Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers

March 15, 2019

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

RE: Medicare National Coverage Analysis for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancer (CAG-00451N)

Dear Ms. Jensen and CAG Team:

I applaud the decision to cover CAR-T therapy and the language in which the coverage decision is crafted, leaving great latitude in the development of other indications of this very powerful quantum leap forward in oncology care.

I also agree with the decision to cover these therapies with coverage with evidence development (CED) in as much as the studies that have led to the approval of these agents have limited number of patients 65 and older and the impact to Medicare beneficiaries is not known.

I will not duplicate many of the other excellent comments already submitted, but would ask CMS to consider two distinct items listed in the coverage decision regarding CED:

Consideration 1
Adding language to Section 4a such as, “The principle purpose of study or arm” to allow innovated and unified data collection efforts.

In 2005 the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) was started to help define evidentiary requirements for determining clinical utility of new technologies. In 2014, they published a summary their efforts. They wrote:

“The most common problem with assessing clinical utility, however, was the paucity of good-quality evidence with which to generate an evidence-based recommendation. This is also a recurring theme and remains a critical issue underlying the successful translation of genomics into improved individual and population health. Our gold standard of evidence, the randomized controlled trial, is constrained by time and resource requirements and can be challenging in the face of rare conditions and relatively small effect sizes as compared with usual care. Existing EWG methods do allow for a determination of adequate clinical utility based on a single nonrandomized controlled trial or even a systematic review based on cohort studies alone, when results warrant. The EWG experience supports the need for additional approaches and methods for evidence generation, such as consideration of novel observational study designs and innovative modeling strategies, along with a careful examination of the evidentiary standards for clinical recommendations.”

Recently, Dr. Scott Gottlieb, FDA commissioner has said,
“Unfortunately, we’ve seen a continued reluctance to adopt innovative approaches among sponsors and clinical research organizations. In some cases, the business model adopted by the clinical trial establishment just isn’t compatible with the kind of positive but disruptive changes that certain innovations can enable. . .”

CMS should support innovative efforts in quality data collection that decrease the overall cost and simplify the time and efforts of institutions especially if these innovative approaches allow use of shared infrastructure and overlapping data collection efforts to answer questions that are important for the advancement of all oncology patients and help unify desires of CMS, FDA and EGAPP.

For example, CMS has said in its decision to cover next generation sequencing in patients with advanced cancer (CAG-000450N):
“We strongly encourage continuing the studies and publishing the results of these important studies especially on the endpoints of overall survival, progression free survival, objective response, and patient reported outcomes relevant to the quality of life for Medicare beneficiaries. This is not only important to ensuring that patients, caregivers and their providers can make informed evidence-based decisions, but it also is important to continue to develop and publish results, which form the basis for the dissemination of new technologies into the healthcare system.”

Innovation in oncology data collection requires looking at the entire care of the patient from start of diagnosis to death and then drilling into to certain components that make up care to understand impact of each intervention. NGS testing is one part of care, CAR-T therapy is another component of the same care of certain advanced cancer patients. To require separate protocols when one master protocol could address both issues will increase cost of data collection and increase the time of institutions and providers. Separate protocols would duplicate IRB approval, patient consent, patient education materials, contracting, education, training of staff, reconsenting of patients, duplicated audit, etc.

Many of the patients that will be receiving CAR-T therapy may already be included in prospective, IRB-approved, consented, well designed and scientifically rigid observational studies that are collecting outcomes as is encouraged in the NGS coverage memo and which with the simple addition of a CAR-T arm could easily fulfill both purposes (NGS and CAR-T). In this broader data collection effort, the protocol should appropriately answer all the questions required by CMS for CED for CAR-T (such written analysis, publication and audit plans) but would not have to duplicate many of the other efforts that two protocols would create. In cases where a provider does not feel a CAR-T patient should have undergone NGS testing, the arm could allow this exception.

Furthermore, protocols that are only looking at CAR-T therapy as one specific point of care will miss patients who may have not opted to receive this treatment thereby discouraging a control arm in the Medicare population and only allowing an indirect comparison of Medicare patients to clinical trial patients which will never completely answer the question of how does CAR-T therapy impact the care of Medicare beneficiaries. In as much as CAR-T is a technology that will likely be introduced in many areas of solid tumors, CMS should support data collection efforts whose purpose is to understand the entire care of a Medicare patient and which can be used to answer multiple questions.

Consideration 2
Consider innovative methods of collecting patient reported outcomes especially in the time right after treatment.

Patient reported outcomes are crucial to understand the full impact of a treatment in a given patient. Yet, the tools that exist and are listed in the draft decision memo are cumbersome and may miss many of the questions that are most crucial to be answered in the time period shortly after treatment (neurotoxicity, cytokine release syndrome, prolonged hospitalizations, impact on larger family groups, financial toxicity, etc.). CMS should be willing to consider focused efforts to collect most crucial patient report outcomes surrounding CAR-T therapy. These efforts would collect specific items more frequently than the interval listed in the coverage memo. Rather than casting a broad net occasionally, a more focused approach will likely give better understanding.

Sincerely,

Dane J. Dickson MD
CEO | Taproot Health
Director Precision Medicine Policy and Registries | Knight Cancer Institute at Oregon Health and Science University

Less

Jeff Allen, PhD
1800 M Street NW
Suite 1050 South
Washington, DC 20036

March 17, 2019

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850

Re: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Jensen,

Friends of Cancer Research (Friends) is an advocacy organization based in Washington, DC that drives collaboration among partners from every healthcare sector to power advances in science, policy, and regulation that speed life-saving treatments to patients. During the past 20 years, Friends has been instrumental in the creation and implementation of policies ensuring patients receive the best treatments in the fastest and safest way possible.

Friends supports the development of a National Coverage Determination (NCD) for Chimeric Antigen Receptor (CAR) T-cell Therapies for cancers as a means to ensure consistent and uniform coverage for seniors and create national policy which supports innovation of therapies with curative potential. We believe that CAR-T therapies are truly innovative treatments that have the potential to provide significant benefits to cancer patients and transform the field of oncology. Although the proposed NCD was opened to address coverage specifically for the two CAR T-cell therapies currently approved by the FDA, tisagenlecleucel-t (CTL019, Novartis) and axicabtagene ciloleucel (Axi-Cel, Kite Pharmaceuticals/Gilead), the final NCD will set an important precedent for national coverage of future cell and gene therapies and indications as well. This only emphasizes the importance of a thoughtful and thorough process to produce a carefully developed proposal and minimize unintended consequences to future innovation of cell and gene therapies.

Supporting Innovation and Expanded Indications

Cell and gene therapies are the subject of extensive research and innovation with significant advances expected in oncology over the next few years. Less than one year after its initial approval for relapsed and refractory pediatric and young adult patients with B-cell acute lymphoblastic leukemia, tisagenlecleucel-t was awarded an expanded indication in diffuse large B-cell lymphoma. In the last 6 months, since CMS conducted its search of recruiting clinical trials in the US on clinicaltrials.gov, the number of actively recruiting clinical trials, searchable by “CAR T” have expanded by 42 newly recruiting trials in the US (from 56 to 98; search criteria: CAR T, actively recruiting, interventional study, age 65+, US). Rapid progress in this field will necessitate consideration of a flexible coverage policy that facilitates continued innovation, with appropriate guardrails that protect patients and are fiscally responsible.

For example, expansion of CAR T-cell therapies into earlier lines of therapy is already being investigated. Axicapbtagene ciloleucel is the subject of a clinical trial for efficacy as a front-line therapy for patients with high risk large B-cell lymphoma (ZUMA 12). The potential benefits of earlier use of cell and gene therapies is clear: the ability to cure a patient of their cancer, eliminating the potential exposure to multiple lines of therapy with associated adverse events and burden to the patient and healthcare system from the accompanying costs. However, CAR T-cell therapy comes with its own high price tag and potentially severe side effects, including cytokine release syndrome and neurotoxicity, which must be weighed against the absence of certain evidence and in the context of other available therapies. Long-term outcomes associated with tisagenlecleucel-t and axicabtagene ciloleucel have not yet been fully established, and it will be years before long-term side effects from these technologies are adequately characterized. Innovative design of CAR T-cell therapies, which include a sort of “safety switch” for activation and combination protocols with checkpoint inhibitors to reduce CAR T-cell dosage, are already being pursued to reduce toxicities¹. Further, allogenic CAR T-cell products are being investigated to bring down the cost of manufacturing these complex products². As CAR T-cell therapies evolve to become safer and less expensive, the possibility of expansion to frontline therapy becomes possible and CMS should prospectively construct a flexible coverage policy to adapt and maintain appropriate access for seniors.

As it is proposed, the NCD will cover FDA-approved CAR T-cell therapies according to an FDA indication or as “indicated for use identified in the National Comprehensive Cancer Network Drugs & Biologics Compendium (NCCN)” and only for patients with relapsed or refractory cancer. We believe that this policy will limit expansion of CAR T-cell therapy as it is investigated for use in earlier lines of therapy. While we agree with the CMS determination in the proposed NCD that the full benefit of CAR T-cell therapies in earlier lines of therapy has not yet been shown, there are active studies investigating these exact questions. Continued patient access to CAR-T therapies following initial approval will be essential to support ongoing evaluation, with Medicare coverage being an important component of ensuring access. Should the evidence supporting such use become available, flexibility will be needed in the coverage policy to allow for expansion of coverage to include earlier lines of therapy without necessitating formal re-evaluation of the NCD. The two FDA approved CAR T-cell therapies, tisagenlecleucel-t and axicabtagene ciloleucel, are indicated for the ”treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.” Therefore, we recommend eliminating the criteria that limits coverage to only patients with relapsed or refractory cancer. We do not believe that this change in language would lead to inappropriate or unnecessary coverage but would, instead, leave sufficient flexibility within the coverage policy to provide adequate coverage of CAR T-cell therapies as FDA approvals or NCCN Compendia potentially expand to support use in earlier treatment settings.

Protecting Patient Access

Cell therapies are extremely complex biologic products. They are comprised of genetically altered, whole cells which make them difficult to fully characterize and complicated to manufacture. In the case of CAR T-cell therapies, manufacturing involves modification of a patient's own cells, adding another layer of complexity and difficulty to the manufacturing process because the starting material is highly variable. Indeed, every CAR T-cell product is different because the cells collected from each patient, are different in quantity and quality, which impacts the efficiency of the production process. Optimization of the complex manufacturing process for CAR T-cells, then, could impact the clinical performance of the therapy. There are potential opportunities for optimization in the multistep manufacturing process for CAR T-cell therapies that impact the final product. For example, there is an ongoing phase II clinical trial in the US to investigate the efficacy of CAR T-cell products with different ratios of CD4+:CD8+ CAR T cells in the final product^3,4. This would result in an additional manufacturing step. Results of other, albeit early, research suggests that the efficacy of CAR T-cell therapies could be increased by reducing the extent of T-cell exhaustion that occurs during the T-cell activation step of manufacturing⁵. If manufacturing optimization results in a more effective product, through higher ratios of more efficacious cells, patients will ultimately benefit from requiring reduced doses of CAR T-cells, which correlated to the severity of side effects in patients with high disease burden^3,6.

Friends has concerns that the proposed NCD requirement to limit coverage to use of CAR T-cell therapies “according to an FDA indication” will unintentionally limit manufacturing improvements and impact patient access to safer doses of CAR T-cell therapies. The FDA-approved package insert for axicabtagene ciloleucel suggests that a “target dose is 2 × 106 CAR-positive viable T cells per kg body weight, with a maximum of 2 × 108 CAR-positive viable T cells” and, for tisagenlecleucel-t, the package insert recommends infusions with “0.6 to 6.0 x 108 CAR-positive viable T cells”. A strict interpretation of the language “according to an FDA indication” could result in a dose comprised of fewer cells than is listed on the package insert being considered off-label and noncovered under the proposed NCD. Further, flexibility in the treatment regimen for CAR T-cell therapies is necessary as the health and condition of each patient varies, requiring adjustments to clinical care that may not fall in line with the exact directions for use on the CAR T-cell therapy label. Clarity will be needed from CMS regarding this proposed requirement and we recommend that CMS explicitly state that the dose or number of cells used to treat a patient less than recommended on the package insert or adjustments in the specific timing or sequence of treatment will not be considered as off-label or be noncovered.

Coverage with Evidence Development

CAR T-cell therapies are innovative technologies which are expected to provide curative benefit and were awarded Breakthrough Therapy Designation due to the demonstration of substantial improvement over existing therapies. However, both sponsors were awarded FDA approval based upon demonstration of significant response rates and the long-term durability of response and adverse events are unknown. CMS must balance the level of evidence to support an evaluation of “necessary and reasonable” with patient access, particularly in relapsed or refractory patients with no or limited treatment options. Friends is encouraged to see the requirement of coverage with evidence development (CED) for CAR T-cell therapies in the proposed NCD which will ensure patient access and support continued generation of evidence as it relates to the Medicare population.

As part of CED, CMS has stipulated that CAR T-cell furnishing hospitals collect data on overall survival (OS), days to disease progression, and days to recurrence, and progression-free survival (PFS) for all registry patients for 2 years. There are certain challenges with collection of clinical measures in registries, particularly for determining progression events, which requires regularly scheduled assessments to consistently and accurately detect, and OS as it relates to CAR T-cell therapies where data collection is required for only 2 years. For example, the JULIET study demonstrated 43% probability of overall survival for patients receiving tisagenlecleucel at 18 months. A registry that monitors patients for only 2 years will not track patients long enough to determine PFS or OS. Both sponsors of the CAR-T therapies have committed to extensive, long-term post-market surveillance to collect data on more traditional clinical endpoints, such as OS, and CMS could consider utilizing the sponsor’s post-market commitments to support continued generation of evidence for use in and access of the Medicare population to these therapies, as opposed to requiring clinical sites to collect through registries. For example, Novartis has announced a collaboration with the Center for International Blood and Marrow Transplant Research (CIBMTR) for long-term tracking of patient outcomes after treatment with Kymriah⁷. CMS could consider allowing use of data collected by CIBMTR or similar registries to fulfill CED data reporting requirements.

Patient-Reported Outcomes for CED

Across the US healthcare system, entities are increasingly interested in providing quality and value-based care for patients. In tandem with this increased interest, access to data about patient experience is also becoming more important. Patient-reported outcomes (PROs) are the gold standard for measuring how patients feel and function as well as their experiences with treatment and underlying disease. Incorporation of PRO data when evaluating products is an essential step to supporting more informed use and a comprehensive assessment of their benefits and risks.

PRO data may be particularly valuable for cell and gene therapies and treatments for ultrarare indications where robust clinical trial data are difficult to obtain, and patient centricity is vitally important to development and patient access. While collection of PROs and other patient experience endpoints does not resolve the difficulty of conducting trials in these populations, they contribute additional empirical evidence regarding these therapies. This may be particularly important for quantifying overall health benefits in the Medicare population, who by simple life expectancy may not experience the same duration of survival as younger patients independent of any prior cancer diagnosis.

Typically administered in the form of a questionnaire, general and disease specific tools have been developed to collect PROs in clinical research and, more broadly, to inform healthcare decision-making. There are substantial ongoing efforts to integrate PROs into real-world datasets and registries, as typical EMR data cannot replace the directly reported experiences of patients. Many private entities are exploring ways to incorporate PROs into value assessments and coverage determinations. CMS has also recognized the value of these patient-centric metrics, incorporating their collection into quality reporting requirements within MACRA and the ACA. Further, the August 2018 Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) for Chimeric Antigen Receptor (CAR) T-Cell Therapy and Patient Reported Outcomes explored incorporation of PRO assessment tools into clinical trials for CAR T-cell therapies.

Friends supports the inclusion of PROs as a supporting factor in coverage decisions, particularly where they pertain to therapies designated as breakthrough by the FDA, and where health-related quality of life has the potential to be significantly improved. Indeed, incorporating PROs in assessments of transformative therapies is an important step to supporting more informed use and a more comprehensive assessment of the value they provide.

We encourage CMS to work with the patient and clinical communities to determine the most critical aspects of CAR-T therapy that would inform optimal future use and hope that CMS will consider some of the recommendations that we provide in this document. A comprehensive list of key data elements for PRO assessment can be found in Table 18. 36

Table 1: Key Data Elements to Assess Chimeric Antigen Receptor (CAR) T-Cell Therapy and Patient Reported Outcomes

Source	Clinical Outcome	Utility of Elements
Efficacy Data	Response rate (RR)	Need to demonstrate efficacy using well recognized endpoints
	Progression free survival (PFS)
	Overall survival (OS)
Clinician-Derived Safety/Tolerability	Common Terminology Criteria for Adverse Events (CTCAE)	Traditionally used signals of adverse reactions/tolerability; reported by the clinician/healthcare professional; remain important for determining tolerability and should continue to be routinely captured
Patient-Derived Adverse Event Data	Symptomatic adverse events	Suitable PRO tools should be selected that capture patient derived data concerning the impact of the adverse events of the therapy and the overall treatment burden for the patient
	Global side effect impact/bother/burden Global health status
Additional Supportive Patient-Derived Data	Physical function	Depending on the objectives of the study and the type and intensity of therapy (including known adverse events of special interest), other elements may contribute to defining the tolerability of a treatment regimen
	Other functional domains (e.g., emotional, social, role, cognitive)
	Specific key symptoms of disease (e.g., pain, fatigue, nausea, vomiting, anorexia) as single items or composite scale
Healthcare Utilization	Hospitalization rates/duration	These items may provide a more holistic healthcare view of the tolerability of a treatment for a patient and may help determine the requirements for managing medical needs
	Emergency department visits
	Supportive care medication use

PRO Collection Tools

Administration of the two FDA-approved CAR T-cell therapies, tisagenlecleucel-t and axicabtagene ciloleucel, have been restricted, as a requirement of their FDA approval, to select clinical locations with specific expertise in CAR T-cell therapies creating a setting highly amenable to post-market collection of high-quality PRO data. Some of these centers were involved in the clinical development of CAR T-cell therapies and already have experience administering PRO instruments as part of the clinical trials, with infrastructure or training for such data collection. Most other sites are academic centers with experience collecting PROs in prior trials.

Given the novelty of the technology and lack of therapy-specific PRO development, it will be necessary to identify key PRO measures and develop recommendations for standard methodologies to ensure they are collected uniformly and obtained from PRO instruments that are well-defined. In the proposed NCD, CMS identified the Patient-Reported Outcome Measurement Information System (PROMIS) and Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) as acceptable tools for collection of PROs for CED. We would like to remind CMS that, in addition to PROMIS and PRO-CTCAE, the August 2018 MEDCAC also endorsed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC—QLQ-C30, core questionnaire) and the MD Anderson Symptom Inventory (MDASI). Notably, while PROMIS and PRO-CTCAE were given an overall average score of 4.15 and 3.54, respectively, representing confidence that the tool is valid and generalizable to the Medicare population, EORTC—QLQ-C30 received a higher average score, 4.0, than PRO-CTCAE indicating that there are other tools which may be equally or more appropriate for use in the particular population. Also, both EORTC-QLQ-C30 and MDASI provide multi-dimensional assessment of patient experience of treatment burden and functioning, similar to PROMIS and PRO-CTCAE. We acknowledge the intention of CMS to ensure ease of compliance with CED and comparability of registry data through identification of specific PRO collection tools, however, we believe that limiting PRO collection to just two tools would limit the adoption, inclusion, and interpretation of data and its usefulness to address questions in the Medicare population. A more constructive approach would be to focus on the relevant concepts to collect for PRO outcomes that are most important to informing CED and developing a list of criteria for PRO collection tools that would be necessary to adequately collect the desired outcomes. Instead of endorsing specific PRO collection tools, CMS should consider the necessary characteristics that could define a CMS-approved tool to allow flexibility to address a greater range of concepts of interest applicable to CED (see below for additional discussion of relevance of timepoints when choosing PRO endpoints).

In addition to the CMS-identified characteristic that a PRO collection tool must be valid and generalizable to the Medicare population, we suggest the following characteristics to be used when designating CMS-validated PRO collection tools:

1. Enable multidimensional assessments of acute and/or long-term, depending on intended use, CAR T-cell therapy treatment burden to inform coverage.
2. Enable multi-dimensional assessments of CAR T-cell therapy on patient physical functioning to inform coverage.

The extent to which PRO collection can adequately inform CED will be dependent upon how quickly sponsors and treatment facilities are able to incorporate PRO tools into clinical trials or registry workstreams. Although PROMIS received the highest overall MEDCAC voting committee rating, PROMIS was used by only two of the 11 CAR T-cell clinical trials identified during the MEDCAC meeting that were collecting PROs and only two used PRO-CTCAE⁹. Further, PROMIS is a computer adapted testing (CAT) tool with a companion short form whose scoring is not yet well defined, which will complicate interpretation of data. Conversely, nine of the 11 trials at the time of the MEDCAC used EORTC-QLQ-C30. CMS should allow greater flexibility in acceptable PRO tools, through publication of characteristics of acceptable collection tools, to include instruments that are more widely used in clinical trials. This will increase the ability of sponsors and treatment centers to comply with the collection requirements and interpretability of outcomes data.

Last, we would like to point out that 7.7% of Medicare beneficiaries have limited English proficiency, according to 2014 data¹⁰. Of the two PRO tools endorsed in the proposed NCD, only PRO-CTCAE is available in multiple translations. CMS should ensure that the PRO tools accepted for use for CED are available in multiple languages that will best characterize the Medicare population.

PRO Collection Methodology

In developing guidelines for PRO collection, CMS should consider previous studies of CAR T-cell therapies to identify the most appropriate and feasible methodologies and endpoints. Since CAR T-cell therapies are expected to have curative effects, methodology for PRO collection should consider that adverse events associated with the therapy could span many years and, thus, may differ depending upon temporal relationship to the time of administration. Design considerations should distinguish between short-term and long-term adverse events in endpoint design, PRO item selection, data collection, and analysis. Further, frequency of collection should be often enough to catch relevant events without burdening the facility or provider responsible for collection and be feasible for collection in the community oncology setting as well. CMS suggested a protocol for collection of PROs to occur at baseline, treatment, and follow-up at 3, 6, 12, and 24 months after treatment administration. However, a three-month lag in PRO collection after treatment initiation will miss key events associated with immediate toxicity associated with treatment (neurological toxicity and cytokine release syndrome) especially when accounting for the possibility that registries may have missing data. We encourage CMS to consider more consistent collection before, during and immediately following active treatment to most accurately assess the patient experience during the acute phase of treatment. Further, because of the expectation of the curative effect of cell therapies, two years of follow-up will likely be insufficient to capture long-term events associated with CAR T-cell therapies or long-term quality of life, a metric which will be of increasing importance as cell therapies become a new treatment paradigm. As such, we encourage extending the long-term follow-up requirements to be more aligned with the long-term patient experience. For monitoring of late toxicities, an approach in which immediate post-treatment questionnaires are administered monthly during the initial 6 months, then spaced out every 6 months for three years, and then annually, is consistent with commonly used approaches. In contrast, during active therapy, weekly PRO collection is more appropriate.

Nonetheless, there is at present a lack of empirical evidence to suggest the benefits of any particular assessment schedule for questionnaires, except that have arisen for research in related contexts, where approaches vary widely. Therefore, timing should be dictated by planned analyses of the data, patient burden, and feasibility of administration. We recommend a protocol that balances consistent collection of PROs in the immediate phase after treatment, at least bi-weekly for the first 12 weeks, followed by less frequent intermediate timepoints at 6- and 12-months post-treatment. Finally, long-term surveillance should be collected yearly starting at 2 years and continuing for 3 years. Timing of questionnaires should be standardized with mechanisms for monitoring compliance and backup data collection when patients do not provide their PROs on schedule.

In addition to considering the timing for PRO collection, CMS should provide some guidance regarding the specific PROs to be collected and how that might vary depending upon proximity of collection to the actual treatment administration. For example, while the adverse events of greatest concern during or immediately following treatment with a CAR T-cell therapy include neurotoxicity and cytokine release syndrome, measuring for these acute side effects may not be appropriate as patient survival extends months and even years past treatment. Long-term survival measures, conversely, should be concerned with the durability of effect of the treatment and patient’s overall quality of life. Therefore, the PRO measures to be collected should be identified that are most appropriate to address relevant questions at the applicable timepoint. This will require a certain level of flexibility within the CED requirements since this methodology will necessitate collection of different PROs and possibly even use of different PRO collection tools at different timepoints.

To assist towards implementation, Appendix 1 includes a list of specific PROs that are common or impactful during treatment with CAR-T therapies, and how MEDCAC-endorsed PRO tools can help measure the symptoms.

Data Collection Infrastructure

The requirements for PRO data reporting, given that administration is limited to a select number of specialized clinical locations, should be relatively straightforward during treatment and the acute phase. However, extended assessment periods required in the proposed NCD will expand data reporting requirements into different care settings. It will be important for CMS to consider CED policies which account for continuity in data collection that could experience disruptions as patients transition from hospital inpatient to outpatient settings or from academic medical centers back into routine care. Oncologists in routine practice, including standard practice and community oncology practices, are less likely to have experience with PRO collection and fewer resources to devote to administration of PRO instruments. CMS should allow flexibilities in PRO tool selection and use of additional resources, such as use of third-party vendors, to support the extended assessment requirements and reduce financial and resource burdens placed on practices in those settings. Electronic data collection (ePRO) is optimal and will facilitate real-time monitoring of compliance for backup data collection and easy data transfer. A number of vendors offer stand-alone ePRO software for data collection, and increasingly electronic health record (EHR) systems offer tools for collection of PRO data within the EHR or accompanying patient portals. CMS could require reporting of PRO data from either source into a patient registry that would provide high-quality and consistent data that would not be onerous to report.

Use of PROs to Inform Coverage Determinations

CAR-T therapy has long been anticipated to revolutionize medicine. Even since its approval for relapsed and refractory pediatric and young adult patients with B-cell acute lymphoblastic leukemia in 2017, tisagenlecleucel-t has already been awarded an expanded indication in diffuse large B-cell lymphoma which occurs most frequently in individuals over 60 years of age. CMS should keep in mind that the evidence to support the appropriate use of these products will continue to evolve over the therapy’s lifecycle and the policies associated with their use should be flexible to incorporate emerging data. Considering that median OS is expected to be extended by a number of years, well beyond the usual scope of a clinical trial, patient access to CAR-T therapies in the post-market setting will be essential to support ongoing evaluation of these technologies, as additional indications expand into the Medicare population. PROs will be an important metric in this ongoing surveillance to ensure a holistic approach to performance evaluations, including:

1. Determining appropriate patient populations
2. Expanding indications
3. Considering new care settings
4. Informing long-term value

In the proposed NCD, PRO collection is required only for FDA-approved CAR T-cell therapies with FDA indications in the out-patient but not in-patient setting or for FDA-approved CAR T-cell therapies with uses listed in NCCN compendia. PROs will be important metrics for informing coverage as new patient populations and new uses of CAR T-cell therapies are identified and we support this requirement. However, since the long-term effects of CAR T-cell therapies are expected to last years, well beyond that of a clinical trial and as the patient transitions back into routine care, the impact of treatment setting will also be relevant to studying long-term effects and should also be included as a consideration in PRO collection requirements. Therefore, we support the collection of PRO information in both the out-patient and inpatients setting. In addition, given the novelty of these therapies, we believe that this NCD provides a unique opportunity to collect clinician reported and patient reported outcomes, as the conclusions from each may not necessarily be the same. Further, special considerations will be needed due to the individualized nature of CAR T-therapy manufacturing. Specifically, little is currently being collected to assess the potential impact that product or process changes have on health outcomes. PRO data could be used to monitor technology progression for changes in patient experience and health outcomes that may not otherwise be identifiable due to the extended timeline of surveillance and coordinated data-sharing infrastructure needed. As the manufacturing process is improved and yields safer, more efficacious therapies and evidence evolves to demonstrate the value of cellular therapy over other treatment options, this may change patient/provider calculations and shared medical decision-making. CMS should consider following the potential impact of manufacturing changes through a CED registry question.

Conclusion

We hope that CMS will consider the recommendations made in this document and look forward to further inform discussions with the agency.

Sincerely,

Jeff Allen, PhD
President & CEO
Friends of Cancer Research

Acknowledgements

Friends would like to thank the following individuals for their contributions to the development of and providing their expert advice to this consensus document: Ethan Basch, Alicyn Campbell, Stacie Hudgens, Allison Leahy, and James Wu.

Appendix 1: CAR-T Applicable PROs and their representation in MEDCAC-approved tools

Concepts	Symptom	Short Term (2 months)	Long Term (1+ years)	Item	Response format, basic scoring
Adverse Events (AE)/Toxicity
AE/GI	Nausea	X		EORTC: Have you felt nauseated? MDASI: Your nausea at its WORST? PRO-CTCAE: Nausea	4 pt likert scale, scored as single item 11 point NRS F(Frequency), S (severity)
	Vomiting	X		EORTC: Have you vomited? MDASI: Your vomiting at its WORST? PRO-CTCAE: Vomiting	4 pt likert scale, scored as single item 11 point NRS F, S
	Diarrhea	X		EORTC: Have you had diarrhea? PRO-CTCAE: Diarrhea	4 pt likert scale, scored as single item F
	Constipation	X		EORTC: Have you been constipated? PRO-CTCAE: Constipation	4 pt likert scale, scored as single item S
	Anorexia	X		EORTC: Have you lacked appetite? MDASI: Your problem with lack of appetite at its WORST? PRO-CTCAE:	4 pt likert scale, scored as single item 11 point NRS S, I (Interference)
AE/CRS	Fever, Chills	X		PRO-CTCAE: Chills Increased sweating Hot flashes Heart palpitations	F, S F, S F, S F, S
	Edema	X		EORTC: Have you experienced any swelling in certain parts of your body (e.g. ankles, legs or around your eyes)? PRO-CTCAE: Swelling	4 pt likert scale, scored as single item F, S, I
AE/Constitutional	Fatigue	X		EORTC: Were you tired? MDASI: Your fatigue (tiredness) at its WORST? PRO-CTCAE: Fatigue	-4 pt likert scale, scored as single item -11 point NRS S, I
	Myalgia	X		EORTC: Have you felt weak? Have you had pain? Did pain interfere with your daily activities? PRO-CTCAE: Muscle pain	-4 pt likert scale, scored as single item F, S, I
	Arthralgia	X		EORTC: Have you had pain? Did pain interfere with your daily activities? PRO-CTCAE: Muscle pain Joint Pain	-4 pt likert scale, scored as single item F,S,I F,S,I
AE/CNS	Headache	X		PRO-CTCAE: Headache	F,S,I
	Tremor	X
	Dizziness	X		PRO-CTCAE: Dizziness	S, I
	Confusion	X		EORTC: Have you had difficulty remembering things? MDASI: Your problem with remembering things at its WORST? PRO-CTCAE: Concentration Memory	-4 pt likert scale, scored as single item -11 point NRS S,I S,I
	Aphasia	X		EORTC: Have you had trouble finding the right words to express yourself? Did you have difficulty speaking? Did you have trouble communicating your thoughts?	-4 pt likert scale, scored as part of a 3 item communication deficit sub-scale
	Insomnia	X		EORTC: Have you had trouble sleeping? MDASI: Your disturbed sleep at its WORST? PRO-CTCAE: Insomnia	-4 pt likert scale, scored as single item -11 point NRS S, I
	Anxiety	X		EORTC: Did you feel irritable? Did you feel depressed? Did you feel tense? Did you worry? MDASI: Your feeling of being distressed (upset) at its WORST? Your feeling sad at its WORST? PRO-CTCAE: Anxious Discouraged Sad	-4 pt likert scale, scored as single item -11 point NRS F, S, I F, S, I F, S, I
AE/Respiratory	Dyspnea	X		EORTC: EORTC: Were you short of breath? 3 item scale: (1) Were you short of breath when you rested? (2) Were you short of breath when you walked? (3) Were you short of breath when you climbed stairs? MDASI: Your shortness of breath, at its worst? PRO-CTCAE: Shortness of breath	4 pt likert scale, scored as single item. ____ 4 pt likert scale, scored as multi-item subscale 11 point NRS S, I
	Cough	X		EORTC: How much did you cough? PRO-CTCAE: Cough	4 pt likert scale, scored as single item. S, I
General Symptom (disease or treatment)	Pain	X		EORTC: Have you had pain? Did pain interfere with your daily activities? MDASI: Your pain at its WORST? PRO-CTCAE: General pain Muscle pain Joint pain	4 pt likert scale, scored as single item. -11 point NRS F, S, I F, S, I F, S, I
Physical Function		X		(EORTC) Do you have any trouble taking a long walk? Do you have any trouble taking a short walk outside of the house? Do you need to stay in bed or a chair during the day? Do you need help with eating, dressing, washing yourself or using the toilet? MDASI (interference scale items)	-4 pt likert scale, scored as single sub- scale -11 point NRS
Instrumental Activities of Daily Living (IADLs)		X		Role Function (EORTC) Have you had difficulty in concentrating on things, like reading a newspaper or watching television? Were you limited in doing either your work or other daily activities? Were you limited in pursuing your hobbies or other leisure time activities?	-4 pt likert scale, scored as single sub- scale
Disease-related symptoms
Psychosocial Impact		X	X	EORTC: Has your physical condition or medical treatment interfered with your family life? Has your physical condition or medical treatment interfered with your social activities?	4 pt likert scale
Financial		X	X	Has your physical condition or medical treatment caused you financial difficulties?	4 pt likert scale

---

1 Duong MT, Collinson-Pautz MR, Morschl E, et al. Two-Dimensional Regulation of CAR-T Cell Therapy with Orthogonal Switches. Mol Ther Oncolytics 2019 (in press).
2 Gouble A, Philip B, Poirot L, et al. In Vivo Proof of Concept of Activity and Safety of UCART19, an Allogeneic “Off-the-Shelf” Adoptive T-Cell Immunotherapy Against CD19+ B-Cell Leukemias. Blood 2014:124:4689.
3 Turtle CJ, Berger C, Sommermeyer D, et al. Immunotherapy with CD19-specific chimeric antigen receptor (CAR)-modified T cells of defined subset composition. Journal of Clinical Oncology. 2015;33:3006-3006. DOI: 10.1200/jco.2015.33.15_suppl.3006
4 ClinicalTrials.gov Identifier: NCT01865617
5 Long AH, Haso WM, Shern JF, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015;21(6):581-90.
6 Hay KA, Hanafi L, Li D, et al. Kinetics and Biomarkers of Severe Cytokine Release Syndrome after CD19 Chimeric Antigen Receptor-modified T Cell Therapy. Blood. 2017:130:2295-2306; doi: https://doi.org/10.1182/blood-2017-06-793141
7 https://www.cibmtr.org/NewsEvents/CIBMTR%20Novartis%20Press%20Release_9.14.18.pdf
8 Table adapted from a Friends of Cancer Research whitepaper: https://www.focr.org/sites/default/files/Comparative%20Tolerability%20Whitepaper_FINAL.pdf
9 Presentation by Ethan Basch. Medicare Evidence Development & Coverage Advisory Committee August 22, 2018. Baltimore, MD.
10 UNDERSTANDING COMMUNICATION AND LANGUAGE NEEDS OF MEDICARE BENEFICIARIES. April 2017. Office of Minority Health. Centers for Medicare and Medicaid.

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SUBMITTED ELECTRONICALLY

March 15, 2019

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

RE: Proposed National Coverage Determination for Chimeric Antigen Receptor (CAR) T-cell therapy for Cancers (CAG-0045IN)

Dear Ms. Syrek Jensen:

Kite Pharma (Kite), a Gilead Company, appreciates the opportunity to submit comments to the Centers for Medicare & Medicaid Services (CMS) in response to the proposed national coverage determination (NCD) for chimeric antigen receptor (CAR) T-cell therapy for cancer.¹ Kite is engaged in the development of innovative cancer immunotherapies, in particular, CAR and T-cell receptor engineered cell therapies. Kite manufactures YESCARTA® (axicabtagene ciloleucel), the first Food and Drug Administration (FDA) approved CAR T-cell therapy for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (transformed follicular lymphoma, or TFL). YESCARTA is currently also being evaluated as a first line therapy for high risk B-cell lymphoma in Kite clinical study ZUMA-12.

We recognize the considerable time and attention CMS has applied to understanding CAR T-cell therapy and hearing from stakeholders. We greatly appreciate your careful consideration of this unique treatment and offer the recommendations below to help improve CMS’ draft NCD which proposes to cover CAR T-cell therapy for cancer within the context of Coverage with Evidence Development (CED). We note that while our comments comprise recommendations intended to refine the proposals to implement CED for CAR T, we continue to believe that CED is not necessary for CAR T labeled indications that have been approved by the FDA. As we described in our comments submitted in June 2018² during the first comment period for the CAR T national coverage analysis (NCA), we believe that the existing and growing body of evidence (24-month follow-up and real world experience data for YESCARTA, presented below) strongly supports that CAR T-cell therapy is reasonable and necessary for Medicare beneficiaries.

That said, if CMS chooses to establish requirements under CED for coverage of CAR T, we suggest that it include recent peer-reviewed articles and abstracts that have been accepted through a peer-review process in its evidence base for the NCD. In addition, we offer the following recommendations to ensure that Medicare beneficiaries have access to this breakthrough therapy. As discussed in more detail below, we recommend that CMS should:

• Remove the CED coverage limit that restricts treatment to patients who have relapsed or refractory cancer to allow coverage for all patients with cancer who receive CAR T therapy for any FDA approved indications or indications recommended by the National Comprehensive Cancer Network (NCCN) with a Category 1 or 2 irrespective of line of therapy.
• Clarify that the determination of whether a patient is experiencing comorbidities that would preclude benefit of CAR T should be made by the patient’s treating hematologist/oncologist for both the registry under Section 3(a) and any clinical study under 3(b).
• Clarify how CMS expects the registry and clinical study design and data collection to answer the four CED questions and that investigators have broad discretion as to selecting the control group against which the CED data is collected.
• Approve qualifying registry and clinical studies on the date of release of the final NCD or provide a mechanism to ensure there are no lapses in coverage between the date that the NCD is finalized and a qualifying registry and clinical studies are approved.
• Clarify whether accreditation of a treatment provider by the Foundation for the Accreditation of Cellular Therapy (FACT) or other nationally recognized organization(s) is sufficient for meeting the facility requirements for coverage.

A. Evidence Supporting Current Use of CAR T Therapy is Strong and Growing

In its review of the current evidence base for CAR T, CMS found that “CAR T-cell therapy is a promising type of cancer immunotherapy” but identified what it considers to be significant gaps in the evidence, particularly related to the number of Medicare beneficiaries who have received CAR T therapy and the length of follow-up. We maintain that existing clinical studies demonstrate substantial improvement of health outcomes in Medicare beneficiaries treated with YESCARTA. ZUMA-1, the pivotal clinical study of YESCARTA, provides compelling evidence that YESCARTA offers a particularly substantial improvement in health outcomes for the Medicare-aged population with relapsed or refractory B-cell lymphomas.

The primary efficacy data for YESCARTA in the ZUMA-1 trial demonstrated a similar objective response rate (ORR) for patients in Phase 2 (N = 101) aged ≥ 65 years and those aged < 65 years (92% vs. 79%).³ The 12-month update of ZUMA-1 demonstrated similar outcomes for these age groups among all patients in the ZUMA-1 trial (Phase 1 and 2; N = 108). Results were as follows for patients aged 65 ≥ and those aged < 65 years: ORR, 89% vs. 80%; complete response (CR) rate, 70% vs. 54%; ongoing response rate, 48% vs. 40%, and 12-month overall survival (OS), 67% vs. 57%. Safety was also comparable for patients ≥ 65 years and those < 65 years in the 12-month update: older patients had a lower incidence of serious adverse events (AEs) (37% vs. 62%) and Grade 3 or higher infections (19% vs. 31%). A higher incidence of Grade 3 or higher neurologic events (NEs) (44% vs. 28%) was driven by events that would be expected to occur more frequently in the ≥ 65 years age group (delirium, agitation, and disturbance in attention). These data demonstrate that subjects in ZUMA-1 who would be eligible for Medicare based on their age had robust durable responses to YESCARTA that were similar to those seen in overall ZUMA-1 population.

Further, we now are able to present additional evidence via the recently published 24-month follow-up data from ZUMA-1 (see Table 1).⁴

Table 1. Comparison of ZUMA-1 12-Month and 24-Month Follow Up

	12 month (n = 101)		24 month (n = 101)
	ORR	CR	ORR	CR
Best Objective Response, %	83	58	83	58
Ongoing Response, %a	42	40	39	37

These overall data, which provide follow-up for a median of 27.1 months, showed a median OS had not been reached. In addition, 93% of patients with ongoing response at 12 months remained in response at 24 months.

A subanalysis of 33 patients with high risk features of double-expressor or high-grade B-cell lymphoma (DE/HGBCL) showed a 91% ORR and a 70% CR rate, with 48% of patients in ongoing CR. Median duration of response (DOR) for complete responders has not been reached. Safety was also consistent between the 12- and 24-month follow up analyses; no new cases of cytokine release syndrome (CRS), NEs, or Grade 5 AEs and no cases of replication-competent retrovirus or YESCARTA–related secondary cancers were reported. At the 24-month follow-up, four patients had serious AEs unrelated to YESCARTA (mental status change, myelodysplastic syndromes, and/or infections). A copy of the Lancet publication is included with these comments and we ask that CMS include these study results and study results discussed further in this letter in the evidence review for the final NCD.

A subanalysis of the ZUMA-1 24-month analysis compared patients ≥ 65 years of age and < 65 years of age. These data have been submitted for presentation at the 2019 American Society of Oncology (ASCO) Annual Meeting. The results show efficacy and safety results consistent with those observed in the 12-month analysis, thus extending and confirming the benefit of YESCARTA in the population of patients aged ≥ 65 years. Data from this analysis will be available via the ASCO website in mid-April and we plan to share it with CMS when it is made publically available.

Notably, additional independent analyses of 72 patients treated with YESCARTA at MD Anderson Cancer Center confirm the results observed in ZUMA-1.⁵ The 72 patients comprised 20 patients ≥ 65 years and 52 patients < 65 years. Thirty-one patients (43%) received YESCARTA in the context of a clinical study and 41 patients (57%) received YESCARTA in the “real world” setting. Among 67 patients evaluable for efficacy, ORR and CR for those ≥ 65 years and < 65 years were not significantly different at day 30 (ORR, 94% vs 78%; CR, 71% vs 50%). With a median follow-up of 4.19 months, the estimated median OS was 15.4 months for both groups. Safety was comparable between the two age groups with respect to incidence and severity of CRS and CAR-related encephalopathy syndrome, tocilizumab usage, length of hospital stay, and intensive care unit admission rates and DOR.

Real world experience was also examined in a retrospective analysis of data from 274 patients treated with YESCARTA across 17 academic centers in the US.⁶ The real world dataset shows a numerically higher proportion of patients 65 years and older compared with ZUMA-1 (33% vs. 25%), a higher median age compared to ZUMA-1 (60 vs. 58 years of age), and a broader range of ages treated compared to ZUMA-1 (21 – 83 vs. 23 – 76 years of age).

The real world analysis examined outcomes in patients with a median follow up of 3.9 months, compared to patients analyzed in the ZUMA-1 12-month update with a median follow up of 15.4 months (see Table 2).⁷ Efficacy and safety for patients treated in the real world and ZUMA-1, respectively, were similar, as follows: OR (81% vs. 82%), CR (57% vs. 58%), Grade 3 or higher CRS (7% vs. 13%) and Grade 3 or higher neurologic toxicity (33% vs. 31%).

Table 2. Efficacy of YESCARTA in a Real-World Study Compared to ZUMA-1 12-Month Follow Up

	Real World YESCARTA Evaluable	Real World YESCARTA	ZUMA-1 N=108
Median follow up, months	3.9	15.4
Best ORR at Day 90, N (%)	248a	201 (81)	89 (82)
Best CR at Day 90, N (%)	142 (57)	63 (58)

Safety was also comparable despite the fact that 43% of real world patients would have been excluded from ZUMA-1 based upon eligibility criteria (see Table 3). Among other exclusion criteria, 8% of patients treated in the real world had prior CD19 or CAR T cell therapy and 8% had a history of CNS lymphoma.

Safety and efficacy data for patients treated with YESCARTA in both clinical trials and the real world setting continue to be collected via long-term follow up. We recommend that CMS include the studies presented in this letter, which have been discussed in peer-reviewed articles and abstracts that have been accepted through a peer-review process, in its evidence base for the NCD.

B. Medicare Should Not Limit Coverage of CAR T to Relapsed or Refractory Cancer

CMS proposes that Medicare will cover CAR T-cell therapy for patients who:

• Have relapsed or refractory cancer; and
• Are currently experiencing any comorbidity that would otherwise preclude patient benefit.

In addition, CMS proposes that Medicare coverage will be limited to FDA-approved indications or to unapproved indications that are recommended by the NCCN with a Category 1 or 2 and only if certain provider requirements, including requirements for registry or clinical study participation, are met. CMS also proposes not to cover CAR T-cell therapy for patients who do not have relapsed or refractory cancer.

By limiting coverage to patients with relapsed or refractory cancer, CMS is peremptorily creating a barrier to future coverage for first line uses of CAR T-cell therapy that may be approved in the future. Because of this restriction physicians may be forced to select sub-optimal treatments for Medicare patients. In particular, proactively implementing a coverage restriction for FDA approved indications for CAR T therapies has the potential to create a situation where commercial, Medicaid, or otherwise ensured beneficiaries could have access to FDA approved therapies that are not available to Medicare beneficiaries.

CAR T is an entirely new therapy that is currently indicated for use in patients with refractory or relapsed cancer but is also being actively studied as a first line therapy for lymphoma patients. For example, Kite clinical study ZUMA-12 explores YESCARTA as first line therapy in high risk patients with historically poor prognosis due to gene rearrangements in the cancer cells that portend resistance to standard first-line chemoimmunotherapy. Specifically, the 2016 revision of the WHO classification for lymphomas included a new category, high grade B-cell lymphoma, which accounts for < 10% of DLBCL cases and is now considered distinct from DLBCL.^8,9 The median age at diagnosis is in the sixth to seventh decade of life.¹⁰

High-grade B-cell lymphoma includes a subcategory characterized by gene rearrangements of MYC and BCL-2 and/or BCL-6 (i.e., double- or triple-hit lymphomas, depending on the number of rearrangements present). Double-hit and triple-hit lymphomas typically do not respond to rituximab-based chemoimmunotherapy and are more likely to involve the central nervous system (CNS).¹¹ Published studies showed that 40% of patients with MYC translocations and 41% of patients with double-hit lymphoma were alive two years following first-line treatment.^12,13 Other high-risk patients eligible for treatment in ZUMA-12 are those with International Prognostic Index (IPI) score ≥ 3. Such scores were shown in previous studies to confer high risk independently from other factors (International Non-Hodgkin's Lymphoma Prognostic Factors Project 1993).^14,15 As described in a recent clinical trials planning meeting from the National Cancer Institute National Clinical Trials Network,¹⁶ patients with double- or triple-hit lymphoma have not been studied in prospective trials to date, and therefore, represent great unmet clinical need in DLBCL.

Patients with high-risk large B-cell lymphoma have an increased risk of relapse and death due to disease progression after first-line rituximab-based chemoimmunotherapy. ZUMA-12 is a Phase 2 multicenter, open-label study evaluating the safety and efficacy of YESCARTA as first-line therapy in adult subjects with high-risk large B cell lymphoma. Adult subjects in the ZUMA-12 study must have high-risk histologically confirmed large B-cell lymphoma. Approximately 40 subjects with high-risk large B-cell lymphoma, either high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 translocations (double-/triple-hit lymphomas) or high and high intermediate risk (IPI score ≥ 3) scores will be enrolled and treated with conditioning chemotherapy followed by a targeted dose of YESCARTA.¹⁷ The primary endpoint for the ZUMA-12 study is the CR rate and secondary endpoints include ORR, DOR, event-free survival (EFS), PFS, OS, AE incidence, and relapse with CNS disease. ZUMA-12 is a feasibility study of axicabtagene ciloleucel as first-line therapy which will lead to a registrational study.

If CMS finalizes the proposed non-coverage for all patients without relapsed or refractory cancer, Medicare beneficiaries without relapsed or refractory cancer would not be able to receive CAR T-cell therapy until CMS has received and completed a NCD reconsideration request. Such a revision to the NCD would take a minimum of nine months, and more likely would take over a year (e.g., to meet with CMS, prepare the request, and go through the NCA process). This would mean that Medicare patients without relapsed or refractory cancer would not have access to CAR T therapy for many months after FDA approval of an indication for patients treated in earlier lines of therapy. As a general matter, if CMS finalizes its proposal, it will need to reconsider the NCD for every new FDA approved indication outside of relapsed/refractory cancer, which means CMS could receive several NCD reconsideration requests in the next two to three years.

Kite recommends that CMS remove the coverage limitation that requires patients to have relapsed or refractory disease, particularly since other provisions of the NCD would limit coverage to only those indications which are approved by the FDA or recommended by NCCN. If CMS declines to completely remove this restriction, then we recommend that CMS allow Medicare Administrative Contractor (MAC) discretion to cover CAR T-cell therapy for non-relapsed/refractory indications. This approach would mitigate the potential for delays in patient access to CAR T-cell therapies approved for first line treatment in cancer by obviating the need for CMS to reconsider an existing NCD in order to establish coverage.

We have included as an attachment a red-lined version of the proposed NCD that shows our recommended refinements to this requirement.

C. Determination of Comorbidities That Would Prohibit CAR T Treatment Should Be Based on Discretion of the Treating Clinician

CMS proposes that Medicare coverage of CAR T will be limited to patients who are not currently experiencing “any comorbidity that would otherwise preclude patient benefit” and applies that requirement to all patients and covered uses, including those who are enrolled in a registry for FDA-approved indications under Section 3(a) of the NCD and those who are enrolled in a clinical study under Section 3(b) of the NCD for an indication recommended by NCCN. We are greatly concerned that CMS may be considering creating a list of comorbidities that would preclude coverage because the benefits and risks of CAR T therapy must be considered on an individual basis by the treating physician and the patient. Patients who are candidates for CAR T-cell therapy have complex medical conditions and have already received intense cancer treatments. The presence, severity, and combination of comorbidities that could affect whether an individual patient may or may not benefit from CAR T therapy must be considered on a patient-by-patient basis by the treating physician. By creating a list of comorbidities that would preclude coverage, CMS would also effectively be restricting coverage so that it is more restrictive than the FDA label.

The recent real-world data with YESCARTA described above underscore the importance of covering the medicine consistent with the label. 43% of leukapheresed patients¹⁸ in a real world study would have been excluded from the ZUMA-1 trial (see Table 3)¹⁹ based upon a range of criteria including thrombocytopenia, active DVT/PE, prior CD19 therapy, kidney disease, history of CNS lymphoma, congestive heart failure and prior allogeneic stem cell transplant. However, those clinical trial exclusions do not preclude patient responses in a real world setting. Notably, 47% of the patients in this real world data set achieved a CR at the three-month tumor assessment. These data suggest that determining candidacy for CAR T treatment is complex and should be determined by the treating physician on patient-by-patient basis.

Table 3. Characteristics Differentiating YESCARTA Patients in the Real-World from ZUMA-1

Criteria Excluded from ZUMA-1	N=124 N (%)
Platelets < 75	37 (13)
Active DVT/PE	27 (9)
Prior CD19 or CAR T cell therapy	24 (8)
GFR < 60	22 (8)
History of CNS lymphoma	22 (8)
Symptomatic pleural effusion	11 (4)
LVEF < 50%	10 (4)
Prior allogeneic SCT	7 (2)

The comorbidities that would prohibit treatment with CAR T per CMS include patients who were excluded from clinical trials for one or more of the following reasons: (1) the patient’s underlying disease may have made data interpretation difficult; and (2) unacceptable risk was perceived to be associated with the condition. Clinicians should be allowed to consider the benefit risk in patients with relapsed or refractory DLBCL and comorbidities, such as HBV and HCV, which could potentially be managed with antivirals, and should not be a priori excluded. Uncontrolled infection is a serious, but very treatable condition and does not necessarily preclude a patient from benefitting from CAR T-cell therapy. Autoimmune disorders remain a hypothetical risk; no evidence of exacerbation of pre-existing autoimmune disease or new onset autoimmune disease has been observed in clinical trials. Determining whether a specific condition would preclude patient benefit from CAR T therapy should be left to the discretion of the patient’s physician guided by the prescribing information in the FDA label.

As noted above, CAR T is an innovative new therapy and clinical understanding of its appropriate use is rapidly evolving. In fact, the real world data discussed in this letter shows that many patients who would not have met the inclusion criteria of ZUMA-1 do benefit from CAR T therapy. Therefore, locking in a specific list of conditions which would preclude Medicare coverage may inappropriately prevent some beneficiaries from receiving beneficial treatment. In summary, we ask that CMS allow individual clinicians to make this determination and not attempt to limit coverage based on specific comorbidities. Clinicians—specifically the hematologist or oncologist treating the patient’s cancer —are best positioned to determine whether the condition of that particular patient at the time of CAR T administration would preclude benefit from CAR T-cell therapy.

We have included as an attachment a red-lined version of the proposed NCD that shows our recommended refinements to this requirement.

D. CMS Should Clarify Expectations Related to Certain Registry/Study Design and Data Collection Elements

We believe that CMS’ intent is to confirm that real-world experience with CAR T-cell therapy is consistent with the results of clinical study data that was the basis for FDA approval and/or NCCN compendium updates and improves health outcomes of Medicare patients. We share CMS’ desire that data gathered under CED address any concerns that CMS may have about the use of CAR T outside of the controlled design of the pivot trials. If CMS finalizes the CED requirement for CAR T, we generally agree with the questions that CMS asks to be addressed and the specific data elements that are to be collected. However, there are several points that we ask CMS to clarify to ensure that the data gathered will be responsive to CMS’ questions regarding the use of CAR T and will ultimately support a NCD without CED requirements. Specifically we ask that CMS clarify the following points:

• Researchers analyzing the data collected through the required registry/clinical have discretion to choose the appropriate cohort for comparison. We ask CMS to state that matched cohorts could but do not have to be part of the data collected by the registry or clinical study and that registry/study results can be compared to pivotal trial data or other published data.
• Any expectations regarding how a study is to be appropriately powered (e.g., to show superiority, non-inferiority).
• Collection of the proposed data elements is expected to be sufficient to answer the four CED questions.
• How CMS expects to use PRO data in future coverage determinations. While these instruments will provide additional information regarding the patient experience, we are concerned that use of that data in CAR T coverage determinations may not be appropriate. Neither instrument is validated in a relapsed/refractory lymphoma population nor for use with CAR T therapies which are uniquely administered as a single infusion.
• We believe that CMS’ intent in covering CAR T under CED is to increase the quantity of clinical evidence related to patient outcomes and experience and not to withhold coverage because one or more data points may be missing for an individual patient. We are particularly concerned that patients who are unable (due to site logistics, patient impairment, or other unforeseen technical issues) or unwilling to provide PRO data not be denied treatment. We understand that CMS has addressed similar issues with other CED registries through outreach to providers and registry leaders. If any issues with missing data develop for the CAR T registry, we ask that CMS commit to working with hospitals and the registry sponsor to improve data collection efforts while continuing to provide coverage for CAR T cell therapy.
• We concur with CMS’ proposal not to require collection of PRO data for cases treated in the inpatient setting. PRO data is not currently being collected for CAR T patients in the existing registry with Center for International Blood and Marrow Transplant Research (CIBMTR) and we believe that any requirement to collect such data for CED coverage when care is provided would create inappropriate delays in approval of a qualifying registry and could create gaps where Medicare beneficiaries would not be able to receive CAR T therapy. Facilities wishing to collect PRO data could voluntarily choose to collect PRO data for a hospital inpatient.
• Specify domains of interest for PRO data and how it is expected to help CMS understand changes in “symptom function health related quality of life”. For example, with symptoms, is the interest related to fatigue? With functioning, is the interest primarily around physical functioning? How will CMS isolate the effect of CAR T on PRO data from the effect of unrelated health conditions and comorbidities that may also affect the patient’s symptoms or function and change over time?
• CMS has proposed that hospitals may use one of two PRO instruments (PROMIS or PRO-CTCAE) to report required data. We believe that the PROMIS instrument is the more appropriate of the two options and strongly encourage CMS to finalize the proposal that data collected through PROMIS will satisfy the PRO requirement.

We ask for these clarifications to ensure that the CED data collection requirement will gather meaningful evidence that will help answer the outstanding questions CMS has identified. Data collection and analysis requires devotion of significant effort and resources from providers, patients, and researchers. To the extent that CMS believes certain elements or requirements will be critical to future evidence reviews, we would prefer to know those expectations in advance. In order to assure that the proposed registry and clinical trial requirements are sufficient to answer the CED questions, we request that CMS clarify, among other things, the type of registry and clinical trial designs that will address the CED questions.

E. CMS Should Approve Qualifying Registry and/or Clinical Studies on the NCD Effective Date

In general, the CED requirements that CMS specifies in the proposed NCD are largely consistent with clinical studies already underway as part of FDA post-market requirements. Those requirements are primarily being met through a post marketing long-term follow up study, via a registry established by CIBMTR. We defer to CIBMTR about operational issues related to the registry and to the requirements for registry approval. That said, we urge CMS to approve a required registry on the same date as the final NCD is issued to eliminate the potential for gaps in coverage for Medicare beneficiaries. Should CMS not be able to approve a registry on the same date as the effective date of the NCD, we ask CMS to address how it intends to handle specific situations that may arise with CAR T patients. For example, we ask CMS to address coverage for a Medicare beneficiary who underwent apheresis prior to the release of the final NCD, but who will be infused with CAR T cell therapy after finalization of the NCD and before CMS has approved a registry. If there is a delay between the effective date of the NCD and the registry approval, we ask that CMS either 1) explicitly state that providers may choose to hold claims for CAR T-cell therapy until such time as an approved registry is available (subject to general claims processing submission requirements; or 2) explicitly state that claims submitted after registry approval but with date of service before approval of registry are covered.

F. CMS Should Adopt Provider Requirements Consistent with High Quality Care

As noted above, CAR T-cell therapy is an entirely new treatment option and we believe that it is appropriate that CMS establish certain requirements for providers who furnish this treatment to Medicare beneficiaries. However, those requirements should be consistent with provider experience for high quality clinical care while and avoiding placing unnecessary burden on CAR T providers. Currently, all of the authorized YESCARTA treatment sites are accredited by FACT. We recommend that CMS clarify that FACT or other national accreditation is sufficient for a site to qualify for coverage and that no additional attestation is necessary to confer coverage.

G. Summary

Kite greatly appreciates the opportunity to continue to engage with CMS on appropriate coverage of CAR T-cell therapy, including by offering comments on the proposed NCD. We offer the above recommendations to help ensure that Medicare beneficiaries have access to this breakthrough therapy and to ensure that, if CMS continues to believe additional evidence development is necessary to support coverage of CAR T, the evidence gathered will fully address the questions CMS has identified.

If you have any questions regarding the above comments, or if we can provide any additional information, please contact Jenna Waltersdorf at (650) 235-3215 or jenna.waltersdorf@gilead.com.

Sincerely,

\s\
Michael Amoroso
Senior Vice President and Head of Worldwide Commercial Cell Therapy
Kite Pharma

Redline of the Proposed NCD

A. The Centers for Medicare & Medicaid Services (CMS) proposes to cover autologous treatment with T-cells expressing at least one chimeric antigen receptor (CAR) through coverage with evidence development (CED) when prescribed by the treating oncologist, performed in a hospital, and all of the following requirements are met:

1. Patient has:

1. Relapsed or refractory c Cancer; and
2. not currently been experiencing any comorbidity that would otherwise preclude patient benefit, as determined by the patient’s treating hematologist/oncologist. This applies to Sections 3(a) and 3(b).

2. The hospital has:

1. a Cellular Therapy Program consisting of an integrated medical team that includes a Clinical Program Director, a Quality Manager, and at least one physician experienced in cellular therapy, and demonstrates that protocols, procedures, quality management, and clinical outcomes are consistent from regular interaction among all team members;
2. a designated care area that protects the patient from transmission of infectious agents and allows for appropriate patient isolation as necessary for evaluation and treatment; and
3. written guidelines when administering CAR T-cell therapy for patient communication, monitoring, and transfer to an intensive care unit.

3. The treatment meets the criteria in section a or b, below:

1. Treatment is an FDA-approved biological, providing targeted therapy for a known antigen expressed in the patient’s cancer according to an FDA indication in a hospital. Repeat treatment when a patient receives more than one therapeutic dose of a specific CAR T-cell product using the same biological in the same patient is covered only when a new primary cancer diagnosis is made by the treating oncologist and the patient conditions are met. In addition, all of the following requirements must be met:
   1. If the patient is administered CAR T-cell therapy in the inpatient hospital setting, then the patient must be enrolled in, and the furnishing hospital is participating in, a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, follows the patient for at least two years, adheres to the standards of scientific integrity and relevance to the Medicare population as identified in section A.4 of this decision, and answers the three following CED questions:
      • How do patient outcomes compare to either the pivotal clinical trial(s) (i.e., the clinical trial(s) that served as the basis for FDA approval of the biological and/or for the FDA indication) of the biological or a cohort of controls receiving standard of care treatment?
      • How do the clinical characteristics of registry patients compare to the pivotal clinical trial(s)?
      • How do the clinical characteristics of registry patients affect the clinical endpoints relative to those in the pivotal clinical trial(s)?
   2. If the patient is administered CAR T-cell therapy in the outpatient hospital setting, then the patient must be enrolled in, and the furnishing hospital is participating in, a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, follows the patient for at least two years, adheres to the standards of scientific integrity and relevance to the Medicare population as identified in section A.4 of this decision, and answers the four following CED questions:
      • How do patient outcomes compare to either the pivotal clinical trial(s) (i.e., the clinical trial(s) that served as the basis for FDA approval of the biological and/or for the FDA indication) of the biological or a cohort of controls receiving standard of care treatment?
      • How do the clinical characteristics of registry patients compare to the pivotal clinical trial(s)?
      • How do the clinical characteristics of registry patients affect the clinical endpoints relative to those in the pivotal clinical trial(s)?
      • How does the patient report their symptom function health-related quality of life changes over the course of their treatment?
   3. The furnishing hospital shall address the CED questions on all registry patients by tracking the following clinical data elements at baseline, at treatment, and at follow-up 3 months, 6 months, 12 months, and 24 months after the treatment is administered.
      • Age, gender and comorbidities;
      • specifics of cancer diagnosis (e.g., sub-classification, stage);
      • number(s) or line(s) of previous therapies, therapeutic agents previously administered;
      • days to disease progression;
      • days to recurrence;
      • overall survival; and
      • progression-free survival.
   4. To address a CED question on health-related quality of life, the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS®) or Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAETM) patient-reported outcome assessment must be used at baseline, at treatment, and at follow-up 3 months, 6 months, 12 months, and 24 months after the treatment is administered.
2. Treatment is an FDA-approved biological, indicated for use identified in the National Comprehensive Cancer Network Drugs & Biologics Compendium with Category 1 or 2 grade 2 or 1 on or after August 2017, and providing targeted therapy in a hospital for a known antigen expressed in the patient’s cancer. In addition, all of the following requirements must be met:
   1. Patients must be enrolled in a CMS-approved clinical study that consecutively enrolls patients and follows the patient for at least two years. The study shall adhere to the standards of scientific integrity and relevance to the Medicare population as identified in section A.4, and collect all data necessary, including health outcomes, and submit to CMS for approval a written executable analysis plan to address all of the following CED questions:
      • How do study patient outcomes compare to a cohort of controls receiving standard of care treatment?
      • How do the clinical characteristics of study patients compare to a cohort of controls receiving standard of care treatment?
      • How do the clinical characteristics of study patients affect the clinical endpoints relative to a cohort of controls receiving standard of care treatment?
      • How does the patient report their symptom function and health-related quality of life changes over the course of their treatment?
   2. The CED study shall address the CED questions on all study patients by tracking all the clinical data elements specified in A.3.a.iii-iv at baseline, at treatment, and at follow-up 3 months, 6 months, 12 months, and 24 months after the first treatment is administered.

Registries must be reviewed and approved by CMS. Potential registry sponsors must submit all registry documentation to CMS for approval including the written executable analysis plan and auditing plan. CMS will review the qualifications of candidate registries to ensure that the approved registry follows standard data collection practices and collects data necessary to evaluate the patient outcomes specified above. Registries and clinical trials approved under this NCD may have a superiority or non-inferiority design. The registry’s National Clinical Trial number must be recorded on the claim.

4. All CED studies must adhere to the following standards of scientific integrity and relevance to the Medicare population:

1. The principal purpose of the study is to test whether the item or service meaningfully improves health outcomes of affected beneficiaries who are represented by the enrolled subjects.
2. The rationale for the study is well supported by available scientific and medical evidence.
3. The study results are not anticipated to unjustifiably duplicate existing knowledge.
4. The study design is methodologically appropriate and the anticipated number of enrolled subjects is sufficient to answer the research question(s) being asked in the National Coverage Determination.
5. The study is sponsored by an organization or individual capable of completing it successfully.
6. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found in the Code of Federal Regulations (CFR) at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it is also in compliance with 21 CFR Parts 50 and 56. In addition, to further enhance the protection of human subjects in studies conducted under CED, the study must provide and obtain meaningful informed consent from patients regarding the risks associated with the study items and/or services, and the use and eventual disposition of the collected data.
7. All aspects of the study are conducted according to appropriate standards of scientific integrity.
8. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements.
9. The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Such studies may meet this requirement only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options.
10. The clinical research studies and registries are registered on the www.ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. Registries are also registered in the Agency for Healthcare Quality (AHRQ) Registry of Patient Registries (RoPR).
11. The research study protocol specifies the method and timing of public release of all prespecified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 12 months of the study’s primary completion date, which is the date the final subject had final data collection for the primary endpoint, even if the trial does not achieve its primary aim. The results must include number started/completed, summary results for primary and secondary outcome measures, statistical analyses, and adverse events. Final results must be reported in a publicly accessibly manner; either in a peer-reviewed scientific journal (in print or on-line), in an on-line publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with negative or incomplete results).
12. The study protocol must explicitly discuss beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations in the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary.
13. The study protocol explicitly discusses how the results are or are not expected to be generalizable to affected beneficiary subpopulations. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.

Consistent with section 1142 of the Act, the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that meet the above-listed standards and address the above-listed research questions.

B. Noncoverage

CMS proposes to non-cover the use of T-cells expressing at least one CAR that is not an FDA-approved biological. We propose treatment using T-cells expressing at least one CAR when cancer patients do not have a cancer that meets any of the indications noted in A.1.a of this proposed decision would be covered at the discretion of the Part A/B Medicare Administrative Contractors non-covered. We propose treatment using T-cells expressing at least one CAR when not indicated in A.2.a or A.2.b of this proposed decision would be non-covered.

C. Other

This policy continues coverage for routine costs in clinical trials that use CAR T-cell therapy as an investigational agent that meet the requirements listed in NCD 310.1.

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1 https://www .cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAid=29 l .
2 Letter from Anna Griffu1, Kite to Tamara Syrek Jensen, CMS (June 15, 2018), https://www.cms.gov/medicarecoverage- database/staticpages/public-comment.aspx?comment!D=30575&Rep01tType=nca.
3 Neelapu, Locke et al. NEJM. 2017 Dec 28;377(26):2531-2544. The efficacy results for ZUMA-] referenced in this letter reflect the investigator assessed responses, as previously published.
4 Locke FL, et al. Long-tenn safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-I): a single-mm, multi center, phase 1-2 trial. Lancet Oncology, published online December 2, 2018.
5 Sano, D et al. Safety of Axicabtagene Ciloleucel CD19 CART-Cell Therapy in Elderly Patients with Relapsed or Refractory Large B-Cell Lymphoma. 2018 ASH Aonual Meeting. Abstract 96.
6 Nastoupil, LJ, Jain, MD, et al. Axicabtagene Ciloleucel (Axi-cel) CD19 Chimeric Antigen Receptor (CAR) T-cell Therapy for Relapsed/Refract01y Large B-cell Lymphoma: Real World Experience. ASH 2018. Abstract 91.
7 Nastoupil, LJ, Jain, MD, et al. Axicabtagene Ciloleucel (Axi-cel) CD19 Chimeric Aotigen Receptor (CAR) T-cell Therapy for Relapsed/Refractory Large B-cell Lymphoma: Real World Experience. ASH 2018. Abstract 91.
8 Swerdlow SH, Campo E, Pileri SA, Hal1'is NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-90.
9 Friedberg JW. How I treat double-hit lymphoma. Blood. 2017;130(5):590-6.
lO Lindsley RC, LaCasce AS. Biology of double-hit B-cell lyrnphomas. Curr Opin Hernatol. 2012; 19: 299-304.
11 Friedberg JW. How I treat double-hit lymphoma. Blood. 2017;130(5):590-6.
12 Oki Y, Noorani M, Lin P, Davis RE, Neelapu SS, Ma L, et al. Double hit lymphoma: the MD AndersonCancer Center clinical experience. Br J Haernatol. 2014;166(6):891-901.
13 de Jonge AV, Roosma TJ, Houtenbos I, Vasrnel WL, van de Hern K, de Boer JP, et al. Diffuse large Bcell lymphoma with MYC gene real1'angements: Cu!1'ent perspective on treatment of diffuse large B-cell lymphoma with MYC gene rearrangements; case series and review of the literature. Eur J Cancer. 2016;55:140-6.
14 Ziepe1t M, Hasenclever D, Kuhnt E, Glass B, Schmitz N, Pfreundschuh M, Loeffler M. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J Clin Oneal. 20!0;28(14):2373-80.
15 Staiger AM, Ziepert M, Horn H, Scott DW, Barth TFE, Bernd HW, et al. Clinical Impact of the Cell-of-Origin Classification and the MYC/ BCL2 Dual Expresser Status in Diffuse Large B-Cell Lymphoma Treated Within Prospective Clinical Trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group. J Clin Oncol. 2017;35(22):2515-26.
16 Nowakowski GS, Blum KA, Kahl BS, Friedberg JW, Baizer L, Little RF, et al. Beyond RCHOP: A Blueprint for Diffuse Large B Cell Lymphoma Research. J Natl Cancer Inst. 2016;108(12).
17 ZUMA-12 high-risk histologically confirmed large B-cell lymphoma includes the following types defined by WHO 2016: (I) Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), including Germinal center B-cell (GCB) type and activated B-cell (ABC) type; intravascular large B-cell lymphoma; T-cell/histiocyterich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBY)+ DLBCL, NOS -these subjects must also have an International Prognostic Index (IP!) score 2:3; (2) High-grade B-cell lymphoma, NOS, with an !PI score 2:3; OR (3) High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rean-angements ( double-hit or triple-hit) as determined by investigator by fluorescent in situ hybridization (FISH). Subjects must also undergo a dynamic assessment prior to em-ailment with confirmed positive interim PET17 (Deauville PET score of4 or 5) after two cycles (PET2+) ofchemoimmunotherapy as follows: 2 cycles ofa dose intense anti-CD20 monoclonal antibody and anthracycline containing regimen (e.g. DA-EPOCH-R) x 2 cycles with or without intrathecal chemotherapy at the discretion of the investigator per standard of care for double-hit or triplehit lymphoma OR 2 cycles of a standard anti-CD20 monoclonal antibody and anthracycline containing regimen ( e.g. R-CHOP) for large B-cell lymphoma with !PI score of?:3.
18 124 of286 patients who underwent leukapheresis and had available data for comparison of baseline characteristics
19 Nastoupil, LJ, Jain, MD, et al. Axicabtagene Ciloleucel (Axi-cel) CD19 Chimeric Antigen Receptor (CAR) T-cell Therapy for Relapsed/Refractmy Large B-cell Lymphoma: Real World Experience. ASH 2018. Abstract 91.

