED.

Summary and Recommendations

We applaud the actions being taken by the FDA and CMS to accelerate the widespread use of improved diagnostic tests that employ NGS-based methods to identify underlying drivers of disease and to guide patients toward appropriate therapies and novel clinical trials. Nevertheless, we are concerned that the Proposed Decision makes too much of two regulatory distinctions: first, the distinction between tests that have been “approved” rather than “cleared” at FDA, and second, the distinction between “companion diagnostics” and “tumor profiling” tests. These are very similar tests with very similar clinical utility, and they should be subject to the same requirements for reimbursement.

We recommend the following changes in part A of the proposed decision:

First, in Part A.2.a., we recommend changing the wording of the first criterion for coverage of a test from “FDA-approved” to “FDA cleared or approved.” The proposed modification would expand coverage to include diagnostic devices that FDA has determined meet the statutory standards for classification as Class II devices. Such devices would still require premarket notification to FDA, along with submission of such information as FDA requires to implement special controls to ensure safety and effectiveness for devices of that type. Most relevant to the proposed decision, should FDA decide in the future to reclassify NGS in vitro companion diagnostic tests as Class II devices, they would be eligible for full coverage, not limited to CED, without the need to go through a further regulatory review that FDA has determined is not necessary to meet its standards.

Second, again in Part A.2.a., we recommend further expanding coverage by deleting the word “companion” in the phrase “companion in vitro diagnostics,” to permit coverage of other types of FDA cleared or approved NGS in vitro diagnostic tests such as tumor profiling tests. As explained above, we believe that this distinction in the proposed decision ignores the substantial similarity in both technical features and clinical utility for tests that are used for the same purposes and should receive the same coverage.

In addition, we recommend the following changes in part B:

First, in Part B.1., we recommend broadening the criteria for CED to support the testing of patients at an earlier stage in the course of their disease and to support repeated testing of patients to detect the appearance of mutations that confer therapeutic resistance.

Second, in Part B.2.b.1, we recommend broadening the set of eligible trials to include trials outside of the NCI National Clinical Trial Network.

Respectfully submitted,

Harold Varmus, M.D.
Weill Cornell Medicine
New York Genome Center