View Public Comments for Positron Emission Tomography

This proposed amendment has the potential for significant expansion of PET without a definite corresponding level of increased patient benefits. Coverage based purely on FDA approval would be a remarkable departure from the previously successful CMS model of using a precise and well defined evidentiary framework for making coverage decisions for imaging technologies.

CMS previously defined this approach to evaluating the clinical utility of diagnostic tests as follows:

• Review; when available, high-quality studies that provide direct evidence that test results improve health outcomes.

• If there is no high-quality direct evidence, determine the extent to which there are changes in patient management, particularly when the management strategy is effective in patients with the disease and does not benefit or harm those without the disease

The National Oncologic PET Registry (NOPR) was designed to determine if the results of PET scans influence physicians' intended plans of patient management. In August 2008, Medicare's Evidence Development and Coverage Advisory Committee (MedCAC) reviewed the NOPR results as well as a technology assessment on FDG-PET scanning for 6 cancers which included 112 research studies.

The committee members were asked to rate their confidence in the evidence that FDG-PET scanning improves physician decision making and patient outcomes, as well as their confidence that the results can be generalized to the Medicare population. CMS then requested additional public input on its proposal to expand coverage for FDG-PET scanning in oncology, inviting experts and stakeholders to offer feedback. In January 2009, CMS issued a proposed decision memorandum outlining its intended coverage determination of FDG-PET scanning on the basis of the results of the NOPR, the technology assessment described above, and other published literature. The NOPR process - a consistent approach to nationwide coverage of new indications for PET, with evidence development - has been judged to be a dramatic success1

The MITA Proposal/appeal does not ensure adequate evaluation of the clinical utility of PET in the setting of new PET radiopharmaceuticals approved by the FDA

Case in Point: Amyvid

In the MITA appeal, they point out that the FDA now requires PET radiopharmaceuticals to demonstrate clinical utility, using the recent FDA advisory meetings on new PET radiopharmaceuticals for amyloid imaging in diagnosing Alzheimer's Disease (AD) to demonstrate this recent and increased focus on clinical usefulness. They state that, “This requirement of the FDA for demonstrating clinical usefulness creates confidence that new PET radiopharmaceuticals will not only be accurate and reliable, but also will have defined benefits for the patients in whom they are used as specified in the FDA-approved label.” However, the recent FDA approval of Amyvid (florbetapir F-18 injection) exemplifies the flaws in this reasoning.

The April 10, 2012 FDA press release regarding its approval of Amyvid (florbetapir F-18 injection) contains several disclaimers. These include a surprising lack of specificity noting that, “A positive Amyvid scan indicates moderate to frequent plaques. However, a positive Amyvid scan does not establish a diagnosis of AD because, although patients with AD always have an increased brain content of plaque, the test also may be positive in patients with other types of neurologic conditions, as well as in older people with normal cognition.” There was also a remarkable limitation in its indications and usefulness with statements such as, “Amyvid is not a test for predicting the development of AD-associated dementia and is not for monitoring patient responses to AD therapy. Amyvid does not replace other diagnostic tests used in the evaluation of cognitive impairment. This is a new type of nuclear medicine test and images should be interpreted only by healthcare professionals who successfully complete a special training program developed by the manufacturer.”2

The Siemens press release has similar disclaimers as well as the warnings that, “Errors may occur in the Amyvid estimation of brain neuritic plaque density during image interpretation”; and the more unusual, “Image interpretation should be performed independently of the patient’s clinical information. The use of clinical information in the interpretation of Amyvid images has not been evaluated and may lead to errors.”3

This troubling issue of interpretation errors with florbetapir-PET scans has been discussed in other forums. For example, the substantial inter-reader variability among independent, extensively trained readers of the Florbetapir-PET scans is a significant problem. It has been addressed in a 2011 JAMA article, which noted that Florbetapir-PET imaging fails to provide an accurate and reliable assessment of amyloid burden. In fact the authors stated, “If widely deployed in the real-world setting, with more variability in reader training and skill and in the patient population for whom florbetapir-PET presumably is intended, the performance of the test will most likely be worse. For these reasons, in our opinion the FDA should not approve florbetapir for diagnosis of Alzheimer’s disease.”4

In fact, the FDA Peripheral and Central Nervous System Drugs Advisory Committee unanimously agreed (16-0) that it could only approve florbetapir after the development of a reader training program. Eli Lilly complied with this stipulation and included a warning of possible scan misinterpretation in its prescribing information.5

The Alzheimer's Association supports FDA approval of florbetapir, but acknowledges that it is a “double-edged sword”. While the approval will expand the clinical and research opportunities, the potential uses of florbetapir are not clearly defined. The association is concerned that it may have some undesirable consequences such as “less than scrupulous operators offering imaging services and making unrealistic promises about the value of florbetapir imaging to sometimes vulnerable and worried individuals.” They feel that additional research is needed to clarify the role of florbetapir-PET imaging in Alzheimer's and have convened a task force with the Society of Nuclear Medicine to develop recommendations for the use of amyloid imaging.6

The procedure will probably have very limited practical indications. Dr. Neill Graff-Radford, professor of neurology at Mayo Clinic in Jacksonville, FL, feels that florbetapir may useful in differentiating frontotemporal dementia (FTD) from AD. He noted that physicians currently use PET scans in these types of cases. For the present, Dr. Neill Graff-Radford described the florbetapir test as “boutique.”7 Interestingly, the MedSolutions Guidelines currently acknowledge that the established role of PET in dementia is limited to differentiating AD from FTD.

Summary

The example discussed above demonstrates that FDA approval alone does not ensure that a test will be accurate, reliable and clinically useful to the same degree as those which were previously evaluated using CMS’s successful NOPR/MedCAC model. As to the MITA’s desire to have these coverage decisions be left to the discretion of the local Medicare Administrative Contractors (MAC), after initial FDA approval, it is unlikely that the local MACs will have the resources to replicate the CMS national model. Developing these infrastructures in each region would be inefficient and probably less effective. Continuing with the national model will also promote uniformity in coverage, preventing confusion among providers and especially patients who may move from one region to another. In MedSolutions’ view, the process described in the MITA letter would represent the abandonment of a proven deliberative process without any clear clinical advantages being associated with the proposed replacement.

REFERENCES:

Stuart Caplan RN, MAS
Lead Analyst
Centers for Medicare and Medicaid Services
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, Maryland 21244-1850

Dear Mr. Caplan:

Thank you for the opportunity to comment on the Centers for Medicare and Medicaid Services’ (CMS’s) National Coverage Analysis Tracking Sheet for Positron Emission Tomography (CAG-00065R2). America’s Health Insurance Plans (AHIP) is the national association for the health insurance industry. Our members provide coverage to more than 200 million Americans, offering a broad range of health insurance products in the commercial market and demonstrating a strong commitment to participation in public programs.

General Comments

AHIP and our member health plans encourage the use of robust evidence-based research to ensure safe and effective treatments. This proposed amendment has the potential for significant expansion of PET without a definitive assessment of improving patient outcomes. Coverage based purely on FDA approval would be a departure from the previously successful CMS model of using a well-defined and rigorous evidentiary framework for making coverage decisions.

The National Oncologic PET Registry (NOPR) was designed to determine if the results of PET scans influence physicians' intended plans of patient management. In August 2008, Medicare's Evidence Development and Coverage Advisory Committee (MedCAC) reviewed the NOPR results as well as a technology assessment on FDG-PET scanning for 6 cancers which included 112 research studies. In January 2009, CMS issued a proposed decision memorandum outlining its intended coverage determination of FDG-PET scanning on the basis of the results of the NOPR, the technology assessment, and other published literature. The NOPR process – a consistent approach to nationwide coverage of new indications for PET, with evidence development – has been judged to be a success[i].