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March 15, 2019

Ms. Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: National Coverage Analysis (NCA) for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen,

I am writing to urge CMS to finalize the NCD without CED, since the CED creates an opt in/opt out issue that has been highlighted by many other stakeholders. In addition, CMS should finalize an NCD for autologous CAR-T cell therapy that is broad enough to cover future FDA-approved products for their labeled indications, leave clinical decision-making in the hands of physicians rather than create comorbidity and retreatment limitations, and should not require mandatory submission of patient-reported outcomes (PROs) measures as a condition of coverage.

Additionally, it will be critical for CMS’ coverage team and the Hospital and Ambulatory Policy Group (HAPG) to be consistent in what they consider covered services. Specifically, on page 8 of the decision memo CMS lists the following steps as part of the treatment protocol for CAR-T cell therapy for which it is considering coverage:

1. lymphocyte harvesting from the patient with cancer;
2. creation of cancer-targeting lymphocytes in vitro using various immune modulators;
3. selection of lymphocytes with reactivity to cancer antigens using enzyme linked immunoassay;
4. depletion of the patient's remaining lymphocytes using immunosuppressive agents;
5. transfusion of the cancer targeting lymphocytes back into the patient with cancer - this transfusion represents one treatment.”

If the CAG finalizes some form of an NCD as expected for CAR-T cell therapy, then the aforementioned services along with others such as laboratory cell processing services, will also be considered covered as the CAR-T protocol cannot be carried out without these services. It stands to reason then that the HAPG would also treat these services as covered. This is why it is troubling that—on March 15, 2019—CMS released Transmittal 4255, “Change Request 11216,” which states that charges for cell collection and cell processing services would be considered non-covered in some instances.

It will be enormously confusing for providers if one part of CMS issues a favorable coverage determinations for services in support of the CAR-T treatment protocol while another part of CMS instructs that the charges for some of these covered services are to be reported as non-covered when reported on an outpatient claim in support of an outpatient administration of CAR-T cell therapy but to be reported as covered charges when reported on an inpatient claim in support of an inpatient administration of CAR-T. To me this seems incongruous with institutional claims processing requirements under the purview of the National Uniform Billing Committee (NUBC).

Furthermore, it is also unclear per the Health Insurance Portability and Accountability Act of 1996’s (HIPAA) transaction claim requirements, whether CMS can even instruct hospitals to report outpatient cell collection and cell processing services—received far in advance of an inpatient admission for administration of CAR-T cell therapy —on an inpatient claim.

I am uncertain as to whether a 0111 type of bill will even be allowed to contain services with a from date two weeks in advance of an inpatient admission. It is also unclear how the hospital would be expected to bill other outpatient services that occur between the cell collection and lab processing and the inpatient administration of the CAR-T cells.

Another important question is whether CMS has the authority to instruct hospitals to report outpatient hospital Part B patient care services on an inpatient claim, when they occur more than three days prior to an inpatient admission. My understanding is that Congress has determined when Part B services can be designated as Part A services, and this occurs explicitly when the services are diagnostic and related non-diagnostic services provided up to three calendar days from the date of inpatient admission.

Hence, it appears, by definition, that Part B services provided four days or more in advance of the date of inpatient admission such as cell collection and some cell processing services would remain as Part B outpatient hospital services. It is therefore unclear under what authority CMS can instruct providers to bill in this very different manner, other than the agency’s demonstration project or innovation center authority.

As a health policy and reimbursement consultant who has worked with the provider community and CMS technical staff over the year, I respectfully request the agency to convene a technical workgroup to address these issues as soon as possible. Representation on this workgroup should be cross-functional and inter-departmental in order for CMS to assess how one group’s decisions impact another (i.e., the HCPCS coding group, the CAG, the HAPG, etc.) and—ultimately—how inconsistent messages and seemingly innocuous decisions can exponentially increase provider burden and potentially decrease patient access to care.

Clearly, CMS has the authority to decide what it will and will not cover, as well as what it will and will not pay for. The agency should however strive to make coverage, coding, and payment decisions in a manner that facilitates accurate claims reporting of all covered patient care CAR-T services with minimal provider burden.

The simplest way for CMS to achieve this goal is to assign status indicator “N” to the cell collection and cell processing codes. This will allow providers to report the services at the time they are rendered which is typically in the outpatient setting; so covered charges for covered services would be reported real-time on outpatient claims.

This will streamline provider operations and charging practices while simultaneously generating data for CMS that it will need to make future coverage decisions and to develop any new/alternative payment model. It will also allow CMS to maintain its current position of not wanting to provide separate payment for services it considers to be part of the manufacturer process.

Assigning status indicator “N” will help CMS align its coverage policies and decisions with the Coverage and Advisory Group’s (CAG) forthcoming NCA. CMS would officially state that cell collection and cell processing are covered hospital services and are separately reportable to Medicare; this will facilitate transparent data collection about services provided in specific care. This could be an easy "win" for all parties. Unfortunately, this is not what CMS released in the March 15th Transmittal 4255, “Change Request 11216” for the April 2019 Update of the Hospital Outpatient Prospective Payment System (OPPS).

By releasing what it did in the March 15th transmittal instead of assigning status “N” to cell collection and cell processing has already begun to raise many questions including but not limited to; what does CMS means by a service being covered in one setting vs another; how can CMS require the use of revenue codes in a manner inconsistent with NUBC; why is CMS going against the use of AMA CPT codes that would allow these services to be tracked which the agency considers important per the data collection requirements in the proposed decision memo, and more.

In summary, if CMS wants to make a tangible difference in reducing hospital operational and administrative burden, it will immediately recognize and allow for the separate reporting of cell collection and cell processing services as covered packaged services, and allow them to be reported on outpatient claims at the time they are rendered. Making this change should cost the agency almost nothing; nothing other than to reissue the March 15th Transmittal and reprogram it’s editor/pricer software program.

Therefore, I urge the CAG to work with the HAPG to make consistent decisions about coverage and data collection of all items and services furnished in support of carrying out a CAR-T cell therapy treatment protocol. This means allowing all covered services to be reported on hospital outpatient or inpatient claims following claims and coding transaction rules. As separate and distinct services that involve hospital resources, CMS must provide appropriate coverage (and ultimately) reimbursement CAR-T cell therapy.

Thank you for your consideration of these comments.

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Thank you for the opportunity to comment. CMS is commended for efforts to increase access to life-saving CAR-T therapy to lymphoma patients in critical need of new therapies. A decision to cover must be matched by a commitment to cover the full costs of care for both inpatient and outpatient care in order to assure access for all Medicare patients. Qualifications proposed for participating centers places appropriate emphasis on capability, but should be more explicit in how such qualifications should be met. A decision for coverage should not restrict to on-label indications, but should acknowledge and support access to CAR-T where data (as ratified by compendia listing, for example) supports new / off-label indications. Similarly, coverage should follow FDA labeling rather than impose a defined set of disease eligibility requirements ("relapsed or refractory cancer") as new therapies may demonstrate efficacy sufficient to gain approval earlier in treatment.

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March 15, 2019

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

RE: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen,

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) appreciates the opportunity to comment on Medicare’s proposed decision memorandum for Chimeric Antigen Receipt (CAR) T-cell therapy for cancers and the tremendous amount of thought that the agency has committed to this important issue.

At the OSUCCC – James, our vision is to create a cancer-free world, one person, one discovery at a time. This underlies everything we do in working to eradicate cancer through research that translates to innovative and highly targeted patient care. The OSUCCC – James is the only cancer program in the United States that features a National Cancer Institute (NCI)–designated comprehensive cancer center aligned with a nationally ranked academic medical center and a freestanding cancer hospital on the campus of one of the nation’s largest public universities. Cancer is no longer defined solely by stage and location, but rather by its biologic and genetic makeup. There is no routine cancer — it is different in each person. Working together and utilizing state-of-the-art facilities and technology, clinicians and researchers at Ohio State are speeding the development and delivery of treatments that target the molecules and markers fueling each person’s unique cancer. The OSUCCC – James is one of only 49 NCI-designated comprehensive cancer centers and one of only a few centers funded by the NCI to conduct both phase I and phase II clinical trials on novel anticancer agents sponsored by the NCI. As the cancer program’s 308-bed, adult patient care component, The James is one of the top cancer hospitals in the nation as ranked by U.S. News & World Report and has achieved Magnet® recognition, the highest honor an organization can receive for quality patient care and professional nursing practice. With 21 floors that collectively contain more than 1.1 million square feet, The James is a transformational facility that fosters collaboration and integration of cancer research and clinical cancer care.

The OSUCCC-James has been involved in the progress in understanding cancer’s biology and the successful development of immunotherapies, including conducting CAR-T clinical trials.

CAR T-cell therapy represents the best of what American innovation has to offer and it is our goal to ensure that these curative treatments are appropriately accessible to the patients they are designed to help. We believe this is also the goal of the Centers for Medicare and Medicaid Services (CMS) in developing its coverage policies. We support the comments submitted by the Alliance of Dedicated Cancer Centers (ADCC) and the National Comprehensive Cancer Network (NCCN). As such, we offer the following comments for consideration (discussed in more detail below):

• CMS should cover CAR-T therapy as a matter of course, rather than subjecting it to a National Coverage Determination (NCD)/Coverage with Evidence Development (CED). The patient benefit and legal underpinning for covering these treatments are clear.
• To the extent CMS subjects CAR-T to a coverage determination, issuing an NCD would be more appropriate than a CED.
• As providers, we would expect to be able to provide the therapy for all FDA-approved uses, as well as off-label uses when following currently established treatment guidelines for doing so. Physicians should also maintain clinical discretion, for example, to determine how comorbidities would affect a patient’s care, or when additional courses of treatment would be warranted.
• Hospitals—as noted by the Foundation for the Accreditation of Cellular Therapy (FACT)—are the providers currently equipped to ensure the safest and most efficacious delivery of CAR-T therapy.
• We are strong supporters of patient-reported outcomes (PROs) data. However, we do not believe that tying Medicare CAR-T coverage to PROs data would provide any desired benefit or be appropriate at this time. It is too early to provide any meaningful data on quality of life for patients who will have a durable response.

Thank you for your consideration of our comments.

Sincerely,

Jennifer Carlson,
Assistant Vice President for External Relations & Advocacy
The Ohio State University Wexner Medical Center
James Cancer Hospital and Solove Research Institute

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March 17, 2019

Katherine B. Szarama, PhD
Lead Analyst
Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Department of Health and Human Services
7500 Security Blvd.
Baltimore, MD 21244

Re: Proposed Decision Memo (PDM) for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Dr. Szarama:

Johnson & Johnson (“J&J”) is pleased to submit comments on the referenced PDM.

J&J is the world’s most comprehensive and broadly-based healthcare company, delivering products and services for the consumer, pharmaceutical and medical devices and diagnostics markets. For more than 125 years, we have supplied the health system with a broad range of products and have led the way in innovation, beginning with the first antiseptic bandages and sutures. We are continuing this heritage of innovation today, bringing important new pharmaceutical products to market in a range of therapeutic areas, as well as developing important advancements in medical devices and new consumer products.

In December 2017, Janssen Pharmaceutical Companies of J&J entered into a worldwide collaboration and license agreement with Legend Biotech, USA Inc. and Legend Biotech Ireland Limited ("Legend"), subsidiaries of GenScript Biotech Corporation, to jointly develop and commercialize LCAR-B38M in multiple myeloma. LCAR-B38M is a CAR-T cell therapy directed against two targeting domains on the B-cell maturation antigen (BCMA) which confers high avidity and affinity binding of the compound to the BCMA-expressing multiple myeloma cells.

We greatly appreciate the opportunity we had to meet with the Coverage Analysis Group in November 2018 to describe our CAR-T program, and we respectfully offer our comments and recommendations for your consideration regarding the following topics within the PDM. In general, our comments are intended to help ensure the final national coverage determination (NCD) can accommodate new developments in this fast-evolving therapeutic area without inadvertently delaying access to transformational treatments for Medicare beneficiaries. Our comments address the following three topics.

• Allow sufficient flexibility within the final NCD to enable appropriate utilization for products indicated for new patient populations and across all appropriate settings of care
• Allow greater flexibility for repeat treatments of patients when consistent with the clinical study protocol
• Clarify the requirements for patient-reported outcomes (PROs) to assess and maintain flexibility in PRO instruments and across settings

Allow Sufficient Flexibility Within The Final National Coverage Determination To Enable Appropriate Utilization For Products Indicated For New Patient Populations And Across All Appropriate Settings of Care

The PDM summarizes the clinical evidence for the two FDA-approved CAR T-cell products, tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™), in patients for indications currently approved by the FDA. It proposes to establish patient criteria for coverage in hospital settings consistent with these two currently approved products. If these coverage criteria are implemented in an NCD they could necessitate an additional national coverage analysis process to be initiated for future CAR T-cell products with different indications. We urge CMS to consider permitting more flexibility in the eligible patient criteria in the final coverage policy.

The PDM proposes to allow Medicare coverage under a coverage with evidence development (CED) policy for patients with relapsed or refractory cancer. While this is consistent with the FDA-approved target populations for the current products, we urge CMS to allow greater flexibility in its final CED policy for all of the FDA-approved indications (e.g., first-line therapies) for future products. Allowing coverage for additional patient populations beyond relapsed and refractory patients should also extend to CMS’ approval of clinical studies under section 3b of the final NCD.

Under the PDM, Medicare would cover CAR T-cell therapy in hospitals that meet specified requirements, including those for a nationally accredited Cellular Therapy Program. We support the focus of CMS on ensuring that providers of CAR-T cell therapy are fully qualified to manage all aspects of these treatments. However, CMS should consider whether it is necessary to also specify that future treatments should be restricted to hospitals in the final NCD. In particular, under both section 3a (CED coverage for FDA-approved indications) and 3b (CMS-approved clinical studies), CMS should allow Medicare coverage for CAR T-cell therapy in (any) sites that follow the safety protocols outlined in the PDM.

There are settings other than hospitals providing advanced cancer care that may be capable of offering CAR-T cell therapy consistent with all of the other safety requirements of the PDM. For example, outpatient infusion centers are highly skilled at providing chemotherapy and (at some centers) outpatient infusion of stem cells for Autologous transplant (ASCT) for multiple myeloma and other hematologic malignancies.

Allow Greater Flexibility For Repeat Treatments Of Patients When Consistent With The Clinical Study Protocol

According to the PDM, “Repeat treatment when a patient receives more than one therapeutic dose of a specific CAR T-cell product using the same biological in the same patient is covered only when a new primary cancer diagnosis is made by the treating oncologist and the patient conditions are met.” We are concerned that this policy limitation may be inconsistent with ensuring Medicare beneficiaries have access to the best available treatments.

For example, the clinical protocol for retreatment of patients within the trials of JNJ-68284528 provides that some patients may be considered for retreatment. There are specific criteria that must be satisfied, and we would be happy to provide specifics to CMS about the criteria and the broader retreatment protocol as needed.

We urge CMS to revise its policy related to repeat treatments in the final NCD to reflect the fact that there are patients who require re-treatment with the same CAR-T cell product for the same cancer diagnosis in order to receive maximum treatment benefit. Precluding Medicare coverage in these situations may limit access to optimal care for some patients consistent with the approved labeling or clinical trial protocol.

We recognize that the PDM would allow repeat treatment with a different second CAR-T cell therapy for the same indication. Again, this is important to provide access to optimal care when necessary.

Clarify The Requirements for Patient-Reported Outcomes (PROs) To Assess And Maintain Flexibility In PRO Instruments And Across Settings

Consistent with the FDA Patient Focused Drug Development initiative, J&J believes understanding the patient perspective within our clinical development programs is important and we support the collection of PROs. We firmly believe PRO data need to be collected with rigor, using PRO instruments validated for the specific context of use and target population. We also recognize the demand for PRO evidence demonstrating the value of new treatments continues to increase and key stakeholders often have different needs and uses.

While our thinking and measurement approach to capturing PROs continually evolves based on changing evidence needs, we are including PRO endpoints in our CAR T-cell therapy program for multiple myeloma. Our specific research objectives are two-fold: 1) to compare PROs after treatment to the individual’s reported health state prior to CAR T-cell therapy; and 2) to assess the sustained benefit over time of the individual’s perceived health-related quality of life (HRQoL) in response to treatment. We believe our measurement approach will generate robust, relevant, and timely evidence on the treatment’s effect on disease-related symptoms and impacts and overall HRQoL providing a clear evaluation of the patient perspective.

Our approach for developing a PRO strategy begins with understanding the disease, recognizing outcomes relevant to patients, identifying what to measure, followed by how best to measure these outcomes of importance.

We compliment CMS for considering the following important considerations:

• Rationale for including PROs as part of a CED
• Key PROs of interest
• Flexibility in measuring PROs
• Need to adjust a PRO measurement strategy depending on the setting of care

CMS should also provide greater clarity regarding the key PROs of interest and use consistent language throughout the final NCD. In various sections of the PDM, it states “symptom function health-related quality of life”, “health-related quality of life”, and “health-related quality of life and function”. We view these as different outcomes to assess how a patient may feel or function. Is there equal interest in each of these outcomes, with some being more proximal (symptoms) than distal (HRQoL) to the treatment’s effect, or do certain outcomes take higher precedent?

We understand why CMS proposed the PRO measurement approach outlined in the PDM regarding the use of required instruments and differences in data collection processes based on settings of care. However, we are concerned about the meaningfulness of the PRO evidence using different instruments and research methods. It is our understanding the purpose of the PRO evidence collected under the CED is to evaluate how disease-related symptoms and HRQoL may change after administration of a CAR T-cell therapy and how these changes may align with evidence generated in pivotal clinical trials.

Within the context of the CED, we would discourage the use of PRO evidence to make cross CAR T-cell therapy treatment comparisons due to potential differences in research methods. We believe all PRO evidence for a given treatment needs to be considered, including evidence both from clinical research trials and clinical practice studies. When assessing the treatment’s effect on a PRO, the rigor of the study design and strength of the evidence should determine whether findings support an association or causal relationship between the treatment and outcome. If a sponsor elects to include additional PRO instruments in a CED (e.g.,disease-specific PRO instruments), how will this evidence be viewed by CMS, particularly if the instruments are not congruent with PROMIS® or PRO-CTCAE™? In consideration of patient burden and the potential overlap of outcomes, we encourage CMS to allow disease-specific PRO instruments to be used in place of PROMIS® or PRO-CTCAE™.

We do not believe a patient’s access to CAR T-cell therapy should be restricted due to PRO data collection efforts and if a patient elects not to complete PRO instruments, this decision should not adversely affect access nor the hospital or site’s coverage and reimbursement. Our research suggests there are opportunities and challenges to adopting PROs in clinical care. Several of the first few steps to increasing effective use of PROs in clinical care are to ensure there is an appreciation for the value of PROs and to decrease barriers to their use. A key barrier to use today is the lack of clearly established practices for implementing and managing PRO data collection. Therefore, we do not believe access to CAR T-cell therapy should be restricted until the infrastructure is established to collected PROs and CMS should allow for a certain period of time for implementation. In addition, collecting PRO data can be relatively resource-intensive and we urge CMS to carefully consider an approach that does not create resource obstacles for hospitals or other sites.

In summary, we have the following requests of CMS regarding the PRO requirements in the CED: provide greater clarity on the key PROs of interest; maintain flexibility in PRO instruments and across settings; discourage CAR T-cell therapy treatment comparisons using PRO evidence collected in the CED; and ensure PRO collection efforts do not lead to patient access issues.

Johnson & Johnson appreciates the opportunity to comment on this PDM, and we hope our comments will be useful to CMS as it develops the final NCD. Please feel free to contact us if there is any further information we can provide or if you have any questions about the topics discussed in our comments.

Sincerely,

Steve Phillips
Senior Director, Global Health Policy
Worldwide Government Affairs & Policy

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March 17, 2019

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

Cc: Katherine B. Szarama, Ph.D., Lead Analyst ; Lori A. Paserchia, MD, Lead Medical Officer

RE: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-Cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen,

We the undersigned organizations are writing in response to the Centers for Medicare and Medicaid Services’ (CMS) Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N). We write today to express our concern with the potential impacts the proposed policy as written will have for Medicare beneficiary access to CAR T-cell therapy and the implications for CMS’ consideration of future innovations in treatment. We therefore ask that in the issuance of the final National Coverage Determination (NCD) policy, CMS do the following:

- Amend the policy’s language to ensure it will be consistent with continued advances in CAR T treatment: The NCD as currently written, does not take into account the continued evolution of CAR T therapies and potential future Food and Drug Administration (FDA) indications beyond relapse or refectory cancer, for which there are ongoing clinical trials. We strongly encourage CMS to ensure that the NCD will provide for coverage of CAR T products per their FDA labels as new CAR T-cell therapies come to market and new indications for therapies currently on the market are approved.

- Amend the policy’s language to ensure coverage for CAR T treatment across all potential sites of care where Medicare patients may be treated: Throughout the language of the NCD, CMS makes reference to “hospitals” as the site of service. We believe that the non-hospital setting will also serve as a necessary site of care for patients to receive CAR T-cell therapy. We understand the need to ensure that CAR T is being delivered by providers with the appropriate expertise and facility capabilities to manage the specialized treatment process and patient follow up. We believe this can be achieved through compliance with CMS’ safety criteria across hospital and non-hospital sites of care.

- Ensure patient care is not disrupted upon implementation of the NCD on May 17, 2019: We believe it is critical that sites of service involved in the delivery of CAR T be able to continue to provide care to Medicare patients while working to appropriately comply with the requirements of the NCD. In particular, we urge CMS to ensure that Medicare beneficiaries who have been deemed eligible candidates to receive CAR T prior to the implementation of the NCD not have their treatment disrupted as a result of the final policy taking effect.

Further, we urge CMS to move carefully in its consideration of the need for national coverage determination policies for future innovations that may have similar characteristics to CAR T-cell therapy (i.e., other cellular, or gene therapies). It is critical that innovation of treatments that deliver more personalized care to patients with serious diseases and produce long-term health outcomes continue to advance. Coverage policies that may hamper access to FDA-approved indications can have impacts for the research and development of future products. We acknowledge CMS’ aim in ensuring appropriate delivery of care, but this must be balanced with adaptability for the treatments coming to market that are revolutionizing the way care is delivered to Medicare patients. We look forward to continuing to work with you to ensure the timely and appropriate delivery of care and treatment. Thank you for your consideration of these comments.

Sincerely,

Arizona BioIndustry Association (AZBio)
Indiana Health Industry Forum (IHIF)
Delaware BioScience Association
Montana BioScience Alliance
BioNJ
Virginia Bio
Massachusetts Biotechnology Council (MassBio)
MichBio
BioForward Wisconsin
Life Science Washington
Maryland Life Sciences
NCBIO
SoCalBio

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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 Boulevard
Baltimore, MD 21244-1850

Dear Ms. Jensen,

We appreciate the opportunity to provide feedback as the Centers for Medicare and Medicaid Services finalize the National Coverage Decision for Chimeric Antigen Receptor T-Cell Therapies. We acknowledge the complicated nature of these therapies and the challenges of developing a universal payment and coverage policy for CAR-T cell therapy. We are commenting based on our experience as a large pediatric cell therapy center, and one of the most experienced CAR-T centers in the world.

We write from a pediatric perspective, and our concern is about pediatric and young adult populations. We see that the NCD memo acknowledges that it will directly impact patients who are 25 and younger who quality as part of the disabled Medicare beneficiary population. However, the impact will go well beyond that – details of the NCD will unquestionably affect commercial and Medicaid payor policies related to CAR-T cell therapy our patients. As leaders in the pediatric CAR-T cell space, we are particularly concerned that this decision will affect pediatric and young adult patients’ ability to access CAR T-cell therapies. Below, we discuss our points of agreement and concern with several aspects of the NCD memo.

We strongly support the proposed requirement that a hospital must have an integrated medical team consisting of a clinical program director, quality manager, and at least one physician experienced in cellular therapy. We similarly support that standards of such a program should include the Common Standards for Cellular Therapies and Standards for Immune Effector Cell Administration established by the Foundation for the Accreditation of Cellular Therapy (FACT).

The policy is missing a critical nuance in terms of PBMC (lymphocyte) collection, and reflects only practice related to the adult-indicated Kite product (axi-cel). In Section III, where it states that “lymphocyte harvesting from the patient with cancer” is inextricably linked to billing for the CAR-T cell product itself, this does not reflect pediatric practice or the way the Novartis product (tisagenlecleucel) is used in pediatric and young adult ALL. PBMC must indeed be collected, but there is substantial evidence that lymphocyte harvesting for potential future use at treatment time points when patients have been identified to have high risk disease, but have not yet received high doses of toxic therapy, is associated with an increase in T-cell expansion capability. In these cases, a patient’s leukapheresis (PBMC collection) may occur well in advance of her ever receiving a CAR T-cell product. We ask that you consider the evidence presented by Singh et. al., Science Translational Medicine, 2016. doi:10.1126/scitranslmed.aad5222. Considering this evidence, we strongly recommend the decoupling of tisagenlecleucel from the clinical leukapheresis procedure within the Q2042 code.

We enthusiastically support the decision to continue coverage for routine costs in clinical trials that use CAR T-cell therapy as an investigational agent that meets the requirements listed in NCD 310.1 without any additional regulatory requirements.

We believe that the safeguards put in place by the FDA at the time of approval provide sufficient protection for patients, including Medicare beneficiaries. We further believe that the many ongoing CAR T-cell clinical trials will provide sufficient evidence to inform future revisions to any CAR T-cell NCD. We encourage CMS to provide an NCD no more restrictive than the standards set forth by the FDA in its approval of these therapies.

At the same time, we acknowledge the critical need to gather real world data in terms of how these products are actually used on label, as outlined in the recent article by Lee et al., Biol Blood Marrow Transplant. 2018. pii: S1083-8791(18)31691-4. doi: 10.1016/j.bbmt.2018.1. This is happening now. CMS need to weigh in, but is a CED the right way to gather the data? There are several considerations:

1. Timing. Establishment of such a registry followed by a subsequent review and approval by CMS in this short timeframe may be unrealistic. Will lack of clarity on this, or an unclear or incomplete mandate, further hinder access to CAR-T?
2. Timely access. We are very concerned that this requirement will create barriers to timely access of CAR T-cell therapy for ill or unstable patients. Please provide clarification on how this risk will be mitigated.
3. Approach. If a CED is required, it is important to be aware that the CIBMTR is already gathering REMS-required toxicity data. Augmenting this approach to gather CED data, if this turns out to be the approach taken, will utilize a pathway that cell therapy centers are already implementing for CAR-T (and have been using for many years for their transplant patients).
4. Opt out. We are concerned that the ability to opt out in a voluntary CED model will create access barriers for Medicare beneficiaries. The real concern is the potential that this could provide a way for centers to avoid treating this population.
5. QOL data. Outpatient infusion, at least of tisagenlecleucel, is cost-effective and safe. We at Children’s Hospital have infused well over 250 patients with CAR-T products in our outpatient clinic. Many patients are admitted and some (~20%) are never admitted. We think the wording of the recommendation about CED QOL/toxicity data collection between infusion and possible admission greatly overstates the toxicity burden during this period. Patients who are not admitted are not experiencing meaningful side effects, and patients who experience any meaningful side effect (including any fever) are admitted. We are happy to provide our perspective on the patient experience in this time frame.

Additionally, we request a rationale of why CED data is to be gathered at the following time points: baseline, treatment, 3, 6, 12, and 24 months specifically, and think that focused data collection might differ significantly between infusion and month 3 and thereafter.

Patient-Reported Outcomes (PROs). Finally, we support CMS’s interest in collecting PROs associated with CAR T-cell treatment. However, this an area which need more specific guidance, regarding the specific PRO items to collect, tools to use, and the timing associated with each. But we ask you to remember the pediatric population. The pediatric CAR-T trials provided the first pivotal study data, which defined the field in terms of what is required to safely and effectively deliver CAR T-cell therapy. We absolutely support the collection of additional PRO data that could help us better understand their experience. However, we are concerned about the applicability of the CMS-endorsed instruments to the pediatric population.

Respectfully yours,

Claire White BSN RN
Access Services Manager
Cancer Immunotherapy Frontier Program
Children’s Hospital of Philadelphia

Allison Barz Leahy MD
Cancer Immunotherapy Frontier Program
Children’s Hospital of Philadelphia

Stephan Grupp MD PhD
Section Chief, Cell Therapy and Transplant Director, Cancer Immunotherapy Frontier Program
CCCR Director of Translational Research
Children’s Hospital of Philadelphia

Professor of Pediatrics
Perelman School of Medicine
University of Pennsylvania

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I strongly recommend for CMS to consider the absolute novel nature of CAR-T and similar therapies. These therapies have the high likelihood to be the wave of future cancer care and management. These therapies also require extensive multi-specialty expertise for some of the most complex patients. While these therapies are new and side-effects are attempting to be minimized, it is very clear that CAR-T is not an outpatient procedure. Although the therapy is giving hope to populations that had a dismal expected survival, many of these patients will require inpatient medical care. Experienced medical centers are developing assisted-management models with intensivists, as well, to ensure these patients are optimally managed.

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March 17, 2019

Lori A. Paserchia, MD
Lead Medical Officer
Evidence and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Katherine B. Szarama, PhD
Lead Analyst
Evidence and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Drs. Paserchia and Szarama:

We write in response to the CMS proposed National Coverage Determination pertaining to the coverage of Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers. We believe CAR T-cell therapy presents great potential in the future treatment of myeloma and we welcome the opportunity to respond.

Founded in 1990, the International Myeloma Foundation (IMF) is the oldest and largest myeloma-specific patient advocacy organization in the world. With more than 525,000 members in 140 countries, the IMF serves myeloma patients, family members, and the medical community. The IMF provides a wide range of programs in the areas of research, education, support, and advocacy. Multiple myeloma is the second most common form of blood cancer and it most frequently impacts individuals between the age of 65 and 74 and is currently without a cure. Because of these factors, we serve many patients who have a great interest in ensuring FDA approved CAR T-cell therapy is accessible for Medicare patients both now and as future products enter the market.

As you state, the proposal decision memo proposes to cover treatment through coverage with evidence development (CED). While IMF understands it is CMS’s intention to examine the effectiveness of this therapy, we strongly believe several aspects of this proposal could be problematic to patient access to future therapies. We believe this proposal appears to create a blanket decision for the entire future class of CAR-T therapies in other malignancies before they have ever been evaluated.

We understand these decisions are based on the two FDA approved therapies currently on the market, Kymriah and Yescarta, but we believe this approach could be shortsighted for several reasons, which we will detail below. We ultimately question whether CMS should limit patient eligibility for all future CAR Tcell therapies based on current FDA-approved therapies.

We would first like to present you with questions we have in regard to the patient eligibility requirements detailed in the proposal and the potential impact they could have on access in the future. The proposal indicates that patients would only be eligible for these therapies if they have relapsed or refractory cancer and are not currently experiencing any of the listed comorbidities (primary central nervous system lymphoma, Burkitt lymphoma, HIV/AIDS, active Hepatitis B or C, active uncontrolled infection, any autoimmune disease currently requiring immune suppression, and active grade 2 to 4 graft-versus-host disease.) While these restrictions are appropriate for existing therapies, we question whether these limitations will be suitable for future therapies. We also question how CMS will determine whether a patient has a relevant comorbidity.

Additionally, we believe it is important to address the section of the proposal that states that a patient must have a cancer that is “relapsed or refractory.” Technology is moving rapidly towards therapies that could treat cancers that are not “relapsed and refractory” and could even one day be first-line therapies. We would like to question whether new FDA-approved indications would be covered if the CAR T therapy is used treat earlier disease stages; we believe it is important to consider future scientific progress leading to expanded use of these therapies.

We would also like to address the sections addressing the barring of re-treatment unless a new primary cancer diagnosis is made. While we understand retreatment is not currently recommended for existing therapies, we again believe it could be beneficial to reexamine this policy keeping future therapies in mind. We question if the requirements for repeat treatment are truly appropriate for future therapies and implore if it is a practical to make this restriction which would also be applicable to future therapies. We also inquire whether the criteria for repeat treatments instead could be articulated in a way that requires repeat treatment to follow product labels.

We also would like to raise concern with certain requirements regarding hospital eligibility. The proposal does not appear to fully address the outpatient usage of CAR-T cell therapies, which is nearly a fait accompli. We question whether the delivery of these therapies will be covered in non-hospital settings, as many centers are already in the process of building outpatient CAR-T centers.

We thank you again for the opportunity to provide our thoughts and concerns regarding the potential future of this technology and how the language detailed in this proposal could stifle patient access to new therapies. Should you or your staff have any questions about how we believe this proposal will affect myeloma patients, or wish to further discuss our concerns, please feel free to contact me at Rlevy@myeloma.org. Our organization is happy to work with you and provide you with additional insights and perspectives from both patients and providers.

Sincerely,

Robin Roland Levy
Senior Director
Public Policy and Advocacy

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I would like to submit the following:

• It is premature for CMS to implement a national coverage decision (NCD) due to the rapidly evolving nature of the science. CMS should hold on making a coverage decision until the field matures.
• However, if CMS does finalize the NCD, we request the a NCD with registry reporting requirement without a CED. A CED may prompt some institutions to "opt out" further limiting access to Medicare beneficiaries.
• Recognize the indications for coverage are likely to extend beyond patients with relapsed or refractory cancer in the very near future. We request the indication for coverage be based on the FDA approved label.
• Please identify CIBMTR as an approved registry.
• Remove the requirement tying PROs to reimbursement for CAR-T. The selected PROs are unlikely to provide valuable information as they have not been routinely used in this population. Further, this seems to dis-incentivize administration in the outpatient since there is no rationale for why it would be pertinent only in one site of care.

Ultimately, site neutral equitable reimbursement is needed to make sure that Medicare beneficiaries have access to care. Going a step further, reimbursing NTAP at a CCR of 1.0 to make sure that institutions have access to the full NTAP payment is essential to expand the number of institutions that can offer this care without compromising ability to deliver a spectrum of care. Inadequate inpatient reimbursement and inequitable differences in site of care payments are barriers in a number of institutions throughout the US. I ask that Medicare acknowledge and address the policies that are associated with this disparity.

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The Honorable Seema Verma, Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Attention: CAG-00451N
P.O. Box 8013
Baltimore, MD 21244-8013

Re: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers; CAG-00451N

Dear Administrator Verma:

I am writing this communication on behalf of Florida Cancer Specialists in reference to the Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N) (the “Coverage Determination”).

Florida Cancer Specialists is the largest physician-owned and managed private practice in the United States with nearly 100 clinical sites in Florida, 450 health care providers, 3500 team members. Our group sees more than 75,000 new patients per year which is significantly more than most academic centers. Florida Cancer Specialists is also known as an innovative institution and has achieved nationally-recognized excellence in clinical trials. In fact we have participated in clinical trials leading to the approval of more than 85% of novel drugs in the last 5 years.

We are very appreciative of CMS’ decision in covering CAR-T therapies, however we are apprehensive with the following points:

1. CMS should not limit CAR-T site of care strictly to hospitals. Hospitals, while clearly important for some procedures and disease-state management, are known to be more expensive sites of care, and there is no clinical or scientific reason that community oncology could not perform CAR-T cell therapy. For example, we at Florida Cancer Specialists perform many dozens of highly complex phase I trials very successfully. If phase I trials were limited to hospital sites only, progress in Medicine would be severely stunned and there would be missed opportunities of saving lives and decreasing suffering. Several procedures related to the process of CAR-T cell therapy are done as outpatient and do not require hospital setting.
2. CAR-T cell therapy eligibility should have a quite more ample language so we do not box-in science progression and coverage concerns;
3. NCD should not avert CMS’ flexibility regarding forthcoming CAR-T therapies;
4. We agree with need to collect information on CAR-T therapy, however your requirements noted in the NCD are complicated and potentially very expensive to the treating physicians and or practices;

I would be more than glad to debate this issue in more detail with you and your team if you would grant me the opportunity.

Yours truly,

Lucio N. Gordan, MD
Managing Physician
President
Florida Cancer Specialists and Research Institute
6420 West Newberry Road
Gainesville, FL 32605
Phone 352-3323900
Fax 352-3325009

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March 17, 2019

VIA electronic delivery

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850

Re: Proposed National Coverage Determination for Chimeric Antigen Receptor (CAR) T-Cell Therapy for Cancers (CAG-00451N)

Dear Director Jensen:

The Pharmaceutical Research and Manufacturers of America (PhRMA) appreciates this opportunity to comment on the Centers for Medicare & Medicaid Services (CMS) Proposed National Coverage Determination (NCD) for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers, issued on February 15, 2019.¹ PhRMA is a voluntary nonprofit organization representing the country’s leading research-based pharmaceutical and biotechnology companies, which are devoted to developing medicines that allow patients to lead longer, healthier, and more productive lives. PhRMA members include manufacturers with currently approved CAR T therapies as well as several manufacturers with CAR T therapies in clinical trials awaiting submission to the U.S. Food and Drug Administration (FDA).

PhRMA appreciates CMS’ time and effort in analyzing the body of evidence, current FDA approvals, available clinical guidelines, and other information supporting the use of CAR T-cell therapies for the treatment of cancer, and we appreciate the opportunity to provide comments on the Proposed Decision Memorandum. The availability of CAR T-cell therapies reflects significant scientific advances that have been achieved in the field of cell and gene therapy, and provides a treatment option for patients that is truly life-saving in many cases.

Currently available CAR T-cell therapies are approved by FDA, included in evidence-based clinical guidelines, and supported by professional societies, clinicians, and other medical experts, as reflected in the evidence discussed in CMS’ proposed decision memorandum. Moreover, additional CAR T-cell therapy options are currently in development, providing a foundation for continued advancement toward the availability of more therapy options to address unmet medical needs for patients diagnosed with serious, life-threatening cancers.

Ensuring that Medicare beneficiaries have appropriate and timely access to existing and future CAR T-cell therapies is essential. We appreciate the steps CMS has taken to date to recognize the value of these therapies, including approval of New Technology Add-on Payments (NTAP) for existing CAR T-cell products. We encourage the agency to build on these steps through further payment reform and in the pending NCD. In these comments, we provide specific observations and recommendations for CMS’ consideration as the agency works toward a final decision for CAR T-cell therapy for treatment of cancers.

I. AS APPLIED TO CAR T-CELL THERAPIES IN THE PROPOSED DECISION, RELIANCE ON THE COVERAGE WITH EVIDENCE DEVELOPMENT PARADIGM IS UNCLEAR AND OVERLY RESTRICTIVE, AND WOULD IMPOSE UNNECESSARY BARRIERS TO ACCESS FOR PATIENTS WITH CANCER

As a threshold matter, we were surprised to see that the Proposed Decision Memo reflects a proposed reliance on the Coverage with Evidence Development (CED) paradigm for purposes of Medicare coverage for available CAR T-cell therapies. As we have stated in prior comments to CMS, CED should not apply in cases where an FDA-approved product’s use is supported by FDA labeling or is recognized as a medically appropriate off-label use under the Medicare statute and existing policy, which provide for coverage of off-label uses that are included in recognized drug compendia or by peer-reviewed literature from an appropriate medical journal.² CMS’ own “Principles governing the application of CED” also expressly state that “CED will not be used when less restricted coverage is justified by the available evidence.”³ CMS’ principles further reflect the agency’s commitment that “CED will generally expand access to medical technologies for beneficiaries.”⁴

We are concerned that reliance on the CED paradigm, as proposed, is unnecessary in the case of current and future CAR T-cell therapies that are approved by FDA, included in evidence-based clinical guidelines and recognized compendia, and supported by medical literature and other evidence. We fear that the use of CED for these therapies would impose access barriers for very sick patients, impeding their ability to receive prescribed and medically appropriate treatment for serious and life-threatening cancers.

PhRMA strongly supports research initiatives and the continued development of robust clinical evidence to help guide and inform health care decision making, via both the FDA regulatory process and development of additional real-world evidence subsequent to FDA approval. We appreciate CMS’ interest in promoting ongoing evidence development for important breakthrough therapies and scientific advances like CAR T-cell therapy. At the same time, we believe it is critical to recognize the importance of avoiding unintended obstacles to patients’ access to these treatments that can result when the goal of evidence generation is pursued via NCDs with CED restrictions.

We are concerned, as well, that CMS has previously indicated a view of the CED paradigm as an option that the agency may use to cover items and services that do not meet the “reasonable and necessary” standard under section 1862(a)(1)(A) of the Social Security Act (SSA). As a result, this proposed NCD raises important questions about how requirements for generating additional data on physician-administered drugs or biologics relates to the agency’s coverage standards under SSA section 1862(a)(1)(A). Under this section, CMS must provide coverage for items and services that are “reasonable or necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.” ⁵ The Proposed Decision Memo addresses the agency’s authority and coverage standards under Section 1862(a)(1)(A), as well as a “second statutory provision”—section 1862(a)(1)(E)—that, as stated by CMS, “may permit Medicare payment for items and services” in the case of research that is conducted pursuant to SSA section 1142 and that is reasonable and necessary to carry out the purposes of that section.⁶

Although CMS discusses and cites both section 1862(a)(1)(A) and section 1862(a)(1)(E) in the Proposed Decision Memo, it is not fully clear to what extent the agency is relying on either or both of these provisions in the context of the proposed coverage requirements for CAR T-cell therapy for cancers. In our view, section 1862(a)(1)(A) supports coverage for these therapies, and we urge CMS to clarify in any final decision memo for CAR T-cell therapies for cancer that the coverage decision is being made under section 1862(a)(1)(A).⁷ As we have stated in prior comments, in order to achieve CMS’ goal of expanded beneficiary access, CED should generally not be applied to drugs or biologicals for indications that are supported in the FDA-approved label or supported in a CMS-recognized drug compendium, because applicable statutory provisions and CMS coverage policy already support appropriate beneficiary access in such cases.⁸ Moreover, in the case of CAR T-cell therapies for cancer, CMS has already determined, in the NTAP context, that these therapies represent a “substantial clinical improvement” over previously existing therapies.⁹ CMS’ prior decision granting NTAP status for these therapies further underscores the importance of clarifying the issue of how the agency’s goals for evidence generation relate to its standards for coverage under other applicable Medicare statutory provisions.

Importantly, coverage decisions made under section 1862(a)(1)(A) can still provide for specific patient criteria, provider/prescriber criteria, and facility qualifications for purposes of coverage. Rather than imposing the restrictive CED paradigm in this determination, coverage criteria for CAR T-cell therapies can be appropriately delineated through a decision articulating the conditions under which CAR T-cell therapies are reasonable and necessary for the treatment of cancers. Such criteria can be appropriately and consistently applied to both currently available CAR T-cell therapies for cancers as well as additional products that may become available in the future. Accordingly, we ask the agency to adhere to its principles governing CED and to follow an approach that avoids the use of the CED paradigm where the available evidence supports less restrictive coverage, consistent with the statutory “reasonable and necessary” standard under section 1862(a)(1)(A).

Alternatively, however, if CMS seeks to rely on an authority other than section 1862(a)(1)(A) to make this coverage decision (e.g., section 1862(a)(1)(E) and the related requirements of section 1142), we ask the agency to clarify how it intends the exercise of this authority to inform future coverage decisions and how it is relating this authority to determinations of whether items or services are reasonable and necessary. In addition, if CMS relies on section 1862(a)(1)(E) for a final decision, the agency should provide clear guidance on when and under what circumstances CED will end and transition to coverage under section 1862(a)(1)(A).

This issue is particularly important for patients who are prescribed these therapies, and for researchers who are developing new items and services and require clarity and predictability regarding coverage standards and decision-making. t also would leave innovators and entrepreneurs with substantial uncertainty as to how their existing and pipeline products may be treated both now and in the future by CMS, particularly when CMS’ CED guidance states that CED “will not be used when less restricted coverage is justified by the available evidence.”¹⁰

The biopharmaceutical sector’s experience to date with CED or CED-like policies, combined with the agency’s apparent but vague co-reliance on Section 1862(a)(1)(A) and (a)(1)(E) as the basis for CED, elevates our concern that the nexus between CED evidence generation and coverage policy remains unclear. We are particularly concerned about the lack of clarity with respect to when a CED policy ends and transitions to a less restrictive paradigm for coverage. For these reasons, in addition to urging CMS to clarify these issues in connection with the current Proposed NCD, we also reiterate here our prior recommendation for CMS to update its underlying CED guidance to promote greater clarity in current and future NCD policies that invoke the CED paradigm.¹¹

II. CMS MUST ENSURE THAT ANY FINAL DECISION MEMO FACILITATES APPROPRIATE AND TIMELY ACCESS TO BOTH EXISTING AND POTENTIAL FUTURE CAR T-CELL THERAPIES

Regardless of the authority under which CMS may proceed for any final decision memo, the NCD, if finalized, must be drafted in a way that addresses both currently available CAR T-cell therapies and additional CAR T-cell therapies that are anticipated to become available in the future. A decision that fails to do so would create potential access gaps or delays for patients, and would lead to significant administrative burdens on the agency if a previously finalized NCD has to be reopened and revised any time a new therapy became available.

For this reason, we appreciate that the Proposed Decision Memo addresses not only the currently FDA-approved indications for available CAR T-cell therapies, but also assessed the use of CAR T-cell therapies for the treatment of other cancers. We support believe CMS’s intent is to provide coverage to FDA-label so as not to impede access, and support CMS’s proposal to provide a pathway for coverage of CAR T-cell therapies for cancers for relapsed and refractory cancers, and we further support the proposed coverage for both an FDA-approved indication as well as certain off-label indications that are recommended by the National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium with a grade 2 or 1.¹²

We note, however, two important points. First, although the current landscape of FDA-approved CAR T-cell therapies reflects approved uses for relapsed and refractory cancers, CAR T-cell therapies in clinical trials are being studied for different indications. For example, a Phase 2 clinical trial is examining the use of CAR T-cell therapy as a first-line treatment for high-risk, for Large B-Cell Lymphoma. ¹³ In addition, a review of clinicaltrials.gov reveals over 450 active or recruiting clinical trials examining CAR T-cell therapies for multiple indications and uses. As the proposed decision is currently written, many CAR-T therapies that are approved going forward could face an automatic non-coverage restriction upon FDA approval, creating an untenable situation where stakeholders (and the agency) would need to repeatedly undertake a lengthy process of revising the existing NCD or developing a new NCD in order to secure coverage. As noted, this would lead to harmful access delays for patients and significant administrative burdens for CMS. It also would conflict with CMS’ stated goal of CED expanding beneficiary access to treatments that otherwise would not be available to them.

For these reasons, we urge CMS to reassess and revise its draft “Noncoverage” language under the Proposed NCD. We believe the language can be less restrictive while also ensuring that only medically appropriate uses of CAR T-cell therapy will be covered under the policy currently and going forward. We believe this is critically important in order to ensure that appropriate and timely coverage is available to patients with respect to both currently available and potential future CAR T-cell therapies and uses that are either approved by FDA or included in statutorily recognized compendia.

Second, with respect to compendia, we note that the current Proposed NCD references only the NCCN. CMS should revise the NCD criteria to better align with existing Medicare policy with respect to coverage of off-label uses for anti-cancer treatments under Medicare Part B. Specifically, CMS should update the coverage criteria to include the full list of compendia that are recognized in the Medicare statute and listed in the CMS Internet Only Manual (IOM) Publication 100-02, Medicare Benefit Policy Manual, Chapter 15, Section 50.4.5.¹⁴ The CMS-recognized and approved compendia are as follows, in no particular order:

• American Hospital Formulary Service-Drug Information (AHFS-DI)
• National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium
• Micromedex DrugDex
• Clinical Pharmacology
• Lexi-Drugs

As an additional point, we urge CMS to clarify a process for considering the use of CAR T-cell therapies in other (non-hospital) settings going forward. The current landscape of FDA-approved CAR T-cell therapies require a Risk Evaluation and Mitigation Strategy (REMS) program,¹⁵ and these REMS programs currently require a hospital affiliation.¹⁶ However, the hospital-based restriction might not always apply for the currently available therapies, and might not be imposed on other CAR T-cell therapies that may be approved in the future. We encourage CMS to consider these possibilities and dynamics for purposes of any final coverage determination affecting access to CAR T-cell therapies. To limit the coverage of these products to only the hospital setting, without any potential for exceptions for possible other options, may create barriers that would limit patient access to care at the most appropriate site of service.

III. CMS SHOULD RELY ON INDEPENDENT, OBJECTIVE SOURCES FOR TECHNOLOGY ASSESSMENT THAT ARE MORE ALIGNED WITH THE AGENCY’S MISSION

CMS should rely on technology assessment organizations other than the Institute of Clinical and Economic Review (ICER) to inform its national coverage determinations. While ICER employs capable researchers, we are concerned that it may be an inappropriate resource for the development CMS public policy, particularly with respect to national coverage determinations, in light of perceived issues that include lack of objectivity, a lack of consistent peer review, a potential for bias in the applicable methods and agendas, and an overarching use of evidence reviews with a cost-effectiveness focus. A wide range of stakeholders that have noted that ICER’s research appears to be biased in favor of a payer perspective and fails to account for the patient perspective.¹⁷

CMS has several additional, and more suitable, resources available to meet its technology assessment needs. The Agency for Healthcare Research and Quality (AHRQ), for example, has a well-established, transparent program for methodologically rigorous technology assessment. AHRQ notes that its program “provides technology assessments for the Centers for Medicare & Medicaid Services (CMS). These technology assessments are used by CMS to inform its national coverage decisions for the Medicare program as well as provide information to Medicare carriers.”¹⁸ We urge CMS to draw on AHRQ and other, more neutral technology assessment resources in connection with any final decision memo here and for purposes of future NCD proposals and policies.

In summary, we appreciate the agency’s focus on and analysis of the evidence base supporting coverage for CAR T-cell therapies for cancer. As CMS considers its options for potentially moving forward with this NCD, we urge the agency to do so in ways that will facilitate, rather than impede, the goal of expanding beneficiary access to current and future therapies. We also urge CMS to provide the clarity and predictability needed by innovators, providers, and patients with respect to how CMS is applying the CED paradigm, and to ensure that CMS is doing so in ways that are consistent with applicable Medicare coverage requirements, policies, and evidence standards.

Thank you again for this opportunity to provide input in response to CMS’ Proposed Decision Memo on CAR T-cell therapy. We appreciate the agency’s consideration of the concerns and recommendations discussed above.

Sincerely,

Kathleen Verb
Director
Policy, Research and Membership

Amanda Pezalla
Assistant General Counsel, Law

1 CMS, Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N) (Feb. 15, 2019).
2 PhRMA Comments Re: Coverage with Evidence Development in the Context of Coverage Decisions: Draft Guidance for the Public, Industry and CMS Staff, submitted January 28, 2013.
3 CMS, Guidance for the Public, Industry, and CMS Staff: Coverage with Evidence Development (Nov. 20, 2014), available at https://www.cms.gov/medicare-coverage-database/details/medicare-coverage-document-details.aspx?MCDId=27.
4 Id.
5 SSA § 1862(a)(1)(A).
6 Proposed Decision Memo Section VIII (“CMS Analysis”) (quoting SSA section 1862(a)(1)(E)).
7 See CMS, Guidance for the Public, Industry, and CMS Staff: Coverage with Evidence Development (Nov. 20, 2014) (recognizing that certain prior CED decisions “were made under section 1862(a)(1)(A) of the Act” even though other CED decisions “have tended to rely on section 1862(a)(1)(E) of the Act”).
8 PhRMA Comments Re: Coverage with Evidence Development in the Context of Coverage Decisions: Draft Guidance for the Public, Industry and CMS Staff, submitted January 28, 2013.
9 See CMS, 83 Fed. Reg. 41144, 41283-99 (Aug. 17, 2018) (2019 final IPPS rule).
10 CMS, Guidance for the Public, Industry, and CMS Staff: Coverage with Evidence Development (Nov. 20, 2014).
11 PhRMA Comments Re: Coverage with Evidence Development in the Context of Coverage Decisions: Draft Guidance for the Public, Industry and CMS Staff, submitted January 28, 2013.
12 CMS, Proposed Decision Memo for CAR T-cell Therapy for Cancers (CAG-00451N) (Feb. 15, 2019).
13 See, National Institute of Health, U.S. National Library of Medicine, Efficacy and Safety of Axicabtagene Ciloleucal as First-Line Therapy in Participants with High-Risk Large B-Cell Lymphoma (ZUMA-12), available at https://www.clinicaltrials.gov/ct2/show/NCT03761056.
14 Medicare Benefit Policy Manual. Chapter 15- Covered Medical and Other Health Services. Table of Contents (Rev. 255, 01-25-190 Transmittals for Chapter
15. https://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Downloads/bp102c15.pdf
15 Food & Drug Administration. Approved Risk Evaluation and Mitigation Strategies (REMS). Kymriah (tisagenlecleucel). https://www.accessdata.fda.gov/Scripts/Cder/Rems/index.cfm?event=IndvRemsDetails.page&REMS=368
16 See, e.g., Kymriah© REMS Program Hospital Enrollment Form. 2018. https://www.accessdata.fda.gov/drugsatfda_docs/rems/Kymriah-2018_05_01_Hospital%20Enrollment%20Form.pdf.
17 See, e.g., The Institute for Patient Access. “The ICER Myth.” April 2018. Available at: http://1yh21u3cjptv3xjder1dco9mx5s.wpengine.netdna-cdn.com/wp-content/uploads/2018/04/IfPA_The-ICER-Myth_April-2018.pdf.
18 Agency for Healthcare Research and Quality. Technology Assessment Program. https://www.ahrq.gov/research/findings/ta/index.html. Accessed March 12, 2019.

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As the director of the Stem Cell Transplant and Cell Therapy Program at Wake Forest Comprehensive Cancer Center I am writing to echo the recommendations of ASTCT with regard to CMS policy statement in regard to CAR T-cell Therapy for cancer. At Wake Forest we have an extensive catchment area that encompasses parts of 4 states. Our patients include an underserved Appalachian population already facing extreme challenges with access to specialized healthcare. CAR T-cell therapy is revolutionary in the treatment of hematologic malignancies and has demonstrated efficacy where no other options for comparable benefit exist. It is essential that Medicare patients have equal access to this life-saving care.

I would like to submit the following:

• It is premature for CMS to implement a national coverage decision (NCD) due to the rapidly evolving nature of the science. CMS should hold on making a coverage decision until the field matures.
• However, if CMS does finalize the NCD, we request the a NCD with registry reporting requirement without a CED. A CED may prompt some institutions to "opt out" further limiting access to Medicare beneficiaries.
• Recognize the indications for coverage are likely to extend beyond patients with relapsed or refractory cancer in the very near future. We request the indication for coverage be based on the FDA approved label.
• Please identify CIBMTR as an approved registry.
• Remove the requirement tying PROs to reimbursement for CAR-T. The selected PROs are unlikely to provide valuable information as they have not been routinely used in this population. Further, this seems to dis-incentivize administration in the outpatient since there is no rationale for why it would be pertinent only in one site of care.

Ultimately, site neutral equitable reimbursement is needed to make sure that Medicare beneficiaries have access to care. Going a step further, reimbursing NTAP at a CCR of 1.0 to make sure that institutions have access to the full NTAP payment is essential to expand the number of institutions that can offer this care without compromising ability to deliver a spectrum of care. Inadequate inpatient reimbursement and inequitable differences in site of care payments are barriers in a number of institutions throughout the US. I ask that Medicare acknowledge and address the policies that are associated with this disparity.

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March 17, 2019

Seema Verma
Administrator
Centers for Medicare and Medicaid Services
U.S. Department of Health and Human Services
P.O. Box 8013
Baltimore, MD 21244-8013

Tamar Syrek Jensen
Director
Evidence and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare and Medicaid Services
7500 Security Boulevard
S3-02-01
Baltimore, MD 21244

Re: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Administrator Verma and Ms. Jensen,

On behalf of the Cancer Support Community (CSC), we appreciate the opportunity to provide comments on the proposed decision memo for chimeric antigen receptor (CAR) T-cell therapy for cancers. CSC is the largest 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. As such, CSC has a unique understanding of the cancer patient experience. Overall, we deliver more than $50 million in free, personalized services each year to individuals and families affected by cancer nationwide and internationally. We are grateful to CMS for recognizing the importance of CAR T-cell therapies in the lives of cancer patients. We also welcome the opportunity to provide these comments and raise inquiries regarding the potential impact on patients of the National Coverage Analysis (NCA).

The Centers for Medicare and Medicaid Services (CMS) has proposed to cover autologous treatment with T-cells expressing at least one chimeric antigen receptor (CAR) through coverage with evidence development (CED) when prescribed by the treating oncologist, performed in a hospital, and a host of requirements are met. Our comments below reflect our commitment to advocacy to help ensure that patients have access to affordable, high-quality, comprehensive cancer care that reflects a shared decision making process between the patient, their support network, and their oncology care team. We believe this NCA must incorporate flexibility in order to prioritize patients and ensure access to timely, appropriate treatments.

Background
CAR T-cell therapies are one way to use the body’s natural defenses to fight cancer. Thus far, two CAR T-cell therapies have been approved by the U.S. Food and Drug Administration (FDA) for patients living with certain kinds of acute lymphoblastic leukemia (ALL) and large B-cell lymphomas. Patients treated with CAR T-cell therapies typically have cancers that have relapsed, recurred, or progressed following other treatments. Patients undergoing CAR T-cell treatment are often extremely ill and may have no other options for treatment. Side effects up to and including nervous system side effects and cytokine release syndrome can be serious. We have great interest in the future of these innovative therapies, including the treatment of solid tumors and first-line therapies and ask that coverage policies do not impede patient access to future cellular therapies.

Cancer Type(s) and Stage(s)
The NCA states that the patient must have relapsed or refractory cancer and not currently been experiencing any comorbidity that would otherwise preclude patient benefit. This includes relapsed or refractory large B-cell lymphoma or relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Based on current FDA indications, contraindications, and the inclusion and exclusion criteria of published articles, these comorbidities include: primary central nervous system lymphoma, Burkitt lymphoma, HIV/AIDS, active Hepatitis B or C, active uncontrolled infection, any autoimmune disease currently requiring immune suppression, and active grade 2 to 4 graft-versus-host disease.

Based on the NCA, it is unclear how CMS will address future CAR T-cell treatments for patients with other disease states and stages. CSC supports a decision that would not preclude access to the appropriate CAR T-cell therapies for current or future cancer patients. Further, how will CMS determine whether a patient has a relevant comorbidity? Will health care providers maintain autonomy within the context of a shared decision making relationship with their patient to determine if CAR T-cell therapy is the most appropriate treatment? How will exclusion based on comorbidities be determined and tracked?

Finally, repeat treatment when a patient receives more than one therapeutic dose of a specific CAR T-cell product using the same biological in the same patient is covered only when a new primary cancer diagnosis is made by the treating oncologist and the patient conditions are met. We support coverage for additional doses as covered by FDA labels or Medicare-approved compendia.

Treatment Setting
CMS states that “CAR T-cell therapy falls under the benefit categories set for in SSA § 1861(b) “inpatient hospital services” and § 1861(s)(2)(B) “hospital services.” This may not be an exhaustive list of all applicable Medicare benefit categories for this item of service.”

The NCA states that the treatment must be administered in a hospital that has: 1) a Cellular Therapy Program consisting of an integrated medical team that includes a Clinical Program Director, a Quality Manager, and at least one physician experienced in cellular therapy, and demonstrates that protocols, procedures, quality management, and clinical outcomes are consistent from regular interaction among all team members; 2) a designated care area that protects that patient from transmission of infectious agents and allows for appropriate patient isolation as necessary for evaluation and treatment; and 3) written guidelines when administering CAR T-cell therapy for patient communication, monitoring, and transfer to an intensive care unit.

While we recognize that current standard of care largely translates to CAR T-cell therapy administration in hospital settings, CSC wants to ensure that no barriers to safe and appropriate therapies will be in place for patients who may be treated in inpatient or outpatient settings in the future. Further, how does CMS intend to monitor compliance with these standards?

Patient Experience
CSC supports the collection of data that are meaningful to patients. We believe that it is incumbent upon the FDA, industry, academic institutions, members of the health care team, patient advocacy organizations, and other stakeholders to consistently collect robust patient feedback and patient experience data at all points along the care continuum. We agree with the Institute of Medicine (2008) that it is not possible to provide high quality cancer care without assessing psychosocial health needs (Institute of Medicine, 2008). An update to the definition of “patient experience data” in the Food and Drug Administration Reauthorization Act (FDARA) of 2017 reflects the importance of measuring the patient experience as it now incorporates not only the physical but also the psychosocial impacts of a disease or condition or related therapy or clinical investigation. As the comprehensive care conversation evolves and becomes more inclusive of the patient, it is no longer acceptable limit patient assessments to disease symptoms, treatment side effects and physical functioning.

Ideally, the data gathered will contribute to the literature based regarding the full range of experiences facing cancer patients. From the perspective of psychosocial health, these data would ideally help us provide leading edge interventions. Such interventions have been proven to improve health outcomes and survival rates including improved functional status and immune biomarkers (Andersen et al., 2007), reduced emotional distress, anxiety, depression, and health related quality of life (Faller et al., 2013), and reduced recurrence and death (Andersen et al., 2008).

While we generally support the collection of data that are meaningful to patients, we also strongly encourage CMS to consider ways to ensure that the use of CED does not impede patient access to CAR T-cell therapy. For example, can we be assured that there will be a registry prepared to collect these data on May 17, 2019? If these data are not collected in their entirety at each collection checkpoint, how might this impact patients? Will there be a bridge period for patients who are undergoing CAR T-cell therapy close to May 17, 2019?

We also support the selection of a single tool with which to collect patient reported outcomes data. As written, there would be an option between Patient Reported Outcomes Measurement Information System (PROMIS) and Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). The content and intent of these tools are very different and will produce datasets and information that will not allow for scientific comparison and will dilute the strength of data across the registry. Further, both of these tools are comprehensive, dynamic, and designed for customization. How will decisions regarding appropriate items, forms, and administration? The NCA does not address what will occur if patients do not wish to participate in CED and share their data. Will they still have an opportunity to receive coverage? If so, this would violate patient self-determination and CSC strongly urges CMS to reconsider the barrier this would create for patients in need of treatment.

Finally, as noted above, this NCA would apply only to relapsed or refractory disease, which would prevent future data collection with patients with different types and stages of disease who will be treated with CAR T-cell therapies.

In closing, we appreciate the opportunity to provide comments on this NCA. We encourage CMS to incorporate flexibility into the CED process to ensure that the goals outlined in the NCA are being met, while also being sensitive to the potential impact on patients. We strongly oppose barriers in access to timely treatment for cancer patients in need of CAR T-cell therapies. We look forward to working with CMS to ensure appropriate access to care for cancer patients. If we can serve as a resource, please do not hesitate to reach out to me at efranklin@cancersupportcommunity.org or 202.650.5369.

Sincerely,

Elizabeth Franklin, LGSW, ACSW
Executive Director, Cancer Policy Institute
Cancer Support Community Headquarters

References
Andersen BL, Farrar WB, Golden-Kreutz D, et al. (2013). Distress reduction from a psychological intervention contributes to improved health for cancer patients. Brain Behavior and Immunity, 21, 953-961.

Andersen BL, Yang H-C, Farrar WB, Golden-Kreutz DM, Emery CF, Thornton LM, et al. (2008). Psychologic intervention improves survival for breast cancer patients. Cancer, 113(12), 3450-3458.

Faller H, Schuler M, Richard M, Heckl U, Weis J, and Kuffner R. (2013). Effects of psycho-oncologic interventions on emotional distress and quality of life in adult patients with cancer: systematic review and meta- analysis. Journal of Clinical Oncology, 31, 782-793.

Institute of Medicine. Committee on Psychosocial Services to Cancer Patients/Families in a Community Setting. (2008). Cancer care for the whole patient: meeting psychosocial health needs. Washington, DC: The National Academies Press.

United States Food and Drug Administration Reauthorization Act of 2017, Pub. L. 115-52, 131 Stat. 005

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Seema Verma
Administrator
Centers for Medicare & Medicaid Services
U.S. Department of Health and Human Services
P.O. Box 8011
Baltimore, MD 21244-1850

Re: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Administrator Verma:

On behalf of the University of Pennsylvania Health System (UPHS), we appreciate the opportunity to comment on the Centers for Medicare & Medicaid Services’ (CMS) Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N).

UPHS is comprised of three academic medical centers, two community hospitals and one community health system that service the city and suburbs of Philadelphia, Central Pennsylvania and Central New Jersey. Our hospitals (the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, Pennsylvania Hospital, Chester County Hospital, Medical Center of Princeton and Lancaster General Hospital) provide this region with a full spectrum of health care services – from Organ Transplantation to advanced Oncology services and treatments. Combined, we provide inpatient services to over 50,000 Medicare inpatients and over 1 million Medicare outpatients on an annual basis.

UPHS is a world leader in immunotherapy. In August of 2017, Kymriah—which was developed at UPHS—became the first CAR-T cell therapy to be approved by the FDA. Furthermore, we are site certified to administer both FDA-approved CAR T cell products, Novartis’ tisagenlecleucel (Kymriah) and Kite’s axicabtagene ciloleucel (Yescarta), and we are the only cancer center in the Philadelphia region approved to administer both Kymriah and Yescarta for patients with diffuse large B-cell lymphoma (DLBCL.) We have treated over 500 patients in CAR-T clinical trials and more than 30 CAR-T commercial products. There are clinical trials currently available at UPHS using CAR-T therapy to treat other cancers. Disclosure: The University of Pennsylvania has licensed some CAR-T cell technologies to Novartis. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives financial benefit, and some of the inventors of the technology have benefited financially and/or may benefit financially in the future.

We would like to address the following provisions of the proposed coverage determination:

• Coverage with evidence development (CED)
• Future implications of a CAR-T NCD

CAR T cells for NHL
As previously noted, two commercial products are currently approved by the FDA for treatment of patients with aggressive B-cell lymphomas, Novartis’ tisagenlecleucel (Kymriah) and Kite’s axicabtagen ciloleucel (Yescarta). Approvals were based on significant activity showing complete response rates of 40%–54% and long-term survival in many patients with highly refractory, relapsed disease (a disease or condition that does not respond to, or is resistant to other attempted forms of treatment) and with no effective treatment options. It is notable that in two large multicenter trials largely responsible for FDA approval, patients up to the age of 76 (Kite) and 77 (Novartis) were included. There was no suggestion of an impact of age in the published literature. Since the majority of patients have no effective treatment options, it has been difficult to compare this approach to other possible treatment strategies. We believe the CAR-T cells provided in this setting is a medically accepted approach and should receive Medicare coverage as such. Given the benefits seen with CAR-T therapy, we believe that limiting reimbursement for treatment only to a CED mechanism has the potential to limit access to therapy.

It is the view of UPHS that Medicare should cover CAR-T therapy for eligible beneficiaries as a reasonable and necessary service.

Coverage with evidence development (CED)
In the agency’s proposed decision memo, CMS proposes to cover autologous treatment with T-cells expressing at least one chimeric antigen receptor (CAR) through coverage with CED when prescribed by the treating oncologist, performed in a hospital, and certain other requirements are met. Of possible solutions to limited coverage, we believe that CED is a reasonable way to approach coverage for this therapy, as we currently use this model for transplant successfully. For instance, we participate in CED protocols led by the Center for International Blood and Marrow Transplant Research (CIBMTR) to collect and share patient outcomes data for the blood and marrow transplant of patients with myelodysplasia and other diseases, and those outcomes are made public.
We feel if executed properly, such as with transplant, CED is an appropriate mechanism for CAR-T. UPHS would support a central clinical trial if managed by a central coordinating partner such as CIBMTR.

However, we feel the mandatory reporting to the CIBMTR already is an underfunded mandate subsidized in part by transplant programs at our institution and others. Additional reporting requirements likely to be mandated via a CED protocol would need to be funded appropriately to be successful.

Another area of concern is with process of collection of patient reported outcomes data. The proposed NCD includes a provision for patient-reported outcomes assessments as part of the CED. We would encourage CMS to include patient reporting as part of a clinical trial conducted by a larger coordinating body. We are concerned that many hospitals do not have the capacity to conduct patient-reported outcomes without significant additional research funding, and it would be a barrier to entry for centers.

We would also note that data collection and presentation should be collected and clearly distinguish commercial vs. research products as specifications may differ between the products. Likewise, there should be a distinction in data collection and presentation for both inpatient and outpatient sites of care.

Future implications of CAR-T NCD
It is critical that any NCD not preclude centers, such as UPHS, from pursuing new modes of innovation in immunotherapy, and does not limit pathways to coverage for new therapies.

We hope the NCD is used to further understand the value that CAR-T provides to patients, and will provide a pathway for CAR-T to be used in other cancers, as clinically appropriate. We strongly believe CAR-T therapy should be available to all Medicare beneficiaries who meet the appropriate clinical definitions for treatment. We currently have a number of clinical trials ongoing in this area, including in lymphoma and multiple myeloma and solid cancers. These trials, many of which enroll Medicare beneficiaries, are designed to show the potential of immunotherapy. It is our hope that Medicare beneficiaries are able to access new immunotherapy as it becomes approved and available, when clinically appropriate.

UPHS remains concerned about continuing barriers to access to CAR-T for Medicare beneficiaries. The financial losses associated with currently providing CAR-T treatment to Medicare beneficiaries in an in-patient setting can adversely impact access to care unless the payment challenges are resolved.
Specifically, current inpatient reimbursement inclusive of the maximum allowable new technology add-on payment is approximately 57% of allowable reimbursement as compared to an outpatient setting. Moreover, reimbursement is significantly below product acquisition costs. Continued underfunding along with potential barriers associated with NCDs threatens continued advances in cell therapy as expected in the foreseeable future.

This is a new, complex and personalized treatment that may require a different approach to payment. We hope that that any final NCD lays the groundwork for future discussions on reimbursement, and we look forward to working with CMS on this issue.

Conclusion
As leading providers of CAR-T therapy, we have seen the tremendous benefit this treatment holds for patients. As such, we appreciate CMS’ attention to Medicare coverage of CAR-T therapy and its further efforts here to enhance access, address issues in payment and reimbursement, and support further innovation in CAR-T therapy. Thank you for the opportunity to share our concerns and recommendations.

With best wishes,
Ralph W. Muller

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March 15, 2019

Tamara Syrek Jensen, JD
Director, Evidence and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244
Via Electronic Submission

RE: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen:

Spectrum Health appreciates the opportunity to provide comments on the Centers for Medicare and Medicaid Services’ (CMS) Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N). Spectrum Health, a not-for-profit, integrated health system, is committed to improving the health and wellness of our communities. We live our mission every day with 30,000 compassionate professionals, 4,100 medical staff experts, 3,200 committed volunteers, and a health plan serving 1 million members. Our talented physicians and caregivers are privileged to offer a full continuum of care and wellness services to our communities through 14 hospitals, including Helen DeVos Children’s Hospital, 225 ambulatory sites, and telehealth offerings. We pursue health care solutions for today and tomorrow that diversify our offerings. Locally-governed and based in Grand Rapids, Michigan, our health system provided $457 million in community benefit in the last fiscal year. Spectrum Health has also been recognized as one of the nation’s 15 Top Health Systems by Truven Health Analytics®, part of IBM Watson HealthTM.

Spectrum Health’s Blood and Marrow Transplant Program was founded in 2013 and since that time has performed over 500 transplants, both autologous and allogeneic, including cord blood and haploidentical allogeneic transplants. Spectrum Health is certified through KitePharma to administer axicabtagene ciloleucel car+ and has completed four (4) infusions.

It is an exciting time in cancer care and the new and evolving CAR-T therapies provide new opportunities for patients with refractory or relapsed lymphoma. With that said, Spectrum Health believes it is premature to implement a National Coverage Determination (NCD) because CAR-T therapy is a new and a rapidly evolving field of medicine and a coverage policy should not be developed until the field matures.

Should CMS proceed, Spectrum Health urges CMS to consider the following modifications due to the evolving nature of the science of CAR-T:

• Eliminate the coverage with evidence development requirement and instead implement an NCD with a data collection requirement.
• Expand coverage to include indications covered on the FDA approved label.
• List the Center for International Blood & Marrow Transplant Research (CIBMTR) as an approved registry as long as they receive their approval prior to the May 17 implementation date.
• Remove the requirement tying Patient-Reported Outcomes to reimbursement for CAR-T.

Thank you for considering these comments on the Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N). Should you have any questions regarding these comments or if you would like any additional information, please contact Dr Stephanie Williams, Division Chief for Spectrum Health Cancer Center Adult Blood and Marrow Transplant Program, at Stephanie.Williams@spectrumhealth.org or by phone at 616.486.5933.

Respectfully Submitted,

Anas Al-Janadi, MD
Vice President, Department Chief, Oncology
Lemmen-Holton Cancer Pavilion
145 Michigan Street, Suite 5120
Grand Rapids, MI 49503
616-486-6314

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March 17, 2019

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

RE: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancer (CAG-00451N)

Dear Ms. Syrek Jensen:

The Personalized Medicine Coalition (PMC), a multi-stakeholder group comprising more than 230 institutions across the health care spectrum, appreciates the opportunity to submit comments regarding the Centers for Medicare & Medicaid Services (CMS)’ proposed decision memo for coverage of chimeric antigen receptor (CAR) T-cell therapy for cancer with evidence development. CAR T-cell therapies represent a significant advancement in cancer care, and we urge you to revise the decision memo to ensure timely beneficiary access to approved therapies, minimize provider burden and continue to foster continued innovation in this therapeutic class.

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.

PMC Statement of Neutrality

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 CAR T-cell therapies for cancer.

Current Landscape and CAR T-cell Therapies

PMC recently released Personalized Medicine at FDA: A Progress & Outlook Report. The report documents a record number of new personalized medicine approvals by the U.S. Food and Drug Administration (FDA). This marks the fifth consecutive year that personalized medicines accounted for more than 20 percent of all new drug approvals. FDA has developed new structures for evaluating cell and gene therapies and has demonstrated remarkable speed in bringing CAR T-cell therapies to market in the last two years. The CAR T-cell therapies approved by FDA are intended to treat children and young adults with acute lymphoblastic leukemia (ALL) and adults with diffuse large B-cell lymphoma (DLBCL).

The expected survival for adults with relapsed ALL is less than six months. Among children with cancer, relapsed ALL is a leading cause of cancer-related death. Treatment with CAR T-cell therapy for ALL resulted in complete remissions in up to 90 percent of adults and children with this disease. In contrast, other available treatments for relapsed ALL have a response rate of 30 percent to 43 percent, depending on the type of treatment. In some patients, remissions have lasted up to two years. Such durable remissions offered many patients the chance to undergo bone marrow transplants, a procedure that can be curative.

DLBCL is the most common type of non-Hodgkin lymphoma. In a multicenter clinical trial of patients with DLBCL that worsened after at least two prior therapies, the cancer responded to a CAR T-cell therapy called tisagenlecleucel in 59 percent of 51 patients and the cancer went into remission in 43 percent of patients. At 6 months, 79 percent of patients had not had a recurrence of lymphoma. In a different clinical trial, patients with relapsed or refractory DLBCL, refractory primary mediastinal B-cell lymphoma, or transformed follicular lymphoma received another CAR T-cell therapy, axicabtagene ciloleucel. Among the first 92 patients who were treated, the response rate was 82 percent, with complete remissions occurring in 54 percent of patients.

Considerations for CMS in Revising the Proposed Decision Memo

ALL and DLBCL are cancers with a very poor prognosis, and CAR T-cell therapies have made a profound impact in extending the lives of some people with these cancers. CMS has signaled a belief that CAR T-cell therapies show promise in improving health outcomes for patients with its thorough investigation of the space since initiating a national coverage analysis. We appreciate the opportunity to provide feedback on how CMS’ coverage with evidence development (CED) proposal should be modified. We respectfully ask you to revise your proposal and address the following considerations in your final National Coverage Determination (NCD).

Final national coverage policy should not negatively impact patient access

PMC stated in its comments submitted to CMS on June 15, 2018, that patients and providers are faced with navigating daunting coverage challenges for CAR T-cell therapies. Our hope was that the NCD process would provide coverage for CAR T-cell therapy in both the inpatient and outpatient settings without further complicating care. It is our understanding that CED requirements in the transplant space have led some facilities to opt out of participation and decline subsequent treatment of Medicare beneficiaries. We therefore believe that implementation of the CED requirement should not be overly burdensome for facilities. If this principle is not adhered to, we fear that the CED requirement may encourage facilities to opt out of Medicare coverage for CAR T-cell therapy.

We are also mindful of the lag time between the issuance of a final NCD and CMS’ approval of CED registries. Because CAR T-cell treatment protocols are multi-step, we are particularly concerned about patients who have started CAR T-cell therapy but have not yet received CAR T-cell infusions at the time the coverage decision is finalized. Adding a Patient-Reported Outcome (PRO) tool to the CED requirement, as proposed by the decision memo, may further extend the time it will take registries to launch. CMS should take steps to ensure that the data collection elements of the NCD do not delay patient access to treatment, which should be the priority. We urge CMS to eliminate the PRO reporting requirement as a condition for coverage. The Center for International Blood and Marrow Transplant Research (CIBMTR) began a PRO pilot program for in the summer of 2018. CMS should consider future collaboration with the CIBMTR to address symptom function and health-related quality of life questions related to CAR T-cell treatment.

Finally, the proposed decision memo states that eligible patients for coverage will not be experiencing any of seven comorbid conditions. However, some patients with comorbidities identified on the proposed list, such as active Hepatitis B and C, are currently receiving CAR T-cell treatment. By including these patient eligibility limits, the coverage proposal may exclude some patients who could benefit from treatment. In place of the current patient eligibility requirements, PMC urges CMS to require that the patient have a cancer that is treatable with an FDA-approved therapy, according to an FDA indication.

Final coverage should be well aligned with FDA Risk Evaluation and Mitigation Strategies (REMS) requirements

Sponsors of existing FDA-approved CAR T-cell therapies have agreed to commitments for extensive post-market surveillance to better understand the long-term benefits and toxicities of these therapies. These REMS requirements are of larger size and longer duration than studies of traditional cancer treatments. While CMS has pointed to limited data available on CAR-T therapies in the Medicare population, emerging data from the post-market studies of currently-approved CAR-T products will produce data to further demonstrate health outcomes for Medicare beneficiaries. Additional data collection requirements should align with, and not duplicate, information gathered from these post-market studies and should be limited to facilities reporting specified clinical data elements to a centralized registry operated by a professional organization.

The CIBMTR conducts post-market surveillance collection for a number of organizations and has implemented CMS CED studies. If the CED requirement moves forward, CMS should consider naming CIBMTR or a similarly qualified entity experienced with data collection studies as a centralized registry for this NCD.

National coverage policy should mitigate the downstream impact on this new class of therapies

Current CAR T-cell therapy is most often a third-line treatment. As such, CAR T-cell treatment is addressing the individual needs of patients who are without other options. CMS has stated that the data collected through the CED for CAR T-cell therapy will inform future decisions by the agency regarding coverage of CAR T-cell treatments for cancer. This raises concern that CMS is regulating a new class of therapies based on what is known from a review of just two therapies.

Experts anticipate that advancement in CAR T-cell therapy will lead us to viable first-line therapy in areas like B-cell malignancies. Clinical trials are already underway to explore whether CAR T-cell therapy is more effective than an autologous stem cell transplant in adult diffuse large B-cell lymphoma. The hope is that CAR T-cell therapy could one day replace chemotherapy and stem cell transplants altogether. This long-term goal will be achievable through earlier detection and treatment of the right patients, a hallmark of personalized medicine. There are also ongoing research studies looking at CAR-T in myeloma, glioblastoma, prostate cancer and breast cancer. Some clinical trials are even looking at whether patients can safely and effectively receive CAR T-cell therapy in the outpatient setting, depending on individual patient characteristics.

There will continue to be specialized considerations for the delivery of each CAR T-cell therapy and for newly approved indications of existing CAR T-cell therapies. CMS’ final coverage decision must ensure that findings on treatment with existing therapies are not applied in ways that have a downstream effect of hindering future innovation. The NCD must be broadened beyond relapsed and refractory cancer patients so that it does not have to be re-opened for future indications. CMS should also establish site requirements that can adapt to rapidly evolving scientific advances in CAR T cell therapy.

Conclusion

Thank you for soliciting a wide range of stakeholder views on the proposed decision memo and for considering our comments. PMC welcomes the opportunity to serve as a resource as you formulate your final decision on coverage of this important class of therapy. We hope that CMS’ coverage decision on this issue can achieve the goal PMC shares with the agency of delivering appropriate, efficient, and accessible health care to every patient in need of treatment. If you have any questions about the content of this letter, please contact me at 202-589-1769 or cbens@personalizedmedicinecoalition.org.

Sincerely,

Cynthia A. Bens
Senior Vice President, Public Policy

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

Lori A. Paserchia, MD
Lead Medical Officer
Centers for Medicare & Medicaid Services

Endnotes-
Centers for Medicare & Medicaid Services. Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T cell Therapy for Cancer. February 15, 2019 https://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=291&bc=ACAAAAAAQCAA&
Personalized Medicine Coalition. Personalized Medicine at FDA 2018 Progress Report. February 12, 2019 http://www.personalizedmedicinecoalition.org/Userfiles/PMC-Corporate/file/PM_at_FDA_A_Progress_and_Outlook_Report.pdf
American Society of Clinical Oncology. At the Leading Edge of Precision Medicine: Souped-up Immune Cell. April 5, 2017. https://www.asco.org/about-asco/press-center/cancer-perspectives/leading-edge-precision-medicine-souped-immune-cells
American Society of Clinical Oncology. At the Leading Edge of Precision Medicine: Souped-up Immune Cell. April 5, 2017. https://www.asco.org/about-asco/press-center/cancer-perspectives/leading-edge-precision-medicine-souped-immune-cells
American Society of Clinical Oncology. Clinical Cancer Advances of 2018. January 30, 2018 https://www.asco.org/sites/new-www.asco.org/files/content-files/research-and-progress/documents/CCA-2018-Report.pdf

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As the President for Strategy and Business Ventures and Vice President of Government Affairs at The City of Hope National Medical Center, we welcome the opportunity to submit comments on behalf of our institution regarding the Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451-N). City of Hope is a national leader in cancer care and is the only institution in the United States whose blood and marrow transplant program has produced allogeneic transplant survival outcomes “above expectation” for all 14 years of federally-mandated outcomes reporting to the Centers for International Blood/Marrow Transplant Research.

City of Hope is also a pioneer and leader in the development and treatment of patients using CAR T-cell therapeutics. Our CAR T-cell research began in the late 1990s, our first CAR T-cell trial patient was infused in January of 2000, and City of Hope treated its first patient with a commercial CAR T-cell product in 2017. City of Hope has treated nearly 300 patients with CAR T-cell treatments since the inception of our program. The City of Hope CAR T program has completed 14 trials and currently has 16 enrolling/ongoing trials. These include on-going or planned clinical trials of CAR T-cells directed at the treatment of patients with solid tumors including glioblastoma, her2-expressing breast cancer metastasized to brain, and prostate cancer. Our commitment to serving patients who require CAR T-cell treatment includes our investment in two good manufacturing practices (GMP) facilities that manufacture CAR T-cells for our institutional clinical trials, as well as, a highly-trained multidisciplinary staff that is expert at managing health complications that may arise following CAR T-cell treatments.

On a daily basis we see the transformative impact of this innovative set of therapeutics in the domain of cancer care. We strongly believe these treatments can be potentially life-saving for patients whose care needs remain unmet and who would otherwise likely receive high-cost, ineffective treatments. We also see this therapeutic technology as a harbinger of a growing and robust future pipeline of innovative, life-saving therapeutics that are profoundly distinct from our current anti-cancer armamentarium.

The Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers proposes to cover autologous treatment with T-cells expressing at least one chimeric antigen receptor (CAR) through a Coverage under Evidence Development model (CED). We are concerned that the proposed CED model may potentially unfavorably impact patient access to new innovations in CAR T-cell treatments, risk a reduction in access to CAR T-cell treatments by Medicare beneficiaries by permitting institutions delivering these treatments to “opt-out” of treating this patient population, and create an additional unfunded administrative burden upon those centers that do deliver these treatments under the data submission requirements of the CED model.

An NCA Must Not Limit or Undermine Medicare Beneficiaries’ Access to Innovations in CAR T-cell Treatments
In this decision memo on CAR T-cell treatments for cancer, the agency proposes to cover autologous treatment with T-cells expressing at least one chimeric antigen receptor (CAR) through CED when prescribed by the treating oncologist, performed in a hospital, and all of the additional outlined requirements are met. There are numerous CAR T-cell products that are in development that are differentiated from the two currently FDA-approved products. These emerging therapeutics may employ a different method of action or represent effector cell populations that are targeted against cancer types other than those targeted by Kymriah and Yescarta.

City of Hope believes that the rule should apply to all current and future FDA-approved CAR T-cell and similar targeted cellular therapeutic products regardless of origin of the effector cells (autologous or allogenic), the subclass of effector cell (Treg vs. NK vs. other cell of origin) or the tumor cell target. We believe that the currently approved CAR T-cell therapeutics represent just the first generation of what will eventually lead to new and more effective cellular-based immunotherapeutics. City of Hope wants to ensure that future innovations in the (CAR) T-cell/gene modified therapeutic domain are not excluded from CMS reimbursement and receive equitable consideration. City of Hope recommends revising “autologous” to “FDA approved” so that as addition types of CAR T-cell therapeutics come to market, this NCA does not prohibit access of new and innovative products that may serve additional patient populations whose cancer care needs remain unmet or more optimally address the needs of the currently served populations.

Medicare Beneficiaries Should Not Lose Access Under the NCA
City of Hope believes that the shift to a CED model should not result in increasing the risk of Medicare beneficiaries losing access to this set of life-saving therapeutics based upon the ability of their local treatment facility to “opt-out” of participation in the requisite data collection trial. If CMS permits institutions to opt out of participating in the CED requirement it will give those institutions who choose not to participate a legal means by which they will be able to avoid providing CAR T-cell treatments to Medicare patients, while still continue to provide it to patients whose care services are reimbursed by a more financially favorable payer. Given the significantly negative financial impact that both prospective payment system (PPS) exempt and PPS institutions experience in delivering inpatient CAR T-cell treatments to Medicare beneficiaries, this would create incentives for institutions to opt-out of providing these treatments to Medicare patients, while paradoxically leaving those institutions who choose to “opt-in” to participate in the CED to suffer significant financial hardship by doing so. For this reason, City of Hope recommends that CMS eliminate the CED requirement and instead implements an NCD with a data collection requirement that applies to all centers which will allow the agency to collect additional data on the real world performance of this set of therapeutics while moving away from a model that would result in centers “cherry picking” the patients that they serve.

This NCA Increases the Administrative Burden and Costs for Centers That Delivery CAR T-cell Treatments to Medicare Beneficiaries
If CMS chooses to proceed with implementation of the CED model, City of Hope requests that the Center for International Blood and Marrow Transplant Research (CIBMTR) be listed in the final National Coverage Determination (NCD) as one of the qualified data registries. Our center, and many others, currently report data to the CIBMTR for patients who receive CAR T-cell treatments using the two current commercially available products. This data set should be sufficient to meet CMS’ goal of tracking long-term outcomes of patients (including overall survival and progression-free survival) for patients who are treated with FDA-approved CAR T-cell therapeutics. Based on CIBMTR’s experience in collecting and analyzing allogeneic hematopoietic cell transplantation outcomes nationally, they would be an ideal qualified registry for the management of CED-related data.

In addition to outcomes data, through this proposed decision memo CMS has also asked for the collection of patient-reported outcomes (PRO) data using two proposed PRO tools: The National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS®) or Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAETM). CMS has proposed that these data be collected at 3 months, 6 months, 12 months, and 24 months after the treatment is administered. While City of Hope regards patient experience and patient-centered outcomes as a foundational part of care delivery, we are concerned that the uncompensated administrative burden of collecting these additional PRO datasets poses a challenge to the institutions who will have to invest in the personnel and infrastructure that are required to perform these activities and creates additional demands upon those patients who have undergone these treatments. The PROMIS tool is less burdensome to implement than the PRO-CTCAE, but both would pose the challenges described above.

As the proposal is currently designed, CMS’ CED policy for CAR T-cell treatments risk exacerbating patient access issues and compounding the financial losses that centers currently experience while serving Medicare beneficiaries. As a result, City of Hope strongly advocates that CMS grant appropriate flexibility to researchers and clinicians as new therapeutics enter the marketplace while granting those institutions that offer these treatments to Medicare beneficiaries sufficient flexibility to deliver these therapeutics in a way that is not unnecessarily burdensome to providers or patients and their families.

Thank you for the opportunity to comment on this NCA. City of Hope joins American Society of Hematology (ASH) and American Society for Transplantation and Cellular Therapy (ASTCT) in urging CMS carefully reconsider this draft memo and exercise care in creating a coverage model that preserves patient access to this set of life-saving therapeutics.

If COH can be of any further assistance in this matter, please do not hesitate to contact either of us at either HLevine@coh.org, (626) 218-7178 or JAlvarnas@coh.org (626) 218-2404.

Sincerely,

Dr. Harlan Levine
President, Strategy and Business Ventures

Dr. Joseph Alvarnas
Vice President of Government Affairs

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March 17, 2019

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

Katherine B. Szarama, PhD, Lead Analyst
Evidence and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Lori A. Paserchia, MD, Lead Medical Officer
Evidence and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Dear Ms. Syrek Jensen, Dr. Szarama and Dr. Paserchia:

The American Society of Gene & Cell Therapy (ASGCT) appreciates the opportunity to provide comments to the Centers for Medicare & Medicaid Services (CMS) regarding the proposed decision memo on the national coverage analysis for chimeric antigen receptor T-cell (CAR T-cell) therapy. ASGCT is a nonprofit professional membership organization comprised of more than 3,000 scientists, physicians, and other professionals working in gene and cell therapy in settings such as universities, hospitals, and biotechnology companies. The mission of ASGCT is to advance knowledge, awareness, and education leading to the discovery and clinical application of genetic and cellular therapies to alleviate human disease.

Maximizing patient access to approved gene and cell therapies is integral to this mission. The Society appreciates CMS efforts to make these lifesaving therapies available to patients, and shares the goal of advancing scientific knowledge about the benefits and risks of CAR T-cell therapies. ASGCT maintains, however, that current Medicare coverage of CAR T-cell therapies is appropriate, as stated in comments to the Agency dated June 15, 2018.

The Society is concerned that, as currently drafted, the proposed decision memo including coverage with evidence development (CED) may limit patient access to CAR T-cell therapies for Food and Drug Administration (FDA)-approved indications now and in the future. The additional administrative burden imposed on providers by coverage with evidence development (CED) may result in providers opting out of CED participation, thereby not providing the therapy to Medicare beneficiaries. ASGCT respectfully requests that the Agency consider the specific concerns and related recommendations below in order to ensure medically appropriate access to these therapies.

Patient Eligibility Requirements

The proposed decision memo requires that a patient has relapsed or refractory cancer for CMS to cover CAR T-cell therapy. While the two FDA-approved CAR T-cell products are only approved for relapsed or refractory indications,^i,ii future FDA-approved indications and products have the potential to be first-line indications.ⁱⁱⁱ To ensure patients do not experience limitations in accessing, or lapses in coverage for, FDA-approved CAR T-cell products with first-line indications, ASGCT recommends removing “relapsed or refractory,” and substituting the following or similar wording as the first eligibility requirement:

Providing sufficient scope of coverage in the final decision memo to address upcoming applications of CAR T-cell therapy is of utmost importance in providing timely patient access to potentially lifesaving treatments, as more of the numerous therapies in the research pipeline receive FDA approval.

Site of Care

ASGCT supports strong criteria for qualified medical facilities that provide these therapies to ensure the best possible patient outcomes. We agree that facilities should meet the FDA’s Risk Evaluation and Mitigation Strategies criteria, as well as the criteria proposed in the decision memo—that the facility has a cell therapy program consisting of an integrated medical team with consistent protocols, procedures, quality management, and clinical outcomes; a designated care area that protects the patient from infectious agents; and written guidelines for patient communication, monitoring, and transfer to an intensive care unit. However, the Society is concerned that by referring to these facilities as “hospitals,” CMS may be limiting the number of sites available to patients that may otherwise be qualified except for how they are licensed or paid. We recommend changing the term “hospital” to “medical facility” throughout the proposed decision memo to prevent potential unnecessary restrictions in coverage due to a lack of clarity in the terminology, and focus only on the standards that these facilities must meet.

Treatment Criteria

ASGCT is pleased that the proposed treatment criteria cover FDA-approved biologicals that meet one of the following two criteria—either providing targeted therapy for a known antigen expressed in the patient’s cancer according to an FDA indication; or indicated for use identified in the National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium. However, the proposed memo specifies that CMS would specifically cover autologous treatment with T cells expressing at least one CAR. While current FDA-approved therapies utilize autologous CAR T-cells, clinical trials are imminent utilizing allogeneic CAR T cells.^iv This innovation has the potential to change these therapies from patient-specific products to patient population-specific products, sometimes referred to as “off-the-shelf” CAR T-cell therapies. ASGCT therefore recommends removing the word “autologous” as a treatment criterion in the following sentence, to accommodate potential FDA approvals of allogeneic CAR T-cell therapy products:

Patient-Reported Outcomes

ASGCT members support efforts to make drug development and the delivery of health care more patient-centered, and believe that the use of patient-reported outcomes (PROs) can help bolster these efforts. From a scientific perspective, the society is concerned by the NCA’s proposed inconsistent collection of PROs only for CAR T-cell therapies, as well as use of two different tools.

A consideration in determining whether to collect this data following CAR T-cell therapy is whether the data is also being collected for an appropriate comparison group, such as historical controls of a cohort of patients receiving alternative therapeutic regimens. Furthermore, if CMS does require collection of PROs, the Society recommends using only a single metric for improved compilation of data, with the most appropriate questions for long-term follow up of patients. The Patient-Reported Outcomes Measurement Information System (PROMIS) is a well validated instrument that meets this requirement. The alternative metric listed is the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events. Collection of information on adverse events would not be applicable beyond the first of four follow-up points occurring between three and 24 months after the procedure.

Registry Considerations

ASGCT encourages the Agency to align the effective date for data collection requirements with the date of broad availability of at least one patient registry with capability to collect required data sets in order to avoid lapses in coverage, which could have fatal consequences for patients with no other treatment options. To facilitate timely initiation of data collection, we recommend that CMS list the Center for International Blood and Marrow Transplant Research (CIBMTR) registry in the final decision memo as an approved patient registry, as it is already being utilized to collect patient data for FDA-required post-marketing studies. FDA post-market study data requirements are consistent with the CMS proposed data requirements except for PRO data. If the patient registry is prepared to collect all required information except for the PRO data at the established effective date of data collection, ASGCT requests that CMS does not delay coverage, but rather allows PRO data to be incorporated as soon as possible. Additionally, the Society recommends CMS clarify that the therapy will be covered for patients who have already undergone lymphocyte harvesting at the time the final memo is issued. These patients will not have reported data elements before beginning therapy, but need to be assured their time-sensitive therapy will be completed and covered.

The Society also requests CMS indicate that the patient registry may collect PRO data at later time points after providers obtain initial patient consent to ease the long-term administrative burdens on providers. ASGCT further requests Agency clarification regarding how CMS will consider coverage for patients who do not consent to participation in PRO data collection.

Thank you for your consideration of these comments. Please consider ASGCT a resource as you work to finalize the decision memo.

Sincerely,

Michele P. Calos, PhD
ASGCT President

i. Kite Pharma, Inc. (2017). Yescarta: Prescribing information. Santa Monica, CA.
ii. Novartis. (2017). Kymriah: Prescribing information. East Hanover, NJ
iii. Efficacy and safety of axicabtagene ciloleucel as first-line therapy in participants with high-risk large B-cell lymphoma (ZUMA-12). (2018). Retrieved from https://clinicaltrials.gov/ct2/show/NCT03761056. (Identification No. NCT 03761056).
iv. Dose-escalation study of safety of PBCAR0191 in patients with r/r NHL and r/r B-cell ALL. (2018). Retrieved from https://www.clinicaltrials.gov/ct2/show/NCT03666000?term=precision+biosciences+allogeneic+CAR+T&rank=1. (Identification No. NCT03666000).

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

Katherine B. Szarama, Ph.D., Lead Analyst
Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Lori A. Paserchia, M.D., Lead Medical Officer
Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen and Drs. Szarama and Paserchia:

As we have reviewed the Proposed Decision Memo for Chimeric Anti Receptor (CAR) T-cell Therapy reimbursed under Medicare Part B for Cancers and our own emerging experience, the areas of congruence and opportunities are patient selection and patient registry. Within each of these broad categories, we have reviewed the draft and our own data to provide insights and opportunities. As an organization serving a largely Medicare Advantage patient population, Humana is encouraged by the opportunity to work collaboratively with CMS and other stakeholders to ensure our patients are able to receive these novel therapies while engaging in shared decision making regarding the risks and benefits.

Patient Selection
We view patient selection as a key method to give patients the best opportunity to experience the most desired outcomes at the best value. We agree with the requirement for coverage that the “patient has not currently been experiencing any comorbidity that would otherwise preclude patient benefit”. To avoid a wide degree of interpretation, the reference to the NCCN guidelines for B-cell lymphomas provides additional details focused on these key areas of performance status and organ function; however this footnote appears to have been removed from the most recent version of the NCCN B-cell lymphoma guidelines (v1.2019). The clinical trial eligibility criteria ensure that patients have adequate physiologic reserve to tolerate the potential intense toxicities associated with these therapies. For example, the following criteria were utilized in the ZUMA1 registration trial for axicabtagene ciloleucel for DLBCL:

• ECOG Performance Status 0 – 1
• Adequate organ function including renal, hepatic, pulmonary and cardiac
• Creatinine clearance (as estimated by Cockcroft Gault) > 60 ml/min
• Serum ALT/AST < 2.5 ULN
• Total bilirubin < 1.5 mg/dl, except in subjects with Gilbert’s syndrome
• Cardiac ejection fraction > 50% with no evidence of pericardial effusion as determine by an ECHO and no clinically significant ECG findings
• No clinically significant pleural effusion
• Baseline oxygen saturation >92% on room air

For currently approved CAR T-cell products and as new CAR T-cell products become FDA approved, Humana strongly supports the inclusion of FDA-registration clinical trials eligibility criteria within the NCD for each individual product and indication.

Our early emerging experience has shown signals that patients infused with a CAR T-cell product may not reflect the eligibility criteria utilized in the registration trials for FDA approved treatment leading to outcomes which are less than desired; particularly in our patient population ages 65 and over. As requested with the draft memo, of the 11 Medicare beneficiaries who received infusion with CAR T-cells between December 2017 – December 2018, 6 patients are age 65 years or older. Four patients did not survive one year post-infusion (2 patients did not survive 30 days post-infusion). The average inpatient length of stay observed in these patients was 19 days; which is consistent with the CMS-reported analysis of 18 days. Of the remaining five Medicare beneficiaries ages < 65, we only have claims data for one of these beneficiaries and outcomes are as follows: currently > 6 months post infusion and currently alive. The length of inpatient stay for this patient was 27 days.

Patient Registry

As a CMS-approved registry is selected and developed in partnership with thought leaders, we would encourage consideration of inclusion of key clinical elements and cost data. Additionally, we would expect formalization related to data sharing strategies and timelines that can accelerate national goals for improving the quality and cost-effectiveness of cancer diagnosis, treatment, followup, and end–of-life care while also providing enhanced data resources through data sharing between the centers and payers.

Key clinical characteristics of registry patients to be included:

• Disease Burden: Within the NCCN CAR-T task force report, low disease burden is noted to be associated with improved overall response rates. Insights like these related to efficacy are necessary to be determined and shared rapidly for incorporation into patient selection criteria for FDA approved products.
• Performance status: Preferably in line with the FDA-registration clinical trials
• Toxicity Identification and Management: Currently, there are multiple toxicity grading scales utilized by different manufacturers and institutions leading to potential variation in the treatment of toxicities. This is notable between the tisagenlecleucel and axicabtagene ciloleucel products which utilized different grading scales in their registration trials for DLBCL. The scientific community should now coalesce around one algorithm to minimize variables in assessing the effectiveness of CAR-T broadly. A collaboration of key leaders has come together to identify grading criteria to be used broadly for CRS and neurotoxicity to eliminate these discrepancies. This is being sponsored and supported via ASBMT as a nationwide grading scale. Any CMS-approved registry should utilize this endorsed standard grading tool.
• Anti-cancer agents utilized secondary to disease progression following infusion with CAR-T cells: In addition to the questions outlined in the CED, we would suggest inclusion of another critical question to monitor: “For patients who received CAR-T cells with an unsuccessful outcome, what is the next treatment planned or what does the patient receive next?” Early experience indicates these patients may proceed to treatment with an anti-PD1 agent, currently provisioned via manufacturer compassionate use programs.

In addition to the clinical elements noted, a CMS approved registry (e.g. CIBMTR) should monitor and track the cost drivers for CAR T-cell therapies across the following time periods: preparation / collection processes, infusion of the CAR T-cell product, immediate post-infusion monitoring / toxicity management and surveillance. The costs of the collection process via apheresis have been a particular pain point as the manufacturers have historically had different approaches to inclusion of this cost as part of the drug cost or not. Tisagenlecleucel included the cost of the apheresis; whereas axicabtagene ciloleucel did not. As of 1/1/19, neither drug manufacturer will reimburse providers for apheresis due to concerns from providers regarding logistics with billing. Given the low cost of apheresis compared to the total cost of therapy, Humana agrees with this decision to ensure accuracy and streamline the processes. Efforts should be focused on a payment methodology that optimizes value and outcomes for the entire course of therapy. Humana is supportive of utilizing registry and clinical trial infrastructure to deepen the body of evidence for utilization of CAR T-cell therapy. Clinical trial CAR T-cell centers have unique clinical expertise and experience in this ever emerging area and many providers already recommend clinical trials to CAR T-cell-eligible patients. Clinical trial centers are likely to lead the field in areas such as:

• Risk-adapted dosing (low CAR T-cell cell infusion numbers or dose splitting over multiple injections) for patients with high tumor burden to reduce the risk of severe adverse events;
• Identification of biomarkers which may predict the patient’s likelihood for efficacy and/or toxicity; and
• Novel methods for managing CAR T-cell associated toxicities and CAR T-cell therapeutic delivery in the outpatient setting.

As a result, we believe treatment in a clinical trial setting creates an opportunity for developing consistency in costs (hospital stays, supportive care, or physician visits) and establishment of payment models with a best case scenario level of care.

Within the draft memo, the collection of patient report outcomes (PRO) is limited to those patients who receive their CAR T-cell infusion in the ambulatory setting. Humana is in agreement that PROs provide essential information regarding treatment effects and the patient experience that cannot be well captured otherwise. Therefore, we would like to better understand the decision to not collect PROs for patients receiving their CAR T-cell infusion as an inpatient. While the site of care for the actual infusion differs, we would expect that other parts of the patient journey would be similar and would benefit from the ability to understand the patient experience. Additionally, we are concerned about social determinants of health and their role in the patient experience for CAR T-cell patients. As patients undergo this intensive therapy, we would like to be able to understand the influence of social isolation, financial toxicity, food insecurity, and transportation challenges in outcomes patients experience from CAR T-cell therapy.

Humana Pharmacy Solutions works directly with pharmaceutical manufacturers to develop and implement outcomes-based contracts to measure the intended outcome of the treatment and to provide financial protection against sub-optimal or failed therapies. As a company we have entered into outcomes-based contracts for predominantly high-cost specialty drugs, and include therapies for auto-immune/inflammatory conditions (rheumatoid arthritis and psoriasis), cardiovascular disease, diabetes, infectious disease, and cancer. Humana is exploring and advocating for outcomes-based contracting for IEC therapy with manufacturers. In the short term, Humana supports the following endpoints for consideration under an outcomes-based agreement: alive 28 days post-infusion of CAR T-cell cells and assuming resolution of acute toxicities, objective response rate (ORR) and progression-free survival (PFS) at 3 months (response rate at 3 months seems to be a surrogate for long-term survival), and overall and treatment-related morbidity and mortality at 30 days, 100 days and 1 year after product administration. Humana would not support any coverage criteria that would preclude value-based contracting.

Thank you for the opportunity to provide our comments and collaborate on efforts to ensure the Medicare-eligible patient population is able to appropriately and safely receive the highest quality care at the best value.

Sincerely,
Bryan Loy M.D., M.B.A.
Humana

References:

Center for International Blood and Marrow Transplant Research (CIBMTR). What we do. https://www.cibmtr.org/About/WhatWeDo/Pages/index.aspx (Last updated 3.26.2018; accessed 11.21.2018)
Foundation for Accreditation of Cellular Therapy. International Standards for Hematopoietic Cellular Therapy Product Collection, Processing and Administration. Version 7.0; March 2018.
Foundation for Accreditation of Cellular Therapy. Standards for Immune Effector Cells. First Edition. January 2017.
Locke FL Ghobadi A, Jacobson CA, et al. Durability of response in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (Axi-Cel) in patients (Pts) with refractory large B-cell lymphoma. ASCO (Chicago, IL) 2018: Abstract 3003.
Maus MV, Nikiforow S. The why, what and how of the new FACT standards for immune effector cells. Journal for ImmunoTherapy of Cancer. 2017;5:36.
NCCN Clinical Practice Guidelines. Management of Immunotherapy Related-Toxicities. V 1.2019 – November 14, 2018. (accessed 11/21/2018). https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf .
Neelapu SS, Tummata S, Kebriael P, et al. Chimeric antigen receptor T-cell therapy – assessment and management of toxicities. Nature Reviews. 2018. 15:47-62.
Ogba N, Arwood N, Barlett NL, et al. Chimeric Antigen Receptor T-Cell Therapy. NCCN Task Force Report. J Natl Compr Canc Netw 2018; 16(9):1092-1106.
Perica K, Curran KJ, Bentjens RJ, et al. Building a CAR Garage: Preparing for the Delivery of Commercial CAR T Cell Products at Memorial Sloan Kettering Cancer Center. Biol Blood Marrow Transplant. 2018;24:1135-1141.
US Food and Drug Administration. BLA Approval for axicabtagene ciloleucel. 10/18/2017. https://www.fda.gov/downloads/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm581259.pdf
US Food and Drug Administration. BLA Approval for tisagenlecleucel 08/30/2017. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM574106.pdf
US Food and Drug Administration. Supplemental Approval for tisagenlecleucel 05/01/2018. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM574106.pdf

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March 18, 2019

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

RE: Proposed National Coverage Determination for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen:

The Advanced Medical Technology Association (AdvaMed) offers the following comments on the Centers for Medicare & Medicaid Services’ (CMS) proposed National Coverage Determination (NCD) for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N).¹

AdvaMed’s member companies produce the life-saving and life-enhancing medical devices, diagnostic products and health information systems that are transforming health care through earlier disease detection, less invasive procedures and more effective treatments. AdvaMed members range from the largest to the smallest medical technology innovators and companies.

CMS’ proposal to cover CAR-T using Coverage with Evidence Development (CED) would require CAR-T patients be monitored using Patient Reported Outcome (PRO) Assessments for two years. AdvaMed supports this proposal.

Traditional methods for PRO Assessments are paper questionnaires, typically with more than 100 questions to be asked of the patient. These questionnaires can be delivered by a nurse or other member of the clinical care team by asking the patient questions and recording their answers on a form. Today, there are PRO software tools available and already in use in clinical settings that can minimize the time and burden associated with traditional patient reported outcomes (i.e., electronic patient reported outcomes, or ePRO). Studies find time savings for busy nurses and care team members with 30-50% fewer clinic calls.² Most importantly, studies show that ePRO tools may help cancer patients live longer.³

ePROs are collected and communicated with digital platforms and have been shown to help with early recognition of severe symptoms and relapses, toxicity management, dose optimization, and reduced treatment duration. Study results of the use of ePRO solutions for cancer patients have shown 20% fewer ER visits, 10% fewer hospitalizations, and 20-35% improved survival rate.⁴

As the medical technology industry increasingly becomes digitally enabled, there is a growing role for technology companies in generating and organizing health information for such tasks as PROs. Medical technology can monitor fatigue remotely, for example, and software advancements are able to improve upon the traditional paper questionnaire PRO Assessments, with easy to use interfaces on popular consumer devices such as tablets and smart phones.

Summary
In conclusion, AdvaMed supports CMS’ proposal in this proposed NCD to include the patient perspective through Patient Reported Outcomes Assessment for two years. This approach allows patients themselves to be included in the evidence development process for this treatment.

Additionally, AdvaMed encourages CMS to provide flexibility for care teams to employ the most current medical technology, including ePROs, to fulfill the PRO Assessment requirements in the NCD.

Thank you once again for the opportunity to comment on this important proposed coverage determination. If you have questions regarding these comments or if you require additional information, please contact me or Chandra Branham, JD, Vice President, Payment and Health Care Delivery Policy, at (202) 434-7219 or cbranham@AdvaMed.org.

Sincerely,

Donald May
Executive Vice President
Payment and Health Care Delivery Policy

1 CMS Proposed National Coverage Determination for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N); see https://www.cms.gov/medicare-coverage-database/details/nca-proposeddecision-memo.aspx?NCAId=291 (accessed February 16, 2019).
2 Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment: A Randomized Controlled Trial, J Clin Oncol. 2016 Feb and the Randomized Trial Comparing a Web-Mediated Follow-up With Routine Surveillance in Lung Cancer Patients, J Natl Cancer Inst. 2017 Sep 1.
3 Id.
4 Id.

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March 14, 2019

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

Katherine B. Szarama, PhD, Lead Analyst
Evidence and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Lori A. Paserchia, MD, Lead Medical Officer
Evidence and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers CAG-00451N

Dear Ms. Jensen and Drs. Szarama and Paserchia:

Duke University Healthy System (Duke) appreciates the opportunity to comment on the recently-published Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy (CAR-T) for Cancers. Duke serves the treatment needs of cancer patients through the collaborative umbrella of the Duke Cancer Institute, which brings together the extensive resources of Duke University, Duke Health, and the Duke Comprehensive Cancer Center.

Background

Duke Comprehensive Cancer Center was established in 1973 as one of the original eight National Cancer Institute (NCI) designated comprehensive cancer centers. We are also part of the National Comprehensive Cancer Network (NCCN), an alliance of the nation’s leading cancer centers dedicated to improving patient care. Our collaborative model fully integrates patient care, research, and education to improve patient outcomes while decreasing the burden of cancer and accelerating scientific progress.

Duke’s Hematologic Malignancies & Cellular Therapy specialists treat over 1,000 people with blood cancer each year. Our lymphoma specialists and researchers have pioneered novel techniques such as less intense stem cell transplants, to offer new hope to people living with lymphoma. Duke’s high level of expertise and integrated infrastructure enabled us to achieve certification to offer Yescarta in January 2018. We were one of the clinical trial sites in Novartis’ pivotal trial leading to FDA approval of tisagenlecleucel (Kymriah) in patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) who didn’t respond to treatment or relapsed at least twice.

Our clinicians and researchers see CAR-T as offering the potential to revolutionize cancer care. The concept of harnessing the immune system’s power to attack cancer has long been a goal in cancer research at Duke and throughout the world. We view CAR-T as an exciting and important step toward this entirely new direction in cancer therapy. Our commitment to research, discovery, and innovation, however, is grounded in our mission to deliver cancer care that gives each of our patients their best hope for a longer, productive, and high-quality life. Innovation without access delivers little hope, and access to cancer treatment is inextricably tied to reimbursement. Delay, unfortunately, is too often an enemy that our patients and their doctors cannot beat.

The Registry Requirements May Impose additional burden on Duke, other Cancer Centers, and its Patients.

Duke is concerned about the additional financial and documentation burden that the requirements will impose upon clinicians and its patients. The proposed NCD requires the use of the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) or Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Duke is not currently utilizing these systems to collect patient reported outcomes. However, we do collect patient satisfaction data utilizing the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS). Requiring the use of yet another patient-experience related platform will prove to be excessively burdensome.

Given the link between administrative workload and quality patient care in the healthcare industry, Duke is concerned about the administrative burden these requirements may have on ensuring positive patient outcomes. If this NCD goes into effect, Duke will have to either decline to commit to registry participation or invest in additional resources to ensure that we have the infrastructure and staff to meet Medicare’s CAR-T coverage requirements. Unless the Agency anticipates fully incorporating the resource use into updated payment rates for CAR-T, Duke believes manufacturers should be permitted to contribute to the costs of fulfilling registry and other CED requirements.

Per the proposed NCD, patient-reported outcomes assessment must be reported at baseline, at treatment, and at follow up 3-month, 6 months, and 12 months after the treatment is administered. This requirement is not clear whether it requires the participating hospital to perform the analysis or the registry. If it is in fact the registry who will be performing the analysis, we recommend that the NCD be revised to provide more specificity around this requirement. However, if CMS is implying that the participating hospital perform their own analysis, this would present another level of undue burden on hospitals.

Situations have and will occur in which a patient cannot be reached to collect the patient-reported outcomes, or fulfill other registry requirements, despite Duke’s best efforts. We are concerned that the proposed NCD creates registry-based contingencies for coverage that could inject financial uncertainties, risks, and even liabilities for providers. To the extent that registry reporting failure would render the CAR-T non-covered, providers could face future offsets, overpayment determinations, or even allegations of a “false claim.” Duke strongly urges CMS to either commit to ensuring that providers will not face registry-related scrutiny on post-payment review, or article a clear, actionable due diligence protocol outlining reasonable steps providers can take to ensure compliance with the CED requirements, even when patients cannot be reached to participate.

Similarly, given the Duke Cancer Center’s standing as a distinguished partner with other nationally-recognized cancer research institutions, we are apprehensive of the potential ramifications this proposed NCD will have on the overall commonwealth of CAR-T providers and their patients. Taking into account the increased burden and uncertain risks in the proposed NCD, combined with a potentially deficient Medicare reimbursement, there may be providers who will opt out of agreeing to the CED reporting requirements. Maintaining the current status quo for CAR-T coverage would preclude Medicare participating facilities from turning away Medicare beneficiaries, regardless of any financial loss incurred. Under the NCD, however, facilities could shield themselves from the financial losses associated with Medicare CAR-T patients by declining registry participation, and informing Medicare patients that the service is simply not covered. The provider would issue an Advance Beneficiary Notice (ABN), and the patient would have to choose between absorbing the costs of the service, seeking care at another CAR-T center, or receiving palliative care. For this reason, we are of the strong opinion that CMS establish criteria and protocols to address these concerns.

The proposed NCD requires hospitals to participate in a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, and follow the patient for at least two years. It also proposed that CMS review and approve these registries. The NCD process, as we understand it, is evidence-driven to determine whether a particular treatment is reasonable and necessary. Duke is already submitting substantive evidence for a myriad of CED studies for sickle cell disease, myelofibrosis, and many others to the Center for International Blood and Marrow Transplant Research (CIBMTR). We are also confident that the center will meet the requirements to become approved by CMS. With Duke Comprehensive Cancer Center being one of many nationally-recognized institutions that report up to the CIBMTR, we strongly believe that CMS should revise the final policy to eliminate the CED requirement and in its place use the existing mechanism for data collection found in the CIBMTR. Furthermore, this will eliminate the possibility of other cancer centers to opt-out of the CED requirement due to the significant burden it will impose.

The Proposed NCD should Focus on Evidentiary Gaps associated with an Over-65 Population

CMS expressed concerns that the clinical trials supporting FDA approval of Yescarta and Kymriah did not include a sufficient number of individuals over age 65 for CMS to assess the potential benefit to Medicare patients. The labeling for both products included FDA’s general disclaimer language on geriatric use that is required when clinical studies fail to include more than 100 patients over age 65.

Duke and its clinicians are accustomed to working with new treatments as part of the practice of medicine. In fact, most standards of care and clinical guidelines in oncology are developed based upon studies for which geriatric patients may be under-represented. The CAR-T clinical trials were relatively small, and patients over 65 comprised 20-24% of the studied populations. More importantly, the data CMS included on CAR-T in its inpatient proposed rule did not support any conclusion that elderly population might have worse outcomes than younger patients. The Yescarta data from one study CMS cited showed 12-month survival of 57% in patients younger than 65 and 71% in patients over age 65.

While adverse events, including serious events, were the rule rather than the exception, none of the studies showed an age-associated difference in adverse events; 98% of patients recovered from CRS and nearly all patients recovered from neurologic events. The single fatal adverse event occurred with a younger patient enrolled in the Kymriah study. For these reasons, Duke believes that CMS should more clearly state its specific concerns that would render this medically accepted, FDA-approved treatment not “reasonable and necessary” within the context of a patient population with no available alternative care options other than palliative care. To the extent that these concerns are compelling and, as the proposed NCD implies, associated with an over-65 patient population, CMS should limit the CED restrictions on use to that population.

Conclusion

Once again, Duke appreciates the opportunity to offer its comments to CMS as it considers coverage of CAR-T. We are excited to offer this treatment to patients, including Medicare beneficiaries, who may benefit from a new approach to treating what would otherwise be a terminal condition.

Should you have any questions, or if you would like me to connect you with a Duke clinician experienced in administering CAR-T, please contact me.

Sincerely,

Momen M. Wahidi, MD, MBA
Director, Interventional Pulmonology and Bronchoscopy
Chief Medical Officer, Duke Patient Revenue Management Organization
Associate Professor of Medicine
Duke University Medical Center
Box 102356
Durham, NC
Office: (919)-668-0340
Fax: (919)-684-3874
momen.wahidi@duke.edu

Nelson Chao, MD, MBA
Donald D. and Elizabeth G. Cooke Professor
Chief, Division of Hematologic Malignancies and Cell Therapy
Director, Global Cancer
2400 Pratt St. Suite 5029, Box 3961m Durham, NC 27710
Duke School of Medicine
Office: (919)-668-1010
Fax: (919)-668-1091
Lab: 919-681-6816
Chao002@duke.edu

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Submitted Electronically

March 16, 2019

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

Cc: Katherine B. Szarama, Ph.D., Lead Analyst; Lori A. Paserchia, MD, Lead Medical Officer

RE: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-Cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen:

The Biotechnology Innovation Organization (BIO) appreciates the opportunity to provide comments on the Centers for Medicare and Medicaid Services’ (CMS or “the Agency”) Proposed Decision Memo for the National Coverage (NCD) for Chimeric Antigen Receptor (CAR) T-Cell Therapy for Cancers (“Proposed Decision Memo”).

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. Our members’ novel therapeutics, vaccines, and diagnostics not only have improved health outcomes, including productivity and quality of life, but also have reduced healthcare expenditures due to fewer physician office visits, hospitalizations, and surgical interventions.

A key goal for BIO is to ensure that Medicare coverage policies promote beneficiary access to the most timely and innovative care and treatment for their specific condition. CAR T-cell therapies fall into a group of new treatment options that represent a significant benefit and value for patient health outcomes and overall delivery of care. These “transformative therapies” generally address very serious diseases with high unmet medical need – including rare and orphan diseases - providing a substantial, durable health benefit. “Transformative therapies” include cellular and gene therapies that are truly personalized medicines targeting treatment to specific patient populations. CAR T therapies are a type of treatment for a subset of incredibly vulnerable and sick patients in which a patient’s own T-cells are reengineered to attack cancer cells through a highly-specific manufacturing process producing a unique and personalized treatment.

For this reason, we have been closely following CMS’ National Coverage Analysis (NCA) process for CAR T therapy to ensure the policy developed does not create uncertainty or access barriers for Medicare beneficiaries. Since the time the NCD was initially proposed, BIO has appreciated CMS’ willingness to meet with and hear additional feedback from stakeholders. Incorporation of stakeholder feedback, particularly from the patient and provider community, received on the Proposed Decision Memo is absolutely critical to implementation of an NCD that is successful in addressing CMS concerns around coverage while balancing access to innovative treatments. It is imperative that the final NCD establish a framework that ensures Medicare coverage evolves with CAR T science.

We strongly encourage CMS to make the following changes in the final NCD:

1. Modify the disease state requirements for coverage to account for all Food and Drug Administration (FDA)-approved indications for CAR T-cell therapy, both presently on market and for future therapies, as this will ensure that all patients eligible for CAR T therapy are able to receive Medicare coverage;


2. Ensure that all qualified sites with appropriate training and safety capabilities are able to deliver CAR T therapy to Medicare patients, across hospital and non-hospital settings of care; and


3. Ensure that care for Medicare beneficiaries eligible for CAR T therapy is not disrupted based on potential confusion or implementation challenges stemming from the NCD.

We strongly urge CMS to make these critical updates, and provide additional clarifications and guidance in order to facilitate implementation of an NCD that allows Medicare patients for whom the treatment is appropriate to benefit from this advance in care. In addition, we express caution to the Agency around similar decisions for other future “transformative therapies” to ensure that coverage policies do not hamper access to or the development of innovative treatment options. We explore our concerns and considerations in more detail below.

1. CMS must modify the disease state requirements for coverage to account for all FDA-approved indications for CAR T-cell therapy, both presently on market and for future therapies, as this will ensure that all patients eligible for CAR T therapy are able to receive Medicare coverage.

BIO raises significant concern with CMS’ proposed language requiring that a patient has “relapsed or refractory cancer; and not currently been experiencing any comorbidity that would otherwise preclude patient benefit” in order to have Medicare coverage for CAR T-cell therapy. The implementation of this coverage policy language will impede Medicare patient access in the future as the FDA approves CAR T-cell therapy for additional indications.

At present, there are ongoing clinical trials in the use of CAR T for first-line cancer treatment.(1) CMS coverage policy should not limit patient access to therapies or indications that the FDA has determined to be safe and effective. It is critical that Medicare beneficiaries be able to access this treatment for approved indications as the field continues to advance and deliver promise in new areas of cancer care. CMS coverage policies must appropriately evolve with the FDA’s approval of new therapies and new indications.

To this end, we strongly urge the Agency to amend the language around the coverage requirements, referring to the FDA label for CAR T products and medically accepted indications in the full range of recognized CMS compendia,(2) to provide seamless coverage for future indications for CAR T-cell therapy. CMS should remove the reference to “relapsed or refractory cancer”, allowing the FDA label and medically accepted indications in Medicare recognized compendia to dictate appropriate treatment.

In addition, we urge the Agency to remove the reference to patients “not currently experiencing any comorbidity that would otherwise preclude patient benefit” as this language is subjective and ambiguous. Decisions around appropriateness of treatment with CAR T-cell therapy for medically accepted indications and based on comorbidities must be left to the discretion of a patient’s physician and/or treatment team, bearing in mind the FDA-approved labeling and clinical evidence. Further, we urge CMS to similarly modify the Proposed Decision Memo to allow the FDA labels for each product to dictate when a patient is eligible for repeat treatment. In a field that is rapidly evolving, the use of language requiring a “new primary cancer diagnosis” for coverage of a repeat treatment will be troubling as CAR T indications advance.

Finally, CMS should incorporate consideration of all CMS recognized compendia for purposes of off-label coverage and not just the National Comprehensive Cancer Network Drugs & Biologics Compendia. The consideration of multiple compendia within a coverage determination is important, as each publication uses its own set of rating measures and is updated on unique timelines to reflect the latest advances in treatment changes. By allowing coverage for off-label uses supported by any of the CMS-recognized compendia – as is the case for other cancer therapies - CMS would help ensure timely and accurate treatment for Medicare patients. BIO reminds the Agency that Medicare policy requires that an alternative or prerequisite therapy “is safe, as effective, or appropriate for a given condition” and shall be based on “medical appropriateness”.(3) The use of a single compendium in a broad policy does not adequately account for potential alternative treatment indications that may be detailed in other compendia.

Establishing an NCD that allows flexibility in coverage for future FDA-approved indications for CAR T is ever the more critical given the lengthy and resource-intensive process that is associated with making changes to an NCD once finalized. It would be untenable, both for the Agency and the broader stakeholder community, to consider working on updates to the NCD as each new product, or new indications for existing products, are approved by the FDA. It is critical that the NCD is sufficiently flexible to account for future indications for CAR T therapies, both those currently on the market and in development.

2. CMS should ensure that all qualified sites with appropriate training and safety capabilities are able to deliver CAR T therapy to Medicare patients, across hospital and non-hospital settings of care.

In the text of the draft NCD, CMS proposes to cover CAR T-cell therapy only when it is furnished in “hospitals”. Throughout the Proposed Decision Memo, CMS references “hospitals” in discussing the site of service, and associated care facility requirements and data collection. BIO acknowledges that most of the clinical experience with CAR T therapies to date has involved therapies furnished in hospital settings, but we also recognize that CAR T therapies could be furnished safely in other settings in the future. BIO believes that the language of the NCD must be modified, finalizing an NCD that allows CAR T therapies to be furnished in appropriate settings that meet the proposed criteria and FDA and manufacturers’ requirements, in order to adequately provide coverage for Medicare beneficiaries across settings of care.

We believe that the safety criteria outlined by CMS should suffice in setting forward the standards for sites with the expertise and interest in delivering CAR T-cell therapy. In section B.2 of the proposed NCD Manual text, CMS proposes criteria that sites must satisfy in order to be able to furnish Medicare-covered CAR T therapies:

- a Cellular Therapy Program consisting of an integrated medical team that includes a Clinical Program Director, a Quality Manager, and at least one physician experienced in cellular therapy, and demonstrates that protocols, procedures, quality management, and clinical outcomes are consistent from regular interaction among all team members;
- a designated care area that protects the patient from transmission of infectious agents and allows for appropriate patient isolation as necessary for evaluation and treatment; and
- written guidelines when administering CAR T-cell therapy for patient communication, monitoring, and transfer to an intensive care unit.

BIO fully agrees with the goal of ensuring that CAR T-cell therapy is being delivered by appropriate sites – that possess the knowledge, expertise and institutional capabilities necessary to manage this specialized treatment process and patient follow up. We support these proposed requirements, but we urge CMS to expect that the settings of care for CAR T therapies could evolve over time. The blanket reference to the hospital setting of care interferes with the ongoing clinical studies in physician offices and community sites of care, limiting options for Medicare beneficiaries. If CMS were to establish coverage limitations based on specific provider types, rather than the capabilities of those providers, the Agency could preclude timely patient access to appropriate care in the future, particularly if future CAR T therapies can be provided safely in non-hospital settings.

For certain patients, the non-hospital setting will represent an important additional site of service – clinical studies for CAR T have continued beyond the hospital site of service. Improvements in preventing and treating adverse events, as well as experience from ongoing clinical trials, could lead to expanded access to these therapies across more settings of care. BIO urges CMS to make critical updates that are agnostic of site of care, and allow for coverage when the proposed requirements of section B.2 of the draft NCD Manual text and the FDA and manufacturer’s requirements are met.

It is crucial that the coverage policy for this new, innovative treatment option recognize the role of the patient-provider decision-making process and the advancing science of CAR T treatment, which extends to ensuring the appropriate setting of care. The NCD should be sufficiently flexible to adopt new FDA-approved indications for CAR T, as well as coverage in all sites of service that comply with the requirements outlined. Given the time consuming and resource-intensive process of updating an NCD, and deficits in care that could occur during that timeframe, it is critical that CMS not establish a policy that covers CAR T therapy exclusively in hospitals. Relying on future updates as therapies come to market is not a sustainable or workable process within CMS’ NCD framework.

3. CMS must ensure that care for Medicare beneficiaries eligible for CAR T therapy is not disrupted based on potential confusion or implementation challenges stemming from the NCD.

BIO believes that as presently written, a number of factors outlined in the Proposed Decision Memo could unduly limit or hinder patient receipt of CAR T-cell therapy, either by creating confusion or significant burden in expectations for sites of care, particularly given the short timeline for implementation. Below we outline our recommendations around how CMS should address key concerns:

- Ensure Medicare patients who are currently in the process of receiving CAR T therapy have their treatment covered and do not experience delays or disruptions in care: BIO strongly urges CMS to grandfather in patients who have been deemed eligible for CAR T cell treatment prior to the May 17, 2019 implementation date and to provide coverage for their care in a timely manner, outside of the requirements of the NCD, as the facility in which they are receiving care may still be ramping up their processes to comply with the NCD data collection requirements.

- Recognize the burden associated with compliance for Coverage with Evidence Development (CED) requirements, and ensure efforts by providers to comply does not hinder patient access in the interim: BIO appreciates CMS’ collection of data points that are aligned with existing provider data registries. However, there is still associated burden with the incorporation of these CED elements into provider workflow and data registries. Sites of care should have time to adapt to the requirements, and CMS should produce guidance that provides for continued coverage of CAR T therapy during this timeframe. It would be particularly troubling to see patient access to CAR T jeopardized as sites make a good faith effort to comply with NCD coverage requirements.

- Ensure compliance with patient reported outcomes (PROs) requirements does not create a barrier to access, and select one tool for collection of PRO data: As BIO has previously expressed, we believe that understanding patient perspectives is critical to the development of new and innovative treatment options for patients, and PROs can serve an important role in this process. We reiterate that the FDA is the appropriate Agency to consider PROs as they relate to product safety, efficacy, and labeling. In the use of PRO tools for the CAR T NCD, we recommend CMS clarify the implications on coverage if patients do not consent to submitting PRO data, to ensure that sites and beneficiaries understand their coverage will not be in jeopardy. Further, BIO believes that based on the attributes and information collected, CMS should select the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS®) tool for application in the NCD. Use of one tool can help ensure a more robust data set, and we believe this tool is more appropriately aligned with the delivery of CAR T and the information CMS seeks to collect through the associated CED requirements.

In addition to these critical updates for the CAR T NCD, we urge CMS to exercise caution in considering the need for coverage policies for other new treatments with similar attributes to CAR T therapy so as not to impede future innovations in treatment and patient access to these critical medicines. We are at an exciting time for the future of care for patients with continued advances in personalized medicine and the development of cell and gene therapies that are highly specialized and have long-term impacts for patient health. We underscore the need to ensure that innovative treatments continued to be advanced for the Medicare population, and the ever growing role of extremely targeted and personalized treatments in our healthcare system.

Innovations in therapies, such as CAR T, eliminate or significantly reduce the need for other healthcare interventions – reducing spending and bringing unprecedented health benefit to patients. We raise concern where CMS policy, such as the CAR T for NCD, may signal that the Agency intends to create a policy that is more restrictive than the label and have impacts for the research and development of future treatments. BIO recognizes CMS’ role in ensuring that patients are receiving appropriate therapy for their given condition, but also raise that timely access to the critical benefit these therapies provide must be a priority for the Agency. We caution CMS against taking a one-size-fits-all approach in considering the need for and potential development of coverage policies for future waves of treatment with similar attributes to CAR T-cell therapy (e.g., cellular or gene therapies, single or limited applications, highly specialized patient populations).

BIO appreciates the opportunity to comment on CMS’ Proposed Decision Memo for the National Coverage Determination for CAR T-Cell Therapy. We are concerned that as presently written, the NCD will negatively impact patient access for future FDA-approved indications and additional sites of care for the therapy, and note that other implementation considerations must be addressed to ensure the implementation and use of such a policy does not unnecessarily place Medicare patient access at risk. We urge the Agency to modify the NCD language and provide clarity for implementation. We look forward to continuing working with CMS to ensure the most appropriate care and access to innovative treatment is delivered to cancer patients in the Medicare program. Please do not hesitate to reach out with any questions at (202) 962-9200.

Sincerely,

/S/
Crystal Kuntz
Vice President, Healthcare Policy & Research
Biotechnology Innovation Organization

/S/
Mallory O’Connor
Director, Healthcare Policy & Federal Programs
Biotechnology Innovation Organization

References
(1) See: Clinicaltrials.gov: Study evaluating efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Participants With High-Risk Large B-Cell Lymphoma (ZUMA-12), available at https://clinicaltrials.gov/ct2/show/NCT03761056?term=NCT03761056&rank=1; A study evaluating EGFRvIII CAR T Cells for Newly-Diagnosed WHO Grade IV Malignant Glioma (ExCeL), available at https://clinicaltrials.gov/ct2/show/NCT02664363?term=NCT02664363&rank=1 ; A study evaluating Up-front CART-BCMA With or Without huCART19 in High-risk Multiple Myeloma, available at https://clinicaltrials.gov/ct2/show/NCT03549442?term=NCT03549442&rank=1.
(2) Social Security Act (SSA) § 1861(t)(2)(B)(2); Medicare Benefit Policy Manual, ch. 12, § 50.4.5
(3) Id.

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March 16, 2019

Ms. Seema Verma
Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Hubert H. Humphrey Building
Room 445-G
200 Independence Avenue, NW
Washington, DC 20201

Tamara Syrek Jensen
Director
Evidence and Analysis Group

Katherine B. Szarama, PhD
Lead Analyst
Evidence and Analysis Group

Lori A. Paserchia, MD
Lead Medical Officer
Evidence and Analysis Group

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

Subject: National Coverage Analysis for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Administrator Verma, Ms. Jensen and Drs. Szarama and Paserchia:

The undersigned organizations represent hundreds of thousands of cancer patient and survivors. With these constituents in mind, we appreciate the opportunity to provide comments on the recently-released National Coverage Analysis for Chimeric Antigen Receptor (CAR) T-cell therapy for the treatment of cancers.

We gratefully acknowledge the effort that the Centers for Medicare & Medicaid Services (CMS) has committed to understanding the impact of CAR T-cell therapy on people with cancer. However, the agency has proposed a coverage with evidence development (CED) process that rejects the principle that U.S. Food and Drug Administration (FDA) approval (a finding that a drug is safe and effective) is adequate to support a finding that a drug is reasonable and necessary and will be covered by Medicare. This is a change from drug coverage policy that may have significant effects on patient access. We ask CMS for clarification of its decision to reject usual coverage principles and to explain how patient access will be protected during the CED process.

The two CAR T-cell therapies which have been approved by the FDA impact patient populations which experience poor outcomes and have limited treatment options; in some cases, no other treatment options exist. In addition to these two treatments, there are more than 250 clinical trials currently studying the use of cellular therapies.

To accelerate access to effective, innovative therapies and collect the data necessary to aid in the delivery of quality cancer care to beneficiaries, CMS must clarify patient eligibility for the CED process. We recommend that coverage not be limited to relapsed and refractory cancers but instead be consistent with FDA-approved indications. We also urge that CMS consider how products that may be approved during the course of this CED process be included.

Similarly, the provision which allows CAR T-cell therapy to be administered only to individuals that have “not currently been experiencing any comorbidity that would otherwise preclude patient benefit” lacks precision. The proposal does not make clear how CMS will define these comorbidities nor which party will be responsible for confirming and monitoring their existence. The patient population currently treated with these therapies is very ill and it is likely that some will suffer from other chronic conditions. To protect the integrity of the patient-doctor relationship and account for the evolving use of CAR T-cell therapy across different disease states, histologies and patient populations, only physicians should determine whether their patient is able to benefit from the therapy. We also believe that additional guidance around “new primary cancer diagnosis” and “the use of more than one therapeutic dose of a specific CAR T-cell product” is necessary. Here too we believe that a patient’s healthcare provider is in the best position possible to determine when and whether a patient will benefit from CAR T-cell therapy and should not be limited by narrow coverage policy.

As the use of CAR T-cell therapy expands, it is clear that CMS seeks to better understand the use of this treatment; its ability to improve patient survival; and patients’ experience with treatment. To ensure that any data collection mechanism succeeds in achieving these goals it is critical that the process and means by which the data will be gathered and aggregated is unambiguous. This includes the process which CMS will use to approve studies and registries that qualify the coverage standards. No standards have been outlined which address whether the questions and requisite data are appropriate, nor the process by which disease-specific experts may be consulted to ensure that questions are suitable to a specific patient population. It is also necessary to define the settings in which therapy is administered - which may change during a single course of treatment - and the factors which qualify an institution and its staff to administer CAR T-cell therapies.

The utility of collecting patient-reported outcomes (PRO) to complement other cancer treatment data is well demonstrated and we recognize CMS for considering the patient perspective. If implemented, consistency of data collection through a single PRO tool is recommended to avoid confusion and guarantee a robust body of data. Acknowledging the functional and health status of the patients currently treated with CAR T-cell therapy is also necessary. Because these patients are severely ill, we recommend that CMS account for patients’ ability and election to participate in any data collection exercise. Coverage should not be jeopardized for those patients who cannot or will not participate. Toward that end, greater clarity is also needed to understand which party will be responsible for patient education and tracking the patient and their participation in required data collection activity. Per federal regulation, National Coverage Decisions (NCD) become effective upon the date of their final publication. In the case of the NCD for CAR T-cell Therapy for Cancers, that date is projected to be May 17, 2019. Given the length of time and complexity of CAR T-cell therapy administration, it is likely that a single date is an unreasonable effective date for this NCD. It is important for CMS to take into consideration the length of time typically required for the entire treatment process to take place and specifically outline its plan to ensure that no patient or hospital risks non-coverage during the NCD’s announcement and implementation. Blood cancer patients currently treated with CAR T-cell therapy cannot afford the time delay which may accompany a lack of clarity in coverage. Such clarification will ensure that patients suffering from life-threatening cancers will have access to this treatment, as recommended by their physicians, without interruption.

We appreciate this opportunity to provide comments to CMS and remain eager to work together to ensure that beneficiaries’ access to this innovative and potentially life-saving therapy is not compromised.

Sincerely,
American Cancer Society Cancer Action Network, Inc.
Blood & Marrow Transplant Information Network
CancerCare
Cutaneous Lymphoma Foundation
International Myeloma Foundation
International Waldenstrom's Macroglobulinemia Foundation
Lymphoma Research Foundation

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The Provider Roundtable is pleased to submit comments on the Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N). The Provider Roundtable (PRT) is a forum for hospital professionals to collaborate on and communicate about health care regulatory issues that are critical to their organizations. The PRT includes representatives from 14 different health systems, serving patients in 18 states. PRT members are employees of hospitals and, as such, we have financial interest in fair and proper payment for hospital services, but do not have any specific financial relationship with vendors.

The members collaborate each year to provide substantive comments with an operational focus for OPPS, MPFS rules, and other regulatory developments upon which CMS seeks input. We do this by presenting at the HOP Panel meeting, submitting written comments on proposed regulations, and meeting with CMS representatives when offered the opportunity.

We understand the issues that CMS faces in balancing costs and providing your beneficiaries (and our patients) with the best care possible. For those reasons, we offer comments that attempt to balance the operational challenges providers face, the concerns our patients cope with, and the goals CMS attempts to meet. Several of our members’ facilities are currently offering CAR T-cell therapy services, and all of the PRT members have oncology services; we all realize that CAT-T is becoming a valuable treatment for leukemia and lymphoma when other options have failed.

The PRT is concerned that this National Coverage Determination (NCD) requires a Coverage with Evidence Development (CED). While we understand CMS’ goal in using the CED to develop evidence, we are concerned that doing so will discourage hospitals from providing this essential service. This NCD will, in fact, become a barrier to care by effectively boxing out beneficiaries who are generally elderly and also very ill. These beneficiaries will either be forced to travel longer distances for treatment in centers that do participate in data collection as part of the CED (and thus are able to treat Medicare patients), or to not receive possibly life-saving care. In addition, the CED requirement will put hospitals that do perform the service in a financially difficult position, since reimbursement for the CAR-T DRG does not cover the cost of this life-saving treatment.

We understand that coverage is separate from reimbursement, and that the proposed NCD discussed CAR T-cell therapy coverage rather than payment. Nonetheless, the PRT members feel that it is important for CMS to recognize that creating additional requirements for coverage that generate more uncompensated work on the part of hospital clinicians and staff. This also creates additional costs that compound the losses hospitals already face when treating patients with CAR T-cell therapy. This will, inevitably, impact the decision on whether or not a specific hospital will provide this new line of treatment.

The PRT also notes that it is not clear why reporting the additional Patient Reported Outcome requirement (PRO) is needed for these outpatients. This is particularly true, given the NCA processes’ stated purpose: to determine if a treatment is reasonable and necessary for Medicare beneficiaries and should be covered. If a physician believes the cells can safely be administered in an outpatient setting, then it should be covered in the outpatient setting. Requiring PRO collection will increase the burden to physicians who might feel it is best for their patients to be treated in the outpatient care setting. Medical necessity will not change based on the PRO data collection. As the PRT has stated in numerous comment letters, we believe the OPPS Inpatient-Only List has increased CMS’ costs by requiring hospitals to admit patients as an inpatient when the procedure could have been done safely in the outpatient setting; we further believe that the Inpatient-Only List exposes patients to the risks of hospitalization when there is no benefit in doing their being admitted to a facility.

For these reasons, the PRT requests that CMS finalize this NCD as an NCD alone, and not as an NCD with CED and required PROs.

An attachment with the same information has been emailed to CAGinquiries@cms.hhs.gov

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March 16, 2019

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

RE: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen:

On behalf of bluebird bio, Inc. (“bluebird”), we appreciate the opportunity to submit comments in response to the Centers for Medicare and Medicaid Services (CMS) Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N) (the “Proposed Decision Memo”).¹

bluebird is a clinical stage company that is developing investigational gene therapy technologies that have the potential to significantly improve clinical outcomes for patients with severe genetic diseases and cancer. Our late-stage clinical development programs are studying an approach to gene therapy that adds functional copies of a faulty gene to a patient’s own blood stem cells. The functional copies of the gene are delivered into the patient’s blood stem cells outside of the patient’s body. This makes the gene therapy. The gene therapy is then administered to the patient through a hematopoietic stem cell transplant, which takes place in an inpatient hospital setting. As part of the transplant process, the patient receives myeloablative chemotherapy to make room in their bone marrow for the gene therapy. After the gene therapy has been infused, the patient’s cells multiply and produce enough new cells with the functional gene. Since these therapies aim to address the underlying cause of disease, not just treat the symptoms, they can provide potentially curative, disease-modifying effects – potentially with life-long clinical benefits, based on a single administration.

Gene therapy technology also can genetically modify a patient’s own T cells with a goal of targeting and destroying cancer cells. Like our programs for hematopoietic stem cells (stem cells from the patient) in rare genetic disorders, our CAR T-cell technology uses a customized lentiviral vector that has been designed to alter T cells, so the T cells can recognize specific proteins on the surface of cancer cells or other diseased cells and kill them.

bluebird's oncology pipeline is built upon the company's expertise in lentiviral gene delivery and T-cell engineering, with a focus on developing novel T cell-based immunotherapies, including CAR T-cell therapies and T-cell receptor (TCR) therapies. Our lead oncology programs are anti-B-cell maturation antigen (BCMA) CAR T-cell programs partnered with Celgene. bluebird’s other clinical programs include its investigational gene therapy for the treatment of cerebral adrenoleukodystrophy (CALD), and its investigational gene therapy product candidate for the treatment of transfusion-dependent beta-thalassemia (TDT) and severe sickle cell disease.

bluebird appreciates the time and consideration CMS has put into evaluating the growing field of CAR T-cell therapies for cancer in this proposed decision. We agree with CMS that longer term evidence needs to be developed to capture the value for these potentially curative treatments while providing patients access to these therapies. However, we think that CMS’s proposal for coverage with evidence development (CED) has the potential to unduly limit or effectively deny Medicare beneficiary access to CAR T-cell therapies unless several refinements are made. Thus, if CMS is intent on moving forward with CED in a final decision memorandum on CAR T-cell therapies (the “Final Decision Memo”), we urge the Agency to recognize that one-size does not fit all with regard to cell and gene therapy technologies and to expand the proposed coverage decision to be more inclusive of future therapies to afford access in the short term and collect the evidence required to move the system toward tying payment directly to value in the longer term.

To achieve this, bluebird makes the following recommendations that we urge CMS to adopt in the Final Decision Memo:

• Clarify that Medicare coverage of FDA-approved CAR T-cell therapies will be aligned with the product’s approved label and/or CMS-approved oncology compendia guidelines;
• Clarify that the setting of care in which a CAR T-cell therapy can be administered (in conjunction with a Cell Therapy Program) and covered under Medicare will be at the discretion of the physician; and
• Clarify the expectations for compliance with a clinical study and/or real-world evidence data registry.

We elaborate on these recommendations in the balance of this letter.

CMS has proposed covering CAR T-cell therapies for relapsed and refractory cancers in inpatient and outpatient hospital affiliated settings with Cell Therapy Programs, that participate in a CMS approved registry.² Given that the Final Decision Memo will govern all CAR T-cell therapy coverage unless and until CMS revisits the decision, we urge the Agency to expand the scope of coverage to take into account not just those therapies approved currently, but therapies that are likely to come to market over the next several years. Specifically, CAR T-cell therapies are currently being investigated for use in earlier lines of oncology therapy. If such uses are approved by the Food and Drug Administration (FDA), they should be covered in accordance with their approved product labels and/or CMS-approved compendia. Expanding the definition of a covered CAR T-cell therapy to take into account potential future uses will more appropriately mirror evolving standards of care as well as defer to the expert judgement of the FDA and physician experts. It also will track the way in which oncology therapies are currently covered under Medicare. Unless the Agency expands the scope of coverage to be able to account for evolving standards of care, CMS risks inappropriately limiting beneficiary access to the detriment of individual patient health.

bluebird appreciates that CMS, in the Proposed Decision Memo, prioritizes patient safety by establishing a standard Cellular Therapy Program requirement across all facilities administering CAR T-cell therapies to ensure they are appropriately administered, and the patient appropriately monitored for the therapies’ safety profiles.³ However, as in the previous recommendation, bluebird urges CMS to consider not just the current standard of care but the reality that this standard will continue to evolve as physicians learn more about how CAR T-cell therapies perform in real world settings and as these therapies continue to be investigated under various conditions in clinical trial settings. For example, evidence is currently being generated by companies in clinical trial programs that examines the safety and efficacy of administering CAR T-cell therapies in the community outpatient setting. While this setting may not be appropriate for all such therapies, and any setting in which CAR T-cell therapies are administered should meet the same standards for a Cell Therapy Program, we do not believe that the Agency should finalize a care setting based only a snapshot of today’s standard of care. Instead, the Final Decision Memo should defer to FDA-approved product labels and CMS-approved compendia guidelines rather than impose a rigid ‘hospital-based’ setting of care standard that may not accurately reflect standard of care in several years’ time. If CMS does not make this change, bluebird is concerned that there could be unintended consequences, including limiting access for patients to valuable, safe, and appropriate therapies for cancer treatments.

bluebird appreciates CMS’s goal of furthering evidence development in the field of CAR T-cell therapy, especially understanding if real world results are similar to those conducted in clinical trials. We would appreciate clarity on the expectations for the registry requirement, which we detail in the balance of this sub-section.

First, bluebird asks CMS to provide clarity on the patient-reported outcomes (PROs) that are proposed for collection in the Proposed Decision Memo. Specifically, we recommend that CMS make collection of PROs voluntary rather than mandatory to account for the reality that not all patients may want to participate in the collection or reporting of these data but that should not prevent a patient from receiving appropriate care with CAR T-cell therapy. We also recommend that CMS encourage—but not require—providers to collect PROs in both the inpatient and outpatient care settings to engender evidence-based comparisons across these settings of care.

Additionally, in the Final Decision Memo, we ask CMS to address the following outstanding issues to avoid confusion among Medicare providers and facilitate timely patient access to CART-cell therapies:

• The criteria or features of currently operating registries that would allow them to fulfill the proposed requirements set forward in the Proposed Decision Memo.
• The Agency’s plan to ensure that a registry (or registries) is (are) operational on the first day the Final Decision Memo is effective to avoid any delays in patient access to CAR T-cell therapies (including CMS’s plan to establish the required data collection and analysis infrastructure by the time the Final Decision Memo is effective, if existing registries cannot meet the standards established).
• CMS’s timeline to phase out the registry requirement (in line with the terms of CED).
• CMS’s expectations surrounding determination of data comparisons across settings of care, sites, and patient populations treated with CAR T-cell therapies and the Agency’s confirmation that providers involved in the study/registry will be the ultimate arbiters of those analyses.
• How CMS expects the data registry required under the Proposed Decision Memo to be funded.
• Whether CMS will accept ongoing manufacturer/provider studies or clinical research grade registries that meet the requirements of the NCD.

bluebird reiterates our appreciation for the opportunity to submit comments on the Proposed Decision Memo. We appreciate CMS’s attention to the important issues surrounding the developing landscape of CAR T-cell therapy for cancers. The healthcare system relies on ensuring that coverage policies facilitate, rather than impede, appropriate and timely uptake of these novel treatments.

If CMS has any questions regarding bluebird’s recommendations, or if I can provide any additional details, please do not hesitate to reach out to me at mbattaglini@bluebirdbio.com. bluebird looks forward to working with CMS moving forward on these critical issues.

Sincerely,

Mark Battaglini, JD
Vice President, Global Government Affairs & Public Policy

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1 CMS, Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N) (February 15, 2019), available at: https://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=291.
2 For example, see CMS Proposed Decision Memo section I(a), p. 4.
3 CMS Proposed Decision Memo section I(b), pp. 4-5.

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March 16, 2019

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

RE: Proposed National Coverage Determination for Chimeric Antigen Receptor (CAR) T-cell therapy for Cancers

Dear Ms. Syrek Jensen:

Autolus Therapeutics plc (“Autolus”) appreciates the opportunity to provide comments on the Centers for Medicare and Medicaid Services (CMS) Proposed National Coverage Determination for Chimeric Antigen Receptor (CAR) T-cell therapy for Cancers.^[1]

Autolus is a biopharmaceutical company developing next-generation programmed T-cell therapies for the treatment of cancer. Using our broad suite of proprietary and modular T-cell programming technologies, we are engineering precisely targeted, controlled and highly active T-cell therapies that are designed to better recognize cancer cells, break down their defense mechanisms and eliminate these cells. We believe our programmed T-cell therapies have the potential to be best in class and offer cancer patients substantial benefits over the existing standard of care, including the potential for cure in some patients.

Our clinical-stage pipeline comprises four product candidates in five hematological indications and one solid tumor indications. We expect to complete the proof-of-concept phases of four Phase 1 and Phase 2 clinical trials in hematological cancer indications in 2019. These clinical programs are adaptive and designed to allow collection of sufficient data in the expansion phase of the trials to potentially support registration.

Autolus uses a semi-automated, fully enclosed system for cell manufacturing, which is designed to provide a common platform suitable for manufacturing all our product candidates and to allow for rapid development of our product candidates through clinical trial phases and the regulatory approval processes. In addition, this platform allows for parallel processing and the ability to scale for commercial supply in a controlled environment and at an economical cost. We plan to build internal manufacturing and supply capabilities as well as to utilize the expertise of collaborators on some of the aspects of product delivery, logistics and capacity expansion. We believe having established manufacturing processes suitable for commercialization early in the development of our T-cell therapies will allow us to focus on expanding manufacturing capacity during our clinical trials.

Cancers thrive on their ability to fend off T-cells by evading recognition by T-cells and establishing other defense mechanisms, such as checkpoint inhibition and creating a hostile microenvironment. Our next-generation T-cell programming technologies allow us to tailor our therapies to address the specific cancer we are targeting and introduce new programming modules into a patient’s T-cells to give those cells improved properties to better recognize cancer cells, overcome fundamental cancer defense mechanisms and increase durability.

We anticipate that the market for T-cell therapies will be characterized by rapid cycling of product improvements. We believe our modular approach to T-cell programming and the common manufacturing platform used across all our T-cell therapies will position us to more quickly develop follow-on, or next-generation, product candidates with enhanced characteristics, such as pharmacological control, insensitivity to checkpoint inhibition or other desirable features. We want to flag the rapid development cycle for CMS, as this will represent a shift in the current paradigm of developing follow-on product candidates.

Due to the nature of this rapid development cycle, we encourage CMS to act within its authority to be more inclusive for future therapies. Allowing for Medicare contractor discretion on other than relapsed or refractory therapies or for situations that may be beyond the scope of the REMS of current therapies will ensure timely access to the best available treatment for Medicare beneficiaries when therapies that are currently in development are approved by the FDA between 2019-2024.

Cover all CAR T-cell therapies with Evidence Development

CMS has proposed to cover relapsed and refractory cancers with evidence development that are FDA-approved or National Comprehensive Cancer Network (NCCN) grade 2 or 1, delivered in inpatient and outpatient hospital affiliated settings with a Cell Therapy Program, and that meet the registry or clinical study requirements. Autolus understands and appreciates CMS’ responsibility and intent to cover FDA-approved or unapproved NCCN compendia recommended therapies for Medicare beneficiaries. We also appreciate that Medicare is concerned about current and future care of its beneficiaries. We understand the coverage decision as currently written focuses on the state of the two therapies currently being marketed for relapsed and refractory cancer.

As written, the NCD would not cover CAR T-cell therapy for first line cancers even if approved by the FDA or recommended by grade 2 or 1 NCCN compendia. However, as we discussed CAR t-cell therapies are in rapid development, and cancer is unique given the potential for Medicare coverage of off label anti-cancer therapies. As such, we would ask that CMS use more flexible language to ensure that as future CAR T-cell therapies are FDA-approved or compendia recommended, patients have access to these therapies. Not only will this change ensure that patient access is not unintentionally limited by language in the NCD, the change will prevent the need for CMS to revisit the coverage decision when therapies with new indications enter the market. We understand that CMS may feel CED is necessary to support anticipatory coverage of future indications, given the unknown character of future evidence.

Replace the term “Hospital” to “Treatment Facility” or “Treatment Site”

Autolus is similarly concerned that the use of the word “Hospital” will limit FDA approved and compendia recommended CAR T-cell therapies by the language that is used in the proposed coverage decision. Autolus understands that the current FDA-approved therapies on the market are FDA-approved with Risk Evaluation and Mitigations Strategy (REMS) program participation.^[2],[3] These REMS programs require hospital-affiliated sites of care.^[4],[5] We would like to request that CMS update the benefit categories that CAR-T cell therapies fall under to include Section 1861(s)(1) and 1861 (s)(2)(A).

CAR T-cell therapies should not be limited to “Hospital” administration only as newer innovative therapies in development are being designed with improved clinical profiles that will not have such high-grade toxicities or the need to be hospitalized. In some cases, these are being studied in clinical trials outside of the hospital setting.  We propose considering the use of criteria that has been set forth in Sec. 2.a-c as CMS’ qualifying criteria for “Treatment Facilities or Sites” without the need to name the facility. By using more flexible language, CMS will ensure appropriate treatment for Medicare Beneficiaries to future CAR T-cell therapies upon approval by the FDA or covered compendia recommendation.

CMS mentions in the Proposed Decision Memo that the list it provides may not be an exhaustive list of all applicable Medicare benefit categories for this service. For clarity purposes, Section 1861(s)(1) and 1861 (s)(2)(A) should be added. This change will reduce any unintended obstacle for Medicare beneficiaries to be able to receive effective and safe treatment in the most appropriate setting. We understand that there is a claims modifier “RE” designating that an item or service was furnished in full compliance with an FDA mandated REMS. Requiring the modifier on all CAR-T claims would allow the site of service to adapt to other REMS requirements without the need to reconsider the NCD.

Approve a CED Registry by May 17

Autolus agrees with the inclusion of a registry and believe CMS should approve the Center for International Blood & Marrow Transplant Research (CIBMTR) as a CMS assigned registry for CAR T-cell therapies. We understand that CMS is actively engaged with CIBMTR and request that CMS clarify what specific information will need to be collected, by whom and how it is intended to be used. Additionally, Autolus requests that if any components of the registry or CED are not ready for rollout by May 17, 2019, that CMS would delay the registry requirement until such time that the registry is available to avoid a potential gap in coverage for beneficiaries.

Do Not Penalize Providers Unable to Collect Patient Reported Outcome (PRO) Data

Autolus agrees with CMS’ sentiment that real-world experience with CAR T-cell therapies is crucial for understanding the durability and effectiveness of these treatments as more patients gain access outside of clinical trials. CMS has proposed that hospitals delivering CAR T-cell therapy in the outpatient setting must collect a patient reported outcome in their registries, in addition to meeting the other requirements of the inpatient registry. We are concerned that the burdensome collection of PROs could possibly deter hospitals from providing CAR T-cell therapy to Medicare beneficiaries in the outpatient setting, unintentionally limiting patients’ access to these treatments. We suggest CMS collect the PROs to not limit patient access in the case a hospital or registry without the resources to be able to collect this data.

Ensure the safety of Medicare beneficiaries post product administration

Autolus would also like to provide recommended language for “Patient Discharge Instructions” in Section A.2.c. We recommended complimenting what CMS has already written with the following language:

Given the serious and non-serious adverse events that can occur following discharge, it is critical that the patient and caregiver receive detailed verbal and written instructions as to actions that should be taken should certain symptoms present. We recommend that you add this requirement as part of the communication requirement referred to in section A.2.c.:

Autolus would like to reiterate its appreciation to CMS for the thoughtful consideration of the exciting and rapidly developing field of CAR T-cell therapy. CMS’ leadership of coverage in this space sets the example for the health care system. We encourage CMS’ to continue to facilitate access to innovative therapies for its beneficiaries.

If you have any clarifying questions or would like to discuss our recommendations further, please do not hesitate to reach out at b.rice@autolus.com or 805.490.004. Autolus looks forward to working with CMS as the cellular therapy space continues to evolve and innovate.

Sincerely,

Brent Rice 
Vice President, Global Market Access

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[1] https://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=291

[2]https://www.accessdata.fda.gov/drugsatfda_docs/rems/Kymriah_2018_05_01_REMS_Full.pdf

[3]https://www.accessdata.fda.gov/Scripts/Cder/Rems/index.cfm?event=IndvRemsDetails.page&REMS=368

[4]https://www.accessdata.fda.gov/drugsatfda_docs/rems/Kymriah-2018_05_01_Hospital%20Enrollment%20Form.pdf

[5] https://www.yescartarems.com/wp-content/uploads/yescarta-rems-knowledge-assessment.pdf

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March 16, 2019

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

Cc: Katherine B. Szarama, PhD, Lead Analyst; Lori Paserchia, MD, Lead Medical Officer

Re: National Coverage Decision (NCD) for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Mrs. Syrek-Jensen:

The Alliance for Regenerative Medicine (ARM) appreciates the opportunity to comment on the recently issued National Coverage Decision (NCD) for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers.¹ ARM is comprised of more than 300 leading life sciences companies, research institutions, investors, and patient groups that represent the regenerative medicine and advanced therapies community. ARM takes the lead on the sector’s most pressing and significant issues, fostering research, development, investment, and commercialization of transformational treatments and cures for patients worldwide. Our diverse membership is united around a singular goal of improving the health and outcomes of patients. Because of this goal, ARM’s members have significant experience in clinical trial development, efficient data collection, and safety monitoring activities. As a result of these experiences, ARM provide the following concerning comments on these issues to CMS’ proposed NCD.

As of year-end 2018, ARM estimates there are 906 regenerative medicine and advanced therapies developers worldwide sponsoring 1,028 clinical trials across dozens of indications, including oncology, cardiovascular, central nervous system, musculoskeletal, metabolic disorders, ophthalmological disorders, and more.²

A subset of these clinical trials focuses on the power of chimeric antigen receptor (CAR T) therapies. These therapies are the first in a wave of new and exciting advanced therapies and technologies that are the next frontier in the fight against some of humankind’s most devastating diseases and disorders. CAR T therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient’s blood, as it flows through a tube to an apheresis machine, which removes the white blood cells, including the T cells, and sends the rest of the blood back to the patient. Then, the gene for a special receptor called a chimeric antigen receptor (CAR) is inserted into the T cells in the laboratory. Millions of the CAR T cells are grown in the laboratory and then given to the patient by infusion. The CAR T cells are able to bind to an antigen on the cancer cells and kill them.³ ARM is currently tracking the outcomes of the approximately 158 ongoing clinical trials using the CAR T technology in a variety of stages of cancer and cancer types. ARM believes that this new and promising technology provides the possibility that most future treatments for many types of cancer at its many stages will focus on using the power of the patient’s own immune system to fight their particular cancer.

ARM believes that we are at the beginning of our scientific journey to curing many of these diseases and urges CMS to work with all stakeholders in order to streamline and ensure broad and safe beneficiary access on the date the NCD is finalized, reduce duplicative data collection efforts for sites of care, and implement a patient reported outcome tool that allows for the agency to appreciate the full breadth and depth of the patient experience. With this focus, CMS’ Coverage with Evidence Development (CED) program will hopefully balance immediate broad access to CAR T technologies while generating the necessary data to further determine the full range of the technology’s clinical power.

I. Regenerative Therapies Represent the Future of Health Care

In addition to CAR T therapies, ARM provides the following primer on the other powerful technologies under clinical development.

• Cell therapy is broadly defined as the administration of viable, often purified cells into a patient’s body to grow, replace, or repair damaged tissue for the treatment of a disease. A variety of different types of cells can be used in cell therapy, including hematopoietic (blood-forming) stem cells, skeletal muscle stem cells, neural stem cells, mesenchymal stem cells (adult stem cells that differentiate into structures as connective tissues, blood, lymphatics, bone, and cartilage), lymphocytes, dendritic cells, and pancreatic islet cells.
• Cell therapies may be autologous, meaning that the patient receives cells from their own body, or they may be allogenic, meaning the patient receives cells from a donor. Allogeneic cell therapies are often referred to as “off-the-shelf” therapies, as they are derived from a donor who is not the patient, enabling advance preparation and available to the patient immediately at the time of need.
• Many cell-based therapies currently being developed utilize induced pluripotent stem cells (iPSCs). Unlike embryonically-derived pluripotent stem cells, these are adult cells that have been genetically reprogrammed back into a pluripotent state, capable of becoming one of many types of cells inside a patient’s body. This technology may enable the development of an unlimited type of a specific type of human cells needed for therapeutic purposes.
• ARM members are currently developing cell therapy approaches to treat diseases and disorders that include chronic heart failure, Crohn’s disease, ALS, ischemic stroke, diabetes, Parkinson’s disease, degenerative disc disease, and more.
• Tissue engineering combines scaffolds, cells and biologically active molecules into functional tissues to restore, maintain or improve damaged tissues. Biomaterials are medical devices designed to interact with living systems, providing physical structures and support for engineered tissues. ARM members are currently developing tissue-engineered products and biomaterials to treat cartilage damage and degeneration, wound repair, spinal cord injury, hernia repair, and more.
• Gene therapy seeks to modify, replace, inactivate or introduce genes into a patient’s body with the goal of durably treating, preventing or even curing disease. Gene therapy techniques include genetically modifying a patient’s cells outside of their body, which are then re-introduced to deliver a therapeutic effect, an approach known as gene-modified cell therapy. ARM members are currently developing gene therapy and genome editing approaches to treat inherited blood disorders beta-thalassemia and sickle cell diseases, blood cancers leukemia and lymphoma, inherited retinal disease, Huntington’s disease, and more.

What is critical about all these technologies is that many of the therapies are transformative – they provide a durable therapeutic benefit or even a cure with a single administration of therapy.

ARM is concerned that based on the details presented in the proposed NCD, beneficiary access to current and future therapies could be limited or delayed and therefore offers its suggestions below on how to improve overall access to these transformative therapies.

II. Current Data Suggests that Trials Used to Support FDA Approval are Generalizable to Medicare Population

ARM agrees with CMS that the CAR T therapies currently on the market and those in the pipeline show great promise for patient populations that have limited options and very poor outcomes with continued chemotherapy. Prior to the approval of the two CAR T therapies, these patient populations had a very short life expectancy. These same patient populations are now being treated with CAR T technology and are experiencing durable responses with some patients in a complete response several years after treatment, specifically those from the original clinical trials.

ARM understands CMS’ desire to collect additional data on Medicare beneficiaries, and believes strongly that these data will continue to demonstrate the promise of CAR T cell therapy for Medicare beneficiaries. For example, Kite/Gilead’s two year follow up of its ZUMA 1 trial included a sub group analysis of Medicare aged population. That analysis confirmed that at the two year follow up, Medicare aged patients treated with YESCARTA had similar clinical and safety outcomes as the younger patient population. Similarly, in the pivotal trial for tisgenlecluecel in DLBCL, the overall response rate was consistent in patients over 65 years of age with those below 65.

Given the strength of the currently available data, ARM believes that CMS should include the data from both clinical trials and post market in its CED analysis as this will help the agency conclude that the data used to support FDA approval is also appropriate for determining coverage because it is generalizable to the Medicare population.

III. Much of the Proposed Data Collection in The NCD Is Ongoing and Should be Leveraged and Not Duplicated by CMS

CMS proposes the collection of certain clinical data elements that are already being collected as part of an existing cellular therapy registry. Therefore, ARM urges CMS to leverage the existence of this registry and the lessons learned from this registry when developing the registry for the CED. ARM believes that selecting a centralized registry to coordinate data collection, from an organization with relevant experience, will make the synthesis of data more efficient, as compared to allowing new individual registries to collect data. Further, allowing new individual registries, without previous experience in capturing cellular therapy outcomes data, will create an additional administrative and financial burden to administering sites.

CMS proposes the collection of certain clinical data elements that are already being collected as part of an existing cellular therapy registry. Specifically, the proposed CED requires the furnishing site of care to track the following data elements at baseline, at treatment, and at follow-up 3 months, 6 months, 12 months, and 24 months after the treatment is administered: age, gender and comorbidities; specifics of cancer diagnosis (e.g., sub-classification, stage); number(s) or line(s) of previous therapies, therapeutic agents previously administered; days to disease progression; days to recurrence; overall survival; and progression-free survival.

ARM notes that the overwhelming majority of these requisite CED data elements are already being tracked, at the above specified intervals, by the Center for International Bone & Marrow and Transplant Research (CIBMTR) Cell Therapy Registry. In addition, the manufacturers of both CAR T products are working with CIBMTR to capture data on safety and efficacy consistent with the FDA requirement of a 15-year post-marketing observational study. The Cell Therapy Registry captures data, including many of the proposed CED requisite data elements, from the FDA-required observational studies for both approved CAR T therapies by following at least 1500 patients for 15 years after CAR T administration.

As part of the final NCD, ARM urges CMS to clarify how it will work with the organization/s operating the registry (e.g., CIBMTR) to establish a process for the organization to share the aggregate clinical data collected on Medicare beneficiaries at set intervals and engage the provider and researcher communities on the CED questions specified in the proposed decision memo. Under this approach, as more data is collected, CMS can adjust, if necessary, the NCD quicker than under a CED.

Finally, ARM reminds CMS that each CAR T cell therapy includes a safety monitoring program through an FDA Risk Evaluation and Mitigation Strategy (REMS), which is in place to ensure hospitals are certified to treat with CAR T and ensure providers are trained on adverse event monitoring. ARM believes that monitoring the safety and adverse event profile of any given therapy is within the jurisdiction of the FDA, as demonstrated by the REMS, which is already driving the collection of much of the proposed CED data elements.

Therefore, ARM urges CMS to leverage current data collection efforts and not duplicate them within the CED.

IV. Patient Inclusion Criteria Must Mirror Current Beneficiary Access to Other Anti-Cancer Treatments.

The promise of cell therapy is uniquely exciting for the patients and their families that have limited effective cancer treatment options and otherwise poor survival outcomes. These patients deserve the same access to cancer treatments as all other Medicare beneficiaries under the law.

The NCD only permits coverage to patients who have relapsed or refractory cancer (R/R). There is no discretion at the local level, and even worse, no consideration of all current therapies being studied in other indications/disease states. ARM believes that CMS must expand its eligibility criteria to create equal access for Medicare beneficiaries to future regimens and those therapies supported in all of CMS’ recognized compendia.

The proposed NCD specifically limits coverage to R/R, but as mentioned above, many current clinical trials are currently investigating the value of CAR T in many types of cancer at many different stages. For example, there are ongoing trials in evaluating CAR T cell therapy’s front-line potential to treat various aggressive cancer subtypes such as glioblastoma, multiple myeloma, and aggressive B-cell lymphomas.⁴ If any one of these trials is successful, there does not seem to be a path to coverage for these patients as the proposed NCD precludes access for Medicare beneficiaries to anything but a R/R indication. ARM believes that this fundamentally discriminates against future Medicare beneficiaries because the agency is denying them coverage to an FDA approved therapy. Specifically, ARM asks the agency to clarify how it will cover future FDA approved CAR T therapies?

As such, in order to preserve access to future FDA approved indications, ARM recommends that CMS amend the NCD to account for and be flexible enough to include future CAR T therapies. If a therapy is FDA approved, this NCD must not preclude Medicare patients from access to that therapy.

The Social Security Act (SSA) states that the term drug includes drugs or biologicals used in an anticancer chemotherapeutic regimen for a medically accepted indication, which is further defined as any use which has been approved by the FDA for the drug and such use is supported by one or more citations which are included in one or more of a CMS approved compendia with certain levels and types of evidence.⁵ ARM is concerned that the agency narrowed coverage to only NCCN guidelines thereby ignoring the statute and Congress’ intent to provide broader coverage to anticancer therapies that are included in a CMS approved compendia. As such, ARM urges CMS to remain consistent with its current coverage policy related to compendia and fully cover all appropriately listed indications in CMS approved compendia.

V. Site of Care Should Focus on The Ability to Safely Administer a CAR T Versus Designation as a Hospital

CMS proposes to cover CAR T-cell therapy in a hospital that meets certain requirements consistent with a nationally accredited Cellular Therapy Program and other site of care requirements including:

1. A Cellular Therapy Program consisting of an integrated medical team that includes a Clinical Program Director, a Quality Manager, and at least one physician experienced in cellular therapy, and demonstrates that protocols, procedures, quality management, and clinical outcomes are consistent from regular interaction among all team members;
2. a designated care area that protects the patient from transmission of infectious agents and allows for appropriate patient isolation as necessary for evaluation and treatment; and,
3. written guidelines when administering CAR T-cell therapy for patient communication, monitoring, and transfer to an intensive care unit.⁶

ARM supports robust safety criteria for sites delivering CAR T cell therapy across the inpatient and outpatient settings of care and appreciates and understands that this is a primary focus for CMS. In particular, written protocols for ensuring patient communication, monitoring and transfer to an intensive care unit are essential to both recognize and manage the unique side effects and adverse events that some CAR T patients experience.

At the same time, ARM understands that there clinical trials underway to demonstrate that, depending upon the characteristics of the individual patient, his or her underlying disease, and the profile of the CAR T cell therapy itself, patients can safely and effectively receive CAR T cells as outpatients, even in non-hospital settings.⁷ ARM therefore has concerns that CMS appears to have unnecessarily limited the site where a CAR T patient can be infused to just the hospital setting.

ARM believes that the safety criteria outlined by CMS should determine the setting in which CAR T cell therapy may be delivered, not a statutorily defined entity. In fact, there are current trials The safety criteria themselves, along with the amount of staff, coordination, and infrastructure required to set up a CAR T cell therapy program, create a natural limitation on the sites where CAR T cell therapy may be delivered. Arbitrary restrictions, such as limiting coverage to sites licensed or billing as hospitals that go beyond these safety criteria are not necessary and could create patient access barriers for patients in certain geographic areas as CAR T cell therapies evolve and provider comfort level with managing these adverse events also evolves.

ARM therefore believes that narrowing the site of care to only hospitals unnecessarily limits beneficiary access to CAR T therapy. ARM believes that rather than confining the CED to just hospitals, the agency should defer to only the requirements above as a condition for administration and not further limit access by also requiring the site of care to be a hospital.

VI. ARM Urges CMS to Clearly State How a Patient Reported Outcome Tool Will be Implemented and Utilized as Part of the CED

CMS proposes that either the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS®) or Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAETM) patient-reported outcome assessment tool be used to address CED questions on health-related quality of life. ARM appreciates that CMS wants to understand the patient experience but is concerned about the impact that including patient reported outcomes (PROs) could have at this juncture on access to the CAR T therapy.

As stated above, ARM’s members have significant experiences with collecting a wide range and types of clinical data. ARM therefore appreciates that establishing and maintaining a registry is a time consuming exercise especially PRO data because of the amount of resources needed to maintain an exhaustive registry that relies on the patient experience. ARM understands from its members’ current registry partners and other stakeholders that implementing a PRO requirement by the expected NCD completion date many not be practicable and therefore urges the agency to only include PROs if the agency is confident that this process will not hamper or delay access to the CAR T therapy.

VII. Should the Agency Proceed with a PRO Tool, ARM Recommends the PROMIS Tool

ARM believes that should CMS proceed with PROs the PROMIS tool is best structured to fully capture the beneficiary’s CAR T experience and is more user friendly than the PRO-CTCAE tool. Specifically, the PROMIS tool is designed to enhance communication between clinicians and patients in a wide range of clinical settings. Given the nature of the proposed CED it is important that communications amongst and between sites of care are efficient and accurate. Further, the PROMIS tool was created to be relevant across all conditions for the assessment of symptoms and functions, is available in multiple formats and is easily integrated into diverse data collection tools. Regardless of the PRO tool utilized, ARM urges CMS to clarify how the agency will cover a CAR T administration under this CED if the patient PRO data is incomplete?

VIII. Consistent with the NCD Completion Date ARM Urges CMS to Ensure that Beneficiary Access Continues to be Available on May 17, 2019

As discussed above, CMS proposes to cover autologous treatment with T-cells expressing at least one chimeric antigen receptor through a CED that includes various types of data collection from both beneficiaries and from the site of care. ARM appreciates that CMS wants to establish a registry and collect PROs. ARM, however, urges CMS to prioritize maintaining beneficiary access as of May 17 over any other procedural aspect of the CED. Unfortunately, many stakeholders are already confused regarding coverage status of CAR T therapies and any other further delay will only further add to this misinformation. ARM believes that Medicare beneficiaries should be able to access a CAR T as of the NCD’s scheduled completion date.

IX. Conclusion

In conclusion, ARM believes that the field of regenerative medicine has the potential to heal people and bend the health cost curve toward lower long-term costs and higher quality outcomes. This trend is already evidenced by several approved and marketed first-generation regenerative medicine products that are demonstrating both clinical and cost reduction value in relation to current “standards of care”. Specifically, by reducing hospital care, the need for physician, clinical and professional services, nursing and home healthcare, we could substantially reduce overall healthcare expenses. ARM is confident that meaningful improvements in clinical outcomes and cost reduction can be accomplished through regenerative medicine technologies.

Much of the dialogue around healthcare in recent years has focused on the issues of broadening access (through insurance reforms) and controlling costs through Medicare and Medicaid reimbursement reforms such as payment cuts to health providers. Clearly, reducing expenditures alone will not enable us to improve clinical outcomes and achieve enhanced patient quality of life if it hampers innovation.

It is critical for CMS to develop and implement policies and programs that support beneficiary access to new technologies when they are deemed most clinically appropriate and stimulate their continued development. This is particularly true for regenerative medicine and other advanced therapies that hold the promise of durably treating and potentially even curing chronic or life-threatening diseases.

In light of this goal, ARM asks CMS to ensure Medicare patients who can benefit from CAR T therapies are covered under the NCD, allow CAR T to be administered in certified, trained, experienced facilities and not limit access to hospitals, and certify a registry to be in place by May 17 to ensure continued access to CAR T by Medicare beneficiaries.

Sincerely,

Director, U.S. Policy and Advocacy

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1 https://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=291&bc=ACAAAAAAQAAA&
2 https://www.alliancerm.org/wp-content/uploads/2019/03/ARM_AR2018_Web_FINAL.pdf
3 https://www.cancer.gov/publications/dictionaries/cancer-terms/def/CAR T-cell-therapy
4 Clinicaltrials.gov: Study evaluating efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Participants With High-Risk Large B-Cell Lymphoma, available at https://clinicaltrials.gov/ct2/show/NCT03761056?term=NCT03761056&rank=1; A study evaluating EGFRvIII CAR T Cells for Newly-Diagnosed WHO Grade IV Malignant Glioma (ExCeL), available at https://clinicaltrials.gov/ct2/show/NCT02664363?term=NCT02664363&rank=1 ; A study evaluating Up-front CART-BCMA With or Without huCART19 in High-risk Multiple Myeloma, available at https://clinicaltrials.gov/ct2/show/NCT03549442?term=NCT03549442&rank=1
5 SSA §§1861(t)(2(A) & (B).
6 NCD at page 51.
7 Clinicaltrials.gov: A Safety Trial of Lisocabtagene Maraleucel (JCAR017) for Relapsed and Refractory (R/R) B-cell Non-Hodgkin Lymphoma (NHL) in the Outpatient Setting, available at https://clinicaltrials.gov/ct2/results?cond=&term=NCT03744676&cntry=&state=&city=&dist=; Lisocabtagene Maraleucel (JCAR017) as Second-Line Therapy (TRANSCEND-NHL-006), available at https://clinicaltrials.gov/ct2/show/NCT03483103?term=NCT03483103&rank=1 See also, . https://clinicaltrials.gov/ct2/show/NCT03744676?term=juno&draw=2&rank=5; https://clinicaltrials.gov/ct2/show/NCT03448978?term=cartesian&rank=1

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March 17, 2019

VIA ELECTRONIC SUBMISSION

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

RE: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Director Jensen:

On behalf of the physicians of The US Oncology Network (The Network), I thank you for the opportunity to comment on the “Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N).”

The US Oncology Network (The Network) is the nation’s largest and most innovative network of community-based oncology physicians, treating more than 850,000 cancer patients annually in over 400 locations across 25 states. The Network unites physicians around a common vision of expanding patient access to the highest quality state-of-the-art care close to home, and at lower costs for patients and the health care system. The Network is committed to working with the Centers for Medicare & Medicaid Services (CMS) to enhance the delivery of cancer care and protect patient access to high-quality care in the most efficient manner.

Under the proposed National Coverage Determination (NCD), CMS would cover autologous treatment with CAR-T through coverage with evidence development (CED). CMS is proposing to cover CAR-T therapies prescribed by a treating oncologist and performed in a hospital when the following requirements are met:

• The patient has relapsed or refractory cancer and is not currently experiencing any comorbidities that would otherwise preclude patient benefit;
• The hospital has:
  • a Cellular Therapy Program consisting of an integrated medical team that includes a Clinical Program Director, a Quality Manager, at least one physician experienced in cellular therapy, and demonstrates that protocols, procedures, quality management, and clinical outcomes are consistent from regular interaction among all team members;
  • a designated care area that protects the patient from transmissions of infectious agents and allows for appropriate patient isolation as necessary for evaluation and treatment;
  • and written guidelines when administering CAR T-cell therapy for patient communication, monitoring, and transfer to an intensive care unit.

We appreciate CMS’ efforts to evaluate Medicare coverage for CAR T-cell therapies, which are among the newest, most groundbreaking, and most promising oncology treatments available. We have a shared goal to ensure rapid, robust, and widespread patient access to these highly innovative therapies in a safe and reliable way. However, under the proposed NCD, CMS would only cover CAR-T in the traditional inpatient and outpatient hospital setting. While some CAR T-cell therapies may require inpatient hospitalization today, this may not be the case for future therapies, and research is already being conducted to demonstrate the safety of administering CAR-T to certain patient populations in the community-based setting. Limiting CAR-T coverage to the traditional hospital setting may cause beneficiaries difficulty in locating a provider. Therefore, in effort to ensure patient access to this life-saving treatment, and in recognition that a significant portion of CAR-T cases are expected to transition to the outpatient setting over time, The Network urges CMS to expand the National Coverage Determination (NCD) to cover treatment beyond traditionally defined hospitals and allow access to CAR T-cell therapy in qualified community oncology clinics.

The appropriate setting for the administration of cellular therapies should be determined by the ability of the treatment center to meet the specific safety requirements for the safe administration and monitoring of patients. Community oncology clinics have considerable experience and capabilities in complex treatments and are highly capable of administering CAR-T treatment. Care for stem cell and bone marrow transplant patients is effectively provided in the community-based setting.

Building upon that model, community-based practices have demonstrated their ability to coordinate interdisciplinary care and close monitoring and follow-up of patients, making them well-positioned to offer CAR T-cell therapies. During the first 30 days after CAR-T infusion, patients require regular follow up by their care team. If CAR-T treatment is expanded to the community clinic setting, this would keep patients close to their homes, families, and support networks and lessens the burden on beneficiaries and their families.

Community oncologists also have a proven track record in meeting research and evidence generation requirements. Within The Network, more than 60 community-based sites across the country comprise the US Oncology Research organization, which has been conducting Phase I-IV clinical trials across many indications, including rare tumor types, for more than 20 years. Our community-based practices have enrolled nearly 77,000 cancer patients into more than 1,700 oncology clinical trials, including more than 2,200 patients into Phase I trials, and played a role in the approval of 75 cancer therapies.

Today, clinical trials are being designed specifically to test the feasibility of outpatient CAR T-cell therapy. At the same time, community oncologists are gaining access to administer the FDA-approved CAR T-cell products, many of which are affiliated with transplant centers. Further, The Network has sites that are currently offering CAR-T through clinical trials and commercial payers to bring this promising technology to our patients.

CAR-T research and development is rapidly evolving. There are numerous ongoing research studies looking at CAR-T in other diseases such as myeloma, Hodgkin’s Disease and solid tumors such as glioblastoma, prostate cancer, pancreatic cancer and breast cancer – many of which are frequently treated in the community setting. Given the potential of this promising treatment, we encourage CMS to cover CAR T-cell treatment in qualified community clinics to provide access to beneficiaries who are unable to travel or who prefer treatment closer to home.

Additionally, we are concerned that the draft NCD is narrowly focused on the approved labels of the only two CAR-T therapies available today, which have very limited indication. The Network encourages CMS to allow flexibility in the NCD language to provide coverage for CAR-T therapies for patient population and indications as approved by the FDA in the future.

Finally, we are concerned that CMS’ requirements around data collection, reporting, and analysis as part of the CED registry would have an impact on the breadth of patient access and successful implementation of CAR-T treatment. The approved products already are subject to a Risk Evaluation Mitigation Strategy (REMS) program with Elements To Assure Safe Use (ETASU), as well as post-marketing requirements to monitor long-term toxicities. While we fully agree that data collection around CAR-T treatment is vital, we urge the CMS to consider the potential overlapping reporting requirements in order to reduce the burden on clinicians.

On behalf of The US Oncology Network and our more than 10,000 oncology physicians, nurses, clinicians, and cancer care specialists nationwide, thank you for the opportunity to provide our comments on the proposed NCD for CAR T- cell therapies (CAG-00451N). We welcome the opportunity to discuss the issues outlined above and other critical issues impacting community cancer care with you and your staff. Should you have any questions, please contact Ben Jones, Vice President of Government Relations and Public Policy, at Ben.Jones@usoncology.com.

Sincerely,

James Essell, MD
Chair Cellular Therapy
The US Oncology Network

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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

RE: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen,

The Alliance of Dedicated Cancer Centers (ADCC) appreciates the opportunity to comment on Medicare’s proposed decision memorandum for Chimeric Antigen Receipt (CAR) T-cell therapy for cancers and the tremendous amount of thought that the agency has committed to this important issue. The ADCC is comprised of the nation’s premier cancer hospitals that are singularly focused on cancer. As such, ADCC members are a critical component of the scientific infrastructure that has led to the discovery of these immunotherapies. In fact, much of the progress in understanding cancer’s biology and the successful development of immunotherapies is directly attributable to the work of ADCC members. Many of the clinical trials for the two CAR-T products that are currently on the market were conducted at our centers. Furthermore, our centers are currently conducting hundreds of clinical trials related to immunotherapy treatments.

Our members also play an outsized role in delivering this care to patients, including Medicare patients. As you may be aware, while our members are among a number of select academic medical centers in the country currently approved to provide this therapy, we represented forty-five percent of the total case volume for Medicare patients the first three quarters of available Medicare data. While these proportions will (and should) shift over time, they demonstrate that we are pioneers in developing innovative treatments and working to ultimately make them safe and accessible in the community at large.

CAR T-cell therapy represents the best of what American innovation has to offer and it is our goal to ensure that these curative treatments are appropriately accessible to the patients they are designed to help. We believe this is also the goal of the Centers for Medicare and Medicaid Services (CMS) in developing its coverage policies. As such, we offer the following comments for consideration (discussed in more detail below):

• CMS should cover CAR-T therapy as a matter of course, rather than subjecting it to a National Coverage Determination (NCD)/Coverage with Evidence Development (CED). The patient benefit and legal underpinning for covering these treatments are clear.


• To the extent CMS subjects CAR-T to a coverage determination, issuing an NCD would be more appropriate than a CED.


• As providers, we would expect to be able to provide the therapy for all FDA-approved uses, as well as off-label uses when following currently established treatment guidelines for doing so. Physicians should also maintain clinical discretion, for example, to determine how comorbidities would affect a patient’s care, or when additional courses of treatment would be warranted.


• Hospitals—as noted by the Foundation for the Accreditation of Cellular Therapy (FACT)—are the providers currently equipped to ensure the safest and most efficacious delivery of CAR-T therapy.


• We are strong supporters of patient-reported outcomes (PROs) data. Indeed, another area where ADCC is at the forefront is in utilizing PROs to gather meaningful information for physicians and patients to improve how we provide care. However, we do not believe that tying Medicare CAR-T coverage to PROs data would provide any desired benefit or be appropriate at this time, for a variety of reasons outlined below.

Thank you for your consideration of our comments. If you have any questions or would like any additional detail, 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).

Sincerely,

Karen Bird
Executive Director

I. CMS Should Cover CAR-T Therapy as a Matter of Course

First and foremost, we do not believe that an NCD (or, by extension, CED) is required for the currently approved Food and Drug Administration (FDA) CAR-T therapies, Kymriah and Yescarta, given that they fit within the statutory definition of “drugs and biologicals” covered by Medicare. This definition includes “any drugs or biologicals” used in an anticancer chemotherapeutic regimen for a medically accepted indication. The statute recognizes FDA-approved uses as not only “safe and effective” but as a “medically accepted” indication of a drug or biological used in an anticancer chemotherapeutic regimen.

II. Coverage with Evidence Development (CED) is Unnecessary

To the extent that CMS moves forward with a coverage decision for CAR-T, a CED for CAR-T therapy is unnecessary. We believe CMS should simply issue an NCD. We ask CMS to examine its experience with the existing four open CEDs for Stem Cell Transplant and consider whether they have been a success in terms of having generated the data and evidence expected to make future coverage decisions before requiring CED for CAR-T therapy. We do, however, understand CMS’ desire to collect data, and we believe there are ways outside of a CED for CMS to gain the information it is seeking.

What is most important to the ADCC is that our patients have access to this therapy—both how they need it, as well as when they need it, and with clinical precautions to manage for any adverse events. Our concern with finalizing a CED is rooted in our deep commitment to patient access to innovative anticancer therapies.

We cannot overemphasize the profound impact these therapies have had and will have on patients. These therapies provide potentially curative treatment for patients who have failed many (for some, all) other treatment options for their cancer. The currently approved products are for patients who have failed two or more lines of therapy. That was similar to the patient cohort in the SCHOLAR-1 study, where patients with refractory Diffuse Large B-Cell Lymphoma (DLBCL) received standard of care salvage therapy. The objective response rate was 26% (complete response, 7%) and the median overall survival was 6.3 months (with 20% of patients alive at two years).¹ In contrast, in the pivotal ZUMA-1 trial patients with refractory DLBCL who were treated with the Yescarta product showed an overall response rate of 83% (complete response, 58%) at two years reported via investigator assessment (n=101).² Median overall survival has not yet been reached, meaning more than half of the patients were alive at two years—compared to just 6.3 months for patients in the SCHOLAR-1 trial receiving salvage therapy. For the Kymriah product, a median 19 month follow up for the global JULIET trial for 93 evaluable DLBCL patients treated with Kymriah showed an overall response rate of 54% (complete response, 40%), and median overall survival of 11.1 months.³ When we see this data, we believe that CAR T-cell therapy gives hopes to patients who may have failed a transplant or are not eligible for one. It is a new option where before, few options existed, especially options associated with good outcomes. Beyond that, there is still more data to come: with most relapses occurring within 5 years of treatment for DLBCL, if we see patients in complete remission years after infusion, we may one day be able to say they have been cured. Delays in access to or denials of coverage for this type of potentially curative therapy are untenable for patients.

III. Any National Coverage Should Ensure that Providers can Utilize all FDA-Approved Products for Their Labeled Indications

Our clinicians follow FDA labeling when prescribing and furnishing CAR-T therapy. Additionally, the CAR-T manufacturers will not produce products for off-label indications, as the manufacturing process is specific to the disease being treated. Furthermore, since immune effector cell therapy is a breakthrough in cancer care, we strongly encourage CMS not to restrict or make access to CAR-T more difficult for FDA-approved products for labeled indications. We are particularly concerned by the explicit language in the “non-coverage” section, which states, “We propose treatment using T-cells expressing at least one CAR when cancer patients do not have a cancer that meets any of the indications noted in A.1.a of this proposed decision would be non-covered.” Section A.1.a of the proposed decision memo states, “Patient has: Relapsed or refractory cancer.”

If CMS finalizes this as written, it appears that new CAR-T products approved for primary, non-relapsed forms of cancer could result in patients facing significant delays for a period of up to 12 months due to the need for CMS to re-open the National Coverage Analysis to update its language. At worst, it would result in outright non-coverage. Either option is unacceptable given how ill these patients are. It may indeed be CMS’ intent to start a new NCA process for each new product as it comes to the market, but this will only lead to a proliferation of dozens and dozens of new NCAs, depending on the variety of products that are approved in the next five to seven years, which would generate a significant amount of administrative burden for both providers and the agency. As the FDA itself has noted,“by 2025, we predict that the FDA will be approving 10 to 20 cell and gene therapy products a year based on an assessment of the current pipeline and the clinical success rates of these products.”⁴

Our institutions are invested in protecting patient access to the treatments available today, in part because it may be the last treatment option the patient has, but as centers who innovate and pioneer new therapies for the eradication of cancer, we know that the future is important too. The best treatment for a patient, as CMS knows, is both necessary and effective.

Future approved products that are not for relapsed or refractory cancer may not be the last option for each patient, but it may be the best frontline option for certain patients. While we have not yet reached that point, we would be concerned if, once we do, this option is not available to Medicare patients for nine months or longer while an existing NCA is reconsidered. Medicare denying access to these patients could dramatically impact the treatment plan for a patient with potential repercussions that include failing to prevent an avoidable death.

Our institutions also recognize that clarity matters to patients. In a recent press release, CMS stated that it values patient choice and wants to give patients clarity around Medicare coverage. It also explained that it has used its agency resources to develop new technologies to make coverage information clearer and more accessible to beneficiaries.⁵ We want our patients to have access to the treatments that are going to be most efficacious for them and for them to be able to clearly understand what is covered. The prospect of the need for multiple NCAs relating to CAR T-cell therapy would create unnecessary complexity.

Consequently, we urge CMS in its final decision to remove the requirement for relapsed or refractory cancer, and instead replace it with simple language that confers coverage of autologous CAR-T cell therapy for FDA-approved products for their labeled indication. By making this change, CMS will allow its coverage policy to keep pace with science and innovation, and ensure timely access to newly approved therapies.

To be clear, this is not an abstract concern. For example, ADCC member institutions have deep institutional experience in treating lymphoma patients with stem cell transplants. There are currently ongoing clinical trials comparing autologous stem cell transplant to CAR T-cell therapy for lymphoma. If, in head-to-head trials, CAR-T cells are more effective than transplant, it could lead to label expansions for the currently approved products and fundamentally change how patients are treated. It could mean that patients do not have to undergo transplants simply to fail those and then to move to CAR-T cell therapy. Therefore, non-coverage of CAR-T therapy for Medicare beneficiaries who do not have relapsed or refractory cancer despite the FDA approving another indication could force Medicare beneficiaries to use a treatment line that is less effective until a new NCA process is complete. This seems unnecessary and discordant with our understanding of the intention of the NCA process, which is to set forth a standard that speaks to care that is “reasonable and medically necessary” for Medicare patients.

Furthermore, we are seeing clinical trials using CAR-T therapy to treat diseases like multiple myeloma, chronic lymphocytic leukemia, and follicular lymphoma, among others, that may support the use of CAR-T beyond lymphoma and beyond relapsed and refractory cancer. The ADCC continues to lead in the cellular therapy space, and our clinicians must have the ability treat Medicare patients with the most appropriate therapy for their disease, and their disease progression, as soon as that therapy is determined to be safe and effective by the FDA and is commercially available to patients.

Therefore, the ADCC respectfully requests that if CMS finalizes a coverage decision, it allows coverage for FDA-approved products for their labeled indications. We believe that this is the best and most appropriate way to preserve Medicare patients’ access to reasonable, medically necessary, and effective cellular therapies.

IV. Leverage Existing Data Reporting Through the Registry Being Run By the CIBMTR

Rather than requiring CED, the ADCC supports the use of national registries to promote consistent data collection with minimal provider burden. We understand that the Center for International Blood and Marrow Transplant Research (CIBMTR) is interested in being named as the registry to conduct this data collection. CIBMTR has a long-standing history working with transplant programs on stem cell data collection. It also has an operational CAR-T cell registry that is currently collecting clinical data on patients receiving commercial CAR-T cell treatment. It has contracted with both manufacturers of the currently approved CAR-T products to collect the required data for the FDA post-approval long-term safety studies (PASS). It is our understanding that CIBMTR has also been awarded a grant to expand its registry infrastructure for cellular therapies for cancer, and that numerous centers in the United States are already reporting data. We believe that the data that CMS is seeking in regard to Medicare beneficiaries is already been collected (with the exception of PRO data), and that there is an entity (CIBMTR) that is already well-equipped to serve as an approved registry.

We would be pleased to see the CIBMTR listed as an approved registry, assuming it will be ready by mid-May, as this will minimize administrative and operational burden for our programs given the experience and infrastructure we have already developed with respect to reporting information to CIBMTR, as well as CIBMTR’s engagement with the provider community to improve data collection practices. Additionally, if CMS keeps the data it is interested in studying through this NCD consistent with what the manufacturer FDA PASS requirements, CMS will be able to proceed in the simplest, most efficient, and least burdensome manner possible. In fact, we strongly believe finalizing an NCD that leverages the PASS studies that are currently reported to CIBMTR is consistent with what CMS intends based on the following statement made in the CMS press release about this coverage policy: “CMS proposes to leverage the FDA’s requirements for post-approval studies for CAR-T to the fullest extent possible in reviewing studies for CMS approval.”⁶

It is our understanding that data collected today for the FDA post-marketing studies, once reported to regulatory agencies, is then more broadly available for research. Because of CIBMTR’s unique position, and because the data that is currently being collected would be available to CMS, we believe that it is important to name CIMBTR as the approved registry, and any finalized NCD should leverage data points that are already being collected.

Finally, we understand that CIBMTR is working towards releasing an electronic PRO (ePRO) data collection tool which will likely prove useful in time, but we do not believe the CIBMTR or any other organization experienced with registry reporting will be ready to collect PRO data starting mid-May 2019 when this decision memo will be final, which is yet another reason why we do not believe it is appropriate to finalize any sort of PRO data collection at this time.

V. Ensure that Patients Receive Treatment Safely and Responsibly (Currently, in Hospitals)

The ADCC supports CMS’ proposal that CAR-T be administered in hospitals meeting the guidelines described in the proposed decision memo, including but not limited to: the hospital being required to have a cellular therapy program consisting of an integrated medical team; the ability to demonstrate that protocols, procedures, quality management, and clinical outcomes are consistent from regular interaction among team members; a designated care area that protects the patient from transmission of infectious agents and one that allows for appropriate patient isolation as necessary; and written guidelines when around patient communication, monitoring, and transfer to an intensive care unit. In short, we agree with the inclusion of hospital requirements that are congruent with FACT Standards in order to promote patient safety and CAR T-cell efficacy at this time.

VI. Allow Physicians to Exercise Judgement Related to Comorbidities and Repeat Treatments

The ADCC does not agree with CMS’ proposed requirement that the therapy only be provided to a patient that is not currently experiencing any comorbidity that would otherwise preclude patient benefit. Clinicians are best suited to determine whether a patient can benefit from the therapy, per the FDA-labeled indication, despite having certain comorbidities, which are generally expected.

We also request CMS clarify the following: “Repeat treatment when a patient receives more than one therapeutic dose of a specific CAR T-cell product using the same biological in the same patient is covered only when a new primary cancer diagnosis is made by the treating oncologist and the patient conditions are met.” Specifically, is CMS saying retreatment is precluded? Additionally, it is possible that a patient could be diagnosed with a separate malignancy or new diagnosis of a previously treated cancer and could benefit from receiving the same CAR-T product. And by “same biological,” does CMS mean that a patient would not be covered for Yescarta and then be given Kymriah at a subsequent point in time if warranted?

If a patient relapses at some point in the future, after receiving CAR-T therapy, clinicians should be responsible for assessing whether the patient would benefit from receiving the same or different biological again. It is premature to ossify such determinations in a coverage decision given how rapidly the cellular therapy field is evolving. As a result, we strongly urge CMS to release an NCD that promotes, rather than limits, access for new and innovative therapies.

VII. It is Premature to Use Patient Reported Outcomes as a Condition of Coverage

As CMS knows, the ADCC is a strong advocate of the use of PROs in quality measurement for several reasons. Dependent upon the timing of survey administration, PROs can provide outcome measurements in a timely manner. By definition, they are sensitive to the patients’ perspective. Furthermore, PROs have been shown to improve symptom control, enhance communication, and increase patient satisfaction and sense of well-being. Recent studies have also reported a relationship between the administration of PROs and increased survival. Nevertheless, despite our strong support for the use of PROs in quality measurement, we do not believe that it would be appropriate to adopt PROs as a requirement for coverage of CAR T-cell therapies at this time.

We outlined our strong concern about the use of PROs for the CAR-T coverage decision to CMS previously, and reiterate them again below. We do not see any of the issues we raised, nor the concerns expressed by numerous presenters at the August 2018 MEDCAC meeting, reflected in the proposed decision memo. While CMS noted the identification of PROMIS and PRO-CTCAE as those voted with the highest scores at the August 2018 MEDCAC meeting, CMS did not include the many caveats, concerns and objections voiced by panelists at the time of the vote. Panelists were required to rank these tools at the meeting, but shared the concerns we submitted to CMS, as well as those raised by presenters at the meeting: namely, these tools have not been vetted for CAR-T specifically and may not produce meaningful reflections of the patient experience during the CAR-T care episode.

Our primary concerns about PROs being included in the NCD include the following:

• There are no standard, widely accepted, validated PRO instruments for patients receiving this novel therapeutic intervention, and while the PROMIS and PRO-CTCAE instruments are robust as far as domain inclusion, their relevance for patients receiving CAR-T therapy is untested and therefore unknown.
• All measures of quality patient reported outcome measures (PROMs) should be thoroughly tested for reliability, validity, and feasibility.
• In fact, CMS through MACRA legislation is currently funding a three-year effort (cooperative agreement) to test and develop a PROM for health-related quality of life (HRQoL) in the solid tumor populations of breast, colon, and non-small cell lung cancer, ensuring appropriate exclusions, risk stratification, and time points. A thorough and scientifically validated process is paramount prior to PROM inclusion in required reporting as patient characteristics could influence a measure such as patient-reported HRQoL.
• Systems and processes for administering and collecting PRO data are immature and not yet widely adopted across organizations. While the potential exists for PROs to yield rich and meaningful data for improving patient care, an unfunded mandate creates a risk that patients will be denied access to centers that lack the infrastructure to develop and implement PRO data collection processes.
• The acute toxicity profile of CAR-T cell therapy, particularly the neurotoxicities, will make PRO data collection challenging, especially during the acute treatment phase.

Furthermore, though CMS referenced PROMIS as one of the two tools that could be used, there are different measure sets within PROMIS. This could mean multiple different tests in different domains within PROMIS—for example, the 80-question tool, which could be particularly burdensome and lead to low-quality data. CAR-T patients today have already failed other lines of treatment—often at other treatment facilities—and are often in poor health, which would likely result in missing PRO data, especially if there are 80 different questions (and data points) to capture. Or, CMS could specify something like the PROMIS global 10 question tool. But this clarification on which tool CMS had in mind when proposing to require the use of PROs would not entirely mitigate issues around missing data. The fundamental question remains: Which tool or measure domain is most appropriate for CAR-T—given that CAR-T cell therapy is a new therapy, and evidence-based interventions designed to address issues identified through PRO data are still under development.

Finally, as the purpose of the NCA process is to determine what is reasonable and necessary for Medicare patients, we simply do not believe that data collection should be a condition of coverage in the outpatient care setting. The lack of PRO data on a particular Medicare patient does not change that patient’s clinical status: the patient’s disease still necessitates treatment with CAR-T therapy, and the patient’s condition may be such that it is reasonable and clinically appropriate to treat them in the outpatient setting. Ultimately, we do not believe PRO data collection should be used as a condition of coverage, at this time, for this patient population.

If, however, CMS disagrees, and does finalizes PRO data collection as proposed, we request CMS clarify the following questions:

• What is meant by “outpatient”? Does this mean that the patient was infused in the outpatient setting—regardless of whether the patient was later admitted as an inpatient? Currently, if a patient is admitted as an inpatient within a certain time period, the charges will roll up to the inpatient claim, and that patient is considered an “inpatient” by the hospital and by CMS for Part A payment. Or would a patient have to be infused in the outpatient setting, and not readmitted within the time period, to be considered an outpatient by CMS? These details matter, as it impacts operational planning.
• What is meant by “baseline”? Is this at cell collection, prior to it, or after it but before some other step of the overall CAR-T process?
• What is meant by “treatment”? Is this at the start of the lymphodepleting chemotherapy regimen or is this the actual infusion/administration of the cells

Without clear definitions provided by CMS through written instruction, the data providers will collect and submit to CMS will be inconsistent, and CMS and/or hospitals will be unable to draw meaningful conclusions.

VIII. Other Technical and/or Operational Concerns

A. Continuity of Coverage and Avoiding Disruption

Generally, the implementation date of an NCD has been the date of the final decision memo’s release. Due to the unique process of receiving this therapy, patients may have already been had their cells collected and sent to the manufacturer for processing into the CAR-T product, prior to the effective date, but have not been infused—and thus fully treated with CAR-T—until on or after the date.

We ask CMS explicitly to address whether patients who have had their cells collected up until May 16th, prior to the release of the final decision and the implementation date, will be covered, and not subject to NCD requirements or specifications. In other words, will patients who have their cells collected on or after the NCD effective date be subject to the finalized policy, but not those who began the process? The latter group of patients should continue to have the same coverage they have had up to date.

B. Permit Off-Label Uses of CAR-T Consistent with Current Practices

The ADCC has two concerns about section 3.b of the proposed memorandum, which requires that: “Treatment is an FDA-approved biological, indicated for use identified in the National Comprehensive Cancer Network Drugs & Biologics Compendium with grade 2 or 1 on or after August 2017.”

Instead of only listing the NCCN, we recommend CMS follow its usual off-label coverage policy for CAR-T cell products rather than creating anything new. This means following what’s outlined in Chapter 15, Section 50.4.5 of the Medicare Benefits Policy Manual on the off-label use of anticancer drugs and biologicals when referenced in any one of the five of compendia listed in the manual (i.e., NCCN, DrugDex, Clinical Pharmacology, American Hospital Formulary Service (AHFS), and Lexi-Drugs).

Additionally, we request CMS clarify what is meant by off-label use to be covered in the context of a “clinical study.” The use of clinical study can be confusing, as we typically think of that as a clinical trial type study. Does CMS intend for separate studies to be opened or does it mean that data would be reported through whatever existing registry reporting requirement it finalizes as described for on-label coverage? If the latter, then would the “clinical study” be a reference to what the named registry (or registries) would do and provide to CMS? Will CMS’ final NCD result in a single national clinical trial (NCT) number that would be tied to registry reporting, or several separate ones?

C. Patient Consent to Data Reporting and Coverage

Finally, we would like to address the issue of patient consent. As we have expressed before, right now, the two therapies that are currently on the market are for patients who are very sick, and it may be their last treatment option. It is our understanding that CMS would require each individual Medicare patient to consent to their data be submitted to a registry (and for the outpatient setting consent to report PRO data), and that their Medicare coverage of CAR-T therapy would be conditional upon this consent.

If a patient does not want to submit their data, they would then have to be given appropriate notice to protect their financial liability (i.e., an ABN/HINN) and the result is that they would be personally responsible for covering the cost of this expensive new therapy. If this is the last viable treatment option for a patient, we do not understand how a patient could choose freely not to consent, if individual patient consent is indeed a condition of coverage. We do not want to create a situation in which such a delicate conversation becomes necessary between clinicians, providers, and beneficiaries.

Therefore, we believe that if CMS finalizes an NCD with CED that requires submission of data elements already being reported to CIBMTR, it should be the hospital that is required to report, rather than the patient consenting to reporting at the individual level. This will allow the hospital to submit the necessary data from all patients who will still be asked to consent—and by and large the vast majority are likely to do so—but we do not want patient’s coverage to their therapy to be inextricably tied to their decision at any point in time about having their data submitted.

Summary

Throughout this letter, the ADCC has raised both clinical and operational concerns. Clinical concerns impact the clinical care patients receive, and operational concerns impact the delivery of that care. Both clinical and operational excellence are pillars that support our fight against cancer.

We strongly believe CMS can achieve its goal of better understanding clinical and outcomes data for patients receiving CAR-T therapy by simply leveraging what is already being collected by CIBMTR. The benefit of this is in accordance with the administration’s goals of reducing hospital and provider burden, and specifically with putting “Patients Over Paperwork.” Eliminating CED while retaining an NCD will allay any questions about coverage, but in finalizing an NCD we reiterate the need for the requirements to be for FDA-approved and labeled indications, rather than being narrowly defined as proposed by CMS. Continuing the work the agency has already begun with our institutions to study and evaluate the use of PROs is vital to us, and we believe that in the future it will be possible to collect appropriate PRO data on CAR-T patients. We do not believe that time is now, however, since there is little evidence on whether the information would be meaningful, nor any consensus on which tools would be most relevant.

Regardless of what policies CMS finalizes in the NCD, we stress the importance of needing clarity around the implementation and effective dates such that patients who are in the process of being treated around the time the final decision is released retain the coverage they already have. It would be harmful to patients to do otherwise.

We appreciate the opportunity to submit our perspectives on this important patient access issue. Our clinicians and other technical experts are available as a resource for you, so please do not hesitate to reach out whenever the ADCC may be of assistance.

Thank you for your consideration.

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1 Crump, Michael, Sattva S. Neelapu, Umar Farooq, Eric Van Den Neste, John Kuruvilla, Jason Westin, Brian K. Link, Annette Hay, James R. Cerhan, Liting Zhu, Sami Boussetta, Lei Feng, Matthew J. Maurer, Lynn Navale, Jeff Wiezorek, William Y. Go, and Christian Gisselbrecht. "Outcomes in Refractory Diffuse Large B-cell Lymphoma: Results from the International SCHOLAR-1 Study." Blood 130, no. 16 (2017): 1800-808. doi:10.1182/blood-2017-03-769620.
2 "Kite Announces Two-Year Data for Yescarta® (Axicabtagene Ciloleucel) in Patients With Refractory Large B-Cell Lymphoma." Gilead. December 02, 2018. Accessed March 11, 2019. https://www.gilead.com/news-and-press/press-room/press-releases/2018/12/kite-announces-twoyear-data-for-yescarta-axicabtagene-ciloleucel-in-patients-with-refractory-large-bcell-lymphoma.
3 "Longer-Term JULIET Results Confirm Sustained Response With Tisagenlecleucel in Relapsed/Refractory DLBCL." AJMC. December 06, 2018. Accessed March 11, 2019. https://www.ajmc.com/newsroom/longerterm-juliet-results-confirm-sustained-response-with-tisagenlecleucel-in-relapsedrefractory-dlbcl
4 U.S. Food & Drug Administration. 2019. Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies. January 15. Accessed March 10, 2019. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm629493.htm.
5 Centers for Medicare & Medicaid Services. 2019. New App Displays What Original Medicare Covers. February 6. Accessed March 10, 2019. https://www.cms.gov/newsroom/press-releases/new-app-displays-what-original-medicare-covers.
6 Centers for Medicare and Medicaid Services. 2019. CMS proposes Coverage with Evidence Development for Chimeric Antigen Receptor (CAR) T-cell Therapy. February 15. Accessed March 10, 2019. https://www.cms.gov/newsroom/press-releases/cms-proposes-coverage-evidence-development-chimeric-antigen-receptor-car-t-cell-therapy.

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Charles N. Kahn III
President and CEO

March 15, 2019

VIA ELECTRONIC MAIL AND ELECTRONIC FILING

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

Re: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen:

The Federation of American Hospitals (“FAH”) is the national representative of over 1,000 investor-owned or managed community hospitals and health systems throughout the United States. Our members include teaching and non-teaching hospitals in urban and rural America who provide a wide range of ambulatory, acute, and post-acute care, as well as inpatient rehabilitation, psychiatric, long-term acute care, and cancer hospitals. We appreciate the opportunity to comment to the Centers for Medicare & Medicaid Services (“CMS”) on the Proposed Decision Memo (“the NCD”) on Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N).

The FAH urges CMS to cover chimeric antigen receptor (CAR) T-cell therapy when the drug product and indication are approved by the Federal Drug Administration (FDA). In the proposed decision memo, CMS proposes to limit coverage of chimeric antigen receptor (CAR) T-cell therapy to situations where the patient has “relapse or refractory cancer.” Providing coverage for FDA-approved products and indications will eliminate the need to reopen this coverage decision as new CAR T-cell therapies are approved.

As drafted, coverage would be limited to only those patients who have relapsed or refractory cancer. Although the two currently FDA-approved CAR T-cell therapies have indications only for relapsed or refractory cancer, the FDA labeling may change as clinical trials are completed, or new agents approved. FAH urges CMS to expand this to include indications covered on the FDA approved label. Expanding patient eligibility in this manner will not only cover life-saving treatment but also help promote innovation.

We are concerned that based on CAR T-cell therapies currently undergoing clinical trials, it may be necessary for CMS to reopen the NCD each time a new indication or new agent is approved in order to provide coverage for CAR T-cell therapies that are likely to be approved by the FDA in that time frame.

The FAH also urges CMS to make the CED NCD effective for patients that have their lymphocytes harvested on or after the date of final CED NCD publication. We understand that final NCDs are typically made effective on the day that they are published. However, CAR T-cell therapy begins in advance of the actual transfusion when lymphocytes are harvested from the patient, and the imposition of more restrictive coverage during the time period between harvesting and transfusion would be detrimental. We therefore recommend that the final NCD be effective for patients that have their cells harvested on or after the date of final NCD publication.

The FAH supports the inclusion of hospital requirements related to the medical team’s leadership, experience, integration, care areas, and guidelines consistent with standards developed by the Foundation for the Accreditation of Cellular Therapy (FACT). These requirements will promote patient safety and CAR T-cell therapy efficacy.

We recommend that CMS revise the requirements related to “the use of more than one therapeutic dose of a specific CAR T-cell product” for repeat treatment. As CMS properly acknowledges, a patient could be diagnosed with a separate malignancy or new diagnosis of a previously treated cancer and could benefit from receiving the same CAR T-cell product. Thus it is appropriate that repeat treatment may be covered “when a new primary cancer diagnosis is made by the treating oncologist.” However, there may also be situations where a patient relapses at some point after receiving CAR T-cell therapy, and in that situation, clinicians should be the ones assessing whether the patient would benefit from receiving the same or different CAR T-cell treatment. This is also consistent with FDA labeling as repeat treatments are not contraindicated. The field of cell therapy is rapidly evolving and therefore CMS’ final NCD should provide access rather than barriers for new and innovative therapies.

The FAH strongly urges CMS to begin reviewing appropriate registries for approval prior to the publication of the final NCD. If a registry has not been approved at the time of publication of the NCD, providers will have no way to meet the NCD requirements, and the NCD would then operate to deprive Medicare beneficiaries of access to this important treatment.

Moreover, we believe that any approved registry should permit participation with de-identified data such that a Medicare beneficiary is not compelled to authorize the disclosure of their protected health information in order to access coverage for CAR T-cell therapy. It is our understanding that the current leading industry registry for CAR T-cell therapy only permits participation if a patient authorizes the use and disclosure of their protected health information. If a patient refuses to provide such an authorization and there are no approved registries that permit participation with de-identified data, the patient would be ineligible for Medicare coverage of CAR T-cell therapy and the patient would then choose between not receiving this potentially life-saving treatment or assuming financial liability for the treatment. This will place providers in the awkward position of presenting the patient with an Advanced Beneficiary Notice of Non-coverage (ABN) or Hospital Issued Notice of Non-coverage (HINN). Moreover, such a registry requirement creates selection bias and may skew registry data. Therefore, as CMS reviews registries for approval, we strongly recommend that only registries that do not require authorization for uses and disclosures of protected health information (i.e., those that use only de-identified data) or that provide an option for participation on a de-identified basis be considered.

Finally, the FAH urges CMS to clarify that each hospital is only responsible for the registry data elements of its own patients. Therefore, we recommend Section 3.a.iii be revised to state that “The furnishing hospital shall address the CED questions on all of its own registry patients . . . .”

Currently, CMS recognizes off-label use of anti-cancer drugs and biologicals when they are referenced in the five compendia listed in the Chapter 15, Section 50.4.5 Off-Label Use of Drugs and Biologicals in an Anti-Cancer Chemotherapeutic Regimen of the Medicare Benefits Policy Manual. We recommend that CMS remain consistent with the instruction provided in the Medicare Benefit Policy Manual and in this NCD recognize all five compendia for off-label use of anti-cancer drugs and biologicals.

We believe that an inadvertent typographical error is present in Section B where two of the three hospital requirements are referenced instead of the treatment criteria. The last sentence of Section B states, “We proposed treatment using T-cells expressing at least one CAR when not indicated in A.2.a or A.2.b of this proposed decisions would be non-covered.” It appears, however, that the cross-references should instead be for “A.3.a or A.3.b”, which set forth the applicable treatment criteria.

We again urge CMS to consider alternative payment solutions for this life-saving therapy. We understand that this proposed NCD addresses coverage and not payment, but overarching concerns about the high cost of this therapy and the inadequate Medicare payment, particularly under the current inpatient prospective payment system. FAH is concerned about beneficiary access to CAR T-cell therapy and similar forthcoming technologies given their costliness. As such, we reiterate the recommendations set forth on pages 6 through 10 of our June 25, 2018 comment letter on the FY 2019 Inpatient Prospective Payment System Proposed Rule.¹

Despite the large financial losses providers face in providing this therapy to Medicare beneficiaries, this treatment is provided to patients that have no other treatment or curative options. Patient access to CAR T-cell therapy can be a matter of life or death and therefore any actual or perceived access to care barriers are of great concern.

* * * * * * * *

The FAH appreciates the opportunity to comment on the proposed NCD. If you have any questions about our comments or need further information, please contact me or Steve Speil of my staff at (202) 624-1529.

Sincerely,

cc: Seema Verma
Joseph Chin, MD, MS
Lori M. Ashby, MA
Daniel A. Caños, PhD
Lori A. Paserchia, MD
Katherine B. Szarama, PhD

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1 These recommendations are consistent with those recently advanced by the American Hospital Association in their February 19, 2019 letter to the Centers for Medicare & Medicaid Services, available at https://www.aha.org/system/files/2019-02/190219-cms-consideralternative-payment-solutions-chimeric-antigen-receptor-t-cell-therapy.pdf.

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March 15, 2019

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

Katherine B. Szarama, PhD, Lead Analyst
Evidence and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Lori A. Paserchia, MD, Lead Medical Officer
Evidence and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen and Drs. Szarama and Paserchia:

The College of American Pathologists (CAP) appreciates the opportunity to provide comments to the Centers for Medicare & Medicaid Services (CMS) on its proposed national coverage policy for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers. As the world’s largest organization of board-certified pathologists and leading provider of laboratory accreditation and proficiency testing programs, the CAP serves patients, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide.

The CAP appreciates CMS’ efforts to nationally cover cell transfer immunotherapy in the treatment of select cancer patients with certain malignancies. While the CAP supports coverage for the current on-label use of the Food and Drug Administration (FDA) approved CAR T-cell therapies, we urge CMS to consider the following recommendations.

Flexibility to allow for new technologies. The quality of care provided to Medicare beneficiaries depends on access to treatments appropriate to their needs, including new technologies. The Coverage with Evidence Development (CED) process has historically taken years to result in a coverage or non-coverage decision. The CAP is concerned that a national coverage policy that depends on CED is too slow to provide reasonable access to new technologies and only offers treatment to a limited population of patients who have access to trials and registries. As a result, Medicare beneficiaries may suffer from delays in coverage of CAR-T therapies. For this reason, we urge CMS to ensure that its national coverage policy be sufficiently flexible to allow for newer therapies as they become available while at the same time providing patients with access to the best treatments. Our recommendation is that CMS establish a process for routinely extending coverage for newer therapies as new technologies advance with the accumulation of scientific evidence through ongoing clinical trials by manufacturers and others.

Recognize the individual services provided by physicians and other health care professionals. Treatment protocols involve several separate and distinct treatment processes required of highly trained physicians and other health care professionals that are separate and distinct from the CAR-T cell manufacturing process. To ensure adequate support for these very intensive treatments when indicated, the CAP seeks to ensure that all provider services are recognized so that their resource requirements may be met. Therefore, we ask that a national coverage policy recognize the critical patient-centered care services provided by physicians and other health care professionals, during both the pre-and post-manufacturing phases of CAR-T cell therapy. For example, pathologists play a critical role as integral members of the cancer patient management team during this therapy. In addition to contributions in diagnosing original diseases and monitoring disease persistence and recurrence, pathologists are also directly involved in the provision of CAR-T Cell therapy clinical services—notably, the harvesting of blood-derived T lymphocytes for development of genetically modified autologous CAR-T Cells. Additional related services such as the preparation for transportation of the harvested T lymphocytes, the receipt and preparation of genetically modified CAR-T Cell products, and the administration of autologous CAR-T Cells to patient recipients, must also be included in the coverage of CAR-T Cell therapy services. All of these services are separate and distinct from the manufacturing facility's genetic modification of T lymphocytes for CAR-T Cell development.

We believe that the inclusion of “leukapheresis” or “harvesting of blood-derived T lymphocytes” which is a clinical service, with the payment for delivery of a CAR-T Cell drug is inappropriate as it conflicts with other CMS-instructed standard provider billing guidance and practices. The CAP joined with other CAR-T Cell therapy providers and stakeholders in pursuing appropriate codes for reporting purposes to recognize the various service elements associated with this technology. Physician services and facility reimbursement can be properly described and captured through the 2019 AMA CPT Codes noted below. Efforts by CMS to develop coverage policies should take these activities into account to align with the services necessary to make these important therapies available to Medicare and Medicaid beneficiaries.

2019 AMA CPT Codes:

CPT	Long Descriptor
0537T	Chimeric antigen receptor T-cell (CAR-T) therapy; harvesting of blood-derived T lymphocytes for development of genetically modified autologous CAR-T cells, per day
0538T	Chimeric antigen receptor T-cell (CAR-T) therapy; preparation of blood-derived T lymphocytes for transportation (eg, cryopreservation, storage)
0538T	Chimeric antigen receptor T-cell (CAR-T) therapy; receipt and preparation of CAR-T cells for administration
0540T	Chimeric antigen receptor T-cell (CAR-T) therapy; CAR-T cell administration, autologous

Do not preclude Medicare Administrative Contractors (MACs) from determining coverage for new technologies at the local level as they become available. Given that CAR-T cell therapy is a rapidly expanding innovative therapy and ongoing clinical trials are likely to identify new biomarker targets for both hematological and solid malignancies which may not all be reviewed by the FDA, we urge CMS to develop a process to update coverage as new evidence emerges so that Medicare beneficiaries may have timely and appropriate access to care. We urge CMS to allow MACs to have the flexibility to cover new technologies not yet reviewed by the FDA, by applying a rigorous review process per national guidelines.

Thank you for your willingness to consider our comments on the Proposed Decision Memo. The CAP welcomes the opportunity to provide additional information to the CMS to support coverage for CAR-T services.

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March 15, 2018

Tamara Syrek Jensen
Director, Evidence and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard S3-02-01
Baltimore, Maryland 21244
tamara.syrekjensen@cms.hhs.gov

RE: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-Cell Therapy for Cancers

Thank you for this opportunity to comment on Medicare’s National Coverage Determination for Chimeric Antigen Receptor (CAR) T-cell therapies. Seattle Cancer Care Alliance (SCCA) is among the limited number of providers of CAR-T therapies. SCCA is the only center in the Northwest selected to offer the two FDA-approved CAR-T therapies. We have administered more CAR-T infusions than any other hospital in the country. Our experience to-date suggests these treatments are a breakthrough for our patients and we appreciate the effort by CMS to make CAR-T therapies available to individuals covered by Medicare.

Coverage determination should include language regarding autologous CAR-T cell therapy for FDA-approved products for their labeled indications, rather than relapsed or refractory cancer.

SCCA believes the requirement for relapsed or refractory cancer should be replaced with language referring to labeled indications for FDA-approved products. Ongoing clinical trials for follicular lymphoma, multiple myeloma, and chronic lymphocytic leukemia may support use of CAR-T therapy beyond lymphoma and beyond relapsed and refractory cancer. Inserting language in CMS’ final decision to require use of CAR-T products conforms with FDA label requirements, rather than restricting use to relapse or refractory cancer, will allow the final decision to evolve with emerging clinical trial data and treatment innovations. Other indications should be covered on clinical trials as is current practice.

Comorbidities that would preclude patient benefit should be defined to ensure coverage eligibility criteria are not interpreted too narrowly so as to restrict treatment accessibility.

Coverage eligibility language stating a patient must not be experiencing ‘any co-morbidity’ allows for broad interpretation and unreasonable restrictions when determining patient eligibility. Criteria should be limited to those comorbid conditions that substantially affect a patient’s prognosis of survival, at the discretion of the treating physician.

The proposed requirement for patients to participate in a clinical trial creates tighter restrictions on off-label uses that will slow SCCA’s treatment of patients.

Limiting coverage of CAR-T therapy off-label uses to only patients in a clinical trial is a significant limitation for an acute patient population without alternative treatment options. Medical necessity should not be decided contingent on participation in a clinical trial as this will delay patient care. For those patients with diseases or conditions that are life threatening where there are no other viable treatment options, it is critically important for patients and providers to have access to the full range of CAR-T cell therapies. Medicare Administrative Contractors should be allowed to determine coverage of other indications that are well supported by clinical evidence and current standards for anticancer therapies.

Repeat treatment eligibility should be clarified regarding coverage of two different manufactured products given to a single patient.

It is unclear whether the proposed language stating ‘the same biological in the same patient is covered only when a new primary cancer diagnosis is made’ is referring only to a circumstance where a patient receives more than one dose of a single patient specific product, or if this language would also preclude treatment with one manufactured product and subsequent treatment with another manufactured product for the same diagnosis. To preserve patient choice, SCCA asks that the final policy language clarifies that a patient is still eligible to receive subsequent treatment with another manufactured product for the same diagnosis, and that a new primary cancer diagnosis is only necessary before a patient receives more than one dose of a single product.

Seattle Cancer Care Alliance appreciates the opportunity to comment and your consideration of our remarks. Please do not hesitate to contact me if you have any questions.

Sincerely,

Keith Eaton, M.D.
Medical Director, Quality, Safety, and Value
Seattle Cancer Care Alliance
kdeaton@seattlecca.org

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Dear Ms. Syrek Jensen:

The Foundation for the Accreditation of Cellular Therapy (FACT) appreciates the opportunity to submit comments regarding the Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N). This letter provides a brief overview of FACT and our comments on the proposed decision memo.

Brief Overview of FACT

The mission of FACT is to improve the quality of cellular therapy through peer-developed standards, education, and accreditation for the benefit of patients. It is the non-profit standards and accreditation arm of the American Society for Transplantation and Cellular Therapy (ASTCT, recently renamed from the American Society for Blood and Marrow Transplantation) and the International Society for Cell and Gene Therapy (ISCT). Some payers require FACT accreditation as a criterion for reimbursement and designation of centers of excellence, and some clinical trial groups require FACT accreditation for participation.

In 2017, FACT published standards and implemented an accompanying accreditation program for immune effector cells (IECs), which includes CAR T-cell therapies. FACT Standards and accreditation require a robust quality and safety program in which the therapies are administered. The Standards and accreditation program were created in response to interest from several stakeholders, including drug manufacturers and IEC clinical programs. Regulators and payers have also used FACT accreditation as an indication of quality. FACT-accredited IEC programs are educated, trained, and well equipped to safely administer and manage these therapies.

At the time of this letter, FACT has accredited 183 hematopoietic progenitor cell (HPC) transplant programs, and 58 of these programs are also accredited for IECs. An additional program is accredited as a stand-alone IEC program. FACT has also conducted or scheduled 21 inspections of other transplant programs seeking IEC accreditation.

For additional details regarding FACT’s history and its standards and accreditation program for IECs, see our comments submitted in regards to the National Coverage Analysis for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers dated June 15, 2018.

Comments Regarding Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

1. Decision Summary, A: “The Centers for Medicare & Medicaid Services (CMS) proposes to cover autologous treatment with T-cells expressing at least one chimeric antigen receptor (CAR) through coverage with evidence development (CED) when prescribed by the treating oncologist, performed in a hospital, and all of the following requirements are met:
   1. Patient has:
      1. Relapsed or refractory cancer; and
      2. not currently been experiencing any comorbidity that would otherwise preclude patient benefit.”

   We agree that the CMS should cover CAR T-cell therapies for its beneficiaries, and that the therapies should be administered in hospitals meeting the guidelines described within the proposed decision memo.

   Congruent with the position of ASTCT, we are concerned that a National Coverage Decision (NCD) with CED increases barriers to access to this lifesaving therapy. We also encourage CMS to cover CAR T-cell therapies approved by the Food and Drug Administration (FDA) in accordance with the product label. There are currently clinical trials underway to study CAR T-cells in different contexts, such as first-line therapy or from an allogeneic donor, and more can be expected. The specification of autologous therapy for relapsed or refractory cancer may cause the NCD to become outdated. Finally, we encourage CMS to clarify that the physician treating a patient determines if the risks of any comorbidities outweigh the potential benefits of CAR T-cell therapy.

2. Decision Summary, A.2: “The hospital has: a. a Cellular Therapy Program consisting of an integrated medical team that includes a Clinical Program Director, a Quality Manager, and at least one physician experienced in cellular therapy, and demonstrates that protocols, procedures, quality management, and clinical outcomes are consistent from regular interaction among all team members; b. a designated care area that protects the patient from transmission of infectious agents and allows for appropriate patient isolation as necessary for evaluation and treatment; and c. written guidelines when administering CAR T-cell therapy for patient communication, monitoring, and transfer to an intensive care unit.”

   We agree with the inclusion of hospital requirements that are congruent with FACT Standards for the medical team’s leadership, experience, integration, care areas, and guidelines. These requirements will promote patient safety and CAR T-cell efficacy.

3. Decision Summary, A.3 and A.4.c:
   • “. . . then the patient must be enrolled in, and the furnishing hospital is participating in, a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, follows the patient for at least two years, adheres to the standards of scientific integrity and relevance to the Medicare population as identified in section A.4 of this decision, and answers the three following CED questions:”
   • “The study results are not anticipated to unjustifiably duplicate existing knowledge.”

   We have some questions related to data collection and reporting, and would appreciate clarification regarding potential noncoverage if patients do not consent to collection and reporting of their health-care related data, or if they become lost to follow-up or refuse additional data collection despite hospitals’ good-faith efforts.

   We support the use of the Center for International Blood and Marrow Transplant Research (CIBMTR) as a national registry to promote consistent data and reduce the reporting burden on providers. We suggest that the CIBMTR be included in decision documents and the National Coverage Determination (NCD) Manual as an example of an existing registry. The CIBMTR has experience with collecting data from providers, auditing data for accuracy, providing data back to the providers for analysis, and establishing risk-adjusted algorithms for evaluating patient outcomes. It administers the Stem Cell Therapeutic Outcomes Database (SCTOD) for HPC transplantation and serves as the Cellular Immunotherapy Data Resource (CIDR) for the Immuno-Oncology Transplantation Network (IOTN). CIBMTR has the ability to provide its services to a wide variety of cellular and gene therapy manufacturers.

   The CIBMTR is currently working with at least two CAR-T manufacturers to incorporate their requirements into data forms, and the manufacturers have indicated they will be using the CIBMTR for their registries. It has also developed an electronic Patient-Reported Outcomes collection system (ePRO). These initiatives allow efficient use of resources and a consistent source and format of data for evaluation.

   Given providers’ experience with CIBMTR, and CIBMTR’s efforts to incorporate IECs (including CAR T-cells) into its databases, use of this organization’s services will support the proposed decision memo’s statement that study results do not unjustifiably duplicate existing knowledge.

   We suggest that CMS begin certifying CIBMTR as a registry for purposes of CED to avoid a gap in coverage between when the decision memo is finalized and when the CIBMTR may be certified.

4. Decision Summary, A.3.a.ii and A.3.b.i and VIII. CMS Analysis, Outpatient Setting:
   • “and answers the four following CED questions: . . . How does the patient report their symptom function health-related quality of life changes over the course of their treatment?”
   • “and submit to CMS for approval a written executable analysis plan to address all of the following CED questions: How does the patient report their symptom function and health-related quality of life changes over the course of their treatment?”
   • “. . . Therefore, we are concerned about seriously ill patients with relapsed or refractory cancer who receive CAR T-cell therapy without a hospital inpatient admission to receive specialized care and monitor for serious AEs. To this end, consistent with NCCN guidelines, and the limited information regarding use of an FDA-approved product inconsistent with an FDA indication for use, we also propose that patients receiving CAR T-cell therapy for any other use and patients provided CAR T-cell therapy without hospital inpatient admission must address the CED question of how the patient feels their health-related quality of life changes over the course of their treatment and to this end collect patient’s health-related quality of life . . .”
   • “. . . we also propose that patients receiving CAR T-cell therapy for any other use and patients provided CAR T-cell therapy without hospital inpatient admission must address the CED question of how the patient feels their health-related quality of life changes over the course of their treatment and to this end collect patient’s health-related quality of life using an NIH patient-reported outcome assessment, including the PRO-CTCAE and PROMIS.”

   We request more clarification on the utility of quality of life data. The proposed decision only requires such reporting after outpatient administration or administration under specific National Comprehensive Cancer Network (NCCN) guidelines. As described in the memo, this is due to concerns related to caregivers’ and support networks’ abilities to recognize and handle adverse events. This is a valid concern that we agree should be addressed; however, additional clarity regarding the required timeframes for submitting quality of life data is requested. The proposed decision requires data to answer the CED questions at 3 months, 6 months, 12 months, and 24 months. Given the proposed decision memo’s explanation for requiring patient-reported outcomes, and the typical onset of adverse events following CAR T-cell administration, it is unclear why quality of life data at six months and beyond are necessary. Obtaining data this frequently from patients may be difficult to achieve and may not address the concern of adverse event management.

   In regards to tools used to report quality of life, we suggest the use of the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS®). This system collects data more applicable to quality of life measures; the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAETM) focuses more on safety. Furthermore, the CIBMTR is incorporating (PROMIS®) into its ePRO system, and use of this tool would promote consistency and harmonization.

   Similar to our suggestion to certify CIBMTR as a registry prior to finalization of the proposed decision memo, we suggest that quality of life data not be required until a patient-reported outcomes (PRO) protocol is approved and operational. CIBMTR has a data collection protocol that is already approved by programs’ Institutional Review Boards (IRBs), is operational, and collects data to answer the other CED questions; however, this activity does not currently include PRO collection. CIBMTR already has infrastructure for PRO collection, but drafting of a protocol and approval of IRBs will be required.

5. Decision Summary, A.3.a.iii: “The furnishing hospital shall address the CED questions on all registry patients by tracking the following clinical data elements at baseline, at treatment, and at follow-up 3 months, 6 months, 12 months, and 24 months after the treatment is administered.”

   If CED data are required, we agree that hospitals furnishing the CAR T-cells should submit follow-up data. Follow-up will not likely be a major priority of primary oncologists, and we believe that reporting should be analogous to HPC transplantation in which a data coordinator obtains data. We suggest aligning required time points for data with existing CIBMTR protocols, FACT Standards, and other regulatory agencies to promote consistency in data and minimize burden to programs.

   Long-term follow-up has been a challenging task in HPC transplantation, especially the posttransplantation period when patients return to health care providers not involved with the transplant. We expect similar challenges with CAR T-cell therapy and request clarification regarding potential retroactive loss in coverage if patient data cannot be obtained.

6. VII.B.6. Professional Society Recommendations / Consensus Statements / Other Expert Opinion: “Foundation for the Accreditation of Cellular Therapy (FACT). Standards for Immune Effector Cell Administration. First edition, version 1.1. March 2018 . . . The objective of the Common Standards is stated to promote quality medical and laboratory practice in cellular therapies as an emerging and evolving field . . .”

   We agree that inclusion of FACT Standards in the proposed decision, and expectations that practitioners and providers comply with them, is important for safe and efficacious administration of CAR T-cell therapies.

   The proposed decision memo references the FACT Standards for Immune Effector Cells, but describes the FACT Common Standards for Cellular Therapies. There is no reference to the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration, which are currently the Standards most commonly applied to accredited IEC programs. FACT Standards are arranged to accommodate the various care delivery models employed by health care institutions so that accredited services are clearly delineated. The following paragraphs better clarify how the FACT Standards apply to IECs.

   Most institutions administer IEC therapies, including CAR T-cells, within their HPC transplant programs. For these programs, the requirements are incorporated into the current edition of the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration. All requirements in these Standards apply to IECs as they are relevant (for example, IECs must be fully incorporated into the program’s Quality Management program, personnel training programs, and process controls).

   For clinical programs that do not perform HPC transplantation, the current edition of the FACT Standards for Immune Effector Cells applies. These Standards include only those requirements that apply to IEC therapies; transplant-specific requirements (for example, monitoring of engraftment) are not included. Future use of these Standards is expected to grow as institutions begin administering IECs outside of transplant programs; however, at the time of this letter, only one program is accredited under these Standards.

   The FACT Common Standards for Cellular Therapies includes the basic fundamentals any type of cellular therapy program should employ, and is the basis of the other, more specific Standards. It is a separate document that does not include specific requirements for IECs.

   For making coverage decisions for CAR T-cell therapies, we believe your decision documents and NCD Manual should reference 1) the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration and 2) the FACT Standards for Immune Effector Cells. The Standards are updated every three years, and we suggest that the “current edition” be referenced rather than specific editions. Information in the proposed decision memo regarding the Standards development process and requirements of clinical programs is correct for both of these sets of Standards.

7. Appendix A, Generalizability of Clinical Evidence to the Medicare Population: “The level of care and the experience of the providers in the study are other crucial elements in assessing a study’s external validity. Trial participants in an academic medical center may receive more or different attention than is typically available in non-tertiary settings. For example, an investigator’s lengthy and detailed explanations of the potential benefits of the intervention and/or the use of new equipment provided to the academic center by the study sponsor may raise doubts about the applicability of study findings to community practice.”

   This section acknowledges the difference in quantity or type of attention given to trial participants in different medical settings, and questions the applicability of study findings to community-based practices. FACT Standards can be applied in any type of health care institution; however, they do require a robust infrastructure that would take time for inexperienced institutions to build. Given that provision of CAR T-cells within the commercial construct is new, we agree that such therapies should only be provided in accredited centers.

8. VIII. CMS Analysis, Practitioner and Provider Requirements: “Standards we would expect to find in a Cellular Therapy Program are included in the Foundation for the Accreditation of Cellular Therapy (FACT) Common Standards for Cellular Therapies (2015) and Standards for Immune Effector Cell Administration (2016) and describe quality management guidelines to incorporate performance data, as well as policies and procedures that address risk management of operations . . . We believe adherence to criteria consistent with a nationally accredited Cellular Therapy Program promotes patient safety, and ensures best patient outcomes and optimal CAR T-cell therapy administration. We note that FACT accreditation, which considers these criteria, is also consistent with current practice by CAR T-cell manufacturers and participating hospitals involved with the administration of CAR T-cell therapy and care of patients.”

   We agree with your determination that CAR T-cell therapies should be administered in hospitals accredited under requirements that are included within the FACT Standards. As the memo states, these therapies have known toxicities that require experience, training, facilities, and procedures for mitigating, responding to, and evaluating adverse events. Additionally, our experience since implementing the IEC accreditation program has shown that implications of commercial access to these therapies, rather than within a research program, introduces additional challenges related to chain of custody, staff training, and data reporting. The FACT Standards and accreditation program requires and verifies processes to address these challenges.

   In addition to CAR T-cell manufacturers’ requirements for FACT accreditation, payers have begun implementing or are considering FACT accreditation as a requirement for reimbursement or centers of excellence. Continued harmonization of this requirement will increase consistency and reduce burden across providing organizations. Stakeholders have expressed with FACT a desire for clarification whether FACT accreditation completely satisfies this requirement or if hospitals would be required to further confirm they meet coverage requirements via other requirements. We suggest that FACT accreditation of immune effector cellular therapy be sufficient.

   We also believe this section should reference the current editions of the following FACT Standards: 1) the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration and 2) the FACT Standards for Immune Effector Cells.

Thank you for considering these comments. We hope you find them useful. If you have any questions, please do not hesitate to contact us.

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Dear Administrator Verma:

On behalf of Northwestern Medicine (NM), I wish to thank the Centers for Medicare and Medicaid Services (CMS) for its Proposed Decision Memo (CAG-00451N) for Coverage of Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers under Coverage Evidence Development (CED). CAR T-cell therapy has the extraordinary potential to save lives. It is imperative that a national standard of coverage be established to ensure that Medicare beneficiaries – and all patients - have adequate access to this medically-indicated therapy. To that end, NM is encouraged by and grateful for this move towards clarity being provided by CMS for this this revolutionary approach to fighting cancer. NM also thanks CMS for the opportunity to review the proposed NCD and provide its thoughts and comments.

By way of background, the Northwestern Medicine health system includes 10 hospital sites throughout Northern and Northwestern Illinois, including its flagship academic medical center, Northwestern Memorial Hospital, which is located in downtown Chicago. NM has a staff of more than 4,000 physicians, medical residents and fellows and operates the second largest clinically-integrated network in Illinois – the Northwestern Medicine Physician Network. NM is also a leading provider of both charity care and Medicaid in the State of Illinois.

In 2018, NM provided more than 89,000 inpatient admissions and 2.3 million outpatient encounters across the metropolitan Chicago area. NM has a long history of working to expand access to care for the communities we are privileged to serve as well as improve the quality and safety of the care we deliver. We pride ourselves on supporting a robust quality and process improvement infrastructure. NM has embraced the transition led by Medicare from fee-for-service payment to value-based payment models that incentivize a patient-centered optimization of care delivery across the care continuum by participating in several Center for Medicare and Medicaid Services (CMS) innovation programs including the Oncology Care Model (OCM), the Medicare Shared Savings Program (MSSP ACO), the Bundled Payment for Care Improvement (BPCI) initiative, the Transforming Clinical Practice Initiative (TCPI), as well as several other commercial payer value-based programs and initiatives. All NM patient sites are fully engaged in efforts to coordinate the delivery of health care.

NM has been an early adopter CAR T-cell therapies. By participating in multiple clinical trials and achieving certification for commercial infusion shortly after FDA approval, NM has established robust knowledge of the clinical, operational, regulatory, and financial challenges associated with this revolutionary therapy. Additionally, as co-chair of the B-Cell lymphoma guidelines committee, NM physician Dr. Leo Gordon, co-authored the NCCN guidelines for CAR T-cell therapy on DLBCL. This background and clinical experience demonstrates NM’s investment in the development of CAR T therapies as a viable and accessible treatment modality in the battle against cancer.

The process of administering CAR T-cell therapy is a time consuming endeavor requiring significant coordination of care for patients with aggressive disease who may have few other treatment options. This includes: obtaining insurance approval; providing patient/family education and support; collecting T-cells from the patient; cell packaging and distribution; clinical manufacturing; lymphodepleting chemotherapy; infusion of CAR T-cells; monitoring and follow up. Complications and adverse reactions are common and can add significant cost and time to the process.

CAR T-cell therapy is associated with extraordinary costs which, since the first FDA approvals, are largely borne by the treatment facility. As of this writing, the price for a hospital to purchase a single infusion for a lymphoma indication is $373,000; and $475,000 for an infusion with a leukemia indication.

Given the clinical complexity of these patients, substantial additional costs are also incurred by hospitals when administering CAR T-cell therapy. This often involves an inpatient admission that can range from weeks to months and may include: Intensive Care Unit (ICU) level monitoring; pressor support; mechanical ventilation; physical therapy; and, the use of high-cost medications such as Tocilizumab and steroids. Hospitals must also comply with the FDA’s risk evaluation and mitigation strategy (REMS) requirements, which include training a plethora of individuals; and, assisting patients with travel and lodging to meet certain FDA requirements after discharge. Additionally, both of the FDA approved products differ such that REMS training must be duplicated for each product. This necessary redundancy is expected to proliferate as new products are approved, which will add to administrative burden and cost. Ultimately, because of these and other factors, the costs for an institution to provide CAR T-cell therapy can easily exceed $500,000 (and, even higher costs are likely if complications arise). To date, reimbursement has not come close to meeting the direct costs of providing CAR T-cell therapy let alone the indirect costs associated with the training, staff support, and regulatory compliance and the administrative and infrastructure needed to develop and maintain a dynamic program. It is our hope that CMS recognizes all of the costs involved with administering CAR T-cell therapy, including but not limited to the acquisition of the product.

A noted previously, NM is very appreciative of CMS’ proposed decision memo. CAR T-cell therapy offers the extraordinary potential to save lives. However, there is no national, standardized Medicare policy for covering CAR T-cell therapy. Coverage decisions are left to discretion of local Medicare Administrative Contractors (MACs). For their part, most commercial insurers also choose to cover CAR T-cell therapy on a case-by-case basis. As a result, reimbursement decisions often lag. Ultimately, CMS’ proposed NCD will both improve access to this important new therapy while deepening CMS’ and the medical field’s understanding of how CAR T-cell therapy can benefit not only Medicare beneficiaries but all patients.

It is NM’s understanding that CMS’ proposal for national coverage determination (NCD) would require Medicare to pay for CAR T-cell therapy treatments provided via a CMS-approved registry or clinical study. Patients would need to be monitored for at least two years after receiving the treatment so the CMS can identify and study the types of patients for whom the therapy is effective.

It is also NM’s understanding that under CED, CMS proposes the following three options for coverage:

• Eligible patients served in an inpatient setting enrolled in a national, audited registry;
• Eligible patients served in an outpatient setting enrolled in a national, audited registry; or
• Eligible patients enrolled in a clinical study and receiving an FDA-approved biological “indicated for used identified in the National Comprehensive Cancer Network (NCCN) Drug and Biologics Compendium with Grade 2 or 1 on or after August 2017.

Also, the patient must have either relapsed or refractory cancer; and, is not currently experiencing any co-morbidity that would otherwise preclude the patient benefit.

It is also NM’s understanding that for a hospital to be eligible under CMS’ proposed NCD, it must:

• Have a Cellular Therapy Program consisting of an integrated medical team that includes a Clinical Program Director, a Quality Manager, and at least one physician experienced in cellular therapy, and demonstrates that protocols, procedures, quality management, and clinical outcomes are consistent from regular interaction among all team members;
• A designated care area that protects the patient from transmission of infectious agents and allows for appropriate patient isolation as necessary for evaluation and treatment; and
• Written guidelines when administering CAR T-cell therapy for patient communication, monitoring, and transfer to an intensive care unit.

Questions and Concerns:

• CMS’ Coverage with Evidence Development (CED) process requires data collection that will undoubtedly mean significant extra administrative costs for hospitals administering CAR-T cell therapy. What does CMS estimate the cost impact to be on providers for collecting the required information? NM urges CMS to also factor in costs associated with the administrative, regulatory, and training components necessary for the safe delivery of high-quality CAR T-cell therapy as it develops its Medicare reimbursement model.
• How will the “registry” be implemented? NM urges CMS to make use of existing reporting metrics and existing registry such as CIBMTR to reduce the administrative burden of establishing new reporting infrastructure and oversight.
• Like CMS, NM is hopeful that by covering CAR-T cell therapy, CMS and providers alike can gain deeper insight as to how well this new therapy will work for Medicare beneficiaries. To that end, what impact will this NCD have on coverage of future product approvals and indications? As technology continues to advance, therapies such as CAR-T cell therapy may become increasingly prevalent. It is critical that a precedent be set which ensures beneficiary access to care. This requires not only appropriate payment, but also provider certainty in terms of coverage determinations.
• How does CMS interpret the NCCN recommendations for off-label indications of CAR T-cell therapies? Specifically, in its Proposed Decision Memo, CMS cites NCCN under the proposed coverage options for eligible patients enrolled in a clinical study and receiving an FDA-approved biological indicated for used identified in the National Comprehensive Cancer Network (NCCN) Drug and Biologics Compendium with Grade 2 or 1 on or after August 2017. Specifically, CMS cites “Grade 2 or 1 rather than Category 1, Category 2A, or Category 2B. As a result, it is unclear which NCCN recommendations would be covered. NM supports the use of the NCCN drug and biologic compendium categories 1, 2A, and 2B.

In closing, I thank you for your leadership and support for this important issue. Your consideration of these comments is greatly appreciated. If you have any questions, please contact me at abresnah@nm.org or by phone at 312.926.9236.

Sincerely,

Andrew Bresnahan
Director, Patient Care - Oncology
Northwestern Memorial Hospital

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Ms. Seema Verma
Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Hubert H. Humphrey Building
Room 445-G
200 Independence Avenue, NW
Washington, DC 20201

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

Katherine B. Szarama, PhD
Lead Analyst
Evidence and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Lori A. Paserchia, MD
Lead Medical Officer
Evidence and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: National Coverage Analysis for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Administrator Verma, Ms. Jensen and Drs. Szarama and Paserchia:

Dana-Farber Cancer Institute (DFCI) is pleased to submit the following comments on the proposed National Coverage Determination (NCD) for Chimeric Antigen Receptor (CAR) T-cell Therapy(CAR-T) for Cancers.

For over 70 years, alongside our clinical colleagues at Boston Children’s Hospital (BCH) and Brigham and Women’s Hospital (BWH), DFCI has led the world by making life-changing breakthroughs in cancer research and patient care, providing the most advanced treatments available. We are proud to be at the forefront of research, discovery and innovation, which has revolutionized cancer diagnosis and treatment for decades. We were among the first to participate in clinical trials as well as commercial administration of CAR-T to Medicare and non-Medicare patients. We were involved in the Kite pivotal clinical trial leading to the FDA approval and were among the first certified centers for both tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta®). Over the past few years we have built a robust immune effector cell (IEC) program, have achieved FACT IEC accreditation, and we are actively reporting outcomes for these therapies to the CIBMTR registry.

DFCI received site certification to provide CAR-T to our patients by Kite on November 1, 2017, and by Novartis on November 20, 2017 for pediatric patients, and on April 19, 2018 for adult patients. DFCI has already treated 8 pediatric patients in conjunction with BCH and 158 adult patients in conjunction with BWH using CAR-T products, 63 of which were using the commercial products Yescarta and Kymriah.

With over 3.5 years of follow-up, we at DFCI have seen many cases of enduring response in patients who were treated as part of a trial. So far, for commercial Yescarta, we have seen an overall response rate of 80% at one month, and 81% of responding patients remain in response at 6 months. Based on trial data, this is a good surrogate for multi-year remission, but we will know more when we begin to see combined data from our center along with the other centers using this therapy who report to the CIBMTR which will be the best route to advancing our understanding of these therapies.

DFCI is currently involved in clinical trials to study CAR-T for use in treating blood cancers (e.g., other types of lymphoma, multiple myeloma, and leukemia) as well as solid tumors, allogeneic CAR-T and use of CAR-T earlier in the treatment pathway and, in combination with other immunotherapies.

DFCI clinicians and staff have been actively working with the ADCC, NCCN, the ASTCT and the ADCC to prepare formal responses to the NCD proposal and we strongly endorse these statements.

DFCI would like to specifically point out a few key concerns and propose solutions that would meet the needs of Medicare beneficiaries and Medicare’s objectives to manage resources and reduce paperwork.

Cover CAR-T Per FDA Label

DFCI believes that CMS should finalize an NCD to cover CAR-T products according to prevailing FDA approved labeled indications. Our center is among many who are actively involved in clinical trials which are rapidly evolving the scope, safety, efficacy, and application of these breakthrough therapies. Limiting the NCD to autologous products with references to refractory or relapsed cancers undermines the development underway through clinical trials testing allogeneic products, off the shelf products, and randomized studies comparing transplant and CAR-T to identify the best therapy for patients, possibly at earlier stages, that may lead to overall reduction in cost of care and improvements in outcomes.

The references in the memo regarding comorbidities are vague and can easily be misinterpreted. We believe that patient selection and comorbidity management is evolving rapidly. As an IEC FACT-accredited center, we comply with the FACT standards that require the clinical program to establish and maintain policies or standard operating procedures addressing recipient evaluation, selection and treatment. In addition, we maintain and actively refer to outcomes data across our patient population to correlate outcomes with co-morbidities and their management prior to and during CAR-T treatment as well as bridging therapies during product manufacturing that will yield insight on tumor burden management. To achieve the most efficacious approach to treatment it is essential that centers, with controls in place that meet FACT standards, will be able to deliver continuously improved therapies commercially as they are approved by the FDA.

We believe off-label use should follow existing CMS practice outlines in the Medicare Claims Processing Manual. CMS has named only one (i.e., NCCN) of the 5 compendia in this proposed NCD. If CMS persists with clinical trials for the off-label use, we ask that CMS continue to recognize all compendia currently listed. We ask that CMS address whether off-label requirements involve opening up new studies with separate NCTs or whether the study is what the named registry will do using data reported by the hospital. We will like clarification as to whether there are any separate reporting or participation requirements for off-label use or if the requirements for the hospital are the same as those described in the covered section related to registry reporting.

Hospital Requirements and Outcomes Data Reporting

DFCI supports the requirements for hospitals as laid out in the memo which are congruent with FACT Standards which will promote patient safety and support improvements in CAR-T efficacy.

We understand and support CMS’ desire for data collection and ask that CMS use the data submitted by certified centers to the Center for International Blood and Marrow Transplant Research (CIBMTR) for IEC treatments to consolidate data at the national level. As CMS knows, CIBMTR has extensive experience in researching and advancing hematopoietic cell transplantation (HCT) and cellular therapy and has implemented outcome reporting forms for immune effector cells including CAR-T. As more patients receive CAR-T, the field will have ready access to an expanding set of outcomes data on clinical benefits, including Medicare beneficiaries. CIBMTR is the registry being used by both manufacturers to comply with the post-market approval studies required by the FDA.

Centers who achieve IEC FACT accreditation must report to the CIBMTR using the applicable Cellular Therapy forms, some of which are very specific and some which are included on the general cellular therapy forms. The CIBMTR audits our data submitted routinely and ensures that our center reports data within specified time periods, currently at intervals of pre-infusion, infusion, 100 day, 6 month and one year, then annually. Similar to FACT accreditation for stem cell transplantation, if a center does not maintain CIBMTR reporting according to specified reporting standards, the accreditation is placed in jeopardy. Virtually all commercial payers require FACT accreditation at this time.

We believe an NCD that covers prevailing FDA approved products coupled with FACT accreditation and data collection from the CIBMTR would impose no new barriers, restrictions on access or administrative burden to providers. Indeed, in a press release for this NCD, Administrator Verma stated that CMS would be leveraging the post-approval studies which we appreciated and believed to mean that there would be no new requirements or burden placed on hospitals. Therefore, we respectfully ask that CMS drop the CED proposal and revert to an NCD with data collection through the CIBMTR registry for CAR-T patients.

We also ask that CMS eliminate the requirement for PROs for outpatient administration for several reasons. On a fundamental level we wholeheartedly support and value the importance of PRO data, and DFCI actively carries out many studies using a number of different patient reported outcome approaches and tools. However, we fail to understand how CMS access to PRO data helps answer the questions of whether CAR-T therapy is reasonable and medically necessary.

If PRO tools are added to the CIBMTR IEC data collected, we would support assisting the CIBMTR with developing a valuable correlative data approach, however this will take time to develop and put into practice. It is a worthy goal but cannot be instituted immediately. In addition, we are altogether unclear as to the applicability for this patient population of the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS®) and Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAETM). We strongly recommend that the PRO requirement be deferred until a suitable model can be developed within the CIBMTR national repository.

We are also concerned that asking for PROs on outpatients could impose barriers when patients are determined to be suitable for outpatient administration. Many centers are actively testing products that are demonstrating lower toxicity levels which will permit outpatient administration and this should be encouraged and supported to drive the development of products that are less toxic while producing better long term outcomes.

Conclusion

In summary, DFCI appreciates the opportunity to submit comments to CMS regarding coverage of CAR-T. We hope CMS recognizes that this important and groundbreaking anti-cancer therapy is, for many patients, the only treatment option available and agrees that questions about coverage and/or payment should not impede patient’s access to care. Therefore, we urge CMS to finalize an NCD for FDA-approved CAR-T drugs for their labeled indications with data collection and, continue to rely on existing off-label coverage mechanisms. In this manner, CMS will avoid creating new, unnecessary, and burdensome processes for providers, patients, and the agency itself.

DFCI also endorses the detailed requests for clarification on some of the language used in the memo that is being provided through letters from the ADCC, NCCN, the ASTCT and the ADCC which DFCI contributed to.

DFCI strongly urges the agency to do everything it can to reduce confusion and provide clarity upon release of the final NCD. This is critical to clinicians’ ability to continue providing critically ill patients with care that has the potential to save their lives.

If you have any questions or would like to speak with our experts or clinical teams, please do not hesitate to contact me at 617-632-5847.

Sincerely,

Caron Jacobson, MD
Assistant Professor of Medicine, Harvard Medical School
Medical Director, Immune Effector Cell Therapy Program, Dana-Farber Cancer Institute

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March 15, 2019

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

Re: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek-Jensen:

The American Society for Transplantation and Cellular Therapy (ASTCT), formerly the American Society for Blood and Marrow Transplantation (ASBMT), appreciates the opportunity to provide comments on the Centers for Medicare and Medicaid Services’ (CMS) Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N). ASTCT is a professional membership association of more than 2,200 physicians, scientists and other health care professionals promoting blood and marrow transplantation and cellular therapy through research, education, scholarly publication and clinical standards. The clinical teams in our society have been instrumental in developing and implementing clinical care standards and advancing cellular therapy science, including participating in trials that led to current FDA approvals for CAR-T cell therapy.

In comments submitted in June 2018 on CMS’ decision to examine coverage for CAR-T therapies, ASTCT opposed the establishment of a National Coverage Determination (NCD) due to concerns that it would cause significant and ongoing barriers to providing current and future CAR-T therapies to beneficiaries in need of these breakthrough treatments. Patients who receive CAR-T have typically exhausted all other available therapies. The Society still believes that it is premature to implement a NCD because this is a rapidly evolving area of medicine. Several CAR-T products are under investigation, including products with better safety profile and for indications other than the ones currently approved by the FDA (lymphoma and acute lymphoblastic leukemia). We recommend that development of a coverage policy be delayed until the field matures. We recognize that the unprecedented costs of these innovative therapies does necessitate evaluation of alternative coverage mechanisms. However, mechanisms other than a NCD need to be considered, and the ASTCT will continue to work with CMS as they explore the same.

If CMS proceeds despite these concerns, ASTCT recommends that the agency eliminate the CED requirement and instead implement an NCD with a data collection requirement that leverages the registry reporting currently in progress. We believe that the CED requirement will create another barrier to patient access. The insufficient Medicare inpatient reimbursement is already creating challenges for the centers where our members practice as they determine whether they can withstand the significant financial losses associated with delivering CAR-T therapy to Medicare patients. As drafted, this coverage policy may further limit access and ultimately stifle innovation because of the associated burden on centers. ASTCT has been working with CMS to address these reimbursement challenges and is hopeful that the FY 2020 Inpatient Prospective Payment System proposed rule will include policies to improve CAR-T reimbursement. We welcome the opportunity to work with the Coverage and Analysis Group to ensure that a final policy meets the needs of CMS, providers, and most importantly, patients.

Please consider the following comments that outline our suggestions on how to improve this proposed decision memo to limit any negative impacts on patient access and innovation should CMS decide to proceed. There are also many aspects of this policy that require further clarification that must be provided before this policy is finalized in order to minimize any disruptions to patient care.

Patient Condition Requirements
As drafted, coverage would be limited to require that patients have relapsed or refractory cancer. ASTCT urges CMS to expand this requirement to indications covered on the FDA approved label. Expanding the covered indications in this manner will not only cover life-saving treatment but also help promote innovation. We are concerned that based on CARs currently undergoing clinical trials, it may be necessary for CMS to reopen the NCD within the next five years in order to provide coverage for CAR-T therapies that are likely to be approved in that timeframe, or label expansions for the current products. One example of a CAR in the pipeline that would not be covered by the relapsed/refractory requirement is the ongoing study of CAR-T in high-risk multiple myeloma.¹ Another example is for lymphoma, where the current FDA approved indication is failure of two lines of therapy. The ongoing ZUMA7 trial is studying CAR-T after failure of first line of therapy.² Other therapies that are pending include CD19-specific CAR-T therapy³ and B cell maturation antigen CAR-T therapy for myeloma.⁴ These examples demonstrate the innovative therapies that can save lives but will be difficult, if not impossible for patients to receive with the proposed coverage decision.

ASTCT also disagrees with the requirement that the therapy can only be provided to a patient that is not currently experiencing any comorbidity that would otherwise preclude patient benefit. It is unclear from the proposal how CMS plans to define this, or monitor for it in its claims processing system. Patients presently receiving these therapies have advanced malignancies that frequently requires ongoing therapy prior to treatment with CAR-T. We recommend that the determination whether a patient can benefit from the therapy despite having certain comorbidities be deferred to their treating clinicians, as this very sick patient population is likely to have one or more comorbidities.

We also request that CMS provide more guidance around what it means by a “new primary cancer diagnosis” and “the use of more than one therapeutic dose of a specific CAR T-cell product” for repeat treatment. The possibility exists that a patient could be diagnosed with a separate malignancy or new diagnosis of a previously treated cancer and could benefit from receiving the same CAR-T product. Moreover, if the patient relapses at some point in the future, after receiving CAR-T therapy, our clinicians should be the ones assessing whether the patient would benefit from receiving the same or different CAR-T treatment. The field of cell therapy is rapidly evolving and therefore CMS’ final NCD should promote access rather than create barriers for new and innovative therapies.

CED Requirement
ASTCT understands that CMS included the CED requirement in order to gather additional data on the effectiveness of CARs in the Medicare population. However, if the agency chooses to finalize an NCD, the same objective can be accomplished with a registry reporting requirement rather than CED. We recognize and appreciate that the proposed CED requirement is less restrictive than others that CMS has implemented. However, we remain concerned that by virtue of this being a CED with additional patient reported outcomes (PRO) requirements in the outpatient setting, some centers will “opt-out”, further restricting access since the agency’s conditions of provider enrollment do not require participation in CED.⁵ The Society requests that CMS’ legal counsel confirm our analysis of the provider enrollment requirements and whether the anti-discrimination provisions in the conditions of participation require hospitals to furnish covered therapy (i.e., NCD covered therapies) to all patients in writing to avoid any confusion amongst centers. This analysis also should address whether or not patients are required to sign a notice of non-coverage (i.e, either an Advanced Beneficiary Notice (ABN) or a Hospital Issued Notice of Noncoverage (HINN)) acknowledging they have been advised that Medicare may not cover and pay for CAR-T therapy should a patient receive care at a hospital that chooses not to participate in data collection for the CED.

The Society strongly recommends that CMS eliminate the CED requirement and instead finalize a NCD with data collection that is tied to existing registry reporting, as this will help avoid the access problems that may result from centers being able to opt-out of the CED requirement. ASTCT strongly opposes the implementation of a coverage policy that allows centers to opt-out of participation if they perceive participation in the CED as imposing a significant burden in addition to the financial burden they already face. Again, we believe a NCD with data collection mechanism will provide CMS the opportunity to obtain data it needs to determine coverage policy for CAR-T therapy (see Registry Requirement below).

ASTCT asks for explicit clarification on the data collection and analysis requirements for the CED in order to ensure this requirement does not further limit patient access. In (3)(a)(iii), the policy states:

It is not clear whether this language would require the furnishing hospital to analyze the data. If CMS intends for the approved registry to do this analysis, we request that this section be redrafted to state more precisely that the registry is required to conduct the analysis. As written, there may be confusion that the furnishing hospitals will be required to conduct their own analysis on all registry patients (i.e. their own and other hospital registry patients), and that would represent an undue burden on hospitals and present yet another reason for centers to opt-out of participation.

ASTCT also requests clarification from CMS on the patient consent requirements applicable to this coverage policy both as it applies to the registry reporting and PRO requirements. The Society believes that there would be no coverage or a coverage denial if a patient does not explicitly consent to have their data reported to the registry and requests that CMS clarify what would happen if patients do not consent. Specifically, ASTCT requests clarification on whether hospitals will be required to provide patients with a notice of non-coverage (i.e., an ABN or HINN) if the patient does not consent to their data being submitted to the registry or to having their PROs submitted if the therapy is delivered on an outpatient basis. The Society does not support coverage being contingent upon a patient’s explicit consent to having their identifiable data submitted.

While it has been our general experience that most patients provide consent and are interested in having their data submitted to a registry to be a part of future scientific learning to benefit other cancer patients, CMS must recognize that there may be patients who do not want to participate, and that they have the right to refuse without penalty. As our Society members have been at the forefront of both clinical trials that led to the current product approvals, and in the first approved centers for commercial delivery of CAR-T therapy, we know that these patients have few realistic treatment alternatives, and certainly none that would potentially be curative. Knowing the poor outcomes for this disease population, and the risks of foregoing this treatment option, we are concerned how patients will perceive providers requesting patient consent regarding identifiable information in order for the patient’s treatment to be covered. Instead of potentially placing patients in this position, we recommend that CMS recognize a hospitals’ participation in a registry as sufficient to meeting the registry reporting requirements.

Registry Requirement
As proposed, the registry requirement requires furnishing hospitals to participate in “a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, and follows the patients for at least two years…” It also requires CMS to review and approve all registries. ASTCT believes the Center for International Blood & Marrow Transplant Research (CIBMTR) will meet the requirements to become an approved registry based on our review of the requirements and conversations with CIBMTR. Therefore, we recommend that CIBMTR be listed as an approved registry in the final NCD, assuming they receive their approval prior to the May 17 implementation date. We also recommend that the agency accept hospital participation with the registry without requiring any other enrollment with CMS.

CIBMTR is already collecting data for several CMS CED studies for myelodysplastic syndrome, myelofibrosis, sickle cell disease, and myeloma with great success. Our members are already familiar with CIBMTR through their work with patients with these conditions. Furthermore, CAR-Ts are already being provided by Foundation for the Accreditation of Cellular Therapy (FACT)-approved bone marrow transplant (BMT) programs, which are required by law to report data on allogeneic BMT to CIBMTR. The two manufacturers with approved products, Novartis and Kite/Gilead, are also using CIBMTR as the registry to meet their FDA post-approval study requirement. ASTCT believes this provides additional support for our request to have CIBMTR listed as an approved registry, which would reduce the burden to providers and institutions. ASTCT is pleased that our members are already familiar with a registry that will most likely be approved. Utilization of a registry other than the CIBMTR will increase reporting burden at centers that are providing CAR-T therapy, and will impact access as some centers may decide not to take on the additional resources and personnel required to report to another registry.

ASTCT believes it is critical that a registry be approved at the time this policy is finalized and implemented to avoid any coverage gaps. Furthermore, it is vital that the policy clarify that coverage is based on cell collection occurring on or after the effective date since there will be patients in the midst of their CAR-T episode of treatment when the policy is finalized. We do not support an effective date that would be based on cell administration that could potentially disrupt coverage of an episode of CAR-T therapy already in progress.

Patient-Reported Outcomes Requirement
In the proposed decision memo, CMS included a PRO requirement for the outpatient setting. ASTCT has several concerns and questions related to this requirement. As we stated in our July 2018 comments regarding MEDCAC’s discussion on PROs, the Society strongly objects to any mechanism that would tie patient access or provider reimbursement to the reporting of PROs, especially in the case of CAR-T therapy.⁶ The Society believes that a PRO requirement would add an additional unreimbursed, administrative burden to the patients being treated with CAR-T therapy. In particular, we believe it is premature to require PRO data for this population and are also concerned that the two PRO tools listed in the policy are not directly applicable to this patient population. Moreover, at the August 2018 MedCAC meeting, we shared that there is insufficient evidence to support the use of these tools for CAR-T patients and believe that this is still the case. The Society is also concerned that the PRO requirement turns a registry-reporting requirement into a study, which will further exacerbate the financial burden on centers. At this time, the appropriate PRO instruments, their characteristics, timing of administration and feasibility of data collection in patients receiving CAR-T therapy is not well described.

If this requirement is retained in the final policy, we request that it continue to be applied only to outpatients and the agency define “outpatient” as used in the proposed decision memo. It is unclear if the setting is based on the physician order when the cells are administered or on how the account is billed. Since some patients may be administered the cells as outpatients, but billed as inpatients, it is important that CMS provide clear guidance on this issue. We also recommend that participation in the PRO component of CED studies be voluntary for patients. In addition, so that access to CAR-T therapy is not compromised, we recommend that CMS allow additional time for development of PRO data collection protocols, IRB approvals, and implementation of appropriate PRO data collection mechanisms while allowing patients to enroll on CED studies that evaluate standard clinical outcomes (other than PROs). Finally, if PROs are included, we strongly recommend that CIBMTR, as our recommended registry of record for this purpose, be the organization that develops and implements the PRO aspect of the CED protocol.

Accreditation Requirements
In the proposed decision memo, CMS included the following requirement for CED:

If CMS retains this requirement in the final NCD, ASTCT urges CMS to define a uniform mechanism for accreditation that conforms to CMS standards in order to ensure that these cells are administered within a cell therapy program as defined. We were pleased that CMS listed Foundation for the Accreditation of Cellular Therapy (FACT) in the proposed decision memo as a mechanism to accredit centers providing CAR-T therapy under the CED. ASTCT urges CMS to require use of FACT or another broadly accepted accreditation program rather than creating a duplicative set of requirements to which centers must comply.

The Society expects that the hospital will not be required to attest to CMS its program meets the outlined accreditation standards. We do not support a requirement that would require a hospital to actively enroll with CMS as a requirement of coverage.

Off-Label Coverage Requirements
In the proposed decision memo, CMS outlines off-label coverage requirements. ASTCT requests that CMS provide clarification on whether this triggers study participation or if the registry reporting requirement would apply. Currently, CMS recognizes off-label use of anti-cancer drugs and biologicals when they are referenced in compendia listed in the Chapter 15, Section 50.4.5 of the Medicare Benefits Policy Manual.

The Society urges CMS not to implement a coverage policy that restricts off-label coverage for CAR-T different from that allowed for Medicare beneficiaries receiving any other anti-cancer drugs and biologicals. As we have repeatedly emphasized, this therapy is currently a therapy of last resort and saves patients’ lives. Appropriate off-label use should not come with additional requirements beyond data collection. The Society requests that CMS clarify if the intent is for a study similar to a full clinical trial be required for off-label use, or if the requirement is similar to the registry reporting requirement already in place.

The Society also seeks clarification on why NCCN was listed as the sole applicable compendium in the proposed decision memo when CMS recognizes others in the above referenced Medicare Benefits Policy Manual.⁷ ASTCT recommends that CMS cover off-label use of CAR-Ts consistent with other anti-cancer drugs and biologicals and clarify that data collection via the registry is also required.

Conclusion
ASTCT appreciates the opportunity to comment on the proposed decision memo and to provide our perspective on the best way to ensure access to medically accepted CAR-T therapies for Medicare beneficiaries. We have included a list of questions in Appendix I, which require clarification before the implementation of the policy. The Society looks forward to working with you to improve this policy to ensure that appropriate patients have access to this lifesaving therapy. If you have any questions regarding the above comments, or if we can provide any additional information, please contact Alycia Maloney, ASTCT’s Director of Government Relations at amaloney@asbmt.org.

Sincerely,

Navneet Majhail, MD, MS
Cleveland Clinic
Taussig Cancer Institute, Department of Hematology & Medical Oncology
Director, Blood and Marrow Transplant Program
President, American Society for Transplantation and Cellular Therapy

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1 https://clinicaltrials.gov/ct2/show/NCT03549442
2 https://clinicaltrials.gov/ct2/show/NCT03549442
3 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410390/
4 https://ash.confex.com/ash/2018/webprogram/Paper116898.html
5 42 CFR 424
6 ASBMT Comments to CMS on MEDCAC meeting held on August 22, 2018. Link to comments here: https://higherlogicdownload.s3.amazonaws.com/ASBMT/43a1f41f-55cb-4c97-9e78-c03e867db505/UploadedImages/ASBMT_CMS_Comment_MEDCAC_CAR_T_PROs_7_16_2018.pdf
7 42 CFR 424

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Ms. Tamara Syrek Jensen
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Department of Health and Human Services

Re: Proposed National Coverage Analysis Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers

Dear Director Syrek Jensen:

We appreciate the opportunity to provide comments on the proposed National Coverage Analysis Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers issued February 15, 2019. 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 1,000,000 people from all 50 states and 140 countries come to Mayo Clinic to receive the highest quality care at sites in Minnesota, Arizona and Florida. In addition, Mayo Clinic Health System , a family of clinics, hospitals and health care facilities that serves communities in Iowa, Minnesota and Wisconsin.

The Mayo Clinic CAR-T program has certified hospitals in Phoenix, Arizona, Jacksonville, Florida and Rochester, Minnesota. Mayo Clinic is committed to safeguard and ensure guidelines set by the FDA provide safety and protection to our patients, including those that are Medicare beneficiaries. We support the need for long term follow-up and study of patients treated with available CAR T-cell therapies and the need for a Coverage with Evidence Development (CED) that will help to inform future revisions of CAR-T therapy National Coverage Determination (NCD). After careful review of the proposed decision memo, we respectfully submit the following comments:

1. Update "treating oncologist" to "treating oncologist or hematologist"

We agree the prescription of CAR T-cells should be written by a physician in the area of expertise who is treating the patient. At Mayo Clinic, the current treating physicians for CART­ cells are board certified hematologists. We request changing the term "treating oncologist" to state "treating oncologist or hematologist". Currently oncologists and hematologists with expertise in aggressive B-cell non-Hodgkin lymphoma, acute lymphoblastic leukemia and multiple myeloma are the physicians with the experience with CAR-T treatment. As more clinical indications for CAR-T treatment become FDA-approved, the scope of expertise is likely to expand. By specifying only oncologist in this decision memo, there is potential to limit those who can prescribe CAR-T treatment in the future.

2. Utilize Foundation for the Accreditation of Cellular Therapy (FACT) to ensure hospital requirements are met

We agree there is a need to have hospital requirements in place to effectively manage these therapies. The manufacturers of the biologicals have a process to certify hospitals in accordance with the Risk Evaluation and Mitigation System (REMS) defined by FDA. One of the requirements for certification by these manufacturers is for the treatment centers to be accredited for the Immune Effector Cell (IEC) Standards through the Foundation for the Accreditation of Cellular Therapy (FACT). The IEC standards include the hospital requirements indicated in the decision memo. If the treatment centers are required to show compliance with these requirements, Mayo Clinic strongly urges the Centers for Medicare & Medicaid Services (CMS) to consider allowing FACT to serve as the auditing organization to reduce redundant inspections/audits. To remain FACT accredited, centers are required to be audited every three years and must show compliance with the indicated hospital requirements.

3. Utilize the Center for International Blood and Marrow Transplant Research (CIBMTR) registry for reporting

The decision memo indicates that CAR-T treatment will be covered by Medicare with a requirement that the patient be enrolled in a prospective, national, audited registry. Since all CAR-T patients are entered into the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, Mayo Clinic strongly recommends the utilization of this registry in place of an additional national registry to avoid duplicate workload. CIBMTR captures all the requested clinical data elements at all the time points indicated with the exception of quality of life (QOL) data. The CIBMTR is also working on a proposal to incorporate patient reported outcomes and quality of life data into the registry which would reduce the requirement of treatment centers to utilize a separate registry. Additionally CIBMTR data is already highly audited to ensure centers are reporting accurate data.

Thank you for the opportunity to comment on the proposed decision memo and for consideration of our comments. If you should have any questions, please contact either Jan Buckner, M.D. at (507) 284-7024 or Robert Diasio, M .D. at (507) 266-4997.

Very truly yours,

Jan C. Buckner, M.D.
Chair, Mayo Clinic Cancer Center
Mayo Clinic

Robert B. Diasio, M.D.
Director, Mayo Clinic's NCI-Designated Comprehensive Cancer Center
Mayo Clinic

cc:
Martha Lacy, M.D.
Yi Lin, M.D., Ph.D.
Januario Castro, M.D.
Mohamed Kharfan Dabaja, M.D.
Francis C. Nichols, M.D.
Donald Hertel
Brenda Mickow
Randy Schubring

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March 14, 2019
Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek-Jensen:

The University of Kansas Cancer Center appreciates the opportunity to provide comments on the Centers for Medicare and Medicaid Services’ (CMS) Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N). As the only National Cancer Institute (NCI)-designated cancer center in Kansas, we feel a deep obligation to cure all cancers in our region and the Nation. The University of Kansas Cancer Center’s multi-disciplinary team of physicians, scientists and other health care professionals have been performing life-saving blood and marrow transplantation and cellular therapy through research for decades and we are currently the only center in Kansas to certified to treat patients with both FDA-approved CAR-T therapies. Patients who qualify for FDA-approved CAR-T therapy today are seeing unprecedented remission rates of 50-85% for their cancers and this represents a remarkable revolution in cancer medicine.

In June 2018 comments regarding CMS’ decision to examine coverage for CAR-T therapies, our center expressed concerns that the proposed National Coverage Determination (NCD) would create uncertainty around reimbursement for Medicare beneficiaries, therein creating access barriers to centers providing current and future CAR-T therapies to beneficiaries in need of these breakthrough treatments. Patients who receive CAR-T have typically exhausted all other available therapies. It is vital that access to CAR-T therapy for Medicare patients is not hindered. Beyond presenting a burden to patients, many of the components of this proposed NCD may cause undue challenges for centers that provide these life-saving therapies because of the rapid advancements being made in the field of CAR-T and immunotherapy. It is our strong belief that it is too early to implement the NCD. However, should CMS proceed with implementing an NCD, we urge CMS to consider the following recommendations.

Coverage with Evidence Development (CED) and Registry Requirements:
In support of the various experts in the field, we recommend the agency eliminate the CED requirement and instead implement an NCD with a data collection requirement that leverages those efforts currently in progress. We believe that the CED requirement will create another barrier to patient access. The insufficient Medicare inpatient reimbursement is already creating challenges for our center and many other non-PPS exempt centers offering CAR-T therapy that results in a daily analysis of the significant financial losses associated with delivering CAR-T therapy to Medicare patients. As drafted, this coverage policy may further limit access and ultimately stifle innovation because of the associated burden on centers.

Please consider the following comments that outline our suggestions on how to improve this proposed decision memo to limit any negative impacts on patient access and innovation should CMS decide to proceed. There are also many aspects of this policy that require further clarification that must be provided before this policy is finalized in order to minimize any disruptions to patient care.

As proposed, the registry requirement requires furnishing hospitals to participate in “a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, and follows the patients for at least two years…” It also requires CMS to review and approve all registries. ASTCT believes the Center for International Blood & Marrow Transplant Research (CIBMTR) will meet the requirements to become an approved registry based on our review of the requirements and conversations with CIBMTR. Therefore, we recommend that CIBMTR be listed as an approved registry in the final NCD, assuming they receive their approval prior to the May 17 implementation date. We also recommend that the agency accept hospital participation with the registry without requiring any other enrollment with CMS.

The CIBMTR is already collecting data for several CMS CED studies for myelodysplastic syndrome, myelofibrosis, sickle cell disease, and myeloma with great success. Furthermore, CAR-T is already being provided by Foundation for the Accreditation of Cellular Therapy (FACT)-approved bone marrow transplant (BMT) programs, which are required by law to report data on allogeneic BMT to CIBMTR. The two manufacturers with approved products, Novartis and Kite/Gilead, are also using CIBMTR as the registry to meet their FDA post-approval study requirement. We strongly believe this provides additional support for our request to have CIBMTR listed as an approved registry, which would reduce the burden to providers and institutions.

We believe it is critical that a registry be approved at the time this policy is finalized and implemented to avoid any coverage gaps. Furthermore, it is vital that the policy clarify that coverage is based on cell collection occurring on or after the effective date since there will be patients during their CAR-T episode of treatment when the policy is finalized. We do not support an effective date that would be based on cell administration that could potentially disrupt coverage of an episode of CAR-T therapy already in progress.

Patient Coverage:
As drafted, coverage would be limited to require that patients have relapsed or refractory cancer. We urge CMS to expand this to include indications covered on the FDA approved label. Expanding the covered indications in this manner will not only cover life-saving treatment, but also help promote innovation. Again, we are concerned that based on CAR-T therapies currently undergoing clinical trials, it may be necessary for CMS to reopen the NCD within five years to provide coverage for those that are likely to be approved in that time frame. As these considerations are already part of the FDA approval process, we recommend that CMS revise this language to indicate coverage for FDA-approved products and to include indications covered on the FDA-approved label. This approach will ensure coverage for effective treatments that have already been approved, as well as guaranteeing coverage for new FDA-approved treatments that will come online as CAR-T research rapidly evolves.

We are also concerned with the other patient condition requirement that the therapy can only be provided to a patient that is not currently experiencing any comorbidity that would otherwise preclude patient benefit. It is unclear from the proposal how CMS plans to define this, or monitor for it in its claims processing system. Clinicians with expertise in treating these complex cancers should be the ones determining whether the patient can benefit from the therapy despite having certain comorbidities, as this is a very sick patient population likely to have one or more comorbidities.

Patient-Reported Outcomes Requirement:
In the proposed decision memo, CMS included a PRO requirement for the outpatient setting. While PRO measurement is important as it provides patient input, its implementation in clinical trials requires significant expenditure of financial and human resources. Like the CED requirement, many centers may not have the ability to launch and support PRO studies, further increasing the possibility that some centers may opt out of providing CAR T therapy for Medicare patients to avoid financial risks. More importantly, asking Medicare patients being treated with CAR T, most of whom are extremely sick, to report outcomes may cause more stress for this population. Therefore, we recommend that PROs not be included as a condition of coverage at this time. If the PRO requirement is included in the final decision, we urge CMS to provide further clarification on the definition of an “outpatient setting,” as this language will impact who will be covered for CAR T treatment and where. In addition, we believe it is premature to require PRO data for this population and are also concerned that the two PRO tools listed in the policy are not directly applicable to this patient population.

Our center is also concerned that the PRO requirement may ostensibly turn a registry-reporting requirement into a study, which will further exacerbate the financial burden on centers. Many centers already face financial risks in providing CAR-T due to low Medicare reimbursement and adding additional reporting requirements would provider another reason for centers to opt-out of providing care to Medicare patients. If CMS does opt to include PRO measures in the NCD, we strongly believe the optimal approach would be to include the PRO requirements within the CIBMTR registry reporting requirements. Implementing PRO requirements independent of the CIBMTR registry reporting would be cumbersome and pose unreasonable logistical challenges for CAR-T centers.

Practitioner and Provider Criteria:
In the proposed decision memo, CMS included the following requirement for CED:

In its analysis, CMS proposes coverage of CAR-T therapy in a hospital that meets requirements “consistent with a nationally accredited Cellular Therapy Program.” The memo further states, “Standards we would expect to find in a Cellular Therapy Program are included in the Foundation for the Accreditation of Cellular Therapy (FACT) Common Standards for Cellular Therapies (2015) Standards for Immune Effector Cell Administration (2016) and describe quality management guidelines to incorporate performance data, as well as policies and procedures that address risk management of operations.” Our center supports the use of FACT as a required accreditation program if CMS requires accreditation for centers. Our center and most of the leading CAR-T centers throughout the U.S. are FACT-accredited, and we believe the program promotes patient safety and ensures exemplary clinical and administrative practice.

Off-Label Coverage Requirements:
In the proposed decision memo, CMS outlines off-label coverage requirements. We urge CMS to provide clarification on whether this triggers study participation or if the registry reporting requirement would apply. Currently, CMS recognizes off-label use of anti-cancer drugs and biologicals when they are referenced in compendia listed in the Chapter 15, Section 50.4.5 of the Medicare Benefits Policy Manual.

Our center also urges CMS not to implement a coverage policy that restricts off-label coverage for CAR-T different from that allowed for Medicare beneficiaries receiving any other anti-cancer drugs and biologicals. CAR-T is a life-saving therapy with unprecedented remission rates for a patient population who historically may have only been offered palliative care options. Appropriate off-label use should not come with additional requirements beyond data collection. Our center requests that CMS clarify if the intent is for a study similar to a full clinical trial be required for off-label use, or if the requirement is similar to the registry reporting requirement already in place.

Lastly, we would also like clarification on why NCCN was listed as the sole applicable compendium in the proposed decision memo when CMS recognizes others in the aforementioned Medicare Benefits Policy Manual. We also recommend that CMS cover off-label use of CAR-T consistent with other anti-cancer drugs and biologicals and clarify that data collection via the registry is also required.

Conclusion:
The University of Kansas Cancer Center appreciates the opportunity to comment on the proposed decision memo and to provide our perspective on the best way to ensure access to medically accepted CAR-T therapies for Medicare beneficiaries. The fields of cancer research and care are on an incredible trajectory and as the exciting field of CAR-T continues to develop and evolve, we believe it is important that CMS ensures all patients can access such treatments if recommended by their physicians.

Sincerely,

Dr. Joseph McGuirk
Professor of Medicine
Schutte-Speas Professor of Hematology-Oncology
Division Director, Hematologic Malignancies and Cellular Therapeutics
Medical Director, Blood and Marrow Transplant
Department of Internal Medicine
The University of Kansas Health System

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March 15, 2019

Tamara Syrek Jensen, Director
Katherine B. Szarama, PhD, Lead Analyst
Lori A. Paserchia, MD, Lead Medical Officer
Evidence and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: National Coverage Analysis for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Submitted electronically via: www.cms.gov

Dear Ms. Jensen, Dr. Szarama, and Dr. Paserchia:

Cleveland Clinic appreciates the opportunity to comment on the National Coverage Analysis (NCA) the Centers for Medicare & Medicaid Services (CMS) has opened with respect to Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N).

Cleveland Clinic 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 3,600 salaried physicians and scientists. Last year, our system had 7.6 million patient visits and over 220,000 hospital admissions. To date, 25% of the patients for whom we are providing CAR T-cell therapy are enrolled in fee-for-service Medicare.

As an institution dedicated to patient care, we strive to make the most recent, ground-breaking advances in medicine available to all patients, including Medicare beneficiaries. The decisions that CMS makes with respect to coverage and payment of these therapies can have a profound impact on our ability to serve critically ill patients.

We are concerned with the decision of CMS to propose Coverage with Evidence Determination (CED) for CAR T-cell therapy. We appreciate that CAR T-cell therapy is new to market, and that CMS is eager to gather more information about the therapy and the care associated with its administration. However, we fear that coverage with evidence development poses a risk to patient access to these therapies by creating burdensome new requirements for coverage, including that patients must be enrolled in a clinical study, and that patients and furnishing facilities must participate in a registry for at least two years post-treatment.

These requirements compound access issues created by the Medicare payment formula. The payment methodology CMS has developed for the administration of CAR T-cell therapy leaves Cleveland Clinic and other medical institutions facing a financial shortfall in the hundreds of thousands of dollars for each Medicare patient treated.

If CMS does finalize coverage with evidence development, including the requirement that patients must be enrolled in a registry and tracked for at least two years post-treatment, we encourage CMS to specify the Center for International Blood and Marrow Transplant Research (CIBMTR) as an applicable registry. Cleveland Clinic – and many other institutions – have a long-standing working relationship with this registry and are already submitting data on patients receiving FDA approved CAR-T therapies to the CIBMTR. Utilizing this existing mechanism for data submission and collection will minimize burden on our institution, in case CMS decides to pursue the CED mechanism.

We also have concerns about limiting coverage to instances of relapsed or refractory cancer. Gene and cell therapy is an evolving field with great potential. Restricting the coverage of CAR T-cell therapy to those cases limits our ability to track the evolution of the field, necessitating an additional coverage determination each time new capabilities of the therapy are identified. CMS should base coverage according to the Food and Drug Administration’s approved uses for the therapy.

Finally, we have concerns with necessitating the reporting of Patient Reported Outcomes (PRO). Consistent with our “Patients First” motto, Cleveland Clinic is committed to providing the best possible care – and care experience – for patients. However, we are concerned that tracking PRO in this case would be unhelpful, particularly given the relative infancy of the field and lack of research on PRO in relation to CAR T-cell therapy. We feel that this is better suited within the context of research, than through a CED mechanism for determining policy.

CAR T-cell therapy holds tremendous promise to impact critically ill patients. We appreciate the opportunity to comment on this important issue. If you have further questions, please do not hesitate to contact our staff.

Sincerely,
Kristen Morris
Chief Government & Community Relations Officer

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Public Comment for: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

March 15, 2019

Sorrento Therapeutics, Inc. based in San Diego, California, USA respectfully submits comments to CMS Decision Memo for coverage of CAR-T therapy for cancers including the standardization of patient reported outcomes.

Sorrento is a clinical stage biopharmaceutical company developing new therapies for cancer. Sorrento is currently designing pivotal clinical trials for various international CAR-T oncology programs and desires to conform our pivotal study designs to current CMS guidance while generating data important to global regulatory health authorities, health technology assessment entities, and government and private payers in the United States and other countries.

The Proposed Decision Memo – [A.3.a.i.] (bullet 1) - states “How do patient outcomes compare to either the pivotal clinical trial(s) (i.e., the clinical trial(s) that served as the basis for FDA approval of the biological and/or for the FDA indication) of the biological or a cohort of controls receiving standard of care treatment?”

To address this question, hospital registries will need to be able to compare their patient outcome data to data generated in clinical trials. For quality of life/patient reported outcome (PRO) measurements, this would be more meaningful if similar instruments were used across clinical trials and registries. This proposal mandates the inclusion of certain QOL/PRO instruments that have not been validated for international oncology trials and may make it more difficult to ensure continuity of data as CAR-T products transition from research into commercial use and patients are followed in registries.

The Proposed Decision Memo states in [A.3.a.iv.]: “To address a CED question on health-related quality of life, the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS®) or Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAETM) patient-reported outcome assessment must be used at baseline, at treatment, and at follow-up 3 months, 6 months, 12 months, and 24 months after the treatment is administered.”

A Medicare Evidence Development & Coverage Advisory Committee evaluated patient-reported outcomes instruments for this Memo (section 4) and “recommended four out of seven PRO assessments (PRO-CTCAE, MDASI, EORTC-QLQ-C30, PROMIS) with greater than intermediate confidence, and believed that those assessments have available supporting evidence on almost all desired characteristics requested by CMS.”

We examined how frequently each instrument was used for cancer-related clinical trials (all types and CAR-T) registered with ClinicalTrials.Gov (analyzed February 26, 2019):

EORTC-QLQ:
-All cancer-related studies = 1,558
International (global) representation, diverse types and stages of cancer, short- and long-term evaluations, clinical trial and real-world settings, pharmacological and non-pharmacological interventions, early to palliative stages of cancer
-CAR-T studies = 7 (pharma and academia)

PRO-CTCAE:
-All cancer-related studies = 87
-CAR-T = 3 (all 3 studies performed at University of NC, Chapel Hill)

MDASI:
-All cancer-related studies = 185
This included the disease-specific MDASI instruments for head and neck, GI, brain tumors, spine, etc.
-CAR-T = zero studies

PROMIS:
-All cancer-related studies = 276
Almost all (265) studies were US based
-CAR-T studies = 3 (all 3 studies performed at University of NC, Chapel Hill)

Sorrento recommends, based on the above evaluation, that Recommendation [A.3.a.iv.] be modified to include options for commonly used, and well-validated instruments to assess PROs in patients living with cancer such as EORTC-QLQ-C30 as well as appropriate disease-specific instruments (for example, QLQ-MY 20, a questionnaire specific for multiple myeloma that includes side effects of treatment). (1)

This will improve the ability of all stakeholders, including pharmaceutical companies, the FDA, CMS, other US government agencies, other payers, and countries outside the US to share common PRO evaluation instruments across pharmaceutical-sponsored trials and registries conducted in real-world settings post-approval.

Camilla S. Graham, MD, MPH
Vice President, Medical Affairs
Sorrento Therapeutics

(1) Cocks, et al. Eur J Cancer 2007; 43:1670

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March 15, 2019

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

SUBMITTED ELECTRONICALLY VIA CMS.GOV

RE: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen:

The American Society of Hematology is pleased to offer comments on the Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers.

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 are pioneers in demonstrating the potential of treating various hematologic diseases and continue to be innovators in the field of stem cell biology, regenerative medicine, transfusion medicine, and gene therapy. ASH membership is comprised of basic, translational, and clinical scientists, as well as physicians providing care to patients in diverse settings including teaching and community hospitals, as well as private practice.

ASH’s members are at the forefront of CAR T-cell therapy, conducting research and providing this lifesaving treatment to patients with lymphoma and leukemia. The Society is concerned that the proposed decision memo has the potential to further limit patient access to this therapy. With this in mind, ASH’s comments focus on access to care, coverage, patient and registry requirements, and the patient reported outcome (PRO) tools.

Access to Care
It is ASH’s understanding that, if the decision memo is finalized as is, institutions will be able to opt out of participating in the coverage with evidence development (CED) requirement, thereby, giving institutions a legal means by which to opt out of providing CAR T-cell therapy to Medicare patients, but to continue providing it to patients with commercial insurance. Since the two commercial products were approved by the FDA, ASH has routinely heard from members regarding the significant negative financial impact on institutions of providing CAR T-cell therapy to Medicare patients due to inadequate reimbursement. Although ASH has been working closely with the American Society for Transplantation and Cellular Therapy (ASTCT) and the Centers for Medicare and Medicaid Services (CMS) to help address this problem, it remains a significant concern, and it is for this reason that ASH believes institutions may choose to opt out of participating in the CED.

Patients receiving CAR T-cell therapy have typically exhausted all other treatment options, including chemotherapy, radiation, and stem cell transplant. Successful treatment with CAR T-cell therapy improves quality of life and increases survival for these patients. ASH has strong concerns that, as written, the proposed decision memo will narrow the already limited access to this therapy. The Society recommends that CMS eliminate the CED requirement and instead implement a National Coverage Determination (NCD) with a registry reporting requirement which will allow the agency to collect additional data on this therapy while mitigating the access concerns raised by the current policy.

Coverage
CMS proposes to cover autologous treatment with T-cells expressing at least one chimeric antigen receptor (CAR) through CED when prescribed by the treating oncologist, performed in a hospital, and all of the outlined requirements are met. ASH recommends revising “autologous” to “FDA approved,” thereby removing the tie to cell source. Kymriah® and Yescarta®, the two approved CARs, are the first therapies of their kind to be approved; however, there are numerous CARs currently under development that employ a different method of action. Because ASH recognizes that CMS prefers not to reopen its NCDs on a regular basis, this recommended change will provide a pathway to coverage for therapies ASH expects to be approved in next five years.

Patient Requirements
The patient requirements as proposed by CMS require a patient to have “relapsed or refractory cancer.” ASH recommends CMS change this to cover patients with “FDA label indications.” Although the two currently approved FDA products are approved for individuals with relapsed and refractory cancers, current clinical trials are underway to employ these constructs earlier in the disease process.^1,2 Furthermore, the decision memo already recognizes treatment according to “FDA indication.” Section 3.a reads, “Treatment is an FDA-approved biological, providing targeted therapy for a known antigen expressed in the patient’s cancer according to an FDA indication in a hospital.”

Registry Requirements
If CMS proceeds with the CED despite our concerns, ASH requests that the Center for International Blood and Marrow Transplant Research (CIBMTR) be listed in the final NCD as a qualified registry. CIBMTR already collaborates with both Kite/Gilead and Novartis to track long-term outcomes of patients treated with CAR T-cell therapy; consequently, institutions currently providing CAR T-cell therapy, already report data to CIBMTR. Based on this and CIBMTR’s additional experience in the hematopoietic cell transplantation (HCT) and cellular therapy space, they are an ideal candidate to be a qualified registry for the CED. ASH recommends that CIBMTR be listed as an approved registry on the effective date of the coverage policy, if possible.

Additionally, ASH requests that CMS clarify section 3.a.iii, which states that “The furnishing hospital shall address the CED questions on all registry patients by tracking the following clinical data elements at baseline, at treatment, and at follow-up 3 months, 6 months, 12 months, and 24 months after the treatment is administered.” If CMS intended for hospitals to collect and analyze the data, then ASH respectfully recommends that CMS reword this provision so that it is clear that the responsibility for the data collection and analysis is with the registry. Our members are very concerned that if centers can opt out of the data collection requirement, that hospitals will opt out of providing CAR-T therapy to Medicare beneficiaries. This would exacerbate the existing patient access problems. Once adequate data are collected, validating the real-world effectiveness of these treatments, this CED should quickly evolve into a standardized coverage policy that ensures that Medicare beneficiaries get timely and unfettered access to evidence-based treatments.

Furthermore, in order to collect robust, complete data, ASH asks that race and ethnicity be added to the requirements for data collection.

Patient Reported Outcomes
For collecting and analyzing patient reported outcomes (PROs), ASH recommends that CMS work closely with CIBMTR to implement a system that is least burdensome for providers and patients. ASH members recognize the importance of collecting and analyzing PROs; however, they have also noted the additional burden this places on the provider and the added difficulty in this particular patient population, due to high rates of adverse events. Additionally, developing the necessary infrastructure and protocols, all of which have to be approved by Institutional Review Boards (IRBs) of all participating centers, to collect PROs, will take time. Therefore, ASH recommends that CMS allow for additional time for this process while allowing patients to enroll on CED studies to evaluate clinical outcomes.

Additional Concerns
ASH wants to ensure that patients who have already begun the process of CAR-T therapy prior to the final proposed decision memo will not have a delay in care, and that patients not be denied appropriate life-saving care while an acceptable data collection trial is undergoing CMS selection, IRB approval, and widespread national deployment. For example, CMS must clarify how coverage will or will not be applied to patients who already underwent leukapheresis but have not yet been infused. The agency should implement this policy in a manner consistent with providing coverage.

Thank you for the opportunity to provide comments on the Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers. We welcome the opportunity to discuss these comments with you and your team. If you have any questions or require further clarification, please contact Leslie Brady, ASH Policy and Practice Manager at lbrady@hematology.org or 202-292-0264.

Sincerely,

Martha Liggett, Esq.
Executive Director

1. ZUMA-7: A phase 3 randomized trial of axicabtagene ciloleucel (Axi-Cel) versus standard-of-care (SOC) therapy in patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL).
2. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia

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Subject: National Coverage Analysis for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Administrator Verma, Ms. Jensen and Drs. Szarama and Paserchia:

UPMC Hillman Cancer Center is pleased to submit comments on the proposed National Coverage Analysis for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers. UPMC Hillman Cancer Center is an NCI designated academic medical center servicing communities in Western and Central Pennsylvania that is actively participating in CART clinical trials, as well serving as a certified center to provide Yescarta and Kymriah commercially. CART has provided our patients with end stage disease hope and a potential cure where there are no other treatments or curative options left. UPMC provides these innovative life changing therapies to our patients in spite cif current reimbursement challenges.

Unintended Consequences of CED and Patient Reported Outcomes Data Requirement
UPMC Hillman Cancer Center is very concerned that if this NCD is finalized as proposed, it would result in other hospitals making a choice to no longer deliver CART under the requirements of this CED to Medicare patients. This could result in the referral of more Medicare patients to the hospitals that do elect to continue delivering CART to Medicare patients by signing up for the CED, like UPMC Hillman. The impact would be a concentration of even more financial losses to an even smaller number of hospitals. This could potentially impact access to care for the Medicare population.

We understand that part of the CED requirement is for hospitals that administer the therapy in the outpatient setting to provide patient reported outcomes (PRO) data. We fundamentally disagree with the notion that simply because PRO data is reported that the therapy becomes "reasonable and medically necessary" for patients.

We do not believe CMS should make reporting PROs a condition of coverage. If hospitals have the capability, and the clinicians believe cell administration can safely be performed on an outpatient basis, it should be covered as it is in the inpatient setting.

UPMC Hillman understands the importance of data collection and tracking new therapies over time to understand long term outcomes. However, we do not agree with PRO collection as outlined in this NCD. Manufacturer certified sites are already submitting data to CIBMTR to meet the FDA post-market approval study requirements. We believe having hospitals continue with their current reporting without increasing administrative burden or hospital cost with enrolling in the CED and providing PRO data will provide CMS, researchers and oncologists with the data they need without hampering access to care for patients.

Therefore, we request that CMS not proceed with its proposal of an NCD with CED nor its proposal to require PROs, but instead simply finalize an NCD.

Cover CART under the FDA Approved Indications
UPMC Hillman Cancer Center supports language to indicate coverage for FDA- approved products and to include indications covered on the FDA-approved label. This will ensure coverage for effective treatments that have been approved, as well as guaranteeing coverage for new FDA-approved treatments that will come online as CART research evolves. As such, we do not believe it's necessary for CMS to limit its policy to patients having relapsed or refractory cancer as a condition of coverage. Therefore, we ask that CMS finalize an NCO (without CED) for FDA approved products per their approved and labeled indications and eliminate any other clinical qualifications.

Comorbidity Language and Repeat Treatments
One element of the proposed memo that we would like to address is the requirement that a patient who is receiving CART is not experiencing any comorbidity that would otherwise preclude patient benefit. From our clinical experience in treating the patient population who would be the best fit for CART-cell therapy, we believe that clinicians will have the best information in each case to determine whether or not a patient will benefit from the therapy, as long as the patient would otherwise meet the FDA labeled indication.

In fact, because of the labeled indication, we often see patients in this population who are sick and experiencing certain comorbidities. We have similar concerns about the language about requiring a "new primary cancer diagnosis" and "the use of more than one therapeutic dose of a specific CART-cell product" for repeated treatment with CART. Patients could either later be diagnosed with a second malignancy, or a patient could have a new diagnosis related to a cancer that was previously treated with CART, and yet could still benefit by having another dose. Again, from our experience, this is something that the treating oncologist will be in the best position to know if a repeat treatment or a different CART product will benefit a particular patient who has relapsed. Adoptive cell therapy is an evolving field, and we want to be able to deliver care to Medicare beneficiaries as soon as that care has been shown to be the best treatment for their particular indication and condition. We would not wish the final NCO to contain language that would quickly date it, and prove to be a barrier between patients and evolving clinical care and science.

Name CIBMTR as a Registry for CAR T
Our hospital is already approved by Novartis and Kite Pharma and currently submits data to the Center for International Blood and Marrow Transplant Research (CIBMTR) not only for CART treatments, but also stem cell transplants. We believe CIBTMR is the appropriate registry for CMS to approve, which will have the most data to contribute to outcomes analyses at the national level. Our understanding is that both of the current CART manufacturers already participate with CIBMTR for the required FDA post­ market approval studies. We do have some concerns about whether CIBMTR will be ready on May 17th. We also question how quickly newly certified sites will be able to contract with CIBMTR. There should be no delays in hospitals being able to provide care to these critically ill Medicare patients due to these reporting burdens.

Therefore, we request CMS name CIBMTR as the registry that will continue to collect the data it already is and that it work with CMS to perform the analyses needed by the agency to better understand the importance and value of CART cell therapy.

Off-Label Use
We request CMS provide clarification about off-label use. One overarching question is, does off-label use trigger clinical study participation or will the registry reporting requirement apply? From the way the section was written in the proposed memorandum, we are not sure and request an answer to this question.

Currently, CMS recognizes off-label use of anti-cancer drugs and biologicals when they are referenced in compendia listed in the Chapter 15, Section 50.4.5 of the Medicare Benefits Policy Manual. We do not understand why CMS deviated from its usual process. Why is NCCN is listed as the only compendium when CMS recognizes other compendia in the Medicare Benefits Policy Manual?

Why should Medicare beneficiaries who receive CART therapy be subject to a coverage policy that restricts off-label coverage to less than that which is provided to Medicare beneficiaries for other anti­ cancer drugs and biologicals? We do not understand why CMS has decided to distinguish CART in this way, and it is not clear from us from the evidence discussed in the proposed memorandum why CMS has proposed this decision.

Therefore, we request CMS clarify what it means by off-label, and that the agency would reconsider mandating requirements beyond data collection; there is no need to reinvent off-label use criteria for CART-cell therapy.

Implementation Questions Regarding the CED if Finalized as Proposed

Hospital Requirements for Analysis
Section 3.a.iii states "[t]he furnishing hospital shall address the CED questions on all registry patients." We need clarity on this point, as our hospital will not have access to all registry data, but rather only to data for own patients. It is burdensome for each hospital to attempt to answer the questions posed by CMS in this section. Each hospital's volume of patients will likely be too small to be meaningful for analysis. We believe that this is more the role of the approved registry to perform and not each individual hospital. Will CMS please clarify that this is not a requirement for each hospital?

How Does CMS Define CAR T Outpatients
As more experience is gained by clinicians furnishing CART therapy and predictions and prophylactics for toxicities are developed, more patients may be able to receive the infusion of CART cells in the outpatient setting. For many patients, clinicians may not know whether a patient will be infused in the outpatient or inpatient setting until the actual day of cell administration. Furthermore, it is unclear what CMS defines as baseline if PRO data is to be collected for outpatients as outlined. Can CMS define what it means by baseline? Can CMS confirm whether an outpatient is determined by the admission status at the time CART cells are administered or if this is based on how the account is billed? It is our understanding that even if cells are administered to an outpatient, if that patient is admitted as an inpatient within 3 days, the claim will be billed as an inpatient claim and therefore, it's unclear whether PRO data would still be required for those patients.

Effective Date of NCD
Our understanding of NCDs is that they are effective on the date published as final - in this case, that date is expected to be May 17, 2019. However, given that CART therapy is a therapy that is initiated upon cell collection that may be weeks prior to cell administration, it is unclear to us what the effective date will mean in practice. Will the effective date apply to patients approved for CART therapy on or after the effective date? Or rather, will patients who had cells collected prior to the effective date be held to the criteria of the finalized NCD immediately? It is important for CMS to answer this question upon publication of the final NCD as no hospital or patient should risk non-coverage if the answer to this question is unclear or left unanswered.

Billing Requirements for CART
Our billing department is familiar with billing claims when patients are enrolled in national clinical trials {NCTs). But this proposed CED references an NCT number for the registry data reporting which we do not believe is considered or associated with a formal clinical trial. We'd like clarification from CMS on the following:

• Given the proposed CED states that "[t]he registry's National Clinical Trial number must be recorded on the claim" we request CMS clarify which claims it needs this information on?
  • Would it be all CART claims, including the outpatient cell collection claim?
  • Will the NCT be required only on off-label CART claims?
  • The NCT number for the registry does not seem to be the same as an NCT number for a clinical trial or study, is this correct?
  • For outpatient cell collection claims, will hospitals be expected to use Q0 on cell collection charges?
• Will the off-label use referenced in in the proposed CED result in different NCT numbers from the registry or is the off-label use also tied to registry reporting and not to the opening of separate studies?

We appreciate the opportunity to submit comments to CMS and look forward to a finalized NCO. We expect that CMS is as concerned as we are about patient access barriers, whether real or simply perceived, for patients access to CART therapy, beyond the payment struggles that providers are already facing and which we recognize are separate from coverage discussions. We appreciate CMS' consideration of our comments.

If you have any questions or would like to speak with our experts or clinical teams, please do not hesitate to contact Kathy Noorbakhsh at 412 864-0547.

Sincerely,

/s/
Richard P. Bondi
Vice President and Chief Financial Officer UPMC Hillman Cancer Centers

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On behalf of the Board of Directors of the Community Oncology Alliance (COA), we are submitting this comment letter regarding the Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N) (the “Coverage Determination”).

As you know, COA is an organization that is dedicated to advocating for the complex care and access needs of patients with cancer and the community oncology practices that serve them. COA is the only non-profit organization in the United States dedicated solely to independent community oncology practices, which serve the majority of Americans receiving treatment for cancer. COA’s mission is to ensure that patients with cancer receive quality, affordable, and accessible cancer care in their own communities where they live and work. For more than 16 years, COA has built a national grassroots network of community oncology practices to advocate for public policies to support patients with cancer.

We appreciate the decision of the Centers for Medicare & Medicaid Services (“CMS”) to issue a proposed National Coverage Determination (“NCD”) for CAR T-cell therapy (“CAR-T”), a highly innovative and promising treatment option for patients with cancer. Providing coverage is an important step to ensuring Medicare patients have access to this treatment when recommended by their oncologist. The proposed coverage with evidence development (“CED”) will help ensure the collection of important evidence that will be crucial in determining the effectiveness and full potential of various CAR-T treatments. This will be especially important when determining future coverage and reimbursement as this emerging technology continues to evolve.

However, while we are pleased that CMS is moving in the direction of covering CAR-T therapies, we have significant concerns regarding the specific language in the proposed decision memo (“PDM”). We are concerned that the agency’s draft coverage determination is not flexible enough to accommodate advances in this rapidly developing field, recognize the progress made towards decreasing toxicity, account for ongoing research on new indications and earlier lines, and adapt existing frameworks to deliver the promise of innovation to patients in the most robust way. Our concerns are summarized as follows:

• CMS should not limit CAR-T site of care appropriateness strictly to hospitals
• Limiting patient eligibility to patients with relapsed or refractory cancer may preclude future CAR-T therapies with different indications from coverage
• CAR-T treatment is just emerging, and the NCD should not prevent CMS’ flexibility regarding future CAR-T therapies
• The draft language on off-label coverage sets a negative precedent for oncology
• While data collection around CAR-T treatment is vital, the evidence development requirements detailed in the NCD are overly onerous

Our detailed comments on the NCD follow. COA requests the opportunity to meet with the appropriate CMS staff to discuss our comments in detail and to educate staff on the complex cancer care provided by community oncology practices, especially those utilizing CAR-T therapy and/or currently participating in CAR-T clinical trials.

Detailed Comments on the NCD

CMS Should Not Limit CAR-T Site of Care Appropriateness Strictly to Hospitals

We are very alarmed by the proposal reiterated throughout the NCD to limit CAR-T therapy coverage to the hospital setting, or more specifically to a subset of hospitals electing to participate in the CED study mechanism. Limiting coverage to the hospital setting will exclude other viable settings of care and limit patients’ options when trying to locate a provider. We urge CMS to revise the language in the PDM to allow for any well-staffed and experienced sites that are able to meet the quality, safety, and operational prerequisites for delivery of CAR-T treatment to be able to participate. CAR-T should be covered in any setting equipped with important core capabilities as appropriate to the patient characteristics and the product utilized.

While Initially Focused Exclusively on Inpatient Care, CAR-T Treatment Has Been Slowly Moving to the Outpatient Setting

In the draft NCD, CMS appears focused on the fact that initial clinical studies were limited to inpatient hospital sites, but in the case of Kymriah approximately 26% of adult patients in trials were infused in the outpatient setting.¹ In addition, one study from Juno Therapeutics showed decreased resource utilization for patients receiving CAR-T infusion in the outpatient setting, including a 40% decrease in their number of hospital days.²

A major focus of ongoing research is on improving the safety of cellular therapies and reducing toxicities, so CAR-T treatment is carefully and slowly transitioning to the outpatient setting. Some CAR-T preparations have been reported with little or no cytokine release syndrome or neurotoxicity, including for cases of glioblastoma and pancreatic cancer. There are many non-hospital specialized cancer centers with the qualifications and experience to administer CAR-T treatment, and these settings of care must be included in the NCD.

Many Community Oncology Practices Have the Experience and Capabilities to Administer CAR-T

COA and our members share in CMS’ goal to ensure patient safety and we understand and agree that safety is of paramount importance when making decisions around site-of-care eligibility. We note that similar concerns and guardrails have been previously debated with other complex treatments and high-risk procedures.

That said, it is important to understand that there are state-of-the-art community oncology practices that have significant experience and capabilities in administering highly complex treatments. For example, stem cell transplants, which are similar in complexity to CAR-T therapy, are performed successfully in the community oncology practice setting. Such procedures often require the same infrastructure that CAR-T requires, with a designated care area that protects patients from transmission of infectious agents and allows for appropriate evaluation and treatment. In cases, community oncology practices conduct these complex procedures on their own. In other cases, they do so in partnership with hospitals. For those practices that would need to partner with hospitals to administer CAR-T therapy, those relationships and capabilities are already in place.

Another example of community oncology practices’ experience with treatments similar in complexity to CAR-T is bispecific antibodies (“BITEs”), which have similar potential toxicity profiles as CAR-T. BITEs are typically administered in the outpatient setting and are already being administered in community, nonacademic settings of care in both hematologic malignancies and solid tumors. There are at least four studies in hematologic malignancies and five in solid tumors.

With this reality, the Cell Therapy Program requirements detailed in the NCD are well within the scope and experience of many community oncology practices. Basic requirements to administer CAR-T therapy, including apheresis, cell processing and infusion, and lymphodepleting chemotherapy, as well as toxicity management, are activities frequently performed in the outpatient setting. As for organizational capabilities to run such a program, community oncology practices have experience with requirements such as REMS programs, distance policies, CAR-T specific nursing support and patient education, registry reporting, and more.

It is extremely important to understand that some community oncology practices already have or are currently participating in studies on CAR-T, as well as T-cell receptor and antibody-coupled T-cell receptor, which are different technologies than CAR-T but that are also considered immune effector cell therapies. As an example, one of our member practices has already participated or is currently participating in 15 such trials for hematologic malignancies and eight for solid tumors. Practices’ direct experience conducting scientific research in CAR-T and related treatment areas demonstrates their ability, in many cases, to meet and exceed the research and evidence generation requirements outlined in the proposed NCD.

We certainly acknowledge that CAR-T administration requires a high level of expertise and infrastructure that not all settings of care possess. However, hospitals are not the only settings of care that meet the necessary qualifications, and CAR-T coverage must encompass those qualified non-hospital settings. We can assure you that community oncologists certainly will take the proper precautions needed to administer CAR-T therapy and will only provide this care after having put in place the appropriate safeguards and requirements. We welcome the opportunity to help CMS develop the appropriate criteria that ensure safety and efficacy while also expanding access to CAR-T therapy. Based on our practices’ collective expertise and experience, we are confident we can offer valuable insights.

Covering CAR-T Therapy in Community Clinic Settings Would Benefit Patients and Medicare

As numerous studies have already confirmed, community oncology practices are also less expensive settings of care for both Medicare and beneficiaries. Studies on cancer treatment show that the cost of care and the rate of emergency department utilization are lower for patients in the community setting than those in hospital outpatient departments.³ Providing coverage in appropriate non-hospital settings will save patients with cancer and Medicare money.

COA’s members are not only skilled at advanced research and high-quality cancer care, but they are also innovators in the area of payment and delivery reform. To that end, many community oncology practices are highly focused on value-based care, including reducing preventable hospitalizations and have a proven commitment to improving outcomes, enhancing quality, and lowering costs.

Limiting Patient Eligibility to Patients with Relapsed or Refractory Cancer May Preclude Future CAR-T Therapies with Different Indications from Coverage

We are concerned by the fact that the proposed NCD would restrict CAR-T therapy coverage to patients who have “relapsed or refractory cancer.” While this limited patient eligibility may make sense in the context of the current FDA-approved CAR-T therapies, it does not encompass the full universe of future CAR-T therapies, some of which may become indicated for patients in earlier disease stages.

In fact, there are already studies accruing in the non-refractory setting in both lymphoma and myeloma (KTE-C19-107 or Zuma-7, and BB2121-MM-003 or KarMMa-3, respectively). Furthermore, there is a study accruing using CAR-T as consolidation in front-line treatment of multiple myeloma patients at higher risk of relapse post-transplant (BB2121-MM-002 or KarMMa-2). If early signals are positive, there are plans for large randomized studies in the front-line settings as well. As it is written, the proposed NCD would not include coverage for patient populations and FDA indications for earlier stages of cancer.

We are also concerned that CMS does not define “relapsed or refractory cancer” in the NCD. The absence of a definition may cause hesitancy among oncologists to prescribe CAR-T therapies out of concern that they are not sure of the requirements for a patient’s cancer to qualify as “relapse or recovery.”

To avoid the patient access issues caused by limiting coverage to patients with relapse or refractory cancer, we urge CMS to broaden the NCD to provide coverage of CAR-T therapies for approved indications in accordance with the FDA label, rather than limiting to relapsed or refractory cancer. This will create flexibility to cover future CAR-T therapies with different indications, reducing potential access barriers and provider prescribing concerns in the future.

CAR-T Treatment is Emerging, and the NCD Should Not Prevent CMS’ Flexibility Regarding Future CAR-T Therapies

While CAR-T treatment is innovative and offers significant potential for patients with cancer, it is a new, emerging technology with only two FDA-approved products to date. Future CAR-T therapies will vary from the products approved today, potentially with different indications for more types of cancer and/or patients. Given the long timeline and significant agency resources required for a potential NCD reconsideration process, it is important that a final NCD not limit CMS’ future coverage flexibility as new CAR-T therapies are approved by the FDA. Maintaining flexibility will ensure that this NCD does not create a barrier between future products and the patients who need them.

It is also important to prevent the NCD from creating barriers for patients because they will face an NCD appeal process that is more complex than the Medicare claims appeal process. It requires that a Medicare beneficiary in need of coverage denied based on an applicable NCD directly initiate a review by filing a written complaint with the Department of Health and Human Services Appeals Board. This process will be very burdensome for sick patients with cancer seeking CAR-T treatment and should be avoided. Ensuring flexibility in the NCD now will help prevent this situation.

The Draft Language on Off-Label Coverage Establishes a Negative Precedent for Cancer Treatment

The proposed NCD states that off-label use of CAR-T treatment will only be permitted when indicated for use in the National Comprehensive Cancer Network (“NCCN”) Drugs & Biologics Compendium with a grade of 2 or 1, and that the patient must be enrolled in a CMS-approved clinical trial and followed for at least two years to access off-label uses. While we understand it is very important to ensure that there is no inappropriate off-label use of CAR-T therapy, we are very concerned that the additional requirements envisioned in the PDM would represent a departure from CMS’ prior treatment of permissible off-label use of oncology drugs.

CMS has had a long-standing policy of providing flexible coverage of anti-cancer therapies that defer to physicians with expertise in the field on the clinical appropriateness of treatment. Medicare typically covers oncology drugs for medically accepted uses per the Food & Drug Administration (“FDA”) approved label as well as compendia-supported off-label uses, but this proposal is much more restrictive. We want to ensure that off-label limitations do not depart significantly from Medicare’s overall policy on off-label coverage and are flexible enough to allow for off-label use supported by appropriate compendia.

To this end, we encourage CMS not to adopt a standard that designates only one compendium as a source for off-label indications. Instead, the NCD should allow for coverage of off-label indications that are in accordance with guidelines from any of the five compendia deemed acceptable for decisions related to off-label uses in Medicare statute. While we recognize that the NCCN compendium is the only current source for evidence-based clinical guidelines that address CAR-T therapy, it would be shortsighted to assume that the other four compendia will not develop guidelines for CAR-T treatment in the future. While off-label use should be carefully considered and appropriately restricted, the NCD should not preclude future evidence-based clinical guidelines produced by other compendia from coverage.

While Data Collection Around CAR-T Treatment is Critical, the Evidence Development Requirements Detailed in the NCD are Overly Onerous

Given the intensive and specific focus on safety by the FDA, manufacturers, and providers, the requirements in the proposed NCD for evaluating the safety of CAR-T treatments may be duplicative to existing post-marketing studies that are already required. The CED requirements would add additional administrative processes and patient consents on top of those that are required by other entities.

We are concerned that the fact that the studies outlined in the NCD would not be funded by CMS, resulting in providers assuming additional costs to administer CAR-T treatments, which may further adversely restrict access. The strict and complex registry approval requirements that are outlined in the NCD would require additional infrastructure investments from providers. If CMS chooses to move forward with a CED decision, COA urges the agency to utilize an observational study format that remains flexible and evolves with newly approved indications and new CAR-T products.

We appreciate the opportunity to comment on this proposed NCD and look forward to discussing our comments and concerns further with you and your staff. We are extremely willing to work with CMS to ensure that the final NCD is appropriately flexible for patients and qualified providers, including community oncologists, and that it appropriately recognizes the full future potential of emerging CAR-T treatments.

Please do not hesitate to reach out with any questions. We repeat our request to meet with the appropriate CMS staff to discuss our comments and concerns in greater detail.

Sincerely,

Michael Diaz, MD
President

Ted Okon
Executive Director

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1 Novartis. Primary analysis results from Novartis pivotal JULIET trial show Kymriah(TM) (tisagenlecleucel) sustained complete responses at six months in adults with r/r DLBCL, a difficult-to-treat cancer. December 10, 2017. https://www.novartis.com/news/media-releases/primary-analysis-results-from-novartis-pivotal-juliet-trial-show-kymriahtm-tisagenlecleucel-sustained-complete-responses-six-months-adults-rr-dlbcl-difficult
2 Juno Therapeutics. Juno Therapeutics Highlights Data and Presentations Supporting Best-in-Class Strategy for JCAR017 at ASH. December 12, 2017. http://ir.junotherapeutics.com/news-releases/news-release-details/juno-therapeutics-highlights-data-and-presentations-supporting
Journal of Oncology Practice. Cost Differences Associated with Oncology Care Delivered in a Community Setting Versus a Hospital Setting: A Matched-Claims Analysis of Patients with Breast, Colorectal, and Lung Cancers. October 31, 2018. http://ascopubs.org/doi/full/10.1200/JOP.17.00040

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Thank you for this opportunity to comment on the proposed National Coverage Determination (“NCD”) of Coverage with Evidence Development (“CED”) for Chimeric Antigen Receptor T-cell (“CAR-T”) therapies. BJC Healthcare, our member teaching institution, Barnes-Jewish Hospital, and our physician partners at the Washington University School of Medicine are among the limited number of providers of CAR-T therapies in the mid-west through our Siteman Cancer Centers. Our experience to date suggests that these treatments represent a dramatic breakthrough for our patients, and appreciate any effort by CMS (“the Agency”) to make them available to the Medicare population.

As part of the National Coverage Analysis (NCA) that preceded this proposed NCD, BJC submitted comments supporting a National Coverage Determination (NCD) for CAR-T therapies. We argued that such an NCD should grant sufficient latitude for approved providers to utilize CAR-T therapies in all clinical settings and for all eligible patients according to FDA-approved indications and compendia-supported uses. We continue to believe that more restrictive coverage, such as the proposed CED policy, will stymie valuable clinical research and ultimately deny patients an often life-saving, last chance therapy.

In our previous commentary we noted that the FDA already mandates a strict compliance program for approved CAR-T therapies, including extensive provider credentialing and participation in a 15-year observational study to determine the long-term efficacy of CAR-T therapies across patient populations (and including Medicare beneficiaries). We also noted that Medicare payment policy in its current form, i.e. absent additional, costly CED requirements, does not adequately cover the high cost of CAR-T. On this basis we argued that any additional regulatory burden associated with providing CAR-T to Medicare patients would deter many institutions from providing these services at all, and force many others to otherwise limit its availability in an effort to prevent financial catastrophe. The proposed CED policy ignores this vital concern with likely deleterious effects for patients.

BJC acknowledges the Agency’s determination that the current body of clinical research on CAR-T therapies lacks results specific to the Medicare beneficiary population. We also understand the Agency’s interest in protecting itself (and, by extension, taxpayers) from undue financial exposure for costly treatments whose benefit to its constituents are uncertain or at least lacking formal research support. We also acknowledge that CED is one way to advance those concerns. However, we believe it is possible for CMS to protect both beneficiaries and its finances while advancing clinical research on these promising therapies, without creating undue regulatory (and thereby financial) burdens on providers that would deter provision of these services.

Rather than adopt the proposed CED policy, BJC recommends CMS pursue a “coverage with data collection” policy. The Agency should cover all CAR-T services performed by providers who meet the FDA’s standards, including all compendia-supported applications, and who submit resulting (patient-consented) data to a CMS-approved registry or otherwise participate in a CMS-approved CAR-T trial. This would ensure development of a robust data repository available to public and private research agencies, including CMS, for evaluating the efficacy of CAR-T across patient populations, and upon which future coverage determinations could be based.

To further reduce provider burden, CMS should also designate the Center for International Blood and Marrow Transplant Research (CIBMTR) as the official Registry for Medicare beneficiaries receiving CAR-T treatment. CIBMTR already serves as the registry for numerous CAR-T adjacent therapies and related studies, many of which are being conducted by institutions certified by the Foundation for the Accreditation of Cellular Therapy (“FACT”), and the two CAR-T manufacturers already use CIBTMR for their post-FDA approval study requirements. Designating an already familiar entity like CIBTMR will enable more providers to begin and continue providing CAR-T therapies and supplying the resulting data to the registry.

There are a host of other problematic issues created by the proposed CED policy, with a great deal of uncertainty about how such a policy could be implemented, particularly in a timely fashion as many CAR-T eligible Medicare beneficiaries cannot wait to receive this “end-of-the-line” treatment. This is yet another reason why CMS should forego CED and instead adopt a much simpler (but no less valuable) coverage with data collection policy—to ensure continuing coverage of these therapies for eligible patients and the continued ability of providers to bill for these expensive services.

For a more thorough review of the additional pitfalls associated with CED, we refer the Agency to comments submitted by colleagues from our peer organizations, such as the American Society for Transplantation and Cellular Therapy (ASTCT), the Association of Academic Medical Colleages (AAMC), and the National Comprehensive Cancer Network (NCCN). We appreciate this opportunity to contribute to the public dialogue about CAR-T cell therapies, and look forward to reviewing the Agency’s final decision later this year.

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The Stanford Blood & Marrow Transplant Program appreciates the opportunity to provide comments on the Centers for Medicare and Medicaid Services’ (CMS) Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N). Stanford Health Care and the Stanford School of Medicine have performed CAR-T therapy since 2016, and we participated in some of the trials that led to current FDA approvals for this life-saving treatment.

In comments submitted in June 2018 on CMS’ decision to examine coverage for CAR-T therapies, the American Society for Transplantation and Cellular Therapy (ASTCT) opposed the establishment of a National Coverage Determination (NCD) due to concerns that it would cause significant and ongoing barriers to providing current and future CAR-T therapies to beneficiaries in need of these breakthrough treatments. The Stanford BMT Program agrees with ASTCT, and believes that it is premature to implement an NCD because this is a rapidly evolving area of medicine; a national coverage policy should not be codified until the field matures.

If CMS proceeds despite these concerns, our program recommends that the agency avoid a CED requirement, and instead implement an NCD with a data collection requirement that leverages efforts currently in progress. We believe that a CED requirement will create significant barrier to patient access. Insufficient Medicare inpatient reimbursement is already creating a challenge for our program, as the maximum NTAP reimbursement of $186,500 is significantly below the costs we face for the CAR-T cell products. Those costs include wholesale prices of $373,000 - $475,000, plus the costs of initial cell collection, cryopreservation, ship-out, receiving and processing for administration. If a CED is put in place that requires an opt-in for center participation, we are extremely concerned that many centers will choose not to participate. This limits access to patients and will cause additional financial stress on centers who do participate.

Please consider the following comments that outline our suggestions on how to improve the proposed decision memo to limit any negative impacts on patient access and innovation should CMS decide to proceed.

Patient Condition Requirements

As drafted, Medicare coverage for CAR-T therapy would be limited to require that patients have relapsed or refractory cancer. Our program strongly urges CMS to expand this to include all indications covered on FDA approved labels. If the coverage language is restricted to the currently-approved indications, it would be necessary for CMS to reopen the NCD in the near future in order to provide coverage for indications that are likely to be approved in the near future. One example of a CAR in the pipeline that would not be covered by the relapsed/refractory requirement is the ongoing study of CAR-T in high-risk multiple myeloma.¹ Another example is for lymphoma, where the current FDA approved indication is failure of two lines of therapy. Stanford is a current study site for the ongoing ZUMA7 trial, which is studying CAR-T after failure of first line of therapy.² Other therapies that are pending include CD19-specific CAR-T therapy³ and B cell maturation antigen CAR-T therapy for myeloma.⁴ These examples demonstrate the innovation that can save lives but will be difficult if not impossible for patients to receive with the proposed coverage decision.

The Stanford BMT Program also disagrees with the patient condition requirement that this therapy can only be provided to a patient that is not currently experiencing any comorbidity that would otherwise preclude patient benefit. It is unclear from the proposal how CMS plans to define this or monitor for it in its claims processing system. Clinicians should be the ones determining whether the patient can benefit from the therapy despite having certain comorbidities, as this is a very sick patient population likely to have one or more comorbidities.

We also request that CMS provide more guidance around what it means by a “new primary cancer diagnosis” and “the use of more than one therapeutic dose of a specific CAR T-cell product” for repeat treatment. The possibility exists that a patient could be diagnosed with a separate malignancy or new diagnosis of a previously treated cancer and could benefit from receiving the same CAR-T product. Moreover, if the patient relapses at some point in the future, after receiving CAR-T therapy, our clinicians should be the ones assessing whether the patient would benefit from receiving the same or different CAR- T treatment. The field of cell therapy is rapidly evolving and therefore CMS’ final NCD should promote access rather than create barriers for new and innovative therapies.

CED Requirement
Our program understands that CMS included a CED requirement to gather additional data on the effectiveness of CARs in the Medicare population. However, if the agency chooses to finalize an NCD, the same objective can be accomplished with a data collection requirement rather than CED. We are concerned that by virtue of this being a CED with additional patient reported outcomes (PRO) requirements in the outpatient setting, some centers will “opt-out,” further restricting access since the agency’s conditions of provider enrollment do not require participation in CED.⁵ We request that CMS confirm whether anti-discrimination provisions in the conditions of participation require hospitals to furnish covered therapy (i.e., NCD covered therapies) to all patients.

We feel strongly that an NCD that leverages ongoing data collection without a CED component will avoid these complications and provide CMS important data regarding safety and efficacy. The Stanford BMT Program strongly recommends that CMS revise the final policy to eliminate the CED requirement and instead include an NCD with data collection that is tied to existing registry reporting, as this will help avoid the access problems that may result from centers being able to opt-out of the CED requirement.

Stanford BMT also joins ASTCT in requesting clarification from CMS on the patient consent requirements applicable to this coverage policy both as it applies to the registry reporting and patient-reported outcomes (PRO) requirements. We are concerned that there would be no coverage if a patient does not explicitly consent to have their data reported to the registry, so we request that CMS clarify what would happen if patients do not consent. Our program does not support coverage being contingent upon a patient’s explicit consent to having their identifiable data submitted.

While it has been our general experience that most patients provide consent and are interested in having their data submitted to a registry to be a part the future scientific learning to benefit other cancer patients, CMS must recognize that there may be patients who do not want to participate and that they have the right to refuse without penalty. Given that these patients face no other treatment alternative, asking providers to request patient consent regarding identifiable information is tantamount to coercion. Instead of potentially placing patients in this predicament, we recommend that CMS recognize a hospitals’ participation in a registry as sufficient to meeting the registry reporting requirements.

Registry Requirement
As proposed, the registry requirement requires furnishing hospitals to participate in “a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, and follows the patients for at least two years...” It also requires CMS to review and approve all registries. ASTCT believes the Center for International Blood & Marrow Transplant Research (CIBMTR) will meet the requirements to become an approved registry based on our review of the requirements and conversations with CIBMTR. Therefore, we recommend that CIBMTR be listed as an approved registry in the final NCD, assuming they receive their approval prior to the May 17 implementation date. We also recommend that the agency accept hospital participation with the registry without requiring any other enrollment with CMS.

CIBMTR is already collecting data for several CMS CED studies for myelodysplastic syndrome, myelofibrosis, sickle cell disease, and myeloma with great success. Furthermore, CAR-Ts is already being provided by Foundation for the Accreditation of Cellular Therapy (FACT)-approved bone marrow transplant (BMT) programs, which are required by law to report data on allogeneic BMT to CIBMTR. The two manufacturers with approved products, Novartis and Kite/Gilead, are also using CIBMTR as the registry to meet their FDA post-approval study requirement. Stanford BMT, along with ASTCT, believe that this provides additional support for our request to have CIBMTR listed as an approved registry, which would reduce the burden to providers and institutions.

ASTCT believes it is critical that a registry be approved at the time this policy is finalized and implemented to avoid any coverage gaps. Furthermore, it is vital that the policy clarify that coverage is based on cell collection occurring on or after the effective date since there will be patients in the midst of their CAR-T episode of treatment when the policy is finalized. We do not support an effective date that would be based on cell administration that could potentially disrupt coverage of an episode of CAR-T therapy already in progress.

Patient-Reported Outcomes Requirement
In the proposed decision memo, CMS included a PRO requirement for the outpatient setting. Stanford BMT joins ASTCT in expressing several concerns and questions related to this requirement. We strongly object to any mechanism that would tie patient access or provider reimbursement to the reporting of PROs, especially in the case of CAR-T therapy. The Society believes that a PRO requirement would add an additional unreimbursed, administrative burden to the patients being treated with CAR-T therapy. We believe it is premature to require PRO data for this population and are also concerned that the two PRO tools listed in the policy are not directly applicable to this patient population.

The Society is also concerned that the PRO requirement turns a registry-reporting requirement into a study, which will further exacerbate the financial burden on centers. These providers already face financial risks in providing CAR-T due to low Medicare reimbursement and adding additional reporting requirements would provider another reason for centers to opt-out of providing care to Medicare patients.

Accreditation Requirements
In the proposed decision memo, CMS included the following requirement for CED:

“The hospital has: a Cellular Therapy Program consisting of an integrated medical team that includes a Clinical Program Director, a Quality Manager, and at least one physician experienced in cellular therapy, and demonstrates that protocols, procedures, quality management, and clinical outcomes are consistent from regular interaction among all team members; a designated care area that protects the patient from transmission of infectious agents and allows for appropriate patient isolation as necessary for evaluation and treatment; and written guidelines when administering CAR T-cell therapy for patient communication, monitoring, and transfer to an intensive care unit.”

If CMS retains this requirement in the final NCD, we ask CMS to define a uniform mechanism for accreditation that conforms to CMS standards to ensure that these cells are administered within a cell therapy program as defined. One option would be to require Foundation for the Accreditation of Cellular Therapy (FACT) accreditation for centers, which CMS included in the proposed decision memo. We urge CMS to require use of FACT or another broadly accepted accreditation program rather than creating a duplicative set of requirements to which centers must comply. We request that hospitals not be required to attest to CMS that they meet the outlined accreditation standards, as we do not support a requirement that would require a hospital to actively enroll with CMS as a requirement of coverage.

The Stanford Blood & Marrow Transplant Program appreciates the opportunity to comment on the proposed decision memo and to provide our perspective on the best way to ensure access to medically accepted CAR-T therapies for Medicare beneficiaries.

Sincerely,

Robert S. Negrin, MD
Professor of Medicine
Chief, Division of Blood & Marrow Transplantation

1 https://clinicaltrials.gov/ct2/show/NCT03549442
2 https://clinicaltrials.gov/ct2/show/NCT03549442
3 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410390/
4 https://ash.confex.com/ash/2018/webprogram/Paper116898.html

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March 17, 2019

Tamara Syrek Jensen, Director
Joseph Chin, MD, Deputy Director
Lori M. Ashby, Director, Policy and Evidence Review
Daniel A. Canos, PhD, Director, Evidence Development
Katherine B. Szarama, PhD, Lead Analyst
Lori A. Paserchia, MD, Lead Medical Officer

Evidence and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed National Coverage Determination for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen and respective colleagues:

The Society for Immunotherapy of Cancer (SITC) appreciates the opportunity to respond to the Centers for Medicare & Medicaid Services’ (CMS) proposal for national coverage of CAR-T therapies approved by the U.S. Food and Drug Administration (FDA) under “Coverage with Evidence Development” (CED). With nearly 2,400 members representing 17 medical specialties, SITC is the world’s leading member-driven organization specifically dedicated to improving cancer patient outcomes by advancing the science and application of cancer immunotherapy. SITC aims to make cancer immunotherapy a standard of care.

SITC commends CMS for evaluating strategies towards providing Medicare/Medicaid coverage for lifesaving CAR-T therapies. Advances in immunotherapy are changing the face of cancer care. Ensuring all cancer patients have equal access to these lifesaving therapies is of the utmost importance. SITC membership wants to ensure the proposed NCD process involving CED, as well as any subsequent policies implemented at the conclusion of the National Coverage Analysis (NCA), does not hinder patient access or measurably slow the development of innovative, new treatments. We, therefore, urge CMS to consider the following key points as it goes through the review process relative to the unique aspects of CAR-T therapy.

• Consideration should be made upon any implementation of CED policies that the results of such policies do not hinder the future development of innovative immunobiologics.
  • Descriptions of how the data will be collected through the CED mechanism should be more clearly articulated.
  • CMS should also clarify that the data collected via CED will not impact current or future policy coverage decisions. Instead, final clinical trial results should dictate these decisions.
  • The CED policy should also be flexible enough that in the event expansions are granted for immunobiologics that are currently approved by the FDA, that each new on-label use is deemed covered under the NCD.


• If CMS deems that CED is necessary, then SITC recommends the agency take steps to use existing infrastructures of data reporting. This could streamline the reporting and data collection process and reduce the administrative burden on hospitals.
  • As an example, the FDA has already mandated post-marketing studies of both of the currently approved CAR-T therapies. These observational studies require manufacturers of such CAR-T products to assess long-term safety by following at least 1,500 patients for 15 years after product administration. This infrastructure could be used if a CED is necessary.
  • Additionally, both CAR-T manufacturers require administering hospitals to be accredited by the Foundation for Accreditation in Cellular Therapy (FACT) prior to offering patients treatment. In turn, hospitals accredited by FACT must submit data to the Center for International Blood and Marrow Transplant Research (CIBMTR).
  • CIBMTR is currently collecting long-term data on patients receiving cellular therapy in the United States for on-going research within the field. CIBMTR has extensive experience collecting and analyzing data described under the current proposal and does so in a way to adjust for differences in patient populations and sites of care. Their current registry platform is widely considered to be the most streamlined and efficient for cellular therapy providers.

SITC actively supports on-going efforts to better study and define the value of CAR-T therapy, including a deeper understanding of the economic impact on patients, payers, industry and other stakeholders. We also welcome the opportunity to work with CMS to serve as a professional resource to CMS during this time of rapidly developing advances in the field.

We again appreciate the opportunity to submit our comments and urge CMS to consider the above key points.

Should you have any questions, please do not hesitate to contact SITC Executive Director, Tara Withington, at twithington@sitcancer.org.

Sincerely,

Tara Withington, CAE,
Executive Director, Society for Immunotherapy of Cancer

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March 15, 2019

BY ELECTRONIC DELIVERY

Tamara Syrek Jensen
Director, Evidence and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
S3-02-01
Baltimore, Maryland 21244
CAGinquiries@cms.hhs.gov

Re: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen:

The Association of Community Cancer Centers (ACCC) appreciates this opportunity to comment on the Centers for Medicare & Medicaid Services’ (CMS) proposed decision memorandum (PDM) for CAR T therapies for cancers.¹ ACCC is a membership organization whose members include hospitals, physicians, nurses, social workers, and oncology team members who care for millions of patients and families fighting cancer. ACCC represents more than 23,000 cancer care professionals from approximately 1,100 hospitals and 1,000 private practices nationwide. It is estimated that 65 percent of cancer patients nationwide are treated by a member of ACCC.

ACCC’s members are committed to offering our patients high quality, innovative cancer care, and we are excited about the potential for CAR T therapies, including Kymriah® (tisangenlecleucel) and Yescarta® (axicabtagene ciloleucel), to save lives and transform cancer care. We recognize that to protect patients, access to these two therapies currently is limited under the requirements for approved sites established by the Food and Drug Administration (FDA)-approved Risk Evaluation and Management Strategies (REMS). Other CAR T cell therapies that have not yet received FDA approval are available to patients only in clinical trials. ACCC strongly supports CMS’s efforts to improve access to these therapies while deepening our understanding of their risks and benefits. We urge CMS to finalize a national coverage determination (NCD) for CAR T cell therapies that will accomplish these goals.

Our comments make four recommendations for the final NCD:

1. Medicare should cover CAR T cell therapies for beneficiaries in accordance with FDA-approved labeling, including repeat treatment and contraindications.
2. Medicare should cover off-label uses for CAR T cell therapies that are supported by any of the Medicare-approved compendia that are used to identify medically accepted indications of drugs used in anti-cancer chemotherapeutic regimens.
3. Medicare should cover CAR T cell therapies in any site of care that meets the FDA and manufacturer’s requirements.
4. Any data collection requirements should collect only relevant information and should be implemented with minimal burdens for patients and providers, ensuring patient access to care.

CMS proposes to cover CAR T cell therapies for patients who have “relapsed or refractory cancer; and [have] not currently been experiencing any comorbidity that would otherwise preclude patient benefit.” Repeat treatment with the same CAR T-cell product using the same biological would be covered “only when a new primary cancer diagnosis is made by the treating oncologist.” CMS explains in the PDM that these proposals are based on the current FDA-approved labeling and clinical literature for Yescarta and Kymriah. As these and other CAR T cell therapies continue to be studied, however, we are hopeful that additional indications will be approved, including uses as first-line treatments. Some CAR T cell therapies also might prove to be effective when used as repeat treatments. We urge CMS to plan ahead for these anticipated advancements and finalize an NCD that allows coverage to expand as the FDA approves new therapies and indications. This would ensure that Medicare’s coverage policies reflect the evolution of CAR T therapies without requiring CMS to dedicate the substantial time and resources necessary to reconsider the NCD. Most important, it would ensure that Medicare beneficiaries have access to new CAR T cell therapies as soon as they are approved by the FDA.

Instead of limiting coverage to patients with relapsed and refractory cancers or identifying specific disqualifying comorbidities, CMS should cover CAR T cell therapies for patients in accordance with each product’s FDA-approved labeling. We recommend that CMS revise the proposed patient eligibility criteria to say that CAR T cell therapies will be covered if the “patient has cancer,” without limitation to relapsed or refractory or excluding certain comorbidities.

CMS proposes to cover off-label indications of FDA-approved CAR T cell therapies that are “indicated for use identified in the National Comprehensive Cancer Network [NCCN] Drugs & Biologics Compendium with grade 2 or 1 on or after August 2017.” We agree that certain off-label uses should be covered, but we support coverage for “medically accepted indications,” as defined by the statute. This definition includes uses “supported by one or more citations which are included (or approved for inclusion) in one or more” of five CMS-approved compendia.² CMS does not explain in the PDM why it would use only the NCCN Drugs & Biologics Compendium and not the other publications CMS has already approved for identification of medically accepted indications of drugs and biologicals used in anti-cancer chemotherapeutic regimens. We urge CMS to cover off-label uses supported by any of the Medicare-approved compendia, as described in the Benefit Policy Manual, in its final NCD.

We also note that the Benefit Policy Manual describes the rating and recommendation systems used by each of the approved compendia and explains how to identify a “medically accepted indication” in each publication. The Manual correctly recognizes that NCCN’s rating system refers to “categories” of recommendations, not “grades.” We urge CMS to use each compendium’s terminology to avoid confusion about which recommended uses are medically accepted.

CMS proposes to cover treatment with CAR T cell therapies – whether furnished for an FDA-approved indication or a compendia-supported use – when furnished in hospitals only. Those hospitals would be required to have:

• a Cellular Therapy Program consisting of an integrated medical team that includes a Clinical Program Director, a Quality Manager, and at least one physician experienced in cellular therapy, and demonstrates that protocols, procedures, quality management, and clinical outcomes are consistent from regular interaction among all team members;
• a designated care area that protects the patient from transmission of infectious agents and allows for appropriate patient isolation as necessary for evaluation and treatment; and
• written guidelines when administering CAR T-cell therapy for patient communication, monitoring, and transfer to an intensive care unit.

Similar to the proposed patient eligibility criteria, these proposed requirements are based on the FDA requirements and clinical literature for the two CAR T cell therapies that currently are on the market. For example, the REMS for Yescarta and Kymriah limit the settings of care in which these therapies can be offered to sites that are specially certified, have immediate access to tocilizumab, and implement required training for staff involved in the prescribing, dispensing, or administering of the therapies. Currently, these therapies are available only in hospital settings.

We expect that CMS proposed requirements for the Cellular Therapy Program, designated care area, and written guidelines will be applicable to future CAR T cell therapies, but the hospital requirement might not be necessary in the future. Similar to the anticipated expansion of the patient population that could benefit from CAR T cell therapies, the settings of care in which these therapies can be furnished safely are likely to evolve as we gain more experience and as technologies improve. Improvements in CAR T technology and lessons learned from ongoing clinical trials could reduce the risks of cytokine release syndrome and neurotoxicity and allow CAR T therapies to be safely administered outside hospital settings. These advancements also may allow CAR T cell therapies to be available in more communities across the country, reducing disparities in access to care.

We urge CMS to not lock in rigid criteria for the settings of care in which CAR T therapies can be furnished. In particular, CMS should not specify in the final NCD that CAR T cell therapy must be furnished in hospitals. Indeed, Medicare’s use of the term “hospital” can be confusing as it is not clear whether it refers to how a site is licensed, the benefit category for its services, or the payment system under which it is reimbursed. A site can meet the statutory definition of a “hospital”⁴ and furnish services that are included in the benefit category for outpatient services,⁵ yet those services might not be reimbursed as “covered outpatient department services”⁶ due to the exclusion for services at certain off-campus provider-based departments. To avoid this confusion, CMS should not use the term “hospital” to describe eligible sites. Instead, CMS should cover CAR T cell therapies in all settings of care that meet the safety criteria outlined in the PDM and that are permitted by their FDA-approved labeling and REMS and manufacturers’ requirements.

CMS proposes that all uses of CAR T cell therapies for cancer would be subject to Coverage with Evidence Development (CED). CMS proposes to require patients and hospitals to be enrolled in registries that collect specific clinical data elements, at specified intervals, for therapies furnished in either inpatient or outpatient settings, and it proposes to require data on health-related quality of life to be collected for therapies furnished in outpatient settings. ACCC shares CMS’s interest in continuing to learn more about the risks and benefits of these therapies, but we also recognize that data collection requirements can impose significant burdens on providers. We urge CMS to ensure that the costs of collecting these data do not discourage providers from offering CAR T cell therapies, especially when Medicare’s reimbursement for these therapies in inpatient settings does not currently cover the cost of care.

To minimize the burden on providers, we urge CMS to collect only the minimum necessary data that is relevant to the questions CMS wants to answer and to use administratively simple mechanisms to collect that data. For collection of clinical data, this means that CMS should approve registries that are easy for sites to join. Sites that furnish the currently available CAR T cell therapies and that participate in clinical trials already report information to registries, such as the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, and should not be required to participate in additional registries to qualify for Medicare coverage.

For the patient-reported outcome (PRO) data that CMS proposes to collect on health-related quality of life, reducing burdens on providers requires selecting reporting tools that collect data that are relevant to CAR T cell therapies. The tools CMS proposes to use, the National Institutes of Health Patient Reported Outcomes Measurement Information System (PROMIS®) and the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™), are not designed specifically for CAR T cell therapies and have not been validated for them. As a result, they collect information on many measures that are not relevant to these patients. We urge CMS to work with stakeholders to identify more appropriate measure sets. Eventually, these appropriate measure sets should be used in all settings of care, especially because when a CAR T is administered, it is not always clear whether the patient will remain as an outpatient or will become an inpatient.

Finally, while CMS and stakeholders work to develop, approve, and implement any registries that would be required under a final NCD that applies CED to CAR T cell therapies, we urge CMS to be flexible about implementing these requirements. Patient access to care should not be delayed or denied due to the lack of a data collection mechanism at the time the final NCD is released or because PRO data cannot yet be collected. Patients eligible for CAR T therapy are extremely ill with limited or no other treatment options. As CMS notes in the PDM, CAR T treatment protocols also have multiple steps, and patients’ treatment already may be in process when the NCD becomes final. We urge CMS to work with the Medicare Administrative Contractors and providers to ensure that there are no disruptions in care and patients are not denied coverage as a final NCD is implemented.

* * *

ACCC appreciates this opportunity to comment on the CAR T therapies PDM. If you have any questions regarding these comments, please do not hesitate to contact Blair Burnett at (301) 984-9496 ext. 213 or bburnett@accc-cancer.org.

Respectfully,

Thomas A. Gallo, MS, MBA
President, Association of Community Cancer Centers

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1 CMS, Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N), Feb. 15, 2019, https://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=291&bc=ACAAAAAAQAAA&.
2 Social Security Act (SSA) § 1861(t)(2)(B)(2); Medicare Benefit Policy Manual, ch. 12, § 50.4.5.
3 What is the Yescarta REMS Program? https://www.yescartarems.com/; Risk Evaluation and Mitigation Strategy (REMS), http://www.kymriah-rems.com/.
4 SSA § 1861(e).
5 SSA § 1861(s)(2)(B).
6 SSA § 1833(t)(1)(B)(v).

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Dear Ms. Syrek,

AdventHealth is pleased to provide comments in response to CMS’ Coverage Decision Memo for Chimeric Antigen Receptor (CAR)-T cell therapy. Our system includes 46 hospital facilities located across nine states and serves four million people every year. Our flagship facility, AdventHealth Orlando, is the largest single-site Medicare provider in the nation.

In the Coverage Decision Memo, CMS proposes to cover (CAR)-T cell therapy in both the inpatient and outpatient settings when the treatment is offered through a CMS-approved registry or clinical study. AdventHealth supports the coverage of CAR-T cell therapy for cancers and urges CMS to finalize the proposed policy. Under this type of immunotherapy, doctors isolate immune cells from a patient’s blood and add an artificial receptor called a “Chimeric Antigen.” Once infused to the patient through an IV, this receptor enables the cells to produce chemicals that help fight cancer. CAR-T cell therapy is unique because it allows clinicians to genetically reprogram patients’ own immune cells to find and attack cancer cells. Multiple studies have demonstrated that this therapy is highly effective in high-risk patients with relapsed or refractory cancers. Given the potential of CAR-T cell therapy to kill cancerous tumors, we recommend that CMS reimburse such therapy.

Currently, there are two approved CAR-T cell therapies: Novartis' Kymriah and Gilead’s Yescarta. Kymriah is FDA-approved for the treatment of acute lymphoblastic leukemia in pediatric patients. Both Yescarta and Kymriah are FDA-approved for the treatment of certain types of non-Hodgkin lymphoma in adults. Inpatient coverage of CAR-T cell therapy is important because patients receiving CAR-T therapy can sometimes experience significant adverse reactions including Cytokine Release Syndrome (CRS) and neutotoxicity after the infusion of the CAR T cells. In most cases, the treatment of adverse reactions requires prolonged hospitalization and a multidisciplinary medical team approach. Due to this reason, we believe it is fundamental for Medicare to cover and reimburse CAR-T therapy in both the outpatient and inpatient settings, as proposed. At AdventHealth’s Cancer Institute in Orlando, Florida, we are developing a Cellular Therapy program that will include clinical trials as well as commercially-available CAR-T cell products. Medicare reimbursement of CAR-T therapy would allow us to expand access to this innovative treatment and improve cancer care for Medicare beneficiaries in the Central Florida area.

According to the proposed Coverage Decision Memo, both the hospitals and the patients receiving the CAR-T cell therapy must be enrolled in a CMS-approved national registry that enrolls patients and follows the patient for at least two years. CMS intends to use data from the registries to help identify the types of patients who benefit from CAR-T therapy. We recommend that CMS provide further clarity on how such national registry would work. For example, how would hospitals know whether a patient is enrolled in a national registry? Additionally, we believe that the coverage of CAR-T cell therapy should not be limited to only those individuals that are part of a national registry. Due to the significant benefits of the therapy, CMS should seek to increase its availability to any Medicare patient eligible for treatment, not just those participating in a national registry. Currently, only 130 medical centers in the U.S. offer CAR-T therapy and it is likely that less than 2,000 patients have been treated, based on data provided by the companies that manufacture the two CAR-T therapies approved by the Food and Drug Administration. Limiting coverage of CAR-T therapy to only those hospitals participating in a national registry would further limit access to cancer treatment, particularly in rural areas. As an option, if CMS’ intent is to collect data on CAR-T therapy and its outcomes, CMS could require providers to report key data elements to the Center for International Blood and Morrow Transplant Research (CIBMTR). The CIBMTR could then share the aggregate data with CMS for further analysis. This policy would enable the Agency to collect data on CAR-T cell therapy without limiting access to the therapy.

Thank you for the opportunity to provide comments on this proposed Coverage Decision Memo. We commend the Agency for exploring new innovative therapies to fight disease and bring wellness to Medicare beneficiaries. Should you have any questions, please do not hesitate to contact Julie Zaiback-Aldinger, Director of Public Policy and Community Benefit, at Julie.Zaiback@AdventHealth.com.

Sincerely,

Michael Griffin
Vice President of Advocacy and Public Policy
AdventHealth

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March 16th, 2019

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

RE: CIBMTR Perspective on the Proposed Decision for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen,

The CMS decision to reimburse for treatment of patients with autologous CAR T-cells through coverage with evidence development (CED) represents an approach to provide coverage to CMS beneficiaries and capture information on safety and efficacy of these products in this population. The Center for International Blood and Marrow Transplant Research (CIBMTR®) recognizes this function of a CED but is concerned that this approach can add unexpected barriers to access, especially in the setting where reimbursement rates for the therapy are considered inadequate to cover costs of treatment by most centers. Implementation of CED requirements to be aligned with existing “real world” data capture efforts could minimize (though not eliminate) this extra burden for centers. The CIBMTR has an operational CAR T-cell registry that is collecting clinical data on a large fraction of the patients receiving commercial CAR T-cell products, including the data being required by the Food and Drug Administration (FDA) for post-approval long-term safety studies (PASS). This letter outlines how this existing infrastructure for capture of CAR T-cell outcomes could be utilized to meet CED requirements and minimize delay in implementation of a CED-compliant protocol. We also outline some concerns about the stated CED requirements that would impose undue burden on centers and patients and delay implementation of a CED-compliant protocol, thereby posing significant barriers to access to this life-saving therapy for Medicare beneficiaries.

CIBMTR is a research collaboration between the Medical College of Wisconsin (MCW) and the National Marrow Donor Program/Be the Match (NMDP) that operates an outcomes database on hematopoietic cell transplantation (HCT) and cellular therapies. Both MCW and NMDP are non-profit organizations and the majority of funding for CIBMTR operations comes from federal grants and contracts. The CIBMTR holds a contract with the Health Resource and Service Administration (HRSA) to operate the Stem Cell Therapeutics Outcomes Database (SCTOD) of the C.W. Bill Young Cell Transplantation Program. Through the SCTOD, the CIBMTR functions as a public health authority to capture data on all allogeneic HCTs performed in the US, along with analyzing data according to the requirements of this contract to assess patients’ survival and center performance. This contract also has some requirements for evaluating use of cellular therapy outside of the HCT setting. The CIBMTR also currently administers five studies under the CMS’s CED mechanism to assess the efficacy of HCT for specific indications and patient populations. One of these studies, an observational study of outcomes of HCT for myelodysplasia among patients 65 years and older, compared to patient ages 55-64, dramatically increased access to HCT for these patients, evidenced by a four-fold increase in the number of HCTs for myelodysplasia in patients older than 65 by the fourth year of the study, which was implemented in 2010. A separate clinical trial addressing complexities of selection criteria and including a comparison group was launched in 2014 and recently completed accrual; follow-up to primary endpoint continues. Other CED studies managed by CIBMTR include CMS-approved protocols in myelofibrosis, sickle cell disease and multiple myeloma. Consequently, CIBMTR is familiar with CMS requirements for these studies and has already been reviewed for the adequacy of its data collection and analysis approaches.

Cellular Therapy Registry Overview
Over the past three years, the CIBMTR greatly expanded its infrastructure to capture data on indications for and outcomes of non-HCT cellular therapies. The resulting infrastructure is flexible, designed to capture data on any cellular therapy infusion, and to provide a mechanism for long-term follow-up for safety and efficacy. The long-term follow-up approach of the cellular therapy registry intentionally aligns with FDA regulatory requirements (see link below). Since the release of the cellular therapy outcomes database in July 2016, the CIBMTR has engaged the community to implement data collection practices and test data collection forms at participating centers. The current forms represent international consensus (including input from the FDA and the European Medicines Agency) on appropriate baseline and post-infusion data elements necessary to assess safety and efficacy. The FDA approvals for CAR T-cell products manufactured by Novartis and Kite/Gilead carry a requirement that manufacturers establish a mechanism for long-term follow up of these patients. The CIBMTR is currently contracted with both Novartis and Kite/Gilead to utilize CIBMTR’s infrastructure to capture data on safety and efficacy to fulfill these regulatory requirements. It is important to note that after these data are collected and reported to the relevant regulatory agencies, they are available for research purposes, following the pattern established with HCT data and the SCTOD.

Additionally, in October 2018, the CIBMTR was awarded a grant from the National Cancer Institute to operate its Cellular Immunotherapy Data Resource (CIDR) program whose main objective is to build an infrastructure for outcomes data collection for cellular therapies for cancer and for data sharing to promote research. The CIBMTR Cellular Therapy Registry is fully functional, with more than 60 centers in the US currently reporting data.

Considerations for the CAR T cells CED
The CIBMTR has carefully reviewed the Proposed Decision Memo and has the following comments.

1. The Decision Memo specifies eligibility as patients with relapsed or refractory cancer and includes autologous CAR T cells products.
   1. The field of cellular immunotherapy is rapidly evolving, and the decision memo attempts to be inclusive of current and future CAR T cell practice. However, this decision memo has the potential to quickly become obsolete as new products (e.g. allogeneic cellular immunotherapy) or other use cases of existing CAR T-cells (e.g. upfront therapy) receive FDA approval. The CIBMTR suggests CMS align with the FDA label, i.e. FDA-approved cellular immunotherapy products used according to the FDA label, without specifying the source of cells or status of the disease being treated. This will allow rapid implementation of CED studies for new products or indications. For off-label use, additional eligibility would apply, as currently specified in the memo.
2. The Decision Memo specifies parameters for CED studies for FDA approved CAR T-cells to treat indications as specified in the label to compare outcomes and demographics of beneficiaries to results reported in pivotal trials.
   1. The CIBMTR recommends CMS expand the options for analytical plans under CED studies. When considering comparison to pivotal trials, comparisons should be made to published results. However, comparison of outcomes between beneficiaries and non-beneficiaries should be considered as a reasonable alternative, when applicable.
3. The Decision Memo outlines specific time points for data collection including baseline, at treatment, 3, 6, 12 and 24 months.

   Patients enter the cellular therapy registry once they receive the therapy. The time immediately prior to initiation of lymphodepleting chemotherapy as appropriate for baseline assessment and initiation of data collection has been agreed upon by the international cellular therapy medical community and regulatory agencies. CIBMTR recommends CMS align with this time point as the time to begin collection of data for CED studies.

4. Patient Reported Outcomes (PRO): Unlike in the traditional clinical registry setting, wherein physicians and their staff provide clinical information from the patient’s medical record into a centralized database, collection of PRO requires compliance from motivated patients, who must be able and willing to report their experiences. If patients feel coerced to participate, they may not supply accurate or complete data. Even under the best of circumstances, there is likely to be significant missing PRO data for unavoidable reasons, especially attrition due to patient death or disease progression/relapse and non-compliance at some time points due to disease severity and/or treatment toxicity and trial fatigue as follow-up continues. Non-compliance resulting from forced participation in a PRO study will further complicate this issue and could compromise the scientific validity of results.

   Additionally, the current FDA-mandated PASS studies and the CIBMTR Cellular Therapy Registry do not include PROs. Although CIBMTR has an infrastructure for collection of PRO data, development of a protocol that includes PROs will take time. That protocol would also have to be approved by Institutional Review Boards (IRBs) of all participating centers. Mandating a PRO component would lead to delayed implementation of a CED protocol by almost a year after the final decision memo. This contrasts with collection of appropriate clinical data which would be covered under CIBMTR’s existing data collection protocol, which is IRB-approved at all current CAR T cell centers. Alignment with that protocol, which is already listed under ClinicalTrials.gov and which is being used for several of CIBMTR’s existing CED protocols, would allow rapid implementation of a CED-compliant protocol for CAR T cells.

   1. CIBMTR acknowledges CMS’s desire for PRO data on patients who receive CAR T cell therapy in the outpatient setting but recommends that participation in any PRO component of CED studies be voluntary for patients.
   2. If PRO collection remains in the final National Coverage Determination for CAR T cells, to avoid excess delays in access to this therapy, CIBMTR recommends that CMS allows additional time for development of PRO data collection protocols, IRB approvals, and implementation of appropriate data systems while allowing patients to enroll on CED studies to evaluate standard clinical outcomes. This could take the form of a staged approach where collection of PRO information for newly enrolled participants becomes required after a specified period of time after the final decision memo, perhaps a year.

Conclusion
The CIBMTR looks forward to continued collaboration with CMS and to use its existing and operational CAR T cell registry to fulfill the requirements of this CED. We understand the opportunity to provide information that informs payment policy and regulatory issues, and are committed to developing the cellular therapy registry as an efficient resource to serve these needs while minimizing provider burden and maximizing access to lifesaving therapy.

Sincerely Yours,

Marcelo C Pasquini, MD, MS
Scientific Director

J. Douglas Rizzo, MD, MS
Scientific Director

References: https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610797.pdf

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March 15, 2019

Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: Proposed Decision Memo for the National Coverage Analysis (NCA) for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen,

On behalf of the National Marrow Donor Program® (NMDP)/Be The Match®, we thank you for the opportunity to provide our comments on the Centers for Medicare and Medicaid Services’ (CMS) Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers.

For the thousands of Americans diagnosed every year with life-threatening blood cancers like leukemia and lymphoma, a cure exists. NMDP manages the largest and most diverse marrow registry in the world through a competitively-bid contract with the Health Resources and Services Administration (HRSA). Each year, the Congress appropriates funds to operate this federal program, which is designated by the Congress as the C.W. Bill Young Cell Transplantation Program (Program). Since the mid-1980s, Congress has reauthorized the Program with virtually unanimous support. Through a public-private partnership, we not only manage a registry of 19 million U.S. volunteers and more than 249,000 cord blood units available for donation, but we also ensure that patients have access to cellular therapies that are potentially curative. Our goal is to ensure that every patient gets the cell therapy that they need when they need it.

In our comments submitted jointly with the American Society for Transplantation and Cellular Therapy (ASTCT), formerly the American Society for Blood and Marrow Transplantation (ASBMT), and the American Society of Hematology (ASH), we strongly opposed a National Coverage Determination (NCD) as we believe that it will cause significant and ongoing barriers to providing current and future CAR T-cell therapies. Patients falling within the indications for current CAR-T therapies represent an especially compelling case for individual, patient-directed decisions within the patient-physician relationship. CAR T-cell therapy is groundbreaking. The currently approved products exist in a class of their own: they are personalized therapies for a group of patients that have no other potentially curative options. Patients that otherwise might have died now have the hope of being cured of their cancer. Because of the nature of this therapy, both in its innovative approach to fighting cancer for patients who otherwise would have no alternatives and the rapidly evolving understanding of the most appropriate timing of therapy, NMDP believes that an NCD is premature to implement at this time until further data and studies are done in this rapidly changing field of medicine.

However, if CMS decides to issue an NCD, NMDP strongly urges CMS to eliminate the coverage with evidence development (CED) study requirement and instead implement an NCD with a registry reporting requirement. We believe the Center for International Blood and Marrow Transplantation Research (CIBMTR) is best-positioned to serve as the CMS approved data-collection registry.

Please consider the following comments that outline our suggestions on how to improve this proposed decision memo to limit any negative impacts on patient access and innovation should CMS decide to proceed. There are also many aspects of this policy that require further clarification that must be provided before this policy is finalized in order to minimize any disruptions to patient care.

Current Patient Access to Coverage
We are concerned that changes in how CMS is covering CAR T-cell therapy could negatively impact Medicare beneficiaries who are currently in the process of being treated with CAR-T, whether already infused or just starting the lymphodepleted regimen and/or awaiting receipt of the manufactured product for infusion. The decision in the final memo should make accommodations to not exclude coverage for those patients whose cells were collected before the effective date.

CMS should cover FDA-approved CAR T-cell therapies for labeled indications
The draft decision memo proposes to cover CAR T-cell therapies that are delivered in a way that meets the label requirements of the two currently FDA approved therapies. Because cell therapy is a fast-growing field with many types of new and emerging therapies in the pipeline for approval, we suggest that the requirements for coverage should be for medically accepted, FDA approved, cellular therapies for on-label uses (rather than explicitly for relapsed and refractory cancer), and compendia-supported uses for off-label usage. This provides the most flexibility for emerging therapies while reducing the need to re-open this decision each time a new CAR T-cell therapy or a new indication is approved by the FDA.

For example, in this memo, CMS proposes to cover therapies for patients with relapsed or refractory cancer, but there could be an approved therapy that is labeled for cancers in first remission, which the current proposal would not address. Furthermore, the draft decision memo specifies coverage for autologous treatment only. Allogeneic products are currently in development and CMS should not limit coverage by indication or disease stage, rather by FDA-approval status. As such, NMDP recommends removing the language in the decision memo specifying “autologous” and “relapsed or refractory cancer” and instead indicate coverage for labeled indications for FDA-approved CAR T-cell therapies. This will give the NCD the flexibility necessary to adapt to a rapidly changing field without the need for repeated NCDs.

Registry and CED Requirement Considerations
Since CAR T-cell therapy is already closely monitored through FDA-required post-marketing safety studies by the manufacturers, NMDP believes that issuing a CED for this therapy creates a barrier for patients and presents an additional burden to treatment centers. Currently, the insufficient Medicare inpatient reimbursement is creating challenges for treatment centers as they determine whether they can withstand the significant financial losses associated with delivering CAR T-cell therapy to Medicare beneficiaries. We understand CMS’ desire to closely track this type of therapy as it represents a novel way of treating hematological malignancies, and long-term effects are currently unknown. However, we believe that questions about long-term outcomes will be adequately answered with data that is currently being collected by CIBMTR. We would urge CMS to rely on the data currently collected on outcomes for patients receiving these therapies, rather than implementing a CED study that would create duplicative efforts by providers but would not generate different data than is already being tracked. NMDP believes that CIBMTR is well equipped to be listed as the approved registry in the final NCD and doing so will reduce administrative burden on hospitals and providers.

CIBMTR has the existing infrastructure, experience, and proven track record in data collection for CAR T-cell therapies. It has decades of experience collecting clinical outcomes data and, more recently, has collected PRO data on select patient populations. CIBMTR is currently serving as the data registry for the post-marketing safety studies being conducted by manufacturers of the existing FDA-approved CAR T-cell therapies, Kymriah® and Yescarta®. These studies require 15 years of follow-up after product administration to assess long-term safety. These data, with identification of patients covered by Medicare, could be made available to CMS on a regular basis without increasing the data reporting burden of centers.

CIBMTR currently administers five studies under the CMS’s CED mechanism for myelodysplastic syndrome, myelofibrosis, multiple myeloma and two sickle cell disease studies. Consequently, CIBMTR has experience over nearly a decade developing, administering and reporting on studies that meet CED requirements using its infrastructure and analytic capabilities. Additionally, CAR T-cell therapy is generally being provided by FACT-approved hematopoietic cell transplant (HCT) programs, which are required by law to report data on allogeneic HCT to CIBMTR, and are therefore familiar with its processes.

If CMS does finalize the decision to use the CED mechanism for CAR T-cell therapy at the end of the NCA process, we are concerned that the additional administrative requirements, including additional patient consent requirements, will place a burden on treatment centers and could result in some centers opting-out of providing this important therapy to patients.

Collecting Patient Reported Outcomes (PRO) data
We are concerned that a mandatory requirement for collection of PRO data for patients treated in the outpatient setting will be a barrier for both patients and centers. We strongly believe that Medicare beneficiaries who wish to be excluded from reporting PRO information should not be excluded from receiving treatment for their disease. We also support CIBMTR’s contention that participation in PRO studies be voluntary to ensure the scientific validity of those studies, which require committed and motivated participants. If patients feel coerced to participate, they may not supply accurate or complete data.

If PRO are required in the final NCD, the NMDP also recommends that CMS utilize CIBMTR as the organization to collect these data. However, we recommend that CMS allows additional time for development of PRO data collection processes, as these are not part of routine data collection or the post-marketing safety studies. Although CIBMTR has experience in collecting PRO data, development of a protocol will take significant time, including time for appropriate Institutional Review Board oversight at all participating centers.

Conclusion
NMDP appreciates the opportunity to provide comments on the proposed decision memo and looks forward to continued collaboration with CMS on the best ways to ensure access to CAR T-cell therapies for Medicare beneficiaries. We welcome the opportunity for discussion with the Agency on these important issues that impact patient access to life-saving care. If you have any questions, please free to contact me with any questions at blindber@nmdp.org or (763) 406-8566 or Susan Leppke, Director, Health and Public Policy at sleppke@nmdp.org or (763) 406-8522.

Sincerely,

Brian L. Lindberg, JD
Chief Policy Officer

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UnitedHealth Group (UHG) supports the Proposed National Coverage Determination for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers. This NCD will ensure Medicare beneficiaries have equal and consistent access to these therapies across the country. In addition to providing beneficiaries access nationwide, UHG believes this NCD will help promote the collection of clinical data to guide evidence based coverage for CAR-T therapies and ensure patient safety in a vulnerable population. UHG supports the Proposed NCD for the additional reasons below.

Coverage with Evidence Development

UHG supports CMS’s decision to cover CAR-T therapies through coverage with evidence development (CED). Because these are new therapies, this will encourage the clinical community to collect critical additional data relating to CAR-T therapies. Too often, clinical trials do not include a substantial or representative number of older patients. CMS’s decision to cover CAR-T therapies through CED is especially important in a vulnerable older population to identify additional risks and clinical outcomes that were not represented in the population for the initial clinical trials.

Facility Criteria

CAR-T is a complex therapy that requires specialized experience with managing the toxicities and administering the therapy that not all facilities and providers currently have. Accordingly, UHG supports CMS’s proposed facility criteria for where CAR-T can be administered as UHG believes these criteria will protect patient safety and promote the best clinical outcomes for very sick beneficiaries.

Compendia

Given the constant innovation in cancer therapy, UHG supports CMS’s decision to require coverage only when supported by compendia that keeps up with changing cancer therapy data and evidence-based medicine and is proven to provide relevant and dependable guidance. Particularly in the area of oncology, it is important to use compendia that keep pace with the developing therapies in cancer treatment.

Significant cost criteria

Finally, as we stated in our request for a National Coverage Determination, for Medicare Advantage (MA) members and plans, these CAR-T therapies clearly meet the significant cost criterion set forth in 42 C.F.R. § 422.109(a), which allows a Medicare Advantage plan to have its members submit the claims to Original Medicare until the contract year for which Medicare Advantage plan payments are appropriately adjusted to take into account the cost of the NCD. CMS should clarify when Original Medicare began covering CAR-T therapies, and issue a determination that CAR-T therapies are considered a significant cost under section 422.109(a). See, e.g., April 10, 2018 HPMS Memorandum “Supervised Exercise Therapy (SET) for Symptomatic Peripheral Artery Disease (PAD),” (determining upon issuance of an NCD for Supervised Exercise Therapy for Symptomatic Peripheral Artery Disease that it was considered a significant cost under section 422.109(a)(2) and retroactively requiring original fee-for-service Medicare to pay for claims for calendar years 2017 and 2018). CMS should also provide adjusted benchmarks for MA bids for the calendar year in which MA plans will be expected to cover CAR-T therapies.

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Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850

Re: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Jensen:

AABB appreciates the opportunity to submit comments in response to the Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-Cell Therapy for Cancers. AABB is an international, not-for-profit association representing individuals and institutions involved in the field of transfusion medicine and cellular therapies. The association is committed to improving health through the development and delivery of standards, accreditation and educational programs that focus on optimizing patient and donor care and safety. AABB individual membership includes physicians, nurses, scientists, researchers, administrators, medical technologists and other health care providers.

AABB values that the Food and Drug Administration (FDA) recently approved two CAR T-cell therapies and recognizes that other cellular therapies, including additional CAR T-cell products, are in development. We appreciate the clinical significance of these new therapies, as well as the challenges they present related to reimbursement. We believe it is imperative for the Centers for Medicare & Medicaid Services (CMS) to ensure that Medicare coverage and reimbursement policies do not restrict beneficiaries’ access to these life-saving therapies. AABB believes that a national coverage determination (NCD) is premature and has the potential to negatively impact patients’ access to important, innovative therapies. Thus, we recommend that CMS refrain from implementing an NCD for CAR T-cell therapies at this time.

If CMS decides to move forward with an NCD, we encourage the agency to: (1) adopt flexible language that can accommodate new technologies and which does not restrict patients’ access to appropriate treatment options; (2) recognize and pay for all the services that must be provided throughout the CAR T-cell treatment protocol; and (3) permit standards-setting and accreditation organizations, including AABB, to continue to ensure the safety and quality of these therapies. In addition, we recommend that CMS replace the reference to the July 2016 Circular of Information for the Use of Cellular Therapy Products with the updated Circular of Information for the Use of Cellular Products, which was released in October 2018.

Finally, if CMS decides to move forward with an NCD, we encourage the Agency to specify that the Center for International Bone and Marrow Transplant Research (CIBMTR) is the registry referenced in the NCD. CIBMTR already collects outcomes and post-market surveillance data for several organizations and has a registry set up for this type of information. In addition, CIBMTR has experience with CEDs and data collection studies that it does with CMS and other agencies.

AABB urges CMS to adopt flexible language that provides Medicare beneficiaries with access to novel immune effector cell therapies and medically necessary treatments.

AABB believes that CMS’ proposed decision to cover “autologous treatment with T-cells expressing at least one chimeric antigen receptor (CAR) through coverage with evidence development (CED)” when certain criteria are satisfied is far too restrictive and may unnecessarily restrict Medicare beneficiaries’ access to available treatment options. For instance, AABB encourages CMS to broaden the coverage language from “autologous treatment” to “FDA approved treatments” since this is a rapidly evolving field and the broader language increases the likelihood that the NCD will apply to future products without needing to be reopened. We are concerned that the proposed decision memo will not allow for repeat CAR T-cell therapy if a patient’s cancer recurs. In addition, the proposed decision memo limits coverage for CAR T-cell therapies to patients with relapsed or refractory cancer. While these eligibility criteria are aligned with the FDA-approved labels for the currently approved CAR T-cell therapies, FDA may approve CAR T-cell therapies for different indications in the future. Thus, we encourage CMS to broaden the eligibility criteria in the NCD by generally providing coverage that is consistent with the requirements in an FDA-approved label. Similarly, we believe CMS should consider using a data collection requirement that is consistent with an FDA post-approval study, rather than CED requirements. We believe that broader eligibility criteria that is consistent with FDA approval and post-approval studies will encourage innovation and expedite patients’ access to novel therapies.

In addition, AABB encourages CMS to consider broadening the language in the NCD by referencing “CAR T and related immune effector cell therapies” rather than CAR T-cell therapies. This alternative language would enable the NCD to cover other novel cell-based therapies that are not derived from T-cells, such as newer products from Natural Killer (NK) Cells. We are concerned that if the narrow language in the draft proposed decision memo is finalized, CMS will need to reopen the NCD each time a new CAR T and related immune effector cell therapy becomes available.

AABB questions whether CMS’ decision to cover CAR T-cell therapy through CED has the potential to limit beneficiaries’ access to care. The CED process is historically slow and takes years to result in coverage or non-coverage decisions. Additionally, if Medicare covers CAR T-cell therapies through a CED with patient reported outcomes, it is possible that some providers may “opt out” of furnishing these treatments, which will restrict patients’ access to care. In addition, we understand that including patient reported outcomes as part of a registry is quite burdensome. While patients must provide clinical data, patients are not required to report data and it is difficult to collect the required data after a patient leaves a provider.

AABB urges CMS to clarify that there must be appropriate coverage and reimbursement for all items and services required throughout a CAR T and related immune effector cell therapy treatment protocol.

We commend CMS for recognizing that CAR T-cell treatment protocols involve several essential steps, which the Agency summarizes as:

1. lymphocyte harvesting from the patient with cancer;
2. creation of cancer-targeting lymphocytes in vitro using various immune modulators;
3. selection of lymphocytes with reactivity to cancer antigens using enzyme-linked immune-assay;
4. depletion of the patient's remaining lymphocytes using immunosuppressive agents; and
5. transfusion of the cancer-targeting lymphocytes back into the patient with cancer-this transfusion represents one treatment.

Thus, CMS acknowledges that CAR T-cell therapies involve separate and distinct processes outside of the in vitro cell manipulations. Importantly, each of these five steps are labor intensive, requiring the expertise of physicians and other health care professionals, oversight and monitoring. In addition to these steps, monitoring for and treatment of therapy related complications, such as cytokine release syndrome and neurotoxicity, are important aspects of CAR T-cell therapy protocols. We urge CMS to recognize that appropriate coverage and reimbursement is necessary for all items and services furnished throughout the continuum of CAR T and related immune effector cell therapy treatments.

AABB encourages CMS to recognize AABB and other qualified standards and accreditation programs in the NCD.

The draft proposed decision memo recognizes a single accreditation program, which is overly restrictive and may provide one accreditor with a competitive advantage. AABB recommends that CMS specifically recognize in the NCD multiple qualified cellular therapy standards programs, including AABB’s Standards for Cellular Therapy Services (CT Standards). The CT Standards are written in a way to allow accredited facilities to be nimble in their ability to add new products and protocols, including the manufacture and provision of CAR T and related immune effector cell therapy treatments. AABB’s CT Standards include all elements of product manufacture, including collection, storage, transport, testing and processing of these products. In addition, the CT Standards contain requirements that focus on the clinical care of the recipient, including cytokine release syndrome, most commonly associated with the infusion of CAR T- cells and potentially, other immune effector cell therapies in the future. Therefore, whether a facility collects these products for further manufacture at another facility or engages in the complete manufacturing process, the CT Standards address important requirements for product quality and patient safety from donor evaluation to product manufacture, infusion and follow up.

Notably, AABB and other standards setting organizations ensure that good manufacturing practices safeguard the quality of CAR T and related immune effector cell therapies. Without a robust laboratory accreditation program, the quality of a CAR T or a related immune effector cell therapy may be compromised due to low product yields, contamination, and logistical and quality mishaps in handling and processing the cells. Not all CAR T or related immune effector cell therapies will be collected, manufactured and infused at a single facility with a Cellular Therapy Program. Rather, it is possible that the collection, manufacture and infusion of CAR T or related immune effector cell therapies will occur at up to three different facilities. In fact, the two currently approved CAR T-cell products are not manufactured in a Cellular Therapy Program. We encourage CMS to adopt a flexible policy that enables qualified facilities to be able to collect, manufacture or administer CAR T and related immune effector cell therapies.

CMS and the State of California have given deemed status to the AABB Accreditation Program for Cellular Therapies, which is based on the CT Standards. In addition, the Health Resources and Services Administration (HRSA) and the National Marrow Donor Program recognize the AABB Accreditation Program for Cellular Therapies as well as the Foundation for the Accreditation of Cellular Therapy (FACT) accreditation. The AABB Accreditation program is accredited by the International Society for Quality in Healthcare (ISQua). AABB is proud of its stellar record as a deemed accreditation organization. We urge CMS to ensure that any policies related to cellular therapies, including CAR T and related immune effector cell therapies, continue to support AABB’s important role in ensuring product quality and patient safety throughout the treatment protocols.

* * * *

Thank you for the opportunity to provide feedback related to the proposed decision memo for CAR T-cell therapy for cancers. If you have any questions or need additional information, please contact Leah Stone, Senior Director, Public Policy and Strategic Partnerships, at lmstone@aabb.org or 301-215-6554.

Sincerely,

Debra BenAvram
Chief Executive Officer
AABB

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March 15, 2019

VIA ELECTRONIC DELIVERY

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

Katherine B. Szarama, PhD, Lead Analyst
Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Lori A. Paserchia, MD, Lead Medical Officer
Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen and Drs. Szarama and Paserchia:

Novartis Services, Inc. is submitting this letter on behalf of Novartis Pharmaceuticals Corporation. We appreciate the opportunity to provide comment on the “Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N),” released on February 15, 2019.

Novartis researches, develops, manufactures, and markets innovative medicines aimed at improving patients’ lives. We offer a broad range of medicines for cancer, cardiovascular disease, inflammatory disease, infectious disease, neurological disease, eye disease, organ transplantation, respiratory disease, and skin conditions. Our mission is to discover new ways to improve and extend people’s lives. We use science-based innovation to address some of society’s most challenging healthcare issues. We discover and develop breakthrough treatments and find new ways to deliver them to as many people as possible.

As you know, Novartis is keenly interested in the proposed decision memo as the manufacturer of KYMRIAH® (tisagenlecleucel), the first CAR T-cell therapy approved by the Food and Drug Administration (FDA) for Medicare beneficiaries with advanced cancer. On August 30, 2017, the FDA approved KYMRIAH for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse. On May 1, 2018, the FDA approved KYMRIAH for a second indication for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma.

I. Summary of Comments

Novartis applauds CMS for issuing a proposed National Coverage Determination (NCD) that would (1) require Medicare to cover CAR-T nationally for FDA-approved indications; and (2) continue coverage for routine costs in clinical trials that use CAR-T. Novartis supports finalizing the NCD but urges CMS to modify the NCD in three ways:

Recommendation 1: replace the Coverage with Evidence Development (CED) requirement with a requirement that hospitals (inpatient and outpatient) report the specified clinical data elements (other than Patient-Reported Outcomes (PROs)) to one centralized registry operated by a professional organization with experience capturing cellular therapy outcomes data;

Recommendation 2: eliminate the requirement that PROs be tracked as part of the NCD; and

Recommendation 3: modify the patient requirement with a requirement that a patient must have a cancer that is treatable with an FDA-approved therapy, according to an FDA-approved indication.

II. Detailed Comments

Novartis applauds CMS for issuing a proposed NCD that would (1) require Medicare to cover CAR-T nationally for FDA-approved indications; and (2) continue coverage for routine costs in clinical trials that use CAR-T. We also appreciate the proposed hospital requirements, effectively ensuring that CAR-T is administered in a Foundation for the Accreditation of Cellular Therapy (FACT) accredited institution that complies with a Risk Evaluation and Mitigation Strategies (REMS) program. However, as described in detail below, we are concerned with certain elements of the proposed NCD, specifically the CED requirement, the PRO data element, and the patient requirement. We respectfully recommend that CMS make the following modifications before issuing a final decision memo.

(1) Recommendation 1: Novartis urges CMS to replace the CED requirement with a requirement that hospitals report the specified clinical data elements (other than PROs) to one centralized registry operated by a professional organization with experience capturing cellular therapy outcomes data.

(a) Eliminate Proposed CED Requirement

Under the proposed decision memo, CMS would require national coverage of CAR-T through CED, when certain requirements are met. Novartis does not support the proposed CED requirement because it is unnecessary, may impede beneficiary access, and is inconsistent with past CMS policy. We urge CMS to finalize the NCD without the CED requirement.

(i) CED Requirement is Unnecessary

The proposed CED is unnecessary because the clinical data elements, other than PRO, that must be tracked are already being collected as part of an existing cellular therapy registry. Specifically, the proposed CED would require the furnishing hospital to track the following data elements at baseline, at treatment, and at follow-up 3 months, 6 months, 12 months, and 24 months after the treatment is administered: age, gender and comorbidities; specifics of cancer diagnosis (e.g., sub-classification, stage); number(s) or line(s) of previous therapies, therapeutic agents previously administered; days to disease progression; days to recurrence; overall survival; and progression-free survival. The CED would also require outpatient hospitals furnishing CAR-T to track PRO data. Other than the PRO data, which we discuss below, all the requisite CED data elements are already being tracked, at the above specified intervals, by the Center for International Bone & Marrow and Transplant Research (CIBMTR) Cell Therapy Registry. Novartis contracts with CIBMTR, and we understand Kite/Gilead has also engaged with CIBMTR, to capture data on safety and efficacy, in order to fulfill an FDA requirement for a 15-year post-marketing observational study. The Cell Therapy Registry captures data, including the proposed CED requisite data elements, from the FDA-required observational studies for both approved CAR-T therapies by following at least 4,000 patients for 15 years after CAR-T administration.

Moreover, requiring CED as part of the NCD for CAR-T is unnecessarily duplicative and contradicts one of the CMS principles for applying CED. According to CMS, a principle governing the application of CED is that: “CED will not duplicate or replace the FDA’s authority in assuring the safety, efficacy, and security of drugs, biological products, and devices.” [1] Here, as part of FDA approval of the CAR-T therapies, the FDA required a 15-year post-marketing observational study, and thus hospitals that treat patients with currently approved CAR-T therapies are already obligated to track the same data elements proposed by the CED, at similar intervals.

(ii) CED Requirement May Impede Beneficiary Access

Novartis is concerned that the proposed CED may impede beneficiary access. As CMS is aware, hospitals are extremely concerned about the current Medicare reimbursement dynamics for CAR-T, especially on the inpatient side. FDA Commissioner Scott Gottlieb shares these concerns of “underpaying hospitals and forcing them to lose money” on CAR-T and has stated that he is “extremely worried that if we don’t adapt the approach to reimbursement soon, we may foreclose therapeutic opportunities.” [2] The additional administrative and financial burden of complying with the proposed CED will make the hospital reimbursement dynamics even more challenging for inpatient CAR-T administration. The prospect of additional costs of furnishing a product that already results in heavy financial losses may deter hospitals from electing to participate in the CED, creating a situation in which only a few hospitals choose to enroll Medicare beneficiaries. If only a small number of hospitals “opt-in” and participate, beneficiaries will face difficulty trying to locate providers in participating hospitals.

Additionally, given the extensive proposed requirements for registries to qualify for the CED, no current registries meet all the requirements and thus will not be operational by May 17, 2019, the date by which the final decision memo must be released and the NCD is technically effective. Existing registries will have to be modified or new registries will have to be developed to conform to the CED registry requirements. We are concerned that during this transition period, there will be a significant delay in beneficiary access to CAR-T therapy, as registries are developed and approved. Should the CED be included in the final decision, we urge CMS to ensure that implementation be delayed by a minimum of 12 months to afford providers and patients adequate time to comply with the CED.

(iii) CED Requirement is Unprecedented and Inconsistent with CMS Policy

The Agency’s long-standing policy under Section 1861(t)(2) of the Social Security Act has been to cover drugs and biologicals for anti-cancer indications approved by the FDA and for other indications that are listed in specific approved compendia – without a CED requirement. In fact, CED has never been used for an FDA-approved anti-cancer therapy. Finalizing CED for CAR-T would be an unprecedented departure from past CMS policy.

(b) Require Data Reporting to a Centralized Cellular Therapy Registry

Novartis urges CMS to replace the proposed CED requirement with a requirement that hospitals report the specified clinical data elements (other than PROs) to one centralized registry operated by a professional organization with experience capturing cellular therapy outcomes data.

(i) Centralized Cellular Therapy Registry

Selecting one centralized registry to coordinate data collection, from an organization with relevant experience, will make the synthesis of data more efficient, as compared to allowing new individual registries to collect data. Further, allowing new individual registries, without previous experience in capturing cellular therapy outcomes data, will create an additional administrative and financial burden to hospitals.

(ii) CIBMTR’s Cell Therapy Registry

In selecting a single centralized registry, we urge CMS to consider CIBMTR, the organization that currently operates the well-regarded Cell Therapy Registry. CIBMTR represents an international network of transplant centers that submit transplant-related data for patients. They are a respected leader in hematopoietic cell transplantation (HCT) research by providing a unique resource of information and expertise to medical and scientific communities. As described above, CIBMTR operates an existing cellular therapy registry, and they currently contract with the manufacturers of both FDA-approved CAR-T products to capture data on safety and efficacy in connection with the FDA-required 15-year post-marketing observational study. The CIBMTR registry will arguably be even more robust than the registry contemplated under the proposed CED, as it will collect more data and for a longer duration than the proposed CED would require. Selecting the CIBMTR registry as the centralized registry under the NCD will provide a feasible and efficient approach to data collection and meet CMS’ goal of generating evidence to inform future coverage decisions.

(iii) Data Reporting

Once CMS selects a centralized registry, Novartis recommends that CMS work with the organization operating the registry (e.g., CIBMTR) to establish a process for the sharing of aggregate clinical data collected on Medicare beneficiaries at set intervals and engage the provider and researcher communities on the CED questions specified in the proposed decision memo. Under this approach, as more data is collected, CMS can adjust, if necessary, the NCD more quickly than under a CED.

(2) Recommendation 2: Novartis urges CMS to eliminate the requirement that PROs be tracked as part of the NCD.

Under the proposed decision memo, CMS would require outpatient hospitals furnishing CAR-T therapy to track PRO data using the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS®) or Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAETM). Although Novartis agrees that measurements of quality of life, including PRO data, can be useful, we urge CMS to eliminate the PRO reporting requirement as a condition for CAR-T coverage because it is unnecessary, burdensome, and provides a data quality challenge. Instead, we urge CMS to consider future collaboration with CIBMTR as it explores options to address symptom function and health-related quality of life questions.

(a) PRO Data Already Collected as Part of Clinical Trials

Novartis appreciates that PRO measures can be useful in understanding the patient’s perspective, especially during the drug development process. As such, we incorporated PRO data collection as part of KYMRIAH’s clinical trials. Specifically, Novartis collected the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) disease-specific PRO measure and the 36-Item Short-Form Health Survey (SF-36) during the JULIET trial. PRO data, along with efficacy and safety data, from KYMRIAH trials have already established a positive benefit risk ratio, as assessed by the FDA.

(b) Administrative and Financial Burden

Collecting PRO data requires significant administrative and data structures to support the collection, storage and analysis of PRO data in a secure manner, which can lead to significant financial burdens for hospitals. Equipping hospitals with the appropriate structures to support PRO data collection is also likely to take time, and these structures are unlikely to be ready for some time after the NCD, if finalized, becomes effective on May 17, 2019. This could further exacerbate potential disparities in CAR-T access for the Medicare population.

(c) Data Quality Challenge

Patients seeking CAR-T treatment have often received many prior therapeutic regimens and are often in a poor health state and condition, which will likely result in substantial missing PRO data. Patients can also receive care at different hospitals during their disease journey; this will likely contribute to incompleteness of PRO data. Further, given concerns with data quality and missing data, instead of permitting one of two PRO measures, we recommend that CMS consider specifying one measure or delineating exact domains or concepts to be collected and reported to potentially improve the sample size and precision of PRO data for future evaluation purposes.

(d) Alternative Approach: CIBMTR Pilot Study

As an alternative to mandating PRO data collection as a condition for CAR-T coverage, we urge CMS to instead address PROs associated with CAR-T through future collaboration with CIBMTR as it explores options for PRO collection and reporting. As we understand, a working group at CIBMTR has been established that could assist CMS with a structured pilot study in CAR-T patients to identify the optimal PRO measures and time points for collection. Moreover, Novartis has PRO experts that would be available to participate in a scientific working committee if CMS is further interested in appropriate applications of PROs.

(3) Recommendation 3: Novartis urges CMS to modify the patient requirement with a requirement that a patient must have a cancer that is treatable with an FDA-approved therapy, according to an FDA-approved indication.

Under the proposed NCD, CMS would require that patients have relapsed or refractory cancer; and not be currently experiencing any comorbidity that would otherwise preclude patient benefit. Although Novartis agrees that a final NCD should include patient requirements, we do not support the proposed patient requirements.

Specifically, we urge CMS to remove the requirement that the patient must have relapsed or refractory cancer. We recognize that this requirement describes the indicated populations for KYMRIAH, as well as the other FDA-approved CAR-T; however, requiring that all patients who receive CAR-T be relapsed or refractory may delay or impede access to patients for future indications and treatments. Furthermore, by requiring that patients have relapsed or refractory cancer, the NCD would effectively have to be re-opened for future indications, triggering a potential lengthy delay (up to 9 months) in accessing CAR-T.

We also urge CMS to remove the requirement that a patient must not be currently experiencing any comorbidity that would otherwise preclude patient benefit because it brings unnecessary subjectivity and ambiguity in the selection process.

In place of the current patient requirements, Novartis urges CMS to require that the patient have a cancer that is treatable with an FDA-approved therapy, according to an FDA indication. We believe these modified patient requirements achieve CMS’ goal in ensuring that CAR-T is only provided to appropriate patients.

III. Conclusion

Novartis applauds CMS for the proposed NCD that would require Medicare to cover CAR-T therapy nationally for FDA-approved indications. Requiring nationwide coverage is critical for this patient population as they have few alternative options and a very limited life-expectancy if they are unable to receive CAR-T.

As such, Novartis supports finalizing the NCD but urges CMS to modify the NCD by: (1) replacing the CED requirement with a requirement that hospitals report the specified clinical data elements (other than PROs) to one centralized registry operated by a professional organization with experience capturing cellular therapy outcomes data; (2) eliminating the requirement that PROs be tracked as part of the NCD; and (3) modifying the patient requirement with a requirement that a patient must have a cancer that is treatable with an FDA-approved therapy, according to an FDA-approved indication.

Moreover, Novartis has experts in data collection and reporting that would be available to participate in a scientific working committee as CMS works to further understand the benefits and outcomes of CAR-T for Medicare beneficiaries.

Novartis again appreciates the opportunity to comment on the proposed decision memo. We look forward to working together with CMS to ensure access to high quality, high value care for patients with cancer. If you have any questions regarding the above comments, or we can provide any additional information, please do not hesitate to contact me at (862) 778-3284.

Sincerely,
Leigh Anne Leas
Vice President and U.S. Country Head, Public Policy
Novartis Services, Inc.

[1] Guidance for the Public, Industry, and CMS Staff: Coverage with Evidence Development, Nov. 20, 2014, available online at: https://www.cms.gov/medicare-coverage-database/details/medicare-coverage-document-details.aspx?MCDId=27.
[2] FDA Commissioner Scott Gottlieb Speech at the Milken Institute’s Future of Health Summit, Oct. 24, 2018.

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March 15 2019

Tamara Syrek Jensen, Director
Joseph Chin, MD, Deputy Director
Lori M. Ashby, Director, Policy and Evidence Review
Daniel A. Canos, PhD, Director, Evidence Development
Katherine B. Szarama, PhD, Lead Analyst
Lori A. Paserchia, MD, Lead Medical Officer
Evidence and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed National Coverage Determination for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen and respective colleagues:

The University of Chicago Medical Center (UCMC) appreciates the opportunity to comment on the CMS National Coverage Determination (NCD) proposal to cover chimeric antigen receptor (CAR) T-cell therapy for certain Medicare patients undergoing cancer care.

The new immunotherapy treatment CAR-T represents a paradigm change in cancer therapy. For the first time, cancer treatment can be directed specifically to the cancer cells, sparing most of the normal cells, and resulting in very high remission rates in patients who have otherwise failed all other available treatment. Many patients who would have otherwise succumbed to their disease, are alive and well today, as a result of the CAR-T treatment.
This treatment is in its early phases and will require more refining through research and clinical trials. We, therefore, urge CMS to consider the unique aspects of CAR-T cell therapy and ensure the agency’s policy decisions do not hinder the future development of innovative immunotherapies or the Medicare patient’s access to these lifesaving therapies. Further, we believe the policy should be flexible enough that in the event expansions are granted for immunotherapies that are currently approved by the FDA, that each new on-label use is deemed covered under the NCD. We recommend that coverage be expanded to trials with solid tumors, allogeneic CAR-T cells, and other cellular therapy trials for malignancy.

We want to ensure that CMS’s proposed coverage with evidence development requirement does not result in duplicate work for our physicians and researchers. To the extent possible, UCMC recommends the agency take steps to use existing infrastructures of data reporting. This could streamline the reporting and data collection process and reduce the administrative burden on hospitals.

As an example, both CAR-T manufacturers require administering hospitals to be accredited by the Foundation for Accreditation in Cellular Therapy (FACT) prior to offering patients treatment. In turn, hospitals accredited by FACT must submit data to the Center for International Blood and Marrow Transplant Research (CIBMTR). CIBMTR has extensive experience collecting and analyzing data described under the current proposal and does so in a way to adjust for differences in patient populations and sites of care. Their current registry platform is widely considered to be the most streamlined and efficient for cellular therapy providers. As such, we would ask that CMS consider using CIBMTR, or another data registry already in use by CAR-T providers, to satisfy the data reporting requirement.

Thank you again for the opportunity to provide feedback on the proposed NCD for CAR-T. We appreciate your consideration of our comments.

Sincerely,

Ben Gibson
Vice President for Governmental Affairs

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March 15, 2019

The Honorable Seema Verma
Administrator, Centers for Medicare & Medicaid Services Department of Health and Human Services
Attention: CAG-00451N 7500 Security Blvd
Baltimore, MD 21244

Re: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Administrator Verma:

The Leukemia and Lymphoma Society (LLS) appreciates the opportunity to submit comments on the Proposed Decision Memo for Chimeric Antigen Receptor T-cell (CAR­T) Therapy for Cancers (CAG-00451N). LLS is committed to working with all stakeholders to ensure cancer patients have access to quality, effective treatment. LLS is dedicated to supporting research on better treatment and cures for those suffering from leukemia, lymphoma, Hodgkin's disease, and multiple myeloma, and to ensuring that blood cancer patients have sustainable and affordable access to care.

Over the last two decades, LLS has funded over $40 million in research and development of CAR-T therapies. More than half of these funds supported the nearly two decades of work on CAR-Tat the University of Pennsylvania, which helped demonstrate the potential of CAR-T therapies and resulted in the development of tisagenlecleucel. Separately, through our Therapy Acceleration Prog ram ® (TAP), LLS also supported the clinical trial that led to the approval of axicabtagene ciloleucel.

These approved therapies and similar therapies in various phases of development have the potential to improve outcomes for patients with certain blood cancers, and LLS supports the Centers for Medicare & Medicaid Services' (CMS) efforts to facilitate appropriate patient access. We support CMS' decision to mandate coverage of CAR-T therapy with Coverage with Evidence Development (CED), as it will provide an opportunity for Medicare beneficiaries to obtain appropriate access while simultaneously ensuring the development of evidence that will help the clinical and payer communities better understand costs and benefits of this new type of therapy.

We share CMS' goal of ensuring that the conditions and parameters set in a final decision memo will provide appropriate access to these therapies today and into the future. We believe it is vital for CMS to incorporate feedback from community stakeholders like LLS in order to ensure that the final decision memo achieves this goal. To that end, we offer detailed comments on the Proposed Decision Memo below, for your consideration.

Registry Requirements
We support CMS' proposal to require participation in a prospective, national, audited registry in both the inpatient and outpatient hospital settings. We believe this registry requirement will generate important evidence about the clinical impact and outcomes of these treatments. CMS should ensure registry data is aligned across both inpatient and outpatient settings. Specifically, we recommend that CMS extend the CED question required of patients treated in the outpatient setting to patients treated in the inpatient setting, as well.

In addition to the primary questions satisfied through a national registry, we urge CMS to consider including a requirement for race and ethnicity data in section A(3)(a)(iii). We recognize CMS' consideration of race/ethnicity in recent coverage decision-making, and we believe such data can assist physicians, researchers, and CMS in understanding and addressing possible health disparities and other issues.

Rather than placing the responsibility for tracking and follow-up on the furnishing hospital, as proposed in the draft decision memo, LLS recommends that CMS place this responsibility on the registry itself. Given the nature of CAR-T therapy, it is likely that a significant portion of treated patients may not be in regular contact with or in reasonable proximity to the furnishing hospital, which may inhibit the collection of data by that hospital. We believe that the registry is more likely to be resourced to complete this follow-up in a manner than maximizes usable data.

In the context of our support for the registry requirement, we believe it is important for CMS to clarify a transition policy in the final coverage memo in order to prevent interruption to access to therapy for Medicare patients who are currently in the process of receiving a CAR-T therapy or need to access a CAR-T therapy prior to the enrollment of their treating facility in a registry. In these cases, CMS should consider allowing facilities to prospectively collect the necessary data and retrospectively enroll patients in an eligible registry. Given that the registry requirement detailed in the final decision memo will take effect immediately, this transition policy will be essential to ensuring appropriate coverage is not denied to a patient who meets the criteria outlined in the final decision memo during the process of establishing an approved registry and facility enrollment.

Patient Reported Outcomes (PROs)
We appreciate CMS' inclusion of PRO tool collection in its proposed decision for assessment at baseline and follow-up for the purpose of addressing health-related quality of life. PROs are indispensable tools that are increasingly used to obtain data about patients' perceptions of their health and experiences while receiving care with the aim of improving quality of care.

We believe specifying the appropriate measuring tools is important in ensuring the collection of validated, reliable, and comparable data, upon which CMS and other stakeholders can rely to better understand the value of CAR-T therapies. We note the National Institutes of Health Patient-Reported Outcomes Measurement Information System [PROMIS®] is an NIH-funded initiative to develop and validate PROs for clinical research and practice, not a single tool in and of itself. We ask CMS to specify the PROMIS® system tools that it considers valid for the purposes of this proposed decision and/or whether a specific tool should be specified for this patient population. We support CMS' proposed use of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE™] tool given its focus on a targeted set of questions for the patient related to adverse events.

Importantly the tools within the PROMIS® system and PRO-CTCAE™ are intended for different purposes-quality of life and adverse events, respectively-and the data incorporated via these tools in not comparable. Requiring use of each PRO tools in the inpatient and outpatient care settings would minimize data discordance from use of either tool at various sites. Therefore, we urge CMS to require use of each of these valid tools in both the inpatient and outpatient care settings.

Compendia
We appreciate CMS' flexibility in proposing to cover FDA-approved biologicals that have been indicated for use in the National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium on or after August 1, 2017. We support CMS' specific reference to the NCCN Compendium when making its coverage determinations. The NCCN Compendium is a nationally-recognized compendium, and it is included in the current list of compendia supporting off-label use in Chapter 15 of the Medicare Benefit Policy Manual. We urge CMS to revisit its NCCN references to ensure the information about NCCN classification and grading is accurate, as we believe the references in the draft decision memo are incorrect as they relate to NCCN nomenclature.

Relapsed/Refractory & Repeat Treatment Limitations
We appreciate CMS proposing coverage for FDA-approved CAR-T therapies currently on the market, and it is true that these therapies have indications to treat relapsed/refractory cancer. However, as these therapies evolve and new therapies are developed, a CAR-T therapy with an indication for first-line treatment could enter the market. We ask CMS to allow coverage for first-line treatment with CAR-T therapies, specifically in cases where the product is approved by FDA with an indication for first-line use. By incorporating this flexibility for CAR-T therapy in the final decision memo, CMS will maintain patient access in the future, without the need to revisit the coverage analysis for a foreseeable advancement in the CAR-T therapy science.

In the proposed decision memo, CMS notes, "Repeat treatment when a patient receives more than one therapeutic dose of a specific CAR T-cell product using the same biological in the same patient is covered only when a new primary cancer diagnosis is made by the treating oncologist and the patient conditions are met." However, we note that more than one dose of CAR-T cells may be required in particular cases, such as when a patient's cell yield is insufficient or the clinical team otherwise suspects an issue with the quality of the therapeutic doses. According to a recent case series report from a single CAR-T center, nearly 25% of cases required more than one dose. We urge CMS to consider broadening the allowance for more than one therapeutic dose beyond a new primary cancer diagnosis and into cases in which the integrated medical team determines that it is medically necessary.

Clinical Study Participation
CMS notes coverage may apply to patients "enrolled in a CMS-approved clinical study that consecutively enrolls patients and follows the patient for at least two years" in cases where a therapy is FDA-approved and indicated for off-label use by the NCCN Compendium. We note that, in other cases of CED, CMS has kept registries and clinical trials separate, and it has tracked registries and clinical trials separately. Because CAR-T is a new treatment modality, we ask CMS to clarify the definition of "clinical study" and its relation to participation in the registry. For example, when may a clinical study based on registry data qualify for coverage? We recommend that CMS consider participation in a prospective study based on registry data as qualifying for a positive coverage determination based on section A(3)(b) of the proposed decision, as long as patients are pre-enrolled for both registry and trial participation when treatment begins.

Clarification Related to Medical Teams
In A(2)a of the proposed decision memo, CMS would require the furnishing hospital to have a Cellular Therapy Program that includes "at least one physician experienced in cellular therapy." Given the desire among providers and payers for greater clarity, we urge CMS to further define this phrase in its final decision memo.

About LLS
LLS is the world's largest voluntary health agency dedicated to the needs of blood cancer patients. Each year, over 150,000 Americans are newly diagnosed with blood cancers, accounting for nearly 10 percent of all newly diagnosed cancers in the United States. The mission of LLS is to find cures for leukemia, lymphoma, Hodgkin's disease, and multiple myeloma and to ensure that blood cancer patients have sustainable access to quality, affordable, and coordinated healthcare. LLS funds lifesaving blood cancer research, provides free information and support services, and advocates for public policies that address the needs of patients with blood cancer; since our founding nearly 70 years ago, LLS has invested more than $1 billion into research for cures and LLS-funded research has been part of nearly all of the FDA-approved therapies for blood cancer.

LLS appreciates the opportunity to provide feedback on this proposed decision memo. We look forward to working with CMS and other stakeholders to ensure patients can access this important new therapy moving forward. If you have any questions or wish to discuss our comments further, please contact me at Bernadette.ODonoghue@lls.org or Brian Connell at Brian.Connell@lls.org.

Sincerely,
Bernadette O'Donoghue
Vice President, Public Policy

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March 15, 2019

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

RE: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen:

The National Comprehensive Cancer Network® (NCCN®) is pleased to comment on the Centers for Medicare & Medicaid Services (CMS) Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N) as it relates to NCCN’s mission of improving and facilitating, quality, effective, efficient, and accessible cancer care.

NCCN Member Institutions have been at the forefront of administering CAR T-cell therapy, first as clinical trial sites and, following the Food and Drug Administration (FDA) approval of two CAR T-cell products, now providing these therapies off-trial following commercialization. Both of the two commercially available CAR T-cell therapies are currently Category 2A recommendations in the NCCN Guidelines in the clinical situations outlined within the Guidelines (please see attached Appendices 1 and 2 for further information). NCCN thanks CMS for recognizing our guidelines within the proposed decision memo. NCCN would like to recommend suggested wording changes to more accurately reflect the language used in our guidelines. Additionally, NCCN has several recommendations and questions related to the implementation of the Proposed Decision Memo as it is currently written.

As an alliance of 28 leading academic cancer centers in the United States that treat hundreds of thousands of patients with cancer annually, NCCN is a developer of authoritative information regarding cancer prevention, screening, diagnosis, treatment, and supportive care that is widely used by clinical professionals and payers alike. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a comprehensive set of guidelines detailing the sequential management decisions and interventions that currently apply to 97 percent of cancers affecting patients in the United States.

NCCN Guidelines® and Library of Compendia products help ensure access to appropriate care, clinical decision-making, and assessment of quality improvement initiatives. The NCCN Drugs & Biologics Compendium (NCCN Compendium®) has been recognized by the Centers for Medicare and Medicaid Services (CMS) and clinical professionals in the commercial payer setting since 2008 as an evidence-based reference for establishment of coverage policy and coverage decisions regarding off-label use of anticancer and cancer-related medications. In 2017, the Wisconsin Physicians Service Insurance Corporation (WPS) finalized a Local Coverage Determinations (LCD) that references the NCCN Guidelines for coverage of "Chemotherapy Drugs and their Adjuncts" (L37205). Further, NCCN Guidelines and Library of Compendia products are utilized by commercial payers that represent more than 85 percent of covered lives in the United States.

NCCN imposes strict policies to shield the guidelines development processes from external influences. The “firewall” surrounding the NCCN Guidelines processes includes: financial support policies; panel participation and communication policies; guidelines disclosure policies; and policies regarding relationships to NCCN’s other business development activities. The guidelines development is supported exclusively by the Member Institutions’ dues and does not accept any form of industry or other external financial support for the guidelines development program.

The NCCN Guidelines are updated at least annually in an evidence-based process integrated with the expert judgment of multidisciplinary panels of expert physicians from NCCN Member Institutions. NCCN depends on the NCCN Guidelines Panel Members to reach decisions objectively, without being influenced or appearing to be influenced by conflicting interests. NCCN panel members are required to complete formal disclosures of potential financial conflicts-of-interest every 6 months. Thresholds of financial conflict, either with an individual company or in the aggregate, exclude individuals from serving on NCCN panels. Panel members with significant conflicts-of-interest are not allowed to participate in the NCCN Panel deliberations where that conflict exists. NCCN’s conflict-of-interest policy is consistent with those of federal agencies and other professional medical organizations. Industry representatives are not allowed to participate in NCCN Panel meetings, and the determinations of the NCCN Panels are strictly confidential until published publicly on the NCCN website. Panel and staff disclosures are published on nccn.org for review by any user of the NCCN Guidelines.

The NCCN Guidelines are transparent, continuously updated, available free of charge online for non-commercial use and through a multitude of HIT vendors. NCCN is grateful for the opportunity to provide comment on the proposed decision memo and will focus our comments on proposed changes to NCCN related language within the proposed decision memo, areas we feel require further clarification, and suggestions for smooth implementation of the CED that will reduce administrative burden.

NCCN Categories of Evidence

NCCN is grateful to CMS for referencing the NCCN Compendium in section (A)(3)(b) of this proposed decision memo. Given the statutory use of compendia under 1861 (t)(2)(B)(ii) is fundamentally about unlabeled uses of drugs, NCCN interprets section (A)(3)(b) of this proposed decision memo to describe off-label indications of FDA approved CAR T-cell products. NCCN is grateful for the confidence that CMS places in the NCCN compendium to determine coverage for clinically appropriate indications for an FDA-approved biological when CED criteria and other requirements outlined in the memo are met.

The proposed decision memo references “the National Comprehensive Cancer Network Drugs & Biologics Compendium with grade 2 or 1.” As noted in the CMS analysis section, “the NCCN guidelines apply a standard grading system, with definitions for each category of evidence grade. Specifically, grades 2 and 1 include NCCN consensus that an intervention is appropriate.”

NCCN Categories of Evidence and Consensus for recommendations are based on both the level of clinical evidence available and the degree of consensus within the NCCN Guidelines Panel, which considers evidence of efficacy and safety of interventions (please see Appendix 3 for additional detail). The specific definitions of the NCCN categories for recommendations are:

• Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate;
• Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate;
• Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate;
• Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

NCCN reads the current proposed decision memo language to imply that Category 1, Category 2A, or Category 2B would be covered. To avoid confusion among practitioners, NCCN respectfully recommends changing the language to include, “the National Comprehensive Cancer Network Drugs & Biologics Compendium with Category 1, Category 2A, or Category 2B.”

Clinical Environment Requirements for the Administration of CAR T

NCCN appreciates CMS’ careful consideration for the management of toxicities, including neurotoxicity and cytokine release syndrome, within the proposed decision memo. As discussed in the proposed decision memo, inappropriate management of associated toxicities within the first weeks of CAR T-cell therapy infusion can result in increased chance of morbidity and mortality. In order to appropriately manage these toxicities, Section (2)(A)(B) of the proposed decision memo covers autologous CAR-T treatment in both inpatient and outpatient hospital settings if:

• Inpatient/Outpatient setting has an integrated medical team with a Clinical Program Director, Quality Manager, and at least one physician experienced in cellular therapy;
• Inpatient/Outpatient setting demonstrates that protocols, procedures, quality management, and clinical outcomes are consistent from regular interaction among all members;
• Inpatient/Outpatient setting has a designated care area that protects the patient receiving CAR-T from transmission of infectious agents and allows for appropriate patient isolation as necessary for evaluation and treatment; and
• Inpatient/Outpatient setting has written guidelines to apply when administering CAR T-cell therapy for patient communication, monitoring, and transfer to an intensive care unit.

CAR T-cell therapy is a relatively new therapeutic treatment with some variability in current evidence as to the protocols for managing toxicities and assuring patient safety. Therefore, NCCN recognizes the standardization proposed in this memo as appropriate and necessary. Further, NCCN finds these requirements to be reasonable as most hospitals experienced in cellular therapy presently meet these standards.

Clinical Study Definition

Under section (A)(3)(b) of the proposed decision memo, criteria for coverage includes patient enrollment in a “CMS-approved clinical study that consecutively enrolls patients and follows the patient for at least two years.” More specifically, the Coverage with Evidence Development (CED) analysis of the memo states:

We believe there is stakeholder confusion regarding mechanisms for data collection for the off-label use of FDA-approved CAR T-cell therapy. NCCN seeks clarification regarding whether participation in, a prospective, national, audited registry stipulated under section (A)(3)(a) of this proposed decision meets the CMS-approved clinical study criteria for coverage under section (A)(3)(b). For the off-label use of FDA-approved CAR T-cell therapy, NCCN understands the importance of CED questions for which evidence is not currently available and generalizable to the population, however, we strongly encourage CMS to consider the onerous requirements of a clinical study and expand coverage criteria to include participation in a registry under section (A)(3)(b).

Quality of Life CED Question

Under section (A)(3)(a)(ii) of the proposed decision memo CMS outlines required CED questions within the outpatient setting. The outpatient setting CED questions include an additional quality of life question not included in the inpatient setting: “How does the patient report their symptom function health-related quality of life changes over the course of their treatment?”. NCCN recognizes the importance of collecting quality of life data but has significant concerns that collecting this in only one clinical setting will unintentionally lead to selection bias.

One example of the unintended consequences of selection bias occurred in the 1990’s with the wide introduction of High-Dose Chemotherapy with Autologous Bone Marrow Transplant (HDC-ABMT) for Breast Cancer. Studies throughout the 1980’s demonstrated efficacy of this treatment but failed to account for selection bias in which healthier patients would receive HDC-ABMT compared to patients receiving standard-dose chemotherapy. Medicare beneficiaries receiving CAR T-cell therapy in an outpatient setting may experience a similar selection bias of being healthier on average than Medicare beneficiaries being served in an inpatient setting. Additionally, given that currently only one of two FDA approved CAR T products is administered in the outpatient setting, this may further bias the results of the data being collected. Axicabtagene ciloleucel is currently administered exclusively in the inpatient setting, while Tisagenlecleucel is typically administered in the inpatient or outpatient setting depending on patient and disease characteristics and treatment center. NCCN urges uniformity of CED questions across settings to reduce bias in the evidence that is received.

Administrative Burden

Under Section(A)(3)(B) of the proposed memo, beneficiaries administered CAR-T in inpatient and outpatient settings must be enrolled in a national, audited, CMS-approved, registry. Approved registries must consecutively enroll patients; accept all manufactured products; follow patient outcomes for at least two years; and adhere to the standards of scientific integrity and relevance to Medicare population as identified in Section (A)(4). Registries must also submit to CMS a written plan to address evidence development questions. Additionally, inpatient and Outpatient hospital settings administrating CAR T-cell therapy are tasked with addressing the above listed registry questions by tracking data at baseline, treatment, and 3 months, 6 months, 12 months, and 24 months after the treatment is administered.

NCCN firmly agrees with the principles of the registry as outlined in Section (A)(3)(B) and (A)(4). We recommend that implementation of registry and data-collection be enacted with considerable focus on reducing administrative burden and supporting patient access to innovation. While NCCN recognizes that coverage determinations are made separate and apart from reimbursement determinations, we feel it is important that CMS implement the CED with an appreciation of the current reimbursement environment. Given that most providers of CAR T-cell therapy are currently being undercompensated by several hundreds of thousands of dollars for each Medicare patient treated, and possibly more if complications arise, NCCN has concern that an overly onerous CED process could lead providers to not participate due to the additional administrative cost. In addition to the high cost of the CAR-T product, administration, and associated services, providers of CAR T-cell therapy are also tasked with maintaining REMS which require extensive and costly staff training and patient coordination. To prevent patient access issues, NCCN encourages CMS to implement CED with as minimal reporting burden as possible.

The use of a registry that is familiar to providers, like the Center for International Blood and Marrow Transplant Research registry (CIBMTR), is one method to reduce administrative burden. Additionally, requiring the collection of data elements that are already being collected may also help to ease implementation and support success of the NCD. In our early stage conversations with NCCN Member Institutions, we have heard that some providers are already collecting PROMIS data so this may be a reasonable tool to integrate into the provider work stream. NCCN encourages CMS to consider the use of a registry that is able to be operational by the enacted date of the final NCD to reduce the likelihood of patient access delays. NCCN encourages the CMS Coverage and Analysis Group to consider NCCN member institutions as a resource. Working closely with provider groups to better understand their current processes will ensure registry and data collection requirements are integrated into hospitals with minimal interruption to clinical workflows.

NCCN appreciates the opportunity to respond to the CMS Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers. We welcome the opportunity to discuss our comments further and look forward to working together to ensure Medicare beneficiary timely access to high-quality cancer care.

Sincerely,

Robert W. Carlson, MD
Chief Executive Officer
National Comprehensive Cancer Network
carlson@nccn.org 215.690.0300

Attachment

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March 15, 2019

Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen:

Dartmouth-Hitchcock Health appreciates the opportunity to submit comments addressing the national coverage determination for chimeric antigen receptor (CAR) T-cell therapy for patients with cancer.

Dartmouth-Hitchcock Health is proud to be New Hampshire's only academic healthcare system, committed to providing our patients with high quality care. We serve a population of 1.9 million in New Hampshire, Vermont and throughout Northern New England, providing access to more than 1,400 primary care physicians and specialists in every area of medicine.

The health system includes Dartmouth-Hitchcock Medical Center, our flagship hospital, as well as member hospitals in Lebanon, Keene, New London, New Hampshire and Windsor, Vermont. Dartmouth- Hitchcock Health is also comprised of the Children's Hospital at Dartmouth-Hitchcock, the Visiting Nurse and Hospice for Vermont and New Hampshire, and 24 clinics throughout New Hampshire and Vermont that provide ambulatory services in their communities. As one of the few academic medical centers in a rural setting, Dartmouth-Hitchcock is classified as both a Rural Referral Center and Sole Community Hospital.

Dartmouth-Hitchcock Health is aligned with the Geisel School of Medicine at Dartmouth College, training about 400 residents and fellows each year and performing world class research. We are also home to the Norris Cotton Cancer Center, one of only 49 NCI-designated comprehensive cancer centers in the country.

Norris Cotton Cancer Center encompasses all cancer-related academic activities, patient care and cancer clinical trials across Dartmouth College and the Dartmouth-Hitchcock health system. Our research portfolio includes groundbreaking initiatives in cancer immunology, cancer engineering, population and behavioral sciences, cancer prevention, and more. We emphasize translating research discoveries to hardto- reach populations, especially those within our rural catchment area of New Hampshire and Vermont.

For thirty-five years, Dartmouth-Hitchcock has run a successful blood and marrow transplant program, transplanting over 1000 patients in the last 18 years alone. This is truly a regional program, commonly treating patients from New Hampshire, Vermont, Maine, Massachusetts and New York. The program is certified by the Foundation for the Accreditation of Cellular Therapy for both autologous and allogenic transplantation, the National Marrow Donor Program and the Center for International Blood and Marrow Transplant. We are participants in a number of nationally-recognized clinical trials and studies, including a multi-center PCORI Grant examining shared care after transplant with Dana-Farber Cancer Institute.

Dartmouth-Hitchcock is proud to be embarking on a CAR T program in fall of 2019. Once established, our multi-disciplinary program will serve patients from across northern New England and will be the only CAR T Program north of Boston. As you are aware, commercially available CAR T cell therapies currently available are incredibly expensive, requiring significant financial investment and potential risks to the institution. Despite these risks and challenges, we believe that it is the right thing to do for our patients.

Dartmouth-Hitchcock Health and the Norris Cotton Cancer Center support the current proposal put forth by CMS to allow Medicare coverage with evidence development for CAR T-cell therapy for cancer. The national coverage determination will improve access to this vital therapy for Medicare beneficiaries in our region and across the country. Dartmouth-Hitchcock's program will qualify with the criteria outlined in the proposal. We are eager to add to the evidence in support of the treatment.

Thank you for the consideration of these comments. Please contact me at Kenneth.R.Meehan@hitchcock.org or 603-650-6432 with any questions.

Sincerely,

/s/
Kenneth Meehan, M.D.
Professor of Medicine
Director . Blood and Marrow Transplantation Program
Dartmouth-Hitchcock Norris Cotton Cancer Center

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March 15, 2019

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

VIA ELECTRONIC SUBMISSION

RE: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG—00451N)

Dear Director Syrek Jensen:

Bristol-Myers Squibb Company (BMS) appreciates the opportunity to submit the following comments on the Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG—00451N) (Proposed Decision Memo).

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

We are firmly committed to high-quality, cost-effective care for patients, patient access to medically necessary drug therapies, and the patient community. In light of this commitment, BMS is submitting comments on the Proposed Decision Memo to help ensure that Medicare coverage policy does not adversely affect patient access to innovative, life changing CAR T-cell cancer therapies. These comments are summarized as follows:

• The Centers for Medicare & Medicaid Services (CMS) should not inappropriately limit coverage of future CAR T-cell therapies by too narrowly defining site of care, patient, and treatment eligibility criteria.
• CMS should not inappropriately limit off-label coverage of CAR T-cell therapies by reference to a single compendium.
• CMS should carefully consider the burden of any data collection requirements on smaller, community-based providers that may in the future be able to administer CAR T-cell therapies.

In addition, BMS supports the comments on the Proposed Decision Memo submitted by the Biotechnology Innovation Organization (BIO).

I. CMS Should Not Inappropriately Limit Coverage of Future CAR T-cell Therapies by Too Narrowly Defining Site of Care, Patient, and Treatment Eligibility Criteria

Below, BMS addresses three key components of the proposed scope of CAR T-cell therapies coverage under the Proposed Decision Memo:

• The limitation on coverage of these therapies to the hospital setting;
• The limitation on coverage of these therapies with respect to patients with “relapsed or refractory cancer;” and
• The limitation on coverage to a single dose of a CAR T-cell therapy, unless the patient receives “a new primary cancer diagnosis” from the treating oncologist.

While these proposed limitations would accommodate coverage of the two currently approved CAR T-cell therapies, they do not anticipate CAR T-cell therapies that may be approved in the future, which could be appropriately provided at different sites of care, to patients with different clinical profiles, under different dosing parameters. In short, they are not sufficiently capacious to accommodate coverage of future innovations. Thus, they would unduly restrict coverage of such innovations, and thereby would fail to ensure patient access to therapies necessary for health and survival.

In addition, we urge CMS to avoid unintended consequences of previous national coverage decisions (NCDs) for cancer care.

A. Site of care eligibility criteria

The Proposed Decision Memo would cover CAR T-cell therapies only when provided in the hospital setting. This requirement would limit coverage of future CAR T-cell therapies that may be provided safely and appropriately outside of hospitals, such as at some community cancer centers.

As a leader in oncology care, BMS understands the important role that alternative outpatient settings, like local clinics or community cancer centers, can play in helping to ensure patient access to cancer treatments. For example, rural cancer patients already face challenges in receiving appropriate cancer care. Research has found that 20 percent of the U.S. population is located in a rural area whereas only 3 percent of oncologists are located in these areas. A study of cancer patients in Iowa from 2004 to 2010 found that only 63 percent lived in a hospital service area with a local oncologist, 29 percent lived in areas with only a visiting oncologist, and 8 percent resided in an area that had no oncologist at all. Patients in areas with no oncologist had to travel 58 minutes on average to receive cancer therapy. Especially given that cancer patients in many areas already struggle to access appropriate cancer services, an overly restrictive NCD that unduly limits where patients may access covered CAR T-cell therapies could have severe consequences for patient access to necessary treatment. Enabling such access is essential to the future of cancer care.

Given the evolving – and increasingly personalized nature of cancer therapy – CMS should provide greater site of service flexibility for CAR T-cell therapy. We believe that community cancer centers and physician office settings could serve as a critical care setting for patients receiving this therapy in the future, and respectfully suggest the NCD remain open to that possibility.

Instead of maintaining a prescriptive view of delivering CAR T-cell therapy in a traditional hospital setting, CMS should cover CAR T-cell therapy and any other innovative oncology medicines as long as the therapy is provided at a site of care that meets CMS’s safety standards and is provided in a setting consistent with its Food and Drug Administration (FDA)-approved label. Doing so would allow CMS’s coverage policy to accommodate potential evolution of CAR T-cell therapies.

Notably, CMS is proposing a number of safety and care coordination standards that sites of care must meet in order for CAR T-cell therapy to be covered. Among other things, sites of care must have:

• “[A] Cellular Therapy program consisting of an integrated medical team that includes a Clinical Program Director, a Quality Manager, and at least one physician experienced in cellular therapy, and demonstrates that protocols, procedures, quality management, and clinical outcomes are consistent from regular interaction among all team members;”
• “[A] designated care area that protects the patient from transmission of infectious disease agents and allows for appropriate patient isolation as necessary for evaluation and treatment;” and
• “[W]ritten guidelines when administering CAR T-cell therapy for patient communication, monitoring, and transfer to an intensive care unit.”

Such standards should further allay concerns about the provision of CAR T-cell therapy services at non-hospital sites of care. These proposed requirements also appear to be aligned with the FDA’s requirements under the Risk Evaluation and Mitigation Strategies (REMS) for the products currently on the market.

It is critical that the FDA remain the key decision-maker in assessing product safety and efficacy for determining labeling and needed follow-on monitoring and site training through REMS requirements. As such, it is critical that CMS coverage policies appropriately balance the role of the FDA in development of product labels and ensure patients are able to access treatments as approved by the FDA.

B. Patient eligibility criteria

Under the Proposed Decision Memo, CAR T-cell therapies are covered only for patients with “relapsed or refractory cancer.” The proposed restriction to patients with “relapsed or refractory cancer” appears to be tied to the terms on which the FDA approved existing CAR T-cell therapies. Again, this limitation does not anticipate how CAR T-cell therapies are likely to evolve. The FDA may, in future, approve additional CAR T-cell therapies for conditions other than relapsed or refractory cancer. CMS implicitly recognizes this possibility in the Proposed Decision Memo by citing clinical trials of CAR T-cell therapies for patients with cancers that are not described as “relapsed or refractory.” These include, but are not limited to, the following clinical trials:

• “T-cells Expressing HER2-specific [(CAR)] for Patients with Glioblastoma;”
• “Genetically Modified T-cells in Treating Patients with Recurrent or Refractory Malignant Glioma;” and
• “BCMA-Specific CAR T-Cells Combined with Gamma Secretase Inhibitor (LY3039478) to Treat Relapsed or Persistent Multiple Myeloma.”

If CMS were to finalize an NCD that limits coverage to patients with relapsed or refractory cancer, it would impede patient access to future CAR T-cell therapies for other conditions. BMS urges CMS to finalize an NCD that it sufficiently flexible to accommodate such future innovation.

C. Treatment eligibility criteria

The Proposed Decision Memo provides that “[r]epeat treatment when a patient receives more than one therapeutic dose of a specific CAR T-cell product using the same biological in the same patient is covered only when a new primary cancer diagnosis is made by the treating oncologist and the patient conditions are met.” CMS goes on to say that it recognizes “there may be circumstances when a patient receives more than one therapeutic dose of a specific CAR T-cell product. For this [Proposed Decision Memo], these circumstances are considered to be repeat treatments. . . . We propose this because there is not sufficient specificity in the evidence available on the health outcomes experienced by patients receiving more than one therapeutic dose of a specific CAR T-cell product.”

CMS should not finalize an NCD in a way that would inappropriately limit coverage of CAR T-cell therapies in the future. As CMS itself points out, we are still learning about these therapies and how they may best be used to treat patients in practice. It may be true that, with respect to future therapies, more than one dose may be medically necessary and clinically appropriate, even without a new primary cancer diagnosis. CMS should not finalize the NCD in such a way that could deny coverage to patients whose treatment protocols appropriately call for multiple doses of a CAR T-cells therapy. Instead, CMS should permit coverage where dosing is consistent with the FDA-approved labeling. Patients may not have the time to wait for CMS to revisit the NCD process to expand the scope of coverage every time the FDA approves a CAR T-cell therapy with a different treatment protocol. The NCD should be drafted to avoid this perverse result.

II. CMS Should Not Inappropriately Limit Off-Label Coverage of CAR T-cell Therapies by Reference to a Single Compendia

CMS proposes coverage for off-label uses of CAR T-cell therapies only where the treatment is an FDA-approved biological and the use is identified in the National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium “with grade 2 or 1 on or after August 2017.” If the NCD is finalized as proposed, the coverage for CAR T-cell therapies will be narrower than that for other Medicare Part B anticancer therapies. Medicare Part B covers “drugs or biologicals used in an anticancer chemotherapeutic regimen for a medically accepted indication,” which includes uses of a drug or biological for an FDA-approved indication, use of an FDA-approved drug or biological in a listed compendium, and use of an FDA-approved drug or biological that is supported by “peer reviewed medical literature appearing in publications which have been identified for purposes of this subclause by the Secretary.” The statutory list of compendia includes the “American Hospital Formulary Service-Drug Information, American Medical Association Drug Evaluations, the United States Pharmacopoeia-Drug Information, and other authoritative compendia as identified by the Secretary . . . .” The current compendia approved by CMS include American Hospital Formulary Service-Drug Information, the NCCN Compendium, Microdemex Drug Dex, Clinical Pharmacology, and Lexi-Drugs, subject to certain conditions about how the use is listed in those compendia.

The Medicare statute clearly contemplates broad coverage of off-label uses of FDA-approved anticancer chemotherapeutic drugs where an off-label use has a threshold level of support in the literature. Inclusion in a listed compendium is a method specified by statute for determining whether a use has met the threshold level of support. The NCCN Compendium, for example, which is the sole compendium referenced in the Proposed Decision Memo, includes only uses that are supported by the NCCN Clinical Practice Guidelines, which are “evidence-based” and “consensus driven” documents that are updated continuously by a panel of members to assist the decision-making processes of practitioners. Other compendia that CMS itself believes support the use of anticancer therapies similarly derive their listings from an evidence-based process. Allowing coverage of uses supported by these compendia with respect to FDA-approved anticancer drugs or biologicals therefore ensures that a drug or biological will not be covered unless supported by an appropriate level of evidence, while also ensuring that coverage of the drug or biological can become available as knowledge about the uses of the drug or biological evolves, thereby ensuring appropriate patient access to life-altering therapies.

CMS should finalize the NCD for CAR T-cell therapies to permit coverage of off-label uses that is supported by any of the full range of compendia. Consistent with CMS’s coverage of other anticancer therapies, CMS should expand the referenced compendia in the NCD to include all that are applicable to non-CAR T-cell anticancer therapies under section 1861(t)(1) of the Social Security Act (SSA), including the American Hospital Formulary Service-Drug Information, Microdemex Drug Dex, Clinical Pharmacology, and Lexi-Drugs. Because CMS has deemed these compendia to be sufficiently authoritative sources of support for coverage of off-label uses of other anticancer therapies, they are sufficient to support new coverage of off-label uses of CAR T-cell therapies, too. BMS therefore urges CMS to add these other compendia to that listed in the Proposed Decision Memo.

III. CMS Should Carefully Consider the Burden of Any Data Collection Requirements on Smaller, Community-Based Providers That May in the Future Be Able to Administer CAR T-Cell Therapies

The Proposed Decision Memo would cover CAR T-cell therapies through on the ground that CMS does not believe such therapies are “reasonable and necessary” but “show[] promise in improving health outcomes in patients with cancer.” In support of CED, CMS is proposing a number of data collection requirements for providers with respect to patients receiving care in a hospital consistent with an FDA approved indication or consistent with a use supported by a specified compendium. As noted above, CMS should not limit coverage to care provided in a hospital setting, as doing so could limit coverage of future CAR T-cell therapies in other appropriate outpatient settings. In expanding site of care eligibility criteria to encompass such other settings, CMS should be mindful of how its proposed data collection requirements would apply to smaller, community-based providers.

While BMS applauds CMS for proposing data collection requirements that could be implemented with reduced administrative burden on hospitals, BMS encourages CMS to finalize the data reporting requirements with an eye to ensuring that smaller, community-based provider types, such as community cancer centers, will be able to readily satisfy them, too. Such provider types may not have the same resources or support systems as larger hospitals and therefore may be disproportionately burdened by data reporting requirements. This could, in turn, limit the patient access to CAR T-cell therapies in these important and often more convenient settings.

IV. CMS Coverage Determinations Should Avoid Unintended Consequences of Previous NCDs for Cancer Care

In 2018, CMS approved an NCD for Next-Generation Sequencing (NGS) tests for patients with advanced cancer. During the comment period, community stakeholders supported continued coverage of NGS-based tests outside of FDA labeling by Medicare Administrative Contractors (MACs). The final NCD reflected that distinction; however, when the agency issued instructions to its contractors to align their policies with the NCD and clarify that NGS tests were “non-covered” in all cancer patients who did not have advanced cancer, this had the effect of changing Local Coverage Determination (LCD) and MolDx coverage of certain germline NGS testing that had been covered for years and has become the standard of care for determining risk of developing certain hereditary cancers. CMS has pushed back the implementation date and appears to be re-thinking its guidance, but the action has created significant confusion and disruption to access to these important tests that connect patients with the right therapies.

* * * * *

BMS appreciates CMS’s efforts to ensure appropriate Medicare coverage of CAR T-cell therapies, but urges CMS to ensure that its policy appropriately accommodates the evolution of such therapies. If you have any questions about these comments, please do not hesitate to contact Amy Demske at (202) 783-8665.

Sincerely,

Tamar Thompson
Head
Federal Executive Branch Strategy & State Government Affairs

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March 15, 2019

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

Re: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Ms. Syrek Jensen:

The Association of American Cancer Institutes (AACI) represents 98 National Cancer Institute (NCI)-designated and academic-based cancer centers in the U.S. and Canada that excel in cancer research, clinical care and education. AACI cancer centers and their regional community-based networks provide care for an estimated 700,000 newly diagnosed patients with cancer, representing as much as 40 percent of the nation’s cancer burden.

AACI appreciates the opportunity to submit comments to the Centers for Medicare & Medicaid Services (CMS) regarding the Proposed Decision Memo for chimeric antigen receptor (CAR) T-cell Therapies for Cancers (CAG-00451N). CAR T therapies represent a critical advancement in treating malignancies, and evidence shows these therapies provide important clinical benefits to patients. More than half of AACI’s cancer centers are approved to offer CAR T therapies to qualified patients.

In June 2018 comments regarding CMS’ decision to examine coverage for CAR T therapies, AACI expressed concern that a national coverage decision (NCD) would create uncertainty surrounding reimbursement for Medicare beneficiaries, thus limiting patient access. It is vital that access to CAR T therapy for Medicare patients is not hindered, but rather expanded. Beyond presenting a burden to patients, many of the components of this NCD, as proposed, may cause undue stress for AACI member centers that provide these life-saving therapies because of the rapid advancements being made to develop new medical therapies. It is AACI’s view that it is too early to implement the NCD at this time. However, should CMS proceed with implementing an NCD, AACI asks CMS to consider the following recommendations.

Patient Coverage
AACI previously requested that CMS issue clarification that YESCARTA® and Kymriah®, which are FDA-approved, are covered by Medicare for their medically-accepted uses. The NCD states that CMS proposes to cover “autologous treatment with T-cells expressing at least one chimeric antigen receptor…,” in patients with “relapsed or refractory cancer.” As these considerations are already part of the FDA approval process, AACI recommends that CMS revise this language to indicate coverage for FDA-approved products and to include indications covered on the FDA-approved label. This will ensure coverage for effective treatments that have already been approved, as well as guaranteeing coverage for new FDA-approved treatments that will come online as CAR T research rapidly evolves.

Coverage with Evidence Development (CED) and Registry Requirements
In consultation with its members and partner organizations, AACI recommends eliminating the CED requirement in favor of a data collection condition that would reduce the burden on cancer centers. Section (3)(a)(iii) of the proposal lists a number of clinical data elements that furnishing hospitals must track, “at baseline, at treatment, and at follow-up 3 months, 6 months, 12 months, and 24 months after the treatment is administered,” as part of the coverage requirements. AACI is concerned that many of its member cancer centers do not have the resources to meet this data analysis requirement, and as a result, many hospitals may opt out of the CED. This could prove especially troublesome for patients living in rural areas who already currently experience difficulties accessing these therapies.

In addition to the CED requirement, the memo states that furnishing hospitals must participate in “a prospective, national, audited registry” reviewed and approved by CMS. AACI supports designation of the Center for International Blood & Marrow Transplant Research (CIBMTR) as an approved registry. Many AACI members are familiar with CIBMTR reporting, and AACI believes using this registry will reduce the burden on many providers. AACI also requests that CMS approve a registry on or before the decision implementation date to allow for consistent coverage for Medicare patients.

Patient Reported Outcomes (PROs)
CMS has also proposed that furnishing hospitals track PROs in the outpatient setting. While PRO measurement is important as it provides patient input, its implementation in clinical trials requires significant expenditure of financial and human resources. Like the CED requirement, many AACI member centers may not have the ability to launch and support PRO studies, further increasing the possibility that some centers may opt out of providing CAR T therapy for Medicare patients to avoid financial risks. More importantly, asking Medicare patients being treated with CAR T, most of whom are extremely sick, to report outcomes may cause more stress for this population. Therefore, AACI requests that PROs not be included as a condition of coverage at this time. If the PRO requirement is included in the final decision, AACI requests that CMS provide further clarification on the definition of an “outpatient setting,” as this language will impact who will be covered for CAR T treatment and where.

Practitioner and Provider Criteria
The proposed decision memo lists practitioner and provider criteria. In its analysis, CMS proposes coverage of CAR T therapy in a hospital that meets requirements “consistent with a nationally accredited Cellular Therapy Program.” The memo further states, “Standards we would expect to find in a Cellular Therapy Program are included in the Foundation for the Accreditation of Cellular Therapy (FACT) Common Standards for Cellular Therapies (2015) Standards for Immune Effector Cell Administration (2016) and describe quality management guidelines to incorporate performance data, as well as policies and procedures that address risk management of operations.” AACI supports the use of FACT as a required accreditation program if CMS requires accreditation for centers. Many AACI cancer centers are FACT-accredited, and AACI believes the program promotes patient safety and ensures exemplary clinical and administrative practice.

Conclusion
As CAR T therapies expand and develop further, it is important that CMS ensures all patients can access such treatments if recommended by their physician. AACI again requests that CMS maintain its commitment to allowing cancer centers to practice medicine. This will allow for treatment decisions to remain with the patient and their physician.

Thank you for considering our views.

Sincerely,

Roy A. Jensen, MD
AACI President

Jennifer W. Pegher, MA
AACI Executive Director

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March 13, 2019

Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell therapy for Cancers (CAG-00451N)

Dear Administrator Verma:

The Blue Cross Blue Shield Association (BCBSA) appreciates the opportunity to provide comments on the Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell therapy for Cancers (CAG-00451N) as posted to the National Coverage Analysis (NCA) page on Feb. 15, 2019.

BCBSA is a national federation of 36 independent, community-based and locally operated Blue Cross and Blue Shield companies (Plans) that collectively provide healthcare coverage for one in three Americans. For more than 80 years, Blue Cross and Blue Shield companies have offered quality healthcare coverage in all markets across America – serving those who purchase coverage on their own as well as those who obtain coverage through an employer, Medicare and Medicaid.  Plans participate in Medicare Advantage, Medicare Part D, and many also contract with CMS as Medicare Administrative Contractors.

In the draft decision memo, CMS proposes to cover autologous treatment with T-cells expressing at least one CAR through coverage with evidence development (CED) when prescribed by the treating oncologist, performed in a hospital, and all of the following requirements are met: 1) a patient has a relapsed or refractory cancer and is not currently experiencing a comorbidity that would otherwise preclude patient benefit; 2) the hospital has an integrated medical team, written guidelines for care and a quality evaluation plan; and 3) the treatment meets specified FDA-approval criteria as laid out by CMS. Additionally, clinical data elements would need to be submitted at identified time points to a prospective, audited, national registry that accepts information on all approved products.

BCBSA acknowledges and supports the Agency’s interest in collecting long-term, real-world data on new therapies, particularly cellular immunotherapies and gene therapies. Our Plans are committed to providing appropriate beneficiary access to new therapies, and we offer the following suggestions to CMS for consideration as part the Final Decision Memo so as to provide additional clarification for the conditions under which CAR-T therapy should be provided.

We recommend that CMS:

• Name specific specialty organizations and their associated clinical practice guidelines as references for the definition of contraindicated comorbidities
• Require treating hospitals to obtain accreditation by the Foundation for the Accreditation of Cellular Therapy (FACT) for the Immune Effector Cell (IEC) or Hematopoietic Cellular Therapy (HCT) standards
• Approve the Center for International Blood and Marrow Transplantation Research (CIBMTR) as a qualified registry for CED clinical data element reporting in conjunction with the issuance of the Final Decision Memo or delay the issuance of the final decision until such an approval can be made in coordination with the memo

Thank you for the opportunity to provide detailed comments and recommendations. We would be pleased to discuss our comments with you at your convenience. Questions regarding these comments may be directed to Jane.Galvin@bcbsa.com.

Sincerely,

Kris Haltmeyer
Vice President, Legislative & Regulatory Policy
Office of Policy & Representation

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DETAILED COMMENTS ON Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell therapy for Cancers (CAG-00451N)

Decision Summary

Requirements for CAR-T Therapy Eligibility

Issue #1: Definition of Comorbidity Contraindications for CAR-T Therapy

CMS states that a beneficiary is eligible for CAR-T therapy if the individual is “not currently experiencing any comorbidity that would otherwise preclude patient benefit” (Decision Summary A. 1. b). Individuals being considered for the provision of CAR-T therapy have a relapsed or refractory cancer that has failed previous lines of treatment. These individuals may be experiencing a variety of complex treatments or disease-related health symptoms at the time of administration of CAR-T therapy.

Recommendation #1: 

BCBSA recommends that CMS reference clinical practice guidelines or position papers, current or in development, issued by the relevant clinical specialty societies, such as the American Society for Transplantation and Cellular Therapy (ASTCT, previously named the American Society for Blood and Marrow Transplantation) or the American Society of Hematology. 

Rationale #1:

Due to the medical complexity inherent to this patient population, there is the potential for discrepancies in the definition of contraindicatory comorbidities during the claims adjudication process. The establishment of clinical decision-making reference benchmarks will provide a consistent resource for both providers and payers to utilize.

While we appreciate the potentially flexible interpretation of “that would otherwise preclude patient benefit” as noted previously, we note the importance of guidance to ensure plans have clarity of information to utilize when processing beneficiary claims.

Issue #2: Lack of Specification in Hospital Qualification Standards

CMS proposes to require the following (Decision Summary A.2):

The hospital has:

1. A Cellular Therapy Program consisting of an integrated medical team that includes a Clinical Program Director, a Quality Manager and, at least, one physician experienced in cellular therapy and which demonstrates that protocols, procedures, quality management and clinical outcomes are consistent from regular interaction among all team members
2. A designated care area that protects the patient from transmission of infectious agents and allows for appropriate patient isolation as necessary for evaluation and treatment
3. Written guidelines when administering CAR T-cell therapy for patient communication, monitoring and transfer to an intensive care unit

BCBSA agrees with CMS’ intention to protect beneficiaries from harm by limiting the administration of CAR-T to a select subset of providers that are capable of the specialized decision-making and clinical response procedures that may be necessary throughout the CAR-T treatment episode. However, the language CMS proposes is relatively flexible, and the level to which facilities meet the specifications outlined may vary dramatically and without oversight.

Recommendation #2:

BCBSA recommends that CMS specify that treating hospitals are required to either obtain accreditation by the Foundation for the Accreditation of Cellular Therapy (FACT) according to the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration or the FACT Standards for Immune Effector Cells or attest to qualifications of substantial equivalence based on the same FACT standards. 

Rationale #2:

FACT published IEC standards and implemented an accompanying accreditation program for the provision of immune effector cells outside of a hematopoietic cellular therapy program in 2017. Those facilities providing immune effector cell therapy within a hematopoietic cellular therapy program follow the FACT-JACIE Hematopoietic Cell Therapy Standards, which are comprehensive to both IEC and HCT.

CMS highlights the importance of quality care as part of its Summary statement in the proposed decision memo:  

CMS also provides additional commentary on the usefulness of the FACT Standards in Section VIII: CMS Analysis:

BCBSA agrees with the perspective of the Agency that specialized provider qualifications are critical to the successful administration of CAR-T therapy. As such, BCBSA requires FACT accreditation for the purposes of participating in the Blue Distinction® Center program[1]. While CMS references FACT in the Provider Requirements analysis section, it stops short of requiring accreditation in the Decision Summary. We ask CMS to require the furnishing hospital to verify FACT accreditation for either the IEC or HCT Standards in order to create clear and consistent quality requirements across the provider community.   

Issue #3: Potential for Delay in Beneficiary Access Associated with Registry Approval

Once a Final Decision Memo has been issued by CMS, all contractors will be required to follow the terms of the decision for the purposes of provider reimbursement from that point forward. If a specific registry is not named in the Final Decision Memo, there will be a time lag of weeks to months before a specific registry is deemed qualified to CMS’ criteria and its associated clinical trial number is assigned and shared with the provider and treatment communities. During this interim period, beneficiaries may not be able to access CAR-T if providers are concerned about moving forward before the required administrative elements are available.

Recommendation #3: BCBSA recommends that CMS include the approval of the Center for International Blood and Marrow Transplant Research (CIBMTR), in tandem with a corresponding data analysis plan, at the time of issuance of the Final Decision Memo or delay the posting of the Final Decision Memo until such a dual issuance could take place.

Rationale #3: In the proposed decision memo, CMS requires the submission of specific data to an approved registry for qualification of provision of CAR-T therapy. BCBSA supports CMS in its intention to collect high-quality, real-world data for each of its beneficiaries and notes that reporting of all CAR-T cases to CIBMTR is required by the Blue Distinction Centers for Cellular Immunotherapy Program Criteria, as well.

CMS stipulates that the process of registry approval is as follows:

Individuals eligible for CAR-T are often critically ill and may not be able to wait for the additional administrative approval processes cited in the CED proposed decision. CMS specifically notes that patients need to be enrolled in an approved registry and that data elements should be tracked from the time of “baseline,” which could preclude beneficiaries receiving treatment until such administrative processes have been finalized and posted to the CAR-T Tracking Sheet. Plans and providers aiming to facilitate beneficiary access will be placed in a position of potential non-compliance with the Final Decision Memo if they proceed with CAR-T therapy provision during such an interim period.

To the best of BCBSA’s knowledge, the CIBMTR is the only organization currently capable of meeting all of CMS’ specifications, is already collecting the data elements CMS requires and was awarded the national contract to administrate the Cellular Immunotherapy Data Resource, funded by the National Cancer Institute Moonshot Initiative, in 2018. We ask CMS to work closely with CIBMTR to establish a realistic time frame for the development of the executable analysis plan needed and to delay issuance of a Final Decision Memo until a point where the CIBMTR and the associated analysis plan can be jointly announced.

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[1] Blue Distinction Centers for Cellular Immunotherapy Program Criteria: https://www.bcbs.com/sites/default/files/file-attachments/page/BDSC_Cellular_Immunotherapy_CAR%20T_Criteria.pdf

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March 15, 2019

VIA ELECTRONIC SUBMISSION

Seema Verma
Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Attention: CMS-1695-P
P.O. Box 8013
Baltimore, Maryland 21244-1850

Re: Centers for Medicare & Medicaid Services (CMS) Proposed National Coverage Determination for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Dear Administrator Verma:

University of Minnesota Blood and Marrow Transplant (UMN BMT) Service Line working with Fairview Health Services under the M Health umbrella (M Health - Fairview), welcomes this opportunity to comment on the Centers for Medicare & Medicaid Services' (CMS' or the Agency's) proposed decision memo entitled, Proposed National Coverage Determination for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N). In this proposal, CMS is proposing to cover autologous treatment with T-cells expressing at least one CAR through coverage with evidence development (CED) when prescribed by the treating oncologist, performed in a hospital, and if all the requisite requirements stated in the proposed national coverage determination (NCD) are met.¹

• UMN BMT Service Line has over 50 years of blood and marrow transplant expertise, and is among the most experienced centers for cord blood transplants. U UMN BMT Service Line has been performing transplants since 1968 and performs both pediatric and adult Autologous and Allogeneic transplants. University of Minnesota is playing a leading role in national clinical trials (NCTs) and has a deep translational research pipeline in cell and immune-therapy. In addition, our institution supports high impact clinical research by nationally recognized faculty and through our NCI-designated Comprehensive Cancer Center. We have authored more than 180 peer - reviewed publications in 2018 and currently have more than 50 clinical trials open.
• University of Minnesota, University of Minnesota Physicians and Fairview's joint venture together has created the M Health brand with the goal of embracing innovation to drive a healthier future through healing, discovery and education. UMN BMT Service Line was created with the goal of integrating clinical operations and translational research through the M Health partnership.
• M Health - Fairview has an Academic Medical Center as well as a Children's Hospital. We are Foundation for the Accreditation of Cellular Therapy (FACT)-accredited to deliver Blood and Marrow Transplants (BMTs) as well as cellular immunotherapy to our patients. We are an active participant in multiple cellular therapy clinical trials at our institute, as well as certified to provide the FDA-approved Kymriah and Yescarta products to our patients.

In our June 2018 comment submission regarding CMS' decision to examine coverage for CAR T-cell therapies, we had opposed the establishment of an NCD due to significant concerns that it would cause barriers to providing current and future CAR T-cell therapies to beneficiaries in most need of these breakthrough treatments. In light of the evolving new developments being made in this field, we continue to believe that it is premature to implement an NCD because a coverage policy should not be developed until this field matures.

If CMS still proceeds with establishing an NCD, then we would like to propose an NCD WITHOUT CED. We would like to request that CMS eliminate the CED requirement and instead implement an NCD with a data collection requirement. We believe that the CED requirement will create a significant barrier to patient access.

M Health - Fairview's comments to this Proposed Rule focus on:

• Patient Condition Requirement - Cover CAR T-cell therapies under the FDA Approved Indications Without Additional Specification
• CED Requirement - Unintended Consequences of CED
• Patient Reported Outcomes (PRO) Data Requirement
• Registry Requirement - Name Center for International Blood and Marrow Transplant Research (CIBMTR) as a Registry for CAR T-Cell Therapy
• Accreditation Requirements
• Off-Label Coverage Requirements

Patient Condition Requirement: Cover CAR T-cell therapies under the FDA Approved Indications Without Additional Specification

M Health - Fairview would like to request that CMS remove the relapsed or refractory cancer requirement as this language may create delays in access to new products as they are approved for additional indications going forward. M Health - Fairview urges CMS to expand this requirement to include indications covered on the FDA approved label. Expanding the covered indications in this manner will not only cover life-saving treatment but also help promote innovation. Again, we are concerned that based on CAR T-cell therapies currently undergoing clinical trials, it may be necessary for CMS to reopen the NCD well before five years in order to provide coverage for therapies that are likely to be approved in that time frame. Some examples of ongoing clinical trials in the pipeline that would not be covered by the relapsed/refractory requirement and will make it impossible for patients to receive these lifesaving therapies include:

1. Study of CAR T-cell therapies in high-risk multiple myeloma and lymphoma .^{2, 3}
2. The ongoing ZUMA7 trials is studying CAR T-cell therapy after failure of first line of therapy.⁴
3. Other therapies that are pending include CD19-specific CAR T-cell therapy and B cell maturation antigen CAR T-cell therapy for myeloma.⁵

In light of the discussion above, M Health - Fairview would like to request that CMS instead finalize an NCD (without CED) for FDA approved products per their approved and labeled indications and eliminate any other clinical qualifications.

CED Requirements: Unintended Consequences of CED

M Health - Fairview understands that CMS included the CED requirement in order to gather additional data on the effectiveness of CAR T-cell therapies in the Medicare population. However, if the Agency chooses to finalize an NCD, the Agency can accomplish this same objective instead with an NCD with data collection. We would like to recommend finalizing an NCD without CED, as doing so would remove issues related to hospitals opting in or out of providing CAR T-cell therapies to Medicare patients. Our institution strongly believes that the creation of a CED will narrow access opportunities for beneficiaries, as centers may elect NOT to participate due to the real and/or perceived burden to participate in registry reporting and/or reporting PRO data for outpatients. As a consequence, a reduction in the number of hospitals providing CAR T-cell therapies to beneficiaries could result in the referral of more Medicare patients to those hospitals that do elect to continue delivering CAR T-cell therapy and could create an unsustainable concentration of financial losses to those providers.

In addition, manufacturer certified sites already submitting data to CIBMTR to meet the FDA postmarket approval study requirements could continue doing so and this data could be made available to CMS and therefore meet the needs that CMS is trying to meet with the proposal for a CED.

Again, an NCD with a data collection requirement will avoid these complications and allow CMS to receive and review these important data. We recommend that CMS revise the final policy to eliminate the CED requirement and instead to be an NCD with a data collection requirement to avoid the access problems that may result from centers being able to opt out of the CED requirement. The implementation of this policy as is, will increase the registry reporting requirements and considerably add to the financial burdens that we as an organization are already facing. This concern is in addition to lack of access that already exists for patients due to restricted reimbursement for the currently licensed products.

In addition, we have several concerns and questions regarding this policy in its current form. We would like to ask for clarification on the data collection and analysis requirements for the CED. In (3)(a)(iii), the policy states:

It is not clear whether this language would require the furnishing hospital to analyze the data. If CMS intends for the registry to do this, we request that this section be redrafted to be more precise that the registry is required to conduct the analysis. As written, there may be confusion that the furnishing hospitals will be required to conduct their own analysis on all registry patients (i.e., their own and other hospital registry patients). If that is the intent, then we strongly urge CMS to change its position as it would place an undue burden on our hospital and present yet another reason for other centers to opt out of participation. Analysis of a larger clinical cohort collected through the CIBMTR will be of much greater value than individual center analyses.

We also would like to request clarification from CMS on the patient consent requirements applicable to this coverage policy both as it applies to the registry reporting and PRO requirements. We are under the impression that there would be no coverage if a patient does not explicitly consent to have his or her data reported to the registry and we request that CMS clarify what would happen if patients do not consent. Requiring consent for data submission may be perceived as coercive to patients with no other access to this valuable treatment.

Also related to patient consent, CMS must address if the consent can reassure patients whether their data will be blinded to CMS and if patients can be told that their data is not identifiable to CMS, but rather submitted to be part of an aggregated dataset for future scientific learning to benefit cancer patients. Patients have the right to refuse to participate without penalty, and we are concerned that we as a health care institution could be penalized for this. Similarly, we also request clarification on whether there will be a requirement to provide patients with a notice of non-coverage (i.e., an ABN or HINN) if the patient does not consent to his or her data being submitted to the registry or to submit PRO if the therapy is delivered on an outpatient basis. Overall, we do not support coverage being contingent upon explicit consent to identifiable data submission.

Several questions that need to be clarified before implementation of the policy include:

• Will Medicare patients have to explicitly consent to their identifiable and personal information being sent to the CMS-approved registry?
• If patients do not consent, is the therapy automatically non-covered for them?
• Will hospitals be asked to issue a notice of non-coverage to patients if they do not agree to have their identifiable data submitted to the registry?
• Will CMS allow blinded or de-identified data submission should it proceed with the CED?
• Will CMS allow each hospital's overall participation in data collection to the registry allow for coverage rather than requiring each individual patient consenting to their identifiable data being reported?

Patient Reported Outcomes (PRO) Data Requirement
M Health - Fairview requests that CMS not make reporting PROs a condition of coverage. While PRO data is valuable, requiring it for coveragedoes not seem appropriate especially as PRO data collection processes are new and are still being tested. M Health - Fairview believes that a PRO requirement would further exacerbate the financial burden on our institution as an additional and unreimbursed administrative cost of providing CAR T-cell therapy to our patients.

Our providers strongly agree with the recommendations that came out of the August 2018 MEDCAC meeting, during which several providers shared their concerns about the use of PROs generally in this patient population and raised many questions about the various tools, including the two named by CMS (i.e., PROMIS and PRO-CTCAE).⁶ In particular, the two PRO tools listed in the policy are not directly applicable to this patient population and therapy and have been included to prevent the therapy from being delivered in the outpatient setting. The ASTCT has concluded that it cannot cannot support a coverage policy that removes decisions, including those related to site of service, about clinically appropriate treatment outside of the physician-patient relationship. We agree that there is insufficient evidence to support the use of these two tools for CAR T-cell therapy patients. For example, it is unclear how providers will collect data from patients with severe toxicity, particularly the neurotoxicity known to be a potential with this treatment.

M Health - Fairview would like to strongly advocate that the determination of providing care in the outpatient setting should be left to the clinician and if FACT-accredited facilities have the capability and clinicians believe cell administration can safely be performed on an outpatient basis, then that should be covered no differently than coverage for inpatient administration.

We would like to further request clarification on how PROs contribute to CMS' determination of the reasonableness and medical necessity of CAR T-cell therapy for the Medicare population as well as information on why the Agency decided to apply this requirement to outpatients only. If this requirement is retained in the final policy, we request that the Agency define "outpatient" as used in the proposed decision memo. It is unclear if the setting is based on the physician order when the cells are administered or on how the account is billed. Since some patients may be administered these cells as outpatients, but billed as inpatients, it is important that CMS provide clear guidance on this issue.

Registry Requirement: Name Center for International Blood and Marrow Transplant Research (CIBMTR) as a Registry for CAR T-Cell Therapy

As proposed, the registry requirement requires furnishing hospitals to participate in "a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, and follows the patients for at least two years¡K" It also requires CMS to review and approve all registries. We recommend that CIBMTR be listed as an approved registry in the final NCD, assuming they receive their approval prior to the May 17 implementation date, and that the Agency will accept hospital participation with the registry without requiring any other enrollment with CMS for the following reasons:

• CIBMTR is already collecting data for several CMS CED studies for myelodysplastic syndrome, myelofibrosis, sickle cell disease, and myeloma with great success. Our institution is already familiar with CIBMTR through their work with patients with these conditions. Furthermore, CAR T-cell therapies are already being provided by FACT-approved BMT programs, which are required by law to report data on allogeneic BMT to CIBMTR.
• The two manufacturers with approved products, Novartis and Kite/Gilead, are also using CIBMTR as the registry to meet their FDA post-approval study requirement. Listing CIBMTR as an approved registry would reduce the burden to our providers and institute.
• Any delays in providing care to these critically ill patients would be detrimental as they will not be able to withstand delays in coverage upon finalization of the NCD. Therefore we urge CMS to ensure that a registry be approved at the time this policy is finalized and implemented to avoid any coverage gaps. Furthermore, it is vital that the policy clarify that coverage is based on cell collection occurring on or after the effective date since there will be patients in the midst of their CAR T-cell therapy episode of treatment when the policy is finalized. We do not support an effective date that would be based on cell administration that could potentially disrupt coverage of an episode of CAR T-cell therapy already in progress.

Accreditation Requirements

In the proposed decision memo, CMS has included the following requirement for CED:

"The hospital has: a Cellular Therapy Program consisting of an integrated medical team that includes a Clinical Program Director, a Quality Manager, and at least one physician experienced in cellular therapy, and demonstrates that protocols, procedures, quality management, and clinical outcomes are consistent from regular interaction among all team members; a designated care area that protects the patient from transmission of infectious agents and allows for appropriate patient isolation as necessary for evaluation and treatment; and written guidelines when administering CAR T-cell therapy for patient communication, monitoring, and transfer to an intensive care unit."

If CMS retains this requirement in the final NCD, M Health - Fairview urges CMS to define a uniform mechanism for accreditation that conforms to CMS standards in order to ensure that these cells are administered within a cell therapy program as defined. One option would be to require FACT accreditation for centers, which we were pleased CMS included in the proposed decision memo. M Health - Fairview urges CMS to require the use of FACT or another broadly accepted accreditation program rather than creating a duplicative set of requirements. This would further increase our financial burden for providing this treatment to our patients.

In the same vein, we are expecting that hospitals will not be required to attest to CMS that its program meets the outlined accreditation standards. We do not support a requirement that would require a hospital to actively enroll with CMS as a requirement of coverage.

Off Label Coverage Requirements

In the proposed decision memo, CMS outlines off-label coverage requirements. We would like to request that CMS provide clarification on whether this triggers study participation or if the registry reporting requirement would apply. Currently, CMS recognizes off-label use of anti-cancer drugs and biologicals when they are referenced in compendia listed in the Chapter 15, Section 50.4.5 of the Medicare Benefits Policy Manual.

M Health - Fairview does not support a coverage policy that restricts off-label coverage for CAR T-cell therapy different from that allowed for Medicare beneficiaries receiving any other anti-cancer drugs and biologicals and recommends that CMS cover off-label use of CAR T-cell therapies consistent with other anti-cancer drugs and biologicals and clarify that data collection via the registry is also required. Appropriate off-label use should not come with additional requirements beyond data collection, particularly if it causes a disproportionate impact on Medicare patients. We would like CMS to clarify if the intent is for a study similar to a full clinical trial is required for off-label use, or if the requirement is similar to the registry reporting requirement already in place.

We also would like CMS to clarify why NCCN was listed as the sole applicable compendium in the proposed decision memo when CMS recognizes others in the above referenced Medicare Benefits Policy (Chapter 15, Section 50.4.5 of the Medicare Benefits Policy Manual lists five compendia).

Additional Questions and Clarifications

We also have a list of questions and clarifications that we believe require attention before the implementation of the policy:

Medicare Advantage Plans

• Finalizing an NCD that is not a CED will resolve financial concerns of Medicare Advantage (MA) plans while also satisfying CMS' desire to collect data on Medicare patients receiving CAR T-cell therapy whether under fee-for-service Medicare or Medicate Advantage.
• Will some/all CAR T-cell therapy claims for Medicare Advantage patients be billed to a Medicare Administrative Contractor (MAC) like other clinical trial claims?
• Will prior authorizations continue to be required from Medicare Advantage plans?

Implementation Questions if CMS Finalizes the NCD as a CED as Proposed

• Can CMS confirm whether an outpatient is determined by the admission status at the time CAR T-cell therapies are administered or if this is based on how the account is billed?
• How does CMS define baseline in the context of capturing PRO data?
• Will the NCD only apply to patients who start with cell collection on or after the effective date or will patients having had their cells collected prior to the effective date be held to the criteria of the finalized NCD retroactively?
• Given the proposed CED states that "[t]he registry's National Clinical Trial number must be on the claim" we request CMS clarify which claims it needs this information on:
  • Would it be all CAR T-cell therapy claims, including the outpatient cell collection claim?
  • Will the NCT be required only on off-label CAR T-cell therapy claims?
  • The NCT number for the registry does not seem to be the same as an NCT number for a clinical trial or study, is this correct?
  • For outpatient cell collection claims, will hospitals be expected to use Q0 on cell collection charges?
• Will the off-label use referenced in the proposed CED result in different NCT numbers from the registry or is the off-label use also tied to registry reporting and not to the opening of separate studies?

Thank you for the opportunity to provide these comments on this proposed NCD. If you have any questions regarding these comments, please do not hesitate to contact Mary Edwards, Fairview's Vice President for Public Policy, at 612-672-4541 or MEdward1@fairview.org.

Sincerely,

/s/
James Hereford
President and CEO
Fairview Health Services

1 CMS, Medicare Program; Proposed National Coverage Determination for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers, CAG-00451N (February 15, 2019).
2 https://clinicaltrials.gov/ct2/show/NCT03549442
3 https://clinicaltrials.gov/ct2/show/NCT03549442
4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410390/
5 https://ash.confex.com/ash/2018/webprogram/Paper116898.html
6 ASBMT Comments to CMS on MEDCAC meeting held on August 22, 2018. Link to comments here: https://higherlogicdownload.s3.amazonaws.com/ASBMT/43a1f41f-55cb-4c97-9e78- c03e867db505/UploadedImages/ASBMT_CMS_Comment_MEDCAC_CAR_T_PROs_7_16_2018.pdf

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March 15, 2019

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

Submitted electronically at: http://www.regulations.gov

Re: CAG-00451N - National Coverage Determination for Chimeric Antigen Receptor T-Cell Therapies

Dear Administrator Verma:

On behalf of the Alliance for Patient Access (AfPA), I write to thank CMS for working to determine appropriate coverage policy for CAR-T therapies, which have the potential to be of great benefit to appropriate cancer patients.

AfPA supports this proposal, which will lead to more uniform coverage and better health outcomes. The organization does have concerns, however, about the reporting requirements. We ask that CMS consider the impact reporting requirements may have on cancer patients living in rural areas and to ensure the reporting requirements do not interfere with patient access to necessary treatments.

Founded in 2006, AfPA is a national network of physicians dedicated to ensuring patient access to approved therapies and appropriate clinical care. AfPA advocates for health policies that support clinical decision making, promote personalized care and protect the physician-patient relationship as the cornerstone of quality health care. Motivated by these principles, AfPA members participate in physician working groups, advocacy initiatives, conferences, stakeholder coalitions and the creation and dissemination of educational materials.

Established in 2014, the Oncology Therapy Access Physicians Working Group is a home for oncologists interested in health policy issues relating to access to cancer therapies. Working group members collaborate in the development of educational resources such as white papers, policy briefs and videos used to encourage informed policymaking, ensuring the physician’s perspective is shared as policymakers consider how to balance access and costs. Past materials have considered how access to precision medicine, precision diagnostics, immuno-oncology therapies and other advanced cancer treatments can impact patients.

CAR-T therapy is yet another example of innovative cancer treatment for which patients can expect to face access barriers. The cutting-edge therapies use a person's own cells to fight lymphoma and acute lymphoblastic leukemia an expensive, but potentially life-saving effort. AfPA commends CMS for recognizing the value in CAR-T therapy and for making this innovative treatment available to Medicare patients. As the medical community moves forward with precision medicine, this is exactly the type of leadership that patients and health care providers need from CMS.

AfPA acknowledges the challenge of high drug prices and the need to spend limited Medicare resources wisely. For AfPA, the measure of any health policy proposal is how well it aligns with AfPA’s guiding principles – organizational values that reflect fundamental, time-tested aspects of quality health care. Thus, the paragraphs below explore several aspects of the CMS proposal, highlighting those components that most obviously impact patient access and affect optimal care.

The Physician-Patient Relationship

Patient-centered health care requires a strong physician-patient relationship, with joint decision-making on treatment decisions leading to optimal health outcomes. Previously, however, patchwork policies have limited physicians’ and patients’ ability to consider CAR-T as a treatment option for patients who might benefit. In particular, gaps in billing and reimbursement left some hospitals and clinics hesitant to provide the medicine.

A national coverage determination will allay these concerns, allowing physicians to determine when CAR-T therapy is appropriate for a given patient.

Impact on Patient Access

CMS’ proposal is an example of promoting innovative medicine in cancer treatment, but policymakers must continue to keep patient access front of mind as immuno-therapies play an increasingly pivotal role in treatment.

As more precision medicines become available, an important consideration is whether cancer patients can actually access these treatments. With regard to the CAR-T coverage determination, CMS’ data collection requirement could pose a challenge. While academic medical centers may have the technology and manpower to accommodate Medicare’s requirements, not all clinics will. That means that CAR-T may become available to patients close to an academic hospital – yet remain out of reach for cancer patients living in rural areas or those who cannot muster the finances to travel for CAR-T treatment. The issue could deepen existing disparities.

AfPA is not opposed to Coverage with Evidence and acknowledges the important data that will be gained from the process. We do, however, ask that CMS ensure the data-collection process does not hinder access to this new treatment. Please take potential barriers into account when finalizing the rule.

Conclusion

The Alliance for Patient Access appreciates the complexity of the health policy challenges facing the Centers for Medicare and Medicaid Services and commends the agency for taking steps to improve patient access to CAR-T therapy. If AfPA can provide further details or aid the Centers for Medicare and Medicaid Services in amending the proposed rule, please contact us at 202-499-4114.

Sincerely,

/s/
Brian Kennedy
Executive Director
1275 Pennsylvania Avenue NW, Suite 1100A
Washington, DC 20004

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March 15, 2019

VIA ELECTRONIC SUBMISSION TO www.cms.gov

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
200 Independence Avenue, SW
Washington, DC 20201

Re: Proposed National Coverage Determination for Chimeric Antigen Receptor T-cell (CAR-T) Therapy for Cancers

Dear Ms. Jensen:

Cigna welcomes the opportunity to respond to the Proposed National Coverage Determination for CAR-T Therapy for Cancers. We appreciate the Centers for Medicare & Medicaid Services' (CMS) efforts to make life saving therapies and treatments available to beneficiaries in the Medicare program, while ensuring patient safety and value in the nation's hea lth care spending. Cigna shares in these goals as part of our broader mission to enable, support, and drive greater value throughout the entire health care delivery c hain. We support CMS's proposed coverage of CAR-T through coverage with evidence development (CED) as a means of providing access to a promising new treatment, while also ensuring ongoing assessment to ensure this new treatment is fulfilling its promise for patients.

Cigna Corporation, together with its subsidiaries (either individually or collectively referred to as "Cigna"), is a global health service organization dedicated to helping people improve their health, well-being, and peace of mind. Our subsidiaries are major providers of med ical, pharmacy, dental, disability, life and accident insurance, and related products and services, with over 160 million customer relationships in the more than 30 countries and jurisdictions in which we operate. Cigna completed its merger with Express Scripts in December 2018, bringing together approximately 74,000 employees around the world. The combination integrates two complementary companies, each with industry-lead ing cost trend capabilities, which together are positioned to deliver better care, expanded choice, and drive down health care costs. The combined company's medical, clinical, pharmacy, behavioral and wellness insights empower us to de liver improved affordability, choice, predictability, and high quality care through connected, personalized solutions that advance whole person health.

CMS recognizes that this is a rapidly evolving field and that initial evidence appears promis ing, but inconclusive to determine whether CAR T-cell therapy improves health outcomes in the Medicare population. Therefore, CMS believes that fu1iher evidence on patients' health outcomes, in defined circumstances, under a national, prospective, audited registry, may lead to additional evidence that physicians, patients, and their caregivers can use to make informed treatment decisions. Therefore, they propose to cover autologous CAR-T treatment through CED, including a number of outlined criteria that must be met to qualify for CED.

We agree with CMS that there is currently limited evidence for CAR-T therapies. To date, studies have cons isted of single-arm trials performed in selected hospitals with small sample sizes; we agree that a CED will allow CMS to collect additional evidence. As CMS continues to collect and assess evidence, we ask the agency to consider:

• Long-term efficacy and safety: While short-term efficacy endpoints are usually the standard outcomes for the Food and Drug Administration, we recommend that CMS collect data on long-term e fficacy and safety through this CED. The optimal long-term efficacy endpoint, established through evidence-based principals, are critical as these therapies are burdened with high financial impact.
• Total cost of therapy: CMS should be aware that CAR-T therapy costs include more than just the cost of the drug. These costs include:
  • The patient receives chemotherapy first for 3 days to wipe out their own existing lymphocytes, and this can be done outpatient. Typically, this consists of Fludarabine and Cytoxan.
  • The patient is then admitted to a hospital for CART-cell infusion.
  • Some 65 - 70 percent of patients develop a severe side effect about one week later called cytokine storm and usually require an lntensive Care Unit stay. Cytokine storm usually indicates that the patient has had a good response to the infusion, but can require an additional hospitalization in a critical care bed.
  • A percentage of those patients with cytokine storm will require a post-acute stay in a ski lled nursing facility or an inpatient rehabilitation facility to regain strength and functioning.
  • Another percentage of patients develop severe mental and psychological problems (referred to as encephalopathy) and may requ ire a third hospitalization, though it is short-lived (four days or so) and is reversible.
  • The various steps in the therapy process suggest a bundled payment structure is most appropriate for CAR-T cell therapy. Because of the high cost of the drug, CAR-T cell therapy will more than likely exceed the outlier threshold, invoking the Outlier Prospective Payment System in addition to the standard diagnosis payment.
  • Lastly, we envision that CAR-T cell infusion therapy may ultimately be a treatment that can be administered in an outpatient setting and CMS may want to evaluate what that payment structure may look like.
  In addition, CMS should evaluate non-medical costs patients might incur as a result of CAR-T treatments (e.g., time off from work, travel expenses, etc.)
• Patient registries: We recommend CMS provide more clarity around who will be administering the patient registries required for patients who will receive CAR-T. The decis ion memo contains some in formation regarding how registries will be approved, reviewed and maintained. However, it is not clear how data will be collected across diffe.rent registries. Further, it is not clear if each institution will be creating its own registry, or if there will be a limited number of national registries established.
• Study design: The CED explains that due to the registry-natured CED approach, pivotal trial results will be used as controls. If this is the desired route, then additional endpoints/outcomes need to be part of CED studies so proper comparative analyses can be conducted. The eventual CED recommendations need to acknowledge the epidemiological limitations from registry-designed stud ies. Another important situation that should be analyzed is the repeat administration of these therapies for the same or different oncological conditions.

Thank you for your consideration of these comments.

Respectfully,

/s/
David Schwartz

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Dear CMS:

I completely agree with the entirety of the American Society statement below. Please do the right thing to ensure equitable access for CMS patients.
Sincerely,
Minoo Battiwalla

March 15, 2019
Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG- 00451N)

Dear Ms. Syrek-Jensen:

The American Society for Transplantation and Cellular Therapy (ASTCT), formerly the American Society for Blood and Marrow Transplantation (ASBMT) appreciates the opportunity to provide comments on the Centers for Medicare and Medicaid Services’ (CMS) Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N). ASTCT is a professional membership association of more than 2,200 physicians, scientists and other health care professionals promoting blood and marrow transplantation and cellular therapy through research, education, scholarly publication and clinical standards. The clinical teams in our society have been instrumental in developing and implementing clinical care standards and advancing cellular therapy science, including participating in the trials that led to current FDA approvals for CAR-T cell therapy.

In comments submitted in June 2018 on CMS’ decision to examine coverage for CAR-T therapies, ASTCT opposed the establishment of a National Coverage Determination (NCD) due to concerns that it would cause significant and ongoing barriers to providing current and future CAR-T therapies to beneficiaries in need of these breakthrough treatments. Patients who receive CAR-T have typically exhausted all other available therapies. The Society still believes that it is premature to implement a NCD because this is a rapidly evolving area of medicine. A coverage policy should not be developed until the field matures.

If CMS proceeds despite these concerns, ASTCT recommends that the agency eliminate the CED requirement and instead implement an NCD with a data collection requirement that leverages the registry reporting currently in progress. We believe that the CED requirement will create another barrier to patient access. The insufficient Medicare inpatient reimbursement is already creating challenges for the centers where our members practice as they determine whether they can withstand the significant financial losses associated with delivering CAR-T therapy to Medicare patients. As drafted, this coverage policy may further limit access and ultimately stifle innovation because of the associated burden on centers. ASTCT has been working with CMS to address these reimbursement challenges and is hopeful that the FY 2020 Inpatient Prospective Payment System proposed rule will include policies to improve CAR-T reimbursement. We welcome the opportunity to work with the Coverage and Analysis Group to ensure that a final policy meets the needs of CMS, providers, and most importantly, patients.

Please consider the following comments that outline our suggestions on how to improve this proposed decision memo to limit any negative impacts on patient access and innovation should CMS decide to proceed. There are also many aspects of this policy that require further clarification that must be provided before this policy is finalized in order to minimize any disruptions to patient care.

Patient Condition Requirements

As drafted, coverage would be limited to require that patients have relapsed or refractory cancer. ASTCT urges CMS to expand this requirement to indications covered on the FDA approved label.

Expanding the covered indications in this manner will not only cover life-saving treatment but also help promote innovation. We are concerned that based on CARs currently undergoing clinical trials, it may be necessary for CMS to reopen the NCD within the next five years in order to provide coverage for CAR-T therapies that are likely to be approved in that timeframe, or label expansions for the current products. One example of a CAR in the pipeline that would not be covered by the relapsed/refractory requirement is the ongoing study of CAR-T in high-risk multiple myeloma.¹ Another example is for lymphoma, where the current FDA approved indication is failure of two lines of therapy. The ongoing ZUMA7 trials is studying CAR-T after failure of first line of therapy.² Other therapies that are pending include CD19- specific CAR-T therapy³ and B cell maturation antigen CAR-T therapy for myeloma.⁴ These examples demonstrate the innovative therapies that can save lives but will be difficult if not impossible for patients to receive with the proposed coverage decision.

ASTCT also disagrees with the requirement that the therapy can only be provided to a patient that is not currently experiencing any comorbidity that would otherwise preclude patient benefit. It is unclear from the proposal how CMS plans to define this, or monitor for it in its claims processing system. Clinicians should be the ones determining whether the patient can benefit from the therapy despite having certain comorbidities, as this very sick patient population is likely to have one or more comorbidities.

We also request that CMS provide more guidance around what it means by a “new primary cancer diagnosis” and “the use of more than one therapeutic dose of a specific CAR T-cell product” for repeat treatment. The possibility exists that a patient could be diagnosed with a separate malignancy or new diagnosis of a previously treated cancer and could benefit from receiving the same CAR-T product. Moreover, if the patient relapses at some point in the future, after receiving CAR-T therapy, our clinicians should be the ones assessing whether the patient would benefit from receiving the same or different CAR- T treatment. The field of cell therapy is rapidly evolving and therefore CMS’ final NCD should promote access rather than create barriers for new and innovative therapies.

CED Requirement

ASTCT understands that CMS included the CED requirement in order to gather additional data on the effectiveness of CARs in the Medicare population. However, if the agency chooses to finalize an NCD, the same objective can be accomplished with a registry reporting requirement rather than CED. We recognize and appreciate that the proposed CED requirement is less restrictive than others that CMS has implemented. However, we remain concerned that by virtue of this being a CED with additional patient reported outcomes (PRO) requirements in the outpatient setting, some centers will “opt-out,” further restricting access since the agency’s conditions of provider enrollment do not require participation in CED.⁵ The Society requests that CMS’ legal counsel confirm our analysis of the provider enrollment requirements and whether the anti-discrimination provisions in the conditions of participation require hospitals to furnish covered therapy (i.e., NCD covered therapies) to all patients in writing to avoid any confusion amongst centers. This analysis also should address whether or not patients are required to sign a notice of non-coverage (i.e, either an Advanced Beneficiary Notice (ABN) or a Hospital Issued Notice of Noncoverage (HINN)) acknowledging they have been advised that Medicare may not cover and pay for CAR-T therapy should a patient receive care at a hospital that chooses not to participate in data collection for the CED.

The Society strongly recommends that CMS eliminate the CED requirement and instead finalize a NCD with data collection that is tied to existing registry reporting, as this will help avoid the access problems that may result from centers being able to opt-out of the CED requirement. ASTCT cannot support the implementation of a coverage policy that allows centers to opt-out of participation if they perceive participation in the CED as imposing a significant burden in addition to the financial burden they already face.

ASTCT asks for explicit clarification on the data collection and analysis requirements for the CED in order to ensure this requirement does not further limit patient access. In (3)(a)(iii), the policy states:

“The furnishing hospital shall address the CED requirements on all registry patients by tracking the following clinical data elements at baseline, at treatment, and at follow-up 3 months, 6 months, 12 months, and 24 months after the treatment is administered.”

It is not clear whether this language would require the furnishing hospital to analyze the data. If CMS intends for the approved registry to do this analysis, we request that this section be redrafted to state more precisely that the registry is required to conduct the analysis. As written, there may be confusion that the furnishing hospitals will be required to conduct their own analysis on all registry patients (i.e. their own and other hospital registry patients), and that would represent an undue burden on hospitals and present yet another reason for centers to opt-out of participation.

ASTCT also requests clarification from CMS on the patient consent requirements applicable to this coverage policy both as it applies to the registry reporting and patient-reported outcomes (PRO) requirements. The Society believes that there would be no coverage if a patient does not explicitly consent to have their data reported to the registry and requests that CMS clarify what would happen if patients do not consent. Specifically, ASTCT requests clarification on whether hospitals be required to provide patients with a notice of non-coverage (i.e., an ABN or HINN) if the patient does not consent to their data being submitted to the registry or to having their PROs submitted if the therapy is delivered on an outpatient basis. The Society does not support coverage being contingent upon a patient’s explicit consent to having their identifiable data submitted.

While it has been our general experience that most patients provide consent and are interested in having their data submitted to a registry to be a part of future scientific learning to benefit other cancer patients, CMS must recognize that there may be patients who do not want to participate, and that they have the right to refuse without penalty. As our Society members have been at the forefront of both clinical trials that led to the current product approvals, and in the first approved centers for commercial delivery of CAR-T therapy, we know that these patients have few realistic treatment alternatives, and certainly none that would potentially be curative. Knowing the poor outcomes for this disease population, and the risks of foregoing this treatment option, we are concerned how patients will perceive providers requesting patient consent regarding identifiable information in order for the patient’s treatment to be covered.

Instead of potentially placing patients in this position, we recommend that CMS recognize a hospitals’ participation in a registry as sufficient to meeting the registry reporting requirements.

Registry Requirement

As proposed, the registry requirement requires furnishing hospitals to participate in “a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, and follows the patients for at least two years...” It also requires CMS to review and approve all registries. ASTCT believes the Center for International Blood & Marrow Transplant Research (CIBMTR) will meet the requirements to become an approved registry based on our review of the requirements and conversations with CIBMTR. Therefore, we recommend that CIBMTR be listed as an approved registry in the final NCD, assuming they receive their approval prior to the May 17 implementation date. We also recommend that the agency accept hospital participation with the registry without requiring any other enrollment with CMS.

CIBMTR is already collecting data for several CMS CED studies for myelodysplastic syndrome, myelofibrosis, sickle cell disease, and myeloma with great success. Our members are already familiar with CIBMTR through their work with patients with these conditions. Furthermore, CAR-Ts is already being provided by Foundation for the Accreditation of Cellular Therapy (FACT)-approved bone marrow transplant (BMT) programs, which are required by law to report data on allogeneic BMT to CIBMTR. The two manufacturers with approved products, Novartis and Kite/Gilead, are also using CIBMTR as the registry to meet their FDA post-approval study requirement. ASTCT believes this provides additional support for our request to have CIBMTR listed as an approved registry, which would reduce the burden to providers and institutions. ASTCT is pleased that our members are already familiar with a registry that will most likely be approved. ASTCT believes it is critical that a registry be approved at the time this policy is finalized and implemented to avoid any coverage gaps. Furthermore, it is vital that the policy clarify that coverage is based on cell collection occurring on or after the effective date since there will be patients in the midst of their CAR-T episode of treatment when the policy is finalized. We do not support an effective date that would be based on cell administration that could potentially disrupt coverage of an episode of CAR-T therapy already in progress.

Patient-Reported Outcomes Requirement

In the proposed decision memo, CMS included a PRO requirement for the outpatient setting. ASTCT has several concerns and questions related to this requirement. As we stated in our July 2018 comments regarding MEDCAC’s discussion on PROs, the Society strongly objects to any mechanism that would tie patient access or provider reimbursement to the reporting of PROs, especially in the case of CAR-T therapy.⁶ The Society believes that a PRO requirement would add an additional unreimbursed, administrative burden to the patients being treated with CAR-T therapy. In particular, the we believe it is premature to require PRO data for this population and are also concerned that the two PRO tools listed in the policy are not directly applicable to this patient population. Moreover, at the August 2018 MedCAC meeting, we shared that there is insufficient evidence to support the use of these tools for CAR-T patients and believe that this is still the case. The Society is also concerned that the PRO requirement turns a registry-reporting requirement into a study, which will further exacerbate the financial burden on centers.

ASTCT requests clarification on how PROs contribute to CMS’ determination of the reasonableness and medical necessity of CAR-T for the Medicare population. If this requirement is retained in the final policy, we request that it continue to be applied only to outpatients and the agency define “outpatient” as used in the proposed decision memo. It is unclear if the setting is based on the physician order when the cells are administered or on how the account is billed. Since some patients may be administered the cells as outpatients, but billed as inpatients, it is important that CMS provide clear guidance on this issue.

Accreditation Requirements

In the proposed decision memo, CMS included the following requirement for CED:

If CMS retains this requirement in the final NCD, ASTCT urges CMS to define a uniform mechanism for accreditation that conforms to CMS standards in order to ensure that these cells are administered within a cell therapy program as defined. One option would be to require Foundation for the Accreditation of Cellular Therapy (FACT) accreditation for centers, which we were pleased CMS included in the proposed decision memo. ASTCT urges CMS to require use of FACT or another broadly accepted accreditation program rather than creating a duplicative set of requirements to which centers must comply.

The Society expects that the hospital will not be required to attest to CMS its program meets the outlined accreditation standards. We do not support a requirement that would require a hospital to actively enroll with CMS as a requirement of coverage.

Off-Label Coverage Requirements

In the proposed decision memo, CMS outlines off-label coverage requirements. ASTCT requests that CMS provide clarification on whether this triggers study participation or if the registry reporting requirement would apply. Currently, CMS recognizes off-label use of anti-cancer drugs and biologicals when they are referenced in compendia listed in the Chapter 15, Section 50.4.5 of the Medicare Benefits Policy Manual.

The Society urges CMS not to implement a coverage policy that restricts off-label coverage for CAR-T different from that allowed for Medicare beneficiaries receiving any other anti-cancer drugs and biologicals. As we have repeatedly emphasized, this therapy is currently a therapy of last resort and saves patients’ lives. Appropriate off-label use should not come with additional requirements beyond data collection. The Society requests that CMS clarify if the intent is for a study similar to a full clinical trial be required for off-label use, or if the requirement is similar to the registry reporting requirement already in place.

The Society also seeks clarification on why NCCN was listed as the sole applicable compendium in the proposed decision memo when CMS recognizes others in the above referenced Medicare Benefits Policy Manual.⁷ ASTCT recommends that CMS cover off-label use of CAR-Ts consistent with other anti-cancer drugs and biologicals and clarify that data collection via the registry is also required.

Conclusion

ASTCT appreciates the opportunity to comment on the proposed decision memo and to provide our perspective on the best way to ensure access to medically accepted CAR-T therapies for Medicare beneficiaries. We have included a list of questions in Appendix I, which require clarification before the implementation of the policy. The Society looks forward to working with you to improve this policy to ensure that appropriate patients have access to this lifesaving therapy. If you have any questions regarding the above comments, or if we can provide any additional information, please contact Alycia Maloney, ASTCT’s Director of Government Relations at amaloney@asbmt.org.

Sincerely,

Appendix 1

Clarifying Questions for CMS Before Implementation of Final Policy
Questions Related to Off-label Use

Will off-label use trigger clinical study participation or simply registry reporting?

Why was NCCN listed as the sole applicable compendium in the proposed decision memo when CMS recognizes four other compendia in Chapter 15, Section 50.4.5 of the Medicare?

Questions Related to Medicare Advantage plans

Will any CAR-T claims for Medicare Advantage patients be billed to a Medicare Administrative Contractor (MAC), as occurs with other clinical trial claims? Will this impact every Medicare Advantage claim or only certain ones?

Will prior authorizations continue to be required from Medicare Advantage plans?

Questions Related to Patient Consent and Data Collection/Reporting Requirements

Will Medicare patients have to explicitly consent to their identifiable and personal information being sent to the CMS-approved registry?

• If patients do not consent, is the therapy automatically non-covered for them?
• Will hospitals be asked to issue a notice of non-coverage to patients if they do not agree to have their identifiable data submitted to the registry?

Will CMS allow blinded or de-identified data should it proceed with the CED?

Will CMS consider each hospital’s overall participation in data collection to the registry as sufficient to allow for coverage, rather than requiring each individual patient to consent to their identifiable data being reported?

How will CMS determine inpatient versus outpatient status? Will the status be determined by the admission status at the time CAR-T cells are administered, or by how the account is billed?

How does CMS define baseline in the context of capturing PRO data?

Will the NCD only apply to patients who start with cell collection on or after the effective date of the policy? Or will patients who have had their cells collected prior to the effective date be held to the criteria of the finalized NCD immediately?

The proposed CED states that, “ Will the off-label use referenced in the proposed CED result in different NCT numbers from the registry? Or is the off-label use also tied to registry reporting as opposed to the opening of separate studies?
[t]he registry’s National Clinical Trial number must be on the claim.”
Which claims will need this information?
Would it be all CAR-T claims, including the outpatient cell collection claim?
Will the NCT be required only on off-label CAR-T claims?
Will the NCT number assigned to the registry be the same number assigned to a clinical trial or a study per the off-label use section of the decision memo?
For outpatient cell collection claims, will hospitals be expected to use Q0 on cell collection charges?

1 https://clinicaltrials.gov/ct2/show/NCT03549442
2 https://clinicaltrials.gov/ct2/show/NCT03549442
3 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410390/
4 https://ash.confex.com/ash/2018/webprogram/Paper116898.html 5 42 CFR 424
6 ASBMT Comments to CMS on MEDCAC meeting held on August 22, 2018. Link to comments here: https://higherlogicdownload.s3.amazonaws.com/ASBMT/43a1f41f-55cb-4c97-9e78- c03e867db505/UploadedImages/ASBMT_CMS_Comment_MEDCAC_CAR_T_PROs_7_16_2018.pdf
7 42 CFR 424

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March 15, 2019

BY ELECTRONIC DELIVERY

Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
S3-02-01
Baltimore, Maryland 21244
CAGinquiries@cms.hhs.gov

Re: Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Celgene Corporation (Celgene) appreciates the opportunity to comment on the Centers for Medicare & Medicaid Services’ (CMS) proposed decision memo (PDM) on CAR T cell therapies for the treatment of cancer.¹

Celgene is a global biopharmaceutical company specializing in the discovery, development, and delivery of therapies designed to treat cancer and inflammatory and immunological conditions. Celgene strongly believes that medical innovation can lead to better health, longer life, reduced disability, and greater prosperity for patients and our nation. To this end, we seek to deliver truly innovative and life-changing therapies for the patients we serve. Presently, we are engaged in 160 clinical trials with 42 novel assets across 60 indications.

Celgene is committed to discovering and developing treatments in disease areas with significant unmet medical needs. Notably, Celgene has played a central role in the significant improvement in outcomes for patients with serious and life-threatening hematological malignancies. We believe that genetic modification of T cells with chimeric antigen receptors (CARs) represents a potential new era for the effective treatment of these cancers.

Celgene is committed to the development of CAR T cell therapies across multiple cancer indications. This commitment to cell therapy is evidenced by our significant investment in the research and specialized manufacturing required to effectively deliver CAR T cell therapies to patients. There are currently 1,885 patients enrolled in 12 Celgene-sponsored clinical trials for CAR T cell therapies in lymphoma and multiple myeloma, and in 2018, we opened our second CAR T manufacturing site in Summit, NJ, in addition to our existing manufacturing site in Bothell, WA.

Celgene believes that CAR T cell therapy offers significant promise for patients with challenging cancer diagnoses, and we are proud of the work that we are doing to bring these innovations to patients. We currently have two CAR T cell therapies in late stage clinical development that we believe have significant clinical potential in the treatment of blood-based cancers that are under-served by existing treatment options:

Summary of Our Comments

Medicare beneficiaries are disproportionately impacted by several of the cancer types currently under study for treatment with CAR T cell therapy. Therefore, CMS’s final National Coverage Determination (NCD) will be critical to ensure patient access to current and future treatment options as CAR T cell therapy continues to rapidly evolve and progress. We believe that the PDM is a positive and productive first step in establishing national Medicare coverage for CAR T cell therapies. We appreciate CMS’s desire to “improve access to this therapy while deepening CMS’s understanding of how patients in Medicare respond to it, so the agency can ensure that it is paying for CAR T-cell therapy for cases in which the benefits outweigh the risks.”⁶ We are confident that data collected through the Coverage with Evidence Development (CED) framework will demonstrate the value of CAR T cell therapy for Medicare patients.

At the same time, we are mindful that NCDs focused on drugs and biologicals are rare, and that reconsidering these decisions can be resource intensive and time-consuming for CMS. As such, the final NCD should incorporate the flexibility required to reflect the rapidly evolving science of CAR T cell therapy. We want to emphasize that CAR T cell therapy as a class of medicines includes multiple therapies, diseases, and targets and that there is significant heterogeneity among both current and anticipated future CAR T treatments. We are concerned that the PDM, as currently structured, would limit CMS’s flexibility to cover future CAR T therapies that could receive FDA approval within the next two years for unique patient populations or that have different characteristics (e.g., safety, dosing) than the two products currently available to patients. We are mindful that any potential inflexibility could create future limitations on patient access given the nature of the rapidly evolving science of CAR T cell therapy. Celgene’s recommendations below would assist CMS in providing the required flexibility in the final decision memo to help to meet our shared objectives of patient access and evidence development.

We urge CMS to make the following changes in the final decision memo:

• Align the patient eligibility criteria for CAR T cell therapies with FDA-approved labeling or medically accepted indications recognized in Medicare-approved compendia, including guidance on eligible patient populations and dosing regimens. Researchers already are evaluating CAR T cell therapy’s front-line potential to treat various aggressive cancer subtypes such as glioblastoma, multiple myeloma, and aggressive B-cell lymphomas.⁷ Limiting coverage to relapsed and refractory cancers could have the unintended consequence of denying Medicare coverage for a therapy’s FDA-approved indications.

Similarly, in the future, some patient populations may benefit from repeated treatment with CAR T cells. We believe that additional doses for a CAR T cell therapy should be covered when supported by that product’s FDA-approved labeling or by Medicare-approved compendia.

• Cover CAR T cell therapy under the CED framework when administered at an appropriately qualified site regardless of the site’s status as a hospital. FDA has outlined robust and appropriate safety criteria for sites through Risk Evaluation and Mitigation Strategies (REMS) that deliver CAR T cell therapy, and CMS has articulated appropriate safety- and quality-based criteria in the PDM. We encourage CMS to focus on these well-defined criteria, rather than the site’s Medicare billing or legal entity status, when determining coverage.
• Ensure that the Patient Reported Outcomes (PRO) tools that are used to collect health related quality of life data are structured in a way that is consistent across care settings, preserves data integrity, and is not overly burdensome for patients or sites.

While CAR T cell therapies share a clinical foundation and the potential to significantly improve on the existing standard of care, each CAR T cell therapy has a unique target patient population; clinical, safety, and dosing profile; and manufacturing process. With that in mind, we provide feedback below on each section of the proposed NCD Manual text in Appendix B of the PDM, including recommendations to ensure that Medicare coverage for CAR T cell therapies remains aligned with the best available clinical and scientific evidence.

Patient Eligibility Criteria

Celgene believes strongly that the final NCD should be a flexible, living document that can accommodate future innovation to meet the shared goals of patient access and data collection. The NCD’s ability to evolve seamlessly with changes in science and technology is particularly critical because it will apply to all autologous CAR T cell therapies and all cancer types.

As currently written, the proposed patient eligibility criteria are not consistent with the expected future of CAR T cell therapy, including the potential to utilize CAR T therapy for non-relapsed or refractory patient populations. There are already clinical trials underway to study CAR T in the front-line treatment of aggressive cancers, such as glioblastoma, multiple myeloma, and aggressive B-cell lymphoma.

We recognize that today, CAR T cell therapy is largely used to target relapsed or refractory indications. However, we believe that CAR T cell therapy will soon show promise in earlier lines of therapy – front-line studies are already underway, as demonstrated by the list of clinical trials included in the PDM as well as footnote 7 of this letter. These front-line studies focus on patients with aggressive subtypes of disease. In clinical practice, these high-risk patients are often identified based on specific factors related to underlying cancer diagnosis that may include risk stratification by molecular subtypes (aggressive B cell lymphomas with MYC and BCL2 translocations and protein-over expression; specific translocations and mutations in multiple myeloma), or advanced disease presentation (high International Prognostic Index (IPI) or International Staging System (ISS) scores). Current standard of care treatments lead to dismal outcomes for these patients and optimization of front-line therapy with CAR T has the potential to result in clinically meaningful outcomes.

As written, there is no flexibility within this PDM to allow coverage of treatment for non-relapsed or refractory patients under any circumstances (including FDA approval or listing in Medicare approved compendia). The non-coverage section of the PDM also explicitly removes any flexibility the Medicare Administrative Contractors would have under current policy to approve claims for non-relapsed or refractory patients when treated with an FDA approved CAR T cell therapy based on new clinical data or a new FDA approved indication for front-line therapy.

Restricting coverage to patients with relapsed or refractory disease could have the unintended consequence of creating a patient access barrier as the science rapidly evolves, the FDA approves new products, and additional indications are recognized as medically accepted by the compendia.

Specifically, the limitation on patient eligibility to relapsed or refractory cancers could have the following detrimental impacts:

• Limiting patient access to FDA-approved biologics for those who may have aggressive cancers that are not relapsed or refractory disease. In a circumstance where FDA approved a CAR T cell therapy for treatment of front-line disease or use of an FDA-approved CAR T therapy for front-line disease is recognized as a medically accepted indication by one of the Medicare-approved compendia, CMS would need to reconsider this coverage decision before any Medicare beneficiary could have access to that CAR T cell therapy. At a minimum, this would cause a six to nine-month delay before Medicare beneficiaries would have access to a new, potentially lifesaving innovation.
• Creating a gap in access between Medicare beneficiaries and other patient populations, even when earlier access is supported by FDA-approved labeling or Medicare-approved compendia.
• Limiting CMS’s ability to develop evidence in non-relapsed or refractory patient populations.

Celgene urges CMS to remove the proposed coverage limitation of CAR T cell therapy to those with relapsed or refractory cancers. CMS instead should cover a CAR T cell therapy for all cancer patients for its FDA-approved indication(s) or for a use that is supported by one or more citations in any of the compendia approved by CMS to identify medically accepted indications of drugs and biologicals used in anti-cancer chemotherapeutic drug regimens.⁹ CMS should simply delete “relapsed or refractory” from section B.1.a of the proposed NCD Manual language. This policy would be consistent with CMS’s longstanding approach to coverage of cancer therapies and would help to ensure that its coverage policy for CAR T cell therapy continues to reflect evolving evidence.

Similarly, Celgene asks CMS to clarify the co-morbid conditions that may preclude a patient from benefiting from CAR T therapy. In section VIII of the PDM, CMS states: “We believe, based on limitations on FDA indications, contraindications, and the inclusion and exclusion criteria of published studies, that these limitations include examples such as primary central nervous system lymphoma, Burkitt lymphoma, HIV/AIDS, active Hepatitis B or C, active uncontrolled infection, any autoimmune disease currently requiring immune suppression, and active grade 2 to 4 graft-versus-host disease.”

Celgene recognizes that this is a representative list of comorbid conditions based upon the FDA labels for the two current FDA-approved CAR T cell therapies. The comorbid conditions that may preclude a patient from benefiting from future CAR T cell therapies will be different based upon the FDA-approved labeling for those therapies and the patient’s underlying disease. Celgene recommends that CMS modify the statement about relevant comorbid conditions in section B.1.b of the proposed NCD Manual language to read “is not currently experiencing any comorbidity that would otherwise preclude patient benefit as identified in the FDA-approved label of the prescribed CAR