FDA approval alone does not ensure that a test will be accurate, reliable and clinically useful to the same degree as those tests previously evaluated using CMS’s successful MedCAC model or a similar rigorous evidentiary model. It is unlikely that the local Medicare Administrative Contractors will have the resources to replicate such a model. Developing these infrastructures in each region would be inefficient, costly, likely less effective, and subject to market influence. Continuing with the national model will also promote uniformity in coverage, preventing confusion among providers and especially patients who may move from one region to another. Our members believe that the process described in the request letter from the Medical Imaging & Technology Alliance to have coverage of particular uses of PET be determined locally would represent the abandonment of a proven effective deliberative process without any clear clinical advantages associated with the proposed replacement.

Sincerely,

Carmella Bocchino
Executive Vice President
Clinical Affairs and Strategic Planning

[i] Tunis S, Whicher D. 2009. The National Oncologic PET Registry: Lessons Learned for Coverage With Evidence Development. Journal of the American College of Radiology: v.6(5); p. 360-5.

Dear Dr. Roche and Mr. Caplan:

As a practicing clinician with two decades of experience working with advanced imaging technologies, I write in strong support of lifting the national non-coverage language for new FDA approved PET diagnostic radiopharmaceuticals. For more than a decade now, significant data has been accumulated to demonstrate the clinical accuracy of FDG-PET and its impact on patient management.

There is increased urgency for CMS to act given the recent FDA approval of florbetapir injection for PET imaging of patients with cognitive impairment who are being evaluated for Alzheimer's disease. Amyloid deposition in the brain is one of the most important pathological hallmarks of Alzheimer's disease. Following the FDA approval, there is a high level of public and professional interest in amyloid imaging.

August 10, 2012

Jeffrey Roche, MD, MPH
Lead Medical Officer
Centers for Medicare and Medicaid Services
Coverage Analysis Group
7500 Security Boulevard
Baltimore, MD 21244

Re: National Coverage Analysis Reconsideration Request for Positron Emission Tomography (CAG-00065R2)

Dear Dr. Roche and Mr. Caplan:

Piramal Imaging SA (a wholly owned subsidiary of Piramal Enterprises) appreciates this opportunity to respond to the Centers for Medicare and Medicaid Services’ (CMS’s) request for comments on the reconsideration request of the National Coverage Determination (NCD) for the use of positron emission tomography (PET) at Section 220.6 of the Medicare Coverage Manual. Piramal Imaging is dedicated to developing innovative imaging technologies and bringing new PET tracers to the market after having acquired Bayer Healthcare’s proprietary molecular imaging PET tracer portfolio in April 2012.

During the past years, preclinical and clinical research in the field of molecular imaging has yielded in a wider range of targeted PET tracers that will provide the Nuclear Medicine community with new options to screen, diagnose and follow-up on patients with disabling and life threatening diseases, and are likely to translate into significant benefits for referring physicians, patients, healthcare providers and payers.

In support of the MITA request, Piramal welcomes the opening of a PET reconsideration request focused on the beta-amyloid imaging class as a highly important initiative. Just a few months ago, Secretary Sebelius announced a commitment to transform the approach to diagnosis and treatment of Alzheimer’s disease. Pursuant to the National Alzheimer’s Project Act (NAPA) the Department of Health and Human Services released the nation’s first ever strategic plan for Alzheimer’s disease. Piramal fully supports the goals associated with this plan and currently pursues a large pre-clinical and clinical development program focused on the earlier and more reliable diagnosis of Alzheimer’s disease.

During the past few years, we have acknowledged a growing level of public and professional interest in beta-amyloid imaging. Amyloid deposition in the brain is considered one of the most important pathological hallmarks of Alzheimer’s disease. You may also have noticed that appropriate recommendations for the use of beta amyloid imaging agents are being developed by the Alzheimer’s Association in partnership with the Society of Nuclear Medicine, and similar efforts are underway by the International Working Group for New Research Criteria for Alzheimer’s Disease.

Piramal Imaging is pleased to work with CMS to ensure Medicare beneficiaries have proper access to this innovative technology and the new category of PET tracers; we appreciate CMS allowing for our request for re-consideration and are pleased to respond to the areas of interest CMS expressed in its request for comments.

Breadth of the request

Piramal’s reconsideration request addresses new FDA-approved PET radiopharmaceuticals. We stand firm in our belief that approving this request would not reverse the existing National Coverage Determination which encompasses 18F-FDG, 18F-NaF, 13-N ammonia, or 82-Rb rubidium. For PET tracers emerging into this important imaging sector now and in the future, the request enables an updated application of the policy, acknowledging the elevated regulatory approval standards for these new PET tracers. CMS’s approval of the request would allow Medicare beneficiaries to access this innovative technology without delay upon FDA-approval of new, targeted PET tracers, leading to earlier, potentially more reliable diagnosis of their condition, expedient treatment decisions by their physicians and more individualized patient management. We also note that by approving this request, CMS will not discriminate newly-approved PET radiopharmaceuticals from other diagnostic radiopharmaceutical agents that earned approval through the FDA marketing authorization process. In doing so, CMS will apply consistent standards and provide coverage for diagnostic radiopharmaceuticals across imaging modalities and tracer categories.

Assuring success by approving the request

We anticipate that any approval for coverage would involve a thorough consideration of the scientific and pharmaco-economic evidence of the imaging technology and respective agents; we further understand that such evidence (clinical utility, PE benefits) is inherent to the newly approved or to be approved PET tracers developed for the detection of amyloid beta, as opposed to the level of evidence that has been demonstrated for 18F-FDG, 18F-NaF, and 13-N ammonia, which are already covered under Section 220.6 of the CMS National Coverage Determinations Manual.

We acknowledge the concerns expressed by some commenters on the reconsideration request that FDA’s approval alone should not equate to coverage because such regulatory process may not make patient outcomes sufficiently transparent. However, we take this opportunity to reiterate our position that a newly approved diagnostic tracer that successfully passes well-controlled clinical trials and demonstrates clinical efficacy and safety as required for the FDA approval process already provides a significant level of evidence to support coverage. Newly developed PET radiopharmaceuticals certainly should receive the same level of consideration.

We also acknowledge CMS’s and local contractors’ ability to impose boundaries for coverage on any new technology and product entering the marketplace. We appreciate that by approving this reconsideration request, CMS would consent to a process change allowing for coverage of newly approved PET radiopharmaceuticals upon or shortly after FDA approval. It would eliminate the significant delay referring physicians and their patients otherwise incur while awaiting a decision through the current National Coverage Analysis process.

We appreciate the open and cooperative nature that CMS has exhibited throughout this process. If you have additional questions, please feel free to contact me, Dr. Ludger Dinkelborg PhD, at ludger.dinkelborg@piramal.com.

Lantheus Medical Imaging, Inc. (“Lantheus”) appreciates the opportunity to submit comments to the Centers for Medicare and Medicaid Services (“CMS”) regarding the National Coverage Analysis for Positron Emission Tomography (CAG-00065R2). We fully support CMS enabling expanded coverage for reasonable and necessary Positron Emission Tomography (“PET”) services with PET agents that demonstrate clinical value in light of all the scientific data and other controls associated with FDA approval. This updating of the PET coverage policy should be accomplished by CMS removing the blanket exclusion of coverage for new PET agents.

Lantheus is the developer and manufacturer of a number of radiopharmaceuticals used for nuclear cardiology and nuclear medicine procedures, including Cardiolite® (Kit for the Preparation of Technetium Tc99m Sestamibi for Injection) for myocardial perfusion imaging (“MPI”), Thallium 201 (Thallous Chloride Tl201 Injection) also for MPI, and TechneLite® (Technetium Tc99m Generator).

Lantheus is a member of the Medical Imaging and Technology Alliance ( “MITA”), and has participated in that group’s work on the request for reconsideration of the PET National Coverage Determination (“NCD”). Lantheus is also a member of the Council on Radionuclides and Radiopharmaceuticals (“CORAR”).

Lantheus is currently conducting a Phase 3, multi-center clinical study with a new positron emitting agent, flurpiridaz F 18, to assess myocardial perfusion by PET imaging in patients with known or suspected coronary artery disease (“CAD”). These clinical studies include Medicare patients and document the clinical efficacy of PET for Medicare patients.

Lantheus comments on the proposed rule for PET coverage are outlined below:

1. Lantheus strongly supports the MITA proposal, which would eliminate the exclusionary policy for new PET radiopharmaceuticals and indications. The denial of coverage for novel PET agents when these are approved by the FDA for uses consistent with current Medicare coverage for PET, limits provider choice of the agent he or she believes is most appropriate for an individual patient, and without reimbursement effectively denies Medicare beneficiaries access to the range of PET agents that have been demonstrated, by substantial evidence, to be safe and effective for their intended uses.

Lantheus does not believe it necessary or appropriate to require a local coverage review of all new FDA-approved PET imaging drugs by the Medicare Administrative Contractors (“MACs”). This would be an extraordinary, labor intensive process as each contractor across the US would perform parallel coverage analyses. Moreover, although the evidence base supporting coverage would be identical in each jurisdiction, there is a risk that some MACs might support coverage and others might not. How would physicians explain to their beneficiaries that they cannot have access to an FDA-approved imaging drug simply because they live in the “wrong state.”

If the exclusionary policy is removed CMS would still have the ability to restrict or withdraw coverage if it determines that based on clinical experience there is not sufficient evidence to fully validate the benefits for Medicare patients of a specific use of a particular agent. CMS still has the option to implement a National Coverage Determination to withdraw or restrict coverage on an agent by use basis if it believes it is necessary to do so.

2. Lantheus strongly believes that since (i) FDA approval of new PET radiopharmaceuticals requires carefully controlled clinical trials which demonstrate appropriate safety and efficacy by meaningful statistical methodology and (ii) an increased rigor of manufacturing has been implemented with new cGMP requirements, it is now appropriate for CMS to eliminate the exclusionary language in the NCD.

3. Lantheus notes that the current NCD, which automatically excludes from coverage any novel PET radiopharmaceutical, is not consistent with CMS policy for lower energy SPECT radiopharmaceuticals nor with CMS policy for any other drugs or biologicals approved by the FDA under an NDA or BLA. Long-established Medicare policy provides coverage for novel drugs and biologicals approved by the FDA when used for their labeled indications. Although CMS and its local contractors may consider whether coverage is appropriate for uses outside of labeling, CMS has very rarely questioned coverage for the FDA-approved indications, and we are not aware of any other example where CMS has actually denied coverage for an FDA-labeled indication for a drug or biological. CMS has not articulated any rationale for singling out PET imaging drugs.

4. We recognize that F18 FDG, an early PET imaging drug, did not go through the traditional requirements for FDA approval involving adequate and well-controlled clinical trials. Because of this limitation in the evidence base to support coverage for F18 FDG, Medicare coverage of this agent was delayed for several years until the findings from the National Oncologic PET Registry (“NOPR”) were evaluated. By contrast, new PET imaging drugs are required to have substantial evidence of safety and efficacy comprising adequate and well-controlled trials in order to obtain FDA approval.

5. For example, as noted above, Lantheus is currently conducting a Phase 3 clinical study on flurpiridaz F 18, a PET radiopharmaceutical. The protocol for this study was reviewed by the FDA prior to patient enrollment. Lantheus has obtained two separate special protocol assessments from the FDA in connection with this study which will consist of two carefully controlled multicenter clinical trials enrolling a total of approximately 1,350 patients. This follows a comprehensive Phase 1 and Phase 2 clinical development program which generated substantial safety and preliminary efficacy information. A summary of this clinical experience was presented to CMS during a meeting with Lantheus in April 2011.

Title - A Phase 3, Open Label, Multicenter Study for the Assessment of Myocardial Perfusion Using Positron Emission Tomography (“PET”) Imaging of Flurpiridaz F18 Injection in Patients With Suspected or Known Coronary Artery Disease (“CAD”)

Primary Outcome Measures:
Blinded Image assessment for PET & SPECT perfusion and for interventional coronary angiography.

6. There has been recent development and acceptance of professional society practice guidelines and Appropriate Use Criteria (“AUC”) for imaging. For example, the American Society of Nuclear Cardiology and the American College of Cardiology have developed evidence-based Appropriate Use Criteria for myocardial perfusion imaging intended to promote appropriate utilization of these procedures and to minimize unnecessary testing. This is a significant development to help ensure the right patient gets the right scan at the right time.

7. The prevalence of Medicare beneficiaries is high among those who are candidates for myocardial perfusion imaging for the diagnosis of CAD. It is not in their best interest to be denied or delayed access to these important imaging drugs that have received rigorous evaluation and FDA approval.

Lantheus congratulates CMS for its decision to open the PET National Coverage Analysis. This is an encouraging step toward the assurance that Medicare beneficiaries will have access to important, clinically-proven PET imaging drugs in procedures which already are covered by Medicare that can provide clinically meaningful information to their physicians and ensure that they receive appropriate care.

If you have any questions please contact Randy VanCoughnett at randy.vancoughnett@lantheus.com or 978-436-7995.

Sincerely,

GE Healthcare
1299 Pennsylvania Ave, NW
Suite 900W
Washington, DC 20004

August 9, 2012
Jeffrey Roche MD, MPH
Lead Medical Officer
Stuart Kaplan, RN, MAS
Lead Analyst
Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Dear Dr. Roche and Mr. Kaplan:

GE Healthcare (“GEHC”) appreciates this opportunity to comment on the reconsideration of the National Coverage Decision (“NCD”) for Positron Emission Tomography (“PET”) which the Centers for Medicare and Medicaid Services (“CMS”) announced on July 11, 2012. It is our understanding that during this 30-day public comment period CMS is particularly interested in comments that include scientific evidence and that address the breadth of the request by the Medical Imaging & Technology Alliance (“MITA PET NCD Request”).

GEHC, a division of General Electric Company, has expertise in medical imaging and information technologies, medical diagnostics, patient monitoring systems, performance improvement, drug discovery, and biopharmaceuticals manufacturing technologies. GEHC’s broad range of products and services enables healthcare providers to offer patients earlier and more accurate diagnosis and treatment of cancer, heart disease, neurological diseases, and other conditions that threaten the quality and length of life. Worldwide, GEHC employs more than 53,000 people committed to serving healthcare professionals and their patients in more than 100 countries.

GEHC is a member of MITA and has participated in that group’s effort to develop the MITA PET NCD Request. We re-affirm our support for MITA’s proposed modification to the Medicare Coverage Manual Section 220.6, as stated below:

This manual section 220.6 lists all Medicare-covered uses of PET scans based on the tracers rubidium, ammonium, sodium fluoride, and fluordexoglucose. Except as set forth below in cancer indications listed as “Coverage with Evidence Development,” a particular use of PET scans with these tracers is not covered unless this manual specifically provides that such use is covered. Although this section 22.06 lists some non-covered uses of PET scans, it does not constitute an exhaustive list of all non-covered uses of these tracers. Coverage of other FDA-approved PET radiopharmaceuticals is at the discretion of the local Medicare Administrative Contractors unless specifically addressed under a National Coverage Determination.

1. It creates the conditions for trained expert clinicians to take a patient-centric approach to the use of PET.
2. It is suitable for the new generation of diagnostic radiopharmaceuticals being investigated for more targeted uses and personalized medicine for appropriate patient populations.
3. It recognizes that radiopharmaceuticals now face a far more rigorous regulatory environment.
4. It acknowledges the appropriate clinical evidence threshold for diagnostic medical innovations.
5. It harmonizes the coverage determination criteria for all diagnostic radiopharmaceuticals.
6. It removes inappropriate coverage restraints from providers working to succeed under new pay-for-performance (P4P) models of care.

We discuss each of these reasons below, and although each is addressed separately, we underscore that they all work together to create the conditions for a new approach to PET coverage. Our comments re-emphasize some of the information included in the MITA PET NCD Request because it provides important justification for the proposed coverage modification. We also provide additional rationale to support this reconsideration of the PET NCD.

Today, unless specifically covered in the current PET coverage policy, CMS categorically denies other uses of PET radiopharmaceuticals for all Medicare beneficiaries (often referred to as the exclusionary clause). We believe this “one-size-fits-all” non-coverage approach for new FDA-approved PET radiopharmaceuticals is inconsistent with the recently published Department of Health and Human Services (“DHHS”) National Quality Strategy (“NQS”) which calls health care providers and payers to redirect their attention to patient-centered care. Specifically, the first aim under the Triple Aim as stated in the NQS is to “Improve the overall quality, by making health care more patient-centered, reliable, accessible, and safe”¹ (emphasis added). [Note: We address reliability and safety aspects of the Triple Aim in Section #3].

Historically, the Medicare program has enabled patient-centric coverage determinations using the criterion that if a particular service or item falls within a benefit category, it is eligible to be covered. When there is no specific coverage policy, a local Medicare Contractor can decide to cover the service or item on a case-by-case basis, based on documentation it requests from the physician to assess the medical necessity and reasonableness of the service for his/her particular patient. We believe that CMS’s current restrictive approach for new FDA-approved PET radiopharmaceuticals, regardless of the patient-specific circumstance, is not in step with DHHS’s new emphasis on accessible, patient-centered care.

We also believe that removing the exclusionary clause for new uses of PET and new radiopharmaceuticals still leaves several safeguards in place for both CMS and patients. There is a well-established common principle that unnecessary services are unpayable, as formalized by an Administrator’s Ruling.² Thus, association guidelines or other commonly available review standards can be applied by Medicare Administrative Contractors, Recovery Audit Contractors, and Zone Program Integrity Contractors, in lieu of a specific local coverage determination (“LCD”). As stated in the MITA PET NCD request, professional societies, including the American College of Radiology (“ACR”), and the Society of Nuclear Medicine and Molecular Imaging (“SNMMI”), are committed to developing appropriateness criteria guidelines to assist referring physicians and other providers in making appropriate decisions regarding PET.³

As summarized in the MITA PET NCD Request, the original context of PET coverage was to address the broad use of the generic tracer, fluorodeoxyglucose F-18 (“FDG”) for which there was no specific FDA labeled indication and for which there was limited published literature for the majority of proposed indications. In contrast, modern diagnostic PET radiopharmaceuticals are studied in adequate and well-controlled in clinical trials as a basis for review of safety and efficacy by the FDA and have more precise and specific mechanisms for detecting and quantifying pathophysiology as one element in the clinical decisions for patient management. These innovations are opening the door to more personalized medicine.

Accelerating the development of and access to technologies that personalize medicine are clear objectives of the President, as stated in the White House National Bioeconomy Blueprint (“Blueprint”).⁴ The Blueprint notes the report by the Personalized Medicine Coalition which states in its introduction that “what is different about medicine today, and the reason the word “personalized” has been added for emphasis, is that technology has brought us much closer to exquisite precision in disease diagnosis and treatment.”⁵ The Blueprint calls for reducing regulatory barriers to adoption of new technology, which in addition to targeted use of coverage with evidence development and regulatory parallel reviews, we believe includes revisiting outdated coverage policies. In this instance, the proposed modifications to the PET NCD will reflect the current environment, which includes among other things, much more rigorous FDA requirements for radiopharmaceuticals. This is addressed in the next section.

The MITA PET NCD Request summarized the history of regulatory approvals for PET radiopharmaceuticals. In sum, for each of the four longstanding PET radiopharmaceuticals — rubidium Rb-82, ammonia N-13, fluorodeoxyglucose F-18, and sodium fluoride F-18, there was generally a lack of FDA-supervised phase II and phase III trials, clear metrics for reporting, or a clear landmark to signify a satisfactory achievement of clinical evidentiary standards as to when clinical use should begin. Rather than review the developer/manufacturer’s exhaustive dossier of data, as is familiar today, in 2000 the FDA issued a public notification of labeling for FDG in oncology (“to assist in evaluating malignancy”) and ammonia N-13 (for myocardial blood flow), as it began to implement 1997 legislation to “establish appropriate procedures for the approval of PET drugs.”^6,7 Today, the FDA requirements are much more rigorous including requirements to demonstrate (i) accuracy & reliability; (ii) clinical usefulness; (iii) competent image interpretation & radiology training; and (iv) GMP standards for PET radiopharmaceutical manufacturing.

Evidence of this is the FDA’s recent approval of Amyvid^TM8, which was approved only after issues of image interpretation were addressed. The FDA label provides substantive information to physicians to guide them in the use of Amyvid, including information on limitations of use and requirements for special training for readers of Amyvid images.⁹ Provision of guidance in drug labeling is not unusual for drugs, generally.

The ability to visualize amyloid in-vivo is an important discovery and is playing a vital role in advancing our understanding of Alzheimer’s Disease (AD). This technology not only identifies individuals with and without amyloid deposition which, when taken with other diagnostic information, is proving useful for early and differential diagnosis of AD,^10,11 it is playing a role in our understanding of the cascade of events that leads to the clinical expression of the disease.¹² Recently amyloid imaging has been incorporated into therapeutic trials of disease modifying anti-amyloid treatments.^13,14 This neuroimaging technique may prove important for subject selection and stratification in therapeutic trials and in monitoring treatment effects.¹⁵

FDA’s more rigorous requirements for radiopharmaceuticals, especially FDA’s requirement for demonstration of clinical utility and the accuracy and reliability of radiologist interpretation, establish a solid basis of evidence for coverage of the labeled use(s). These requirements also satisfy the other components of the aforementioned first aim of the Triple Aim, namely, ensuring that uses of new FDA approved PET radiopharmaceuticals are safe, effective, and reliable.

CMS has frequently stated in previous PET NCD Decision Memoranda that diagnostic tests should not be evaluated with the same standards as therapeutics, but rather a diagnostic test should be evaluated on the basis of its clinical usefulness to change patient management, i.e. “a diagnostic test affects health outcomes through changes in disease management brought about by physician actions taken in response to test results.”¹⁶ In other words, if a new radiopharmaceutical is approved under rigorous regulatory requirements, and this new FDA-approved PET radiopharmaceutical leads physicians to prescribe different treatment than they would otherwise have prescribed, leading to a greater likelihood of improved health outcomes (either clinically or in quality of life, as per the demonstrated efficacy of the therapeutic intervention planned), the standard of evidence for coverage has been met. We believe relegating new FDA-approved PET radiopharmaceuticals to immediate non-coverage without even de minimis review by CMS disregards CMS’s standard evidentiary requirements for diagnostics by assuming that new FDA-approved PET radiopharmaceuticals do not meet the evidentiary standard for diagnostics.

Other nuclear medicine coverage policies, such as the policy for Single Photon Emission Computed Tomography (“SPECT”), do not impose categorical non-coverage restrictions on new uses of the nuclear medicine procedure or new FDA-approved radiopharmaceuticals. The SPECT national coverage policy lists several clinical conditions for which SPECT is useful for diagnosis, and defers to the discretion of local Medicare Contractors, coverage decisions for remaining patient conditions.¹⁷

6. Proposed Modification Removes Inappropriate Coverage Restraints from Providers Working to Succeed under New P4P Models of Care

The transition under both public and private health reform initiatives from volume-based to value-based reimbursement often means paying for bundles of services rather paying separately for each service. For example, under one of Medicare’s most far-reaching innovations, the Pioneer Accountable Care Organization (“ACO”) program, those Pioneer ACOs that show savings over the first two years will be eligible to move to a population-based payment model in the third year of the program, where payment is a per-beneficiary per month payment amount. This capitated bundle is intended to replace some or all of the ACO’s fee-for-service payments with a prospective monthly payment.¹⁸ The goal for all of these initiatives is to support the Triple Aim: Better Care, Healthy People/Healthy Communities, Affordable Care, all of which are objectives of DHHS’s National Quality Strategy.¹⁹

To participate in these initiatives, and others like them (e.g., Medicare Shared Savings Program, Bundled Payment for Care Improvement), CMS requires provider organizations to have governing processes in place to document and support adherence to evidence-based medicine.^20,21 For this reason, it seems inconsistent that CMS would tie the hands of the very providers to whom it is giving more flexibility in choosing the most appropriate health care services for a patient. Again, we believe non-coverage of future FDA-approved radiopharmaceuticals without even de minimis review by CMS is incongruous with these new models of care, and will stifle adoption of new technologies in these initiatives.

In summary, much has changed over the last several years that we believe makes the current national non-coverage policy for new radiopharmaceuticals outdated and inconsistent. The new focus on patient-centric care and personalized medicine; the more rigorous regulatory standards for radiopharmaceuticals to ensure safety, reliability, and clinical utility; the continued acknowledgement that the role of diagnostic tests to change patient management as a step towards improved health outcomes; and the push for payment incentives that give providers and patients flexibility to choose the most appropriate health care services all call for revising the current PET national coverage determination. We believe that the proposed modification which removes the exclusionary clause for the breadth of future new FDA-approved PET radiopharmaceuticals is appropriate for conditions of today’s health care market and which will be in play for the foreseeable future.

GEHC very much appreciates the opportunity to submit comments on these important issues. If you have any questions on our comments, please do not hesitate to contact me at richard.frank@ge.com or (609) 933-0007.

Sincerely,

1 DHHS. Report to Congress: National Strategy for Quality Improvement in Health Care. March 2011.p.2.
2 Administrator’s Ruling 95-1. https://www.cms.gov/Rulings/CMSR/list.aps. Medicare contractors can rely on “acceptable standards of practice” which are reflected in “consensus of expert opinion” and “published medical literature” that is “well-recognized.” Services failing these standards may be non-payable.
3 For example through a joint task force, the SNM and the Alzheimer’s Association, are already developing recommendations for the use of amyloid imaging for physicians, imaging and other medical specialists, Alzheimer families and the general public. Alzheimer's Association statement on FDA approval of florbetapir (Amyvid). April 6, 2012. Last accessed July 31, 2012 at http://www.alz.org/news_and_events_approval-of-florbetapir.asp
4 The White House. National Bioeconomy Blueprint. April 2012, p. 9.
5 Personalized Medicine Coalition. “The Case for Personalized Medicine.” p. 2. last accessed on July 27, 2012 at www.personalizedmedicinebulletin.com/files/2011/11/Case_for_PM_3rd_edition1.pdf
6 65 Fed. Reg. 13002, March 10, 2000, implementing the 1997 FDA Modernization Act, § 121(c).
7www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm181434.htm
8 Amyvid™ is a registered trademark of Eli Lilly and Company.
9 FDA Label for Amyvid. Last accessed July 31, 2012 at
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails
10 Laforce R Jr, Rabinovici GD. “Amyloid imaging in the differential diagnosis of dementia: review and potential clinical applications.” Alzheimers Res Ther. 2011 Nov 10;3(6):31.
11 Fodero-Tavoletti MT, Cappai R, McLean CA, Pike KE, Adlard PA, Cowie T, Connor AR, Masters CL, Rowe CC, Villemagne VL. “Amyloid imaging in Alzheimer's disease and other dementias.” Brain Imaging Behav. 2009 Sep;3(3):246-61
12 Jagust WJ, Mormino EC. “Lifespan brain activity, ß-amyloid, and Alzheimer's disease.” Trends Cogn Sci. 2011 Nov;15(11):520-6.
13 Reiman EM, Langbaum JB, Fleisher AS, Caselli RJ, Chen K, Ayutyanont N, Quiroz YT, Kosik KS, Lopera F, Tariot PN. “Alzheimer's Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments.” J Alzheimers Dis. 2011;26Suppl 3:321-9.
14 Cummings JL. “Biomarkers in Alzheimer's disease drug development.” Alzheimers Dement. 2011 May;7(3):e13-44.
15 Scheinin NM, Scheinin M, Rinne JO.”Amyloid imaging as a surrogate marker in clinical trials in Alzheimer's disease”. Q J Nucl Med Mol Imaging.” 2011 Jun;55(3):265-79.
16 CMS. “Decision Memorandum for PET for Initial Treatment Strategy in Solid Tumors and Myeloma (CAG-00181R3). August 4, 2010. p. 10
17CMS. National Coverage Determination (NCD) for Single Photon Emission Computed Tomography (SPECT) (220.12).
18 CMS. “Fact Sheet: Pioneer Accountable Care Organization Model: General Fact Sheet.” December 19, 2011.
19 DHHS. Report to Congress: National Strategy for Quality Improvement in Health Care. March 2011. p. 2.
20 CMS. Federal Register. 76(212) November 2, 2011. p. 67826 (Medicare Shared Savings Program Final Rule.)
21 Center for Medicare and Medicaid Innovation. “Bundled Payments for Care Improvement Initiative Request for Application.” August 22, 2011. V4, p. 33.

Re: National Coverage Analysis (NCA) Tracking Sheet for Positron Emission Tomography (CAG-00065R2)

Dear Dr. Jacques:

On behalf of World Molecular Imaging Society (WMIS), we appreciate the opportunity to submit public comments to the Centers for Medicare & Medicaid (CMS) in support of the reconsideration of the non-coverage language in Section 220.6 of the Medicare National Coverage Determinations Manual for PET scans.

WMIS is the foremost and authoritative society in molecular imaging. Since the inception of Positron Emission Tomography PET, the society (formerly known as the Academy of Molecular Imaging) has participated in all major coverage and payment determinations and educational activities related to PET. WMIS is the sponsor of the National Oncologic PET Registry (NOPR). Additionally, we are a cosignatory for the Formal Request. Given our experience and involvement with PET and our objective viewpoint which comes from our academic roots, we would like to again reiterate our support for a lifting the national non-coverage language for new FDA approved PET diagnostic radiopharmaceuticals. Our clinical and scientific rational is as follows:

Since first reviewing PET imaging in the late 1990s, the technology is now widely recognized in the medical communityas an important diagnostic modality. For more than a decade now, significant data has been accumulated to demonstrate the clinical accuracy of FDG-PET and its impact on patient management. In light of the robust NOPR data collected since 2009, we are now convinced that there remains no clinical need to continue CED data collection for FDG-PET oncologic indications.

Based on the past review of FDG-PET, and now NaF-18, we strongly believe that future FDA approved imaging agents should not be non-covered by Medicare following FDA approval. In the next decade we expect to see the commercialization of a new generation of highly targeted radiopharmaceuticals. Furthermore, we believe that the improvements in the FDA approval process for new radiopharmaceuticals have led to the evolution of significant protocols and rigor to evaluate and determine the safety and efficacy of these new agents. Obviously, the final determination for CMS purposes is whether new FDA approved agents meet the "reasonable and necessary" criteria for coverage of the Medicare specific population. We believe that the most appropriate framework for the next generation of PET tracers in oncology, neurology (Dementia, Alzheimer’s disease), and cardiology would be the elimination of the overly restrictive national non-coverage language. Coverage could be reviewed through the local contractor process and when appropriate through a national coverage analysis framework.-.

We look forward to working with you in the future both on issues relating to the NOPR as well as new imaging technologies. Thank you.

Best Regards,

August 9, 2012

RE: National Coverage Analysis for Positron Emission Tomography (CAG-00065R2)

Dear Dr. Roche and Mr. Caplan:

Siemens Molecular Imaging Biomarker Research (MIBR) thanks the Centers for Medicare and Medicaid Services (CMS) for opening a comment period on the reconsideration of the National Coverage Determination (NCD) for the use of positron emission tomography (PET) at Section 220.6 of the Medicare National Coverage Determinations Manual.

MIBR, the discovery and development unit of Siemens Molecular Imaging, is actively engaged in the discovery and development of new imaging biomarkers for applications in oncology, cardiology, neurology and other important clinical indications. Siemens Molecular Imaging develops vertically integrated solutions that include innovative imaging biomarkers, preclinical and clinical imaging equipment and software applications, and is a business unit within Siemens Healthcare, the global healthcare business of Siemens AG.

In addition, PETNET Solutions is a manufacturing and distribution unit for Siemens Molecular Imaging, providing a broad portfolio of PET radiopharmaceutical products and services to imaging centers nationwide. Siemens’ PETNET Solutions will be providing complementary comments in a separate letter.

Siemens MIBR appreciates the opportunity to comment on the reconsideration of the current NCD for PET. We believe that enabling a pathway for coverage of recent and future Food and Drug Administration (FDA) approved PET radiopharmaceuticals through the removal of the exclusionary rule would be a positive development for patient care.

MIBR’s pipeline

Below is a list of publications on our PET imaging tracers:

Zhang W et al, A Highly Selective and Specific PET Tracer for Imaging of Tau Pathologies J Alzheimer’s Disease 31 (2012) 1-12

Chen L et al. 18F-HX4 hypoxia imaging with PET/CT in head and neck cancer: a comparison with 18F-FMISO Nucl Med Commun 2012 July 24 [Epub ahead of print]

Doss M et al. Biodistribution and radiation dosimetry of the Integrin Market 18F-RGD-K5 Determined from Whole-Body PET/ET in Monkeys and Humans. J Nucl Med 2012; 53:787-795

Dubois LJ et al. Preclinical evaluation and validation of [18F]HX4, a promising hypoxia marker for PET imaging. PNAS August 30, 2011 vol.108 no. 35 14620-14625

Doss M et al. Biodistribution and radiation dosimetry of the hypoxia marker 18F-HX4 in monkeys and humans determined by using whole body PET/CT Nucl Med Commun 2010, Vol 31 No 12 1016-1024

Van Loon J et al. PET Imaging of hypoxia using [18F]HX4: a phase I trial Eur J Nucl Med Mol Imaging. 2010 Aug; 37(9):1663-8

FDA requirement for approval

In CFR Title 21 Part 315 of FDA Rules and Regulations, the FDA defines the requirement for the determination of safety and effectiveness for a diagnostic radiopharmaceutical.

Sec. 315.5 Evaluation of effectiveness

(a) The effectiveness of a diagnostic radiopharmaceutical is assessed by evaluating its ability to provide useful clinical information related to its proposed indications for use. The method of this evaluation varies depending upon the proposed indication(s) and may use one or more of the following criteria:

(1) The claim of structure delineation is established by demonstrating in a defined clinical setting the ability to locate anatomical structures and to characterize their anatomy.

(2) The claim of functional, physiological, or biochemical assessment is established by demonstrating in a defined clinical setting reliable measurement of function(s) or physiological, biochemical, or molecular process(es).

(3) The claim of disease or pathology detection or assessment is established by demonstrating in a defined clinical setting that the diagnostic radiopharmaceutical has sufficient accuracy in identifying or characterizing the disease or pathology.

(4) The claim of diagnostic or therapeutic patient management is established by demonstrating in a defined clinical setting that the test is useful in diagnostic or therapeutic patient management.

(5) For a claim that does not fall within the indication categories identified in 315.4, the applicant or sponsor should consult FDA on how to establish the effectiveness of the diagnostic radiopharmaceutical for the claim.

(b) The accuracy and usefulness of the diagnostic information is determined by comparison with a reliable assessment of actual clinical status. A reliable assessment of actual clinical status may be provided by a diagnostic standard or standards of demonstrated accuracy. In the absence of such diagnostic standard(s), the actual clinical status must be established in another manner, e.g., patient follow up.

These requirements ensure that new radiopharmaceuticals coming on the market will already have significant data on effectiveness for the label indication.

Current policy deters innovation of new products and national non-coverage language should be removed accordingly

For any drug developers of therapeutic or diagnostic compounds, the risk of drug development is enormous. The first risk is the FDA approval process, which can be lengthy and costly with a high level of uncertainty.

In 1964, the FDA withdrew the “new drug“ requirement for radiopharmaceuticals. This decision greatly reduced the cost of bringing a new imaging agent to the clinic, which is especially critical for a diagnostic agent that has a smaller market than a therapeutic agent. In 1977, FDA withdrew this exemption and required manufacturers to obtain an approved new drug application for new and existing radiopharmaceuticals, implementing essentially the same requirements as therapeutic drugs. The deterent to innovation is evident in the fact that “there are only 23 radiopharmaceuticals in clinical use today and the average age of these agents is 25 years.“

Even with FDA approval, the second uncertainty a manufacturer has to overcome is coverage by CMS. Both uncertainities give any drug development program a highly unpredictable return on investment (ROI). As in any business, ROI calculation plays a critical role in the decision of whether to move a compound forward in its development program. As such, many potentially beneficial compounds may never be developed despite potential value to patients due to the extreme uncertainty of CMS coverage. Alternatively, compounds with larger market potential are more likely to be considered whereas compounds addressing the needs of smaller patient populations have a smaller chance of development.

At Siemens, we are facing this uncertainty on the ROI of a PET tracer with the potential to assist in the evaluation of Alzheimer’s disease. If this tracer proves to have unique uptake in the brain of patients with pre-symptomatic Alzheimer’s, there is a potential to intervene with the proper patient population that may benefit from therapeutic agents that are currently in phase III development.

The cost of bringing a therapeutic compound from research stage to market has been quoted as over $1 billion and more than seven years. While diagnostic agents may take somewhat lower investment, without CMS coverage, the ROI on a new tracer is highly uncertain, given the time and cost of clinical development. As a business with responsibilities towards our shareholders, Siemens is at a crucial point of deciding the path forward for a number of our compounds, including the PET tracer with the potential to assist in the evaluation of Alzheimer’s disease. Removing the national non-coverage language from section 220.6 of the National Coverage Determinations Manual on PET scans when PET is furnished with new FDA-approved radioisotopes, would help encourage manufacturers to bring new tracers to market, ultimately benefiting patients. Accordingly, we encourage CMS to adopt this modification, as recommended by the Medical Imaging Technology Alliance (MITA), the American College of Radiology (ACR), the Society of Nuclear Medicine (SNM), the Council on Radionuclides and Radiopharmaceuticals (CORAR), and the World Molecular Imaging Society (WMIS).

Conclusion

Siemens Molecular Imaging Biomarker Research is actively engaged in the discovery and development of new imaging biomarkers for applications in oncology, neurology and cardiology. These novel imaging biomarkers, when approved for clinical use and covered by CMS will increase imaging-based disease characterization, improve therapy management and ultimately, enable personalized medicine for Medicare patients.

However, the current non-coverage language contained in section 220.6 of the National Coverage Determinations Manual on PET scans is limiting the clinical trial program for our broad portfolio of PET imaging biomarkers due to the uncertainty of Medicare coverage despite receiving FDA approval. We ask CMS to remove this pre-emptive national non-coverage language for new PET radiopharmaceutical agents in light of the fact that the imaging technology to enable personalized medicine has been evolving quickly. Doing so will help ensure that innovative, emerging PET tracers are brought from the research stage to the market where they will benefit patients.

Thank You,

Hartmuth Kolb, PhD
Vice President, Molecular Imaging Biomarker Research
Siemens Molecular Imaging

We encourage CMS to require high quality evidence that supports superior results from PET scanning when compared to other less costly imaging. Required evidence or results should go beyond a determination that the imaging is non-inferior. Determinations regarding PET techniques should continue to be made at the NCD level rather than individual MAC’s. We also encourage CMS to support use of PET scanning of any kind only when the results will significantly affect critical treatment decisions.

Jeffrey Roche MD, MPH
Centers for Medicare & Medicaid Services
7500 Security Boulevard,
Baltimore, MD 21244

Dear Dr. Roche:

We appreciate this opportunity to submit comments to the Centers for Medicare & Medicaid Services (CMS) regarding the National Coverage Analysis for Positron Emission Tomography (CAG-00065R2).1 We support expanded coverage of reasonable and necessary Positron Emission Tomography (PET) services with PET radiopharmaceuticals that have FDA approval. We respectfully request that CMS remove from section 220.6 of the National Coverage Determination (NCD) manual the blanket exclusion of non-coverage for new PET drugs for the reasons outlined below.

Current State of PET

Mayo Clinic has witnessed the astonishing transformation of PET scanning from a research-only modality to a full fledged clinical tool that provides accurate metabolic targeting of disease. More importantly, numerous studies have proven that PET has very significant impact on patient treatment strategies.

The current pathway for CMS approval of PET radiopharmaceuticals has created a stumbling block to delivering the diagnostic benefits of PET to many patients. Currently there are only three PET drugs covered by CMS in addition to fludeoxyglucose F 18 injection (F-18 FDG). However, any new drugs are subject to a pre-emptive national non-coverage policy for new PET radiopharmaceutical agents. Given the increasingly strict FDA (Food and Drug Administration) criteria for approval, this pre-emptive non-coverage approach may no longer be practical.

For example, a recently reported research study demonstrated the effectiveness of F-18 florbetapir (Amyvid) imaging of in-vivo neuritic plaques, found in Alzheimer’s disease (Lancet Neurol 2012; 11: 669–78).2 Concerns were raised during the FDA approval process about whether or not non-expert imagers could be taught to properly interpret these studies in a community (non-academic) setting. The FDA then required the manufacturer to develop a validated reader training program be implemented to ensure proper reader interpretations. This was done, and the data reviewed favorably by the FDA before formal approval. However, despite this intensive and rigorous FDA process, the existing CMS policy currently prohibits coverage of this tracer, which in turn effectively results in non-utilization. In other words, despite the requirement that any physician interpreting florbetapir studies first complete the training course, patients are denied the chance for more accurate diagnosis of their disease.

Although the above is only one example, the same reasoning can be applied to the many other new PET drugs that have been shown to be effective in a variety of diseases. Advances in imaging and CMS’ past experience with PET coverage no longer support a clinical rationale for a pre-emptive national non-coverage policy for new PET radiopharmaceutical agents that have already undergone a rigorous FDA review and approval process as indicated below.

Food and Drug Administration Modernization and Accountability Act of 1997 (FDAMA)

The origin of current federal regulations for PET drugs is the Food and Drug Administration Modernization and Accountability Act of 1997 (FDAMA).3 Section 121(c)(1)(A) of this act directed the FDA to establish appropriate approval procedures and current good manufacturing practice (CGMP) requirements for PET drugs.4 Section 121(c)(2)(A) of the act specified that PET drug manufacturers and compounders would be required to submit applications for approval within 24 months of the establishment of such procedures and requirements. It is worthy to note that U.S. Senate issued a report to provide background information, as well as the reasons for the establishment of the statutes of FDAMA.5 This report clearly depicts why the Senate felt strongly that it was vital to revamp the regulatory framework, as well as to expand reimbursement for PET drugs. The following statements are taken from the Senate Report No. 43, 105th Congress, 1st Session and provide a glimpse into PET situations prior to FDAMA 1997:5

• PET radiopharmaceuticals have been used in patients in the United States for over 30 years. Recent research and advances in imaging technology have enhanced the clinical importance of PET
• At present [July 1, 1997], there are 70 PET centers in the United States, almost all of which are part of academic medical centers. PET technology and its applications were developed in large part with almost $2 billion in federal research funds. Yet, while PET is widely used in Europe, its benefits have not been widely available to American patients,
• Academic medical centers are facing unprecedented cost pressures. …many PET centers are likely to close, and the benefits of PET will be unavailable to the taxpayers who funded their development.

One cause for this dismal situation as stated in this report is the lack of reimbursement (particularly reimbursement from the Medicare program), as well as inappropriate and costly regulations promulgated by FDA.5 Under current FDA regulations, PET centers which compound PET radiopharmaceuticals on an individual dose basis would be required to meet FDA’s CGMP and to file new drug application (NDAs) and abbreviated new drug application (ANDAs) for each type of PET drug and for each indication for which the PET radiopharmaceutical might be used.4 This is the same type of regulation which the FDA applies to large pharmaceutical manufacturers.

Regulatory Status for PET Drugs

The regulatory status for PET drugs dates back to 1997 where the FDA conducted several public meetings to discuss FDA proposals for PET drug approval procedures and CGMP requirements. In March 2000, the FDA presented its findings of safety and effectiveness for F-18 FDG, ammonia N 13 injection, and sodium fluoride F 18 injection, as well as described the types of applications that can be submitted for these three PET drugs.6,7 Guidance for the applications (i.e., NDAs and ANDAs) for these three PET drugs was initially issued by the FDA in March 2000, and a final version of this guidance was released by the FDA in August 2011.7,8

FDA recognized that, due to the following unique aspects of PET drugs, application of certain provisions of the CGMP regulations for conventional drugs to the manufacturer of PET drugs might result in unsafe handling or be otherwise inappropriate:

• Short physical half-lives of PET radioisotopes – prolonged manufacturing (including quality control) time significantly erodes the useful life of PET drugs.
• The quantities of radioactive ingredients vary from nanogram to milligram amounts – reported instance of any adverse reaction to PET drugs is almost non-exist or very rare.
• PET drugs usually do not enter a general drug distribution chain – distribution may occur to other PET centers when the geographic proximity will allow for distribution and use within the drug product’s half-life parameters.

In April 2002, FDA issued a preliminary draft proposed CGMP regulation for PET drugs, and draft guidance on CGMP requirements for public comments; a proposed rule and revised draft guidance were issued in September 2005, to solicit additional public input. In December 2009, FDA published a final CGMP for PET drugs – this release triggered the two-year clock for applications (NDAs and/or ANDAs) to be submitted for any PET drug used clinically.

FDA was supposed to enforce the requirement that all producers of PET drugs submit applications after December 12, 2011.12 However, this deadline was extended to June 12, 2012 possibly due to some PET centers unable to meet the deadline.13 If PET drug producers submit the required application(s), FDA will not object if clinical use of the PET drug(s) continues during the application review period, provided that the facility complies with all other FDA requirements, including CGMP.13 Nevertheless, all PET drug producers must be operating under an approved NDA or ANDA, or effective IND, by December 12, 2015.13

Recommendations to CMS

Since the establishment of this act (i.e., 1997 FDAMA),3 the FDA has worked closely and diligently with professional associations, manufacturers, and other interested persons (e.g., patient advocacy groups and physicians and scientists licensed to make or use PET drugs, etc.) to develop PET drug approval procedures (i.e., NDA and ANDA), as well as CGMP regulations specifically for PET drugs. FDA’s early recognition of the unique natures of PET drugs, and its open-minded approaches contributed a great deal in offering a significant regulatory relief to the PET community for meeting the requirements on NDA/ANDA approvals and CGMP.

The objective of Section 121 was to establish a regulatory framework for PET drugs that will enable PET centers to continue to make this valuable technology available to patients at reasonable cost and assure that the public health will be protected.4,5 To achieve this objective we sincerely hope that CMS will expand coverage to new FDA-approved PET drugs. The scientific evidence of efficacy and safety of each approved PET drug have been thoroughly reviewed and accessed by the FDA. Thus, it is not necessary to waste any precious resources to reevaluate these aspects. As pointed out in the Senate Report, we need to ensure that the valuable PET drugs are available to our patients at reasonable cost since this technology was originally developed in our country with research funding from our taxpayers.5 We should not prevent the general public (in particular Medicare/Medicaid patients) from accessing useful PET drugs because of the lack of reimbursement.

Mayo Clinic praises CMS for its decision to open the PET NCA (National Coverage Analysis).1 Allowing coverage of new FDA approved drugs will provide beneficiaries greater access to clinically-proven PET imaging drugs in procedures that provide clinically meaningful information to their physicians. Should you have any questions, please free to reach us at the telephone numbers or e-mail addresses provided below.

Sincerely,

Michael C. Roarke, M.D.
Consultant, Diagnostic Radiology
Section Head, Nuclear Medicine
Assistant Professor of Radiology, College of Medicine
Phone: 480-301-5523
E-mail: roarke.michael@mayo.edu

Mark A. Nathan, M.D.
Consultant, Department of Radiology
Chair, Division of Nuclear Medicine
Phone: 507-284-4399
E-mail: nathan.mark@mayo.edu

Joseph C. Hung, Ph.D., BCNP
Consultant, Department of Radiology
Director, Mayo Clinic PET Radiochemistry Facility
Phone: 507-284-4104
E-mail: jhung@mayo.edu

References

Removal of the exclusionary language is an appropriate decision utilizing radiotracers currently FDA approved along with future tracers bearing FDA approval for PET scans.

I urge you, on behalf of patients who benefit from PET scans using current FDA approved tracers, to adopt inclusionary language for additional FDA approved tracers to the current CMS NCD coverage of PET scans. Streamlining of services with reliance of FDA approval of additional tracers will prove a cost savings for CMS but more importantly patients will benefit.

THE FOLLOWING COMMENTS WILL ALSO BE SUBMITTED AS AN ATTACHEMENT TO CAGInquiries@CMS.HHS.GOV.

Dear Dr. Roche and Mr. Caplan:

The Medical Imaging & Technology Alliance (MITA) appreciates this opportunity to respond to the Centers for Medicare and Medicaid Services’ (CMS’s) request for comments on the reconsideration request of the National Coverage Determination (NCD) for the use of positron emission tomography (PET) at Section 220.6 of the Medicare Coverage Manual. As the leading trade association representing medical imaging, radiotherapy technology, and radiopharmaceutical manufacturers, we have an in-depth understanding of the significant benefits to the health of Medicare beneficiaries that medical imaging, radiotherapy and proton therapy provide. MITA is pleased to work with CMS to ensure Medicare beneficiaries have proper access to these life-saving technologies. We appreciate CMS’s steps forward in considering MITA’s reconsideration request and are pleased to respond to the areas of interest CMS expressed in its request for comments.

Breadth of the request
MITA’s reconsideration request appropriately addresses new FDA-approved PET radiopharmaceuticals. We stand firm in our belief that approving this request would not reverse the existing National Coverage Determination which encompasses 18F-FDG, 18F-NaF, 13-N ammonia, or 82-Rb rubidium. For PET tracers emerging onto the marketplace now and in the future, this request allows for or enables an updated application of the policy, acknowledging the higher regulatory approval standards for the new tracers. CMS’s approval of the request would also allow Medicare beneficiaries access to these innovative technologies upon FDA-approval, leading to potentially more expedient treatment decisions and individualized patient management. We also note that by approving this request, CMS will treat newly-approved PET radiopharmaceuticals in the same manner as any other diagnostic radiopharmaceutical drug that earns approval through the FDA process. In doing so, CMS will level the playing field and afford all diagnostic radiopharmaceuticals the same opportunity for coverage.

MITA would like to express its appreciation to all of the organizations that joined us as cosigners on the reconsideration request: American College of Radiology (ACR); Council on Radionuclides and Radiopharmaceuticals (CORAR); Society of Nuclear Medicine and Molecular Imaging (SNMMI); and the World Molecular Imaging Society (WMIS). We also are pleased that CORAR has agreed to join us in signing this comment. Collectively, we appreciate CMS’s willingness to open this request and receive input from various stakeholders and interested parties. In some responses to CMS’s request for comments, MITA member companies may provide examples of the types of evidence being gathered to demonstrate coverage for the product.

Assuring success by approving the request
We would like to reiterate that any approval for coverage would involve consideration of the evidence for coverage; MITA’s position is that this evidence is inherent to the newly approved tracers, as opposed to the evidence that was needed for 18F-FDG, 18F-NaF, and 13-N ammonia, which are now covered under Section 220.6 of the CMS National Coverage Determinations Manual.

We acknowledge the concerns expressed by some commenters on the reconsideration request that FDA approval alone should not equate to coverage because there may be circumstances in which FDA approval does not show patient outcomes. However, we reiterate our statement that a newly approved tracer that overcomes the rigorously well-controlled clinical trials that demonstrate safety and efficacy for the FDA approval process also provides a level of evidence which is sufficient to merit coverage. Thus, PET radiopharmaceuticals should receive the same level of consideration.

We also acknowledge CMS’s, including local contractors’, ability to impose boundaries for coverage on any new item entering the marketplace. We appreciate that by approving this reconsideration request, CMS will allow for coverage rather than specifically disallowing coverage for new products. This request is simply a process change allowing for coverage of newly approved PET radiopharmaceuticals upon or shortly after FDA approval. It would eliminate the significant delay incurred while awaiting a decision through the current National Coverage Analysis process.

MITA also understands that CMS needs to ensure that coverage of new products utilized by Medicare beneficiaries may not deserve interminable coverage. It would be unfortunate to withdraw coverage from a particular item or service, but in cases where evidence emerges that Medicare patients do not benefit from a new product, and that evidence outweighs the benefits of coverage, we acknowledge that CMS has recourse in such provision of coverage.

As always, MITA appreciates the open and cooperative nature that CMS has exhibited throughout this process. If you have additional questions, please contact Brian Abraham, Sr. Policy Director, at babraham@medicalimaging.org or 703-841-3258.

Sincerely,

Gail M. Rodriguez, Ph.D.
Executive Director, MITA
Vice President, National Association
of Electrical Manufacturers (NEMA)

Dear Dr. Roche and Ms. Kaplan:

USAgainstAlzheimer's, the national mobilization network committed to stopping Alzheimer's disease by 2020, encourages the Centers for Medicare & Medicaid Services (CMS) to remove the blanket national non-coverage policy for new Food and Drug Administration (FDA) approved PET radiopharmaceuticals (Section. 220.6 of the NCD). At the same time, USAgainstAlzheimer's urges that coverage decisions made at either the national or local levels carefully consider the full body of evidence to ensure access to reasonable and necessary care for beneficiaries while guarding against inappropriate and unnecessary testing.

The field of Alzheimer's disease exemplifies the need for a more discriminating CMS approach to PET technologies, one that does not begin with a presumption of non-coverage of any new FDA-approved PET radiopharmaceuticals. It is increasingly clear that preventing and treating Alzheimer's disease will require treatments that identify at-risk patient populations in the presymptomatic or mildly symptomatic but pre-dementia stages of the disease. Effective PET and other advanced diagnostic tools are essential to identifying targeted patients and measuring the impact of a therapy during these early stages of the disease course. Last year, the National Institute on Aging (NIA) and the Alzheimer's Association issued updated criteria and guidelines for diagnosing Alzheimer's disease, the first updated guidance on this topic in nearly 30 years. The use of functional imaging modalities, including PET scans, is an important element in the use of these new guidelines.

Earlier this year, the FDA approved Eli Lilly and Company's radiopharmaceutical Amyvid™ to detect beta-amyloid plaque levels in patients being evaluated for Alzheimer's disease. While Amyvid™ alone is not intended as a diagnostic tool for Alzheimer's, it provides patients, their families, and their physicians with information that is useful in developing differential diagnoses and informing treatment and therapies. The current blanket non-coverage policy on all new PET radiopharmaceuticals, however, effectively prevents any Medicare patient presenting signs of cognitive impairment from having access to this diagnostic tool without consideration of its clinical value in light of the available evidence.

In addition to the current comment request, USAgainstAlzeheimer's is aware of a request made by Lilly focused narrowly and specifically on beta-amyloid imaging. Given the recent FDA approval and subsequent availability of Amyvid™ and the recently adopted National Plan to Address Alzheimer's Disease that establishes as a national goal the prevention and effective treatment of the disease by 2025, now is a critical time for CMS to revisit the issue and consider the body of available evidence demonstrating the value of such an approach.

On behalf of the more than 5 million Americans currently suffering from Alzheimer's and the tens of millions more who stand to develop this disease in the coming years, we respectfully urge the agency to remove the blanket national non-coverage policy on all new PET radiopharmaceuticals and to revisit the beta-amyloid coverage request specifically as quickly as possible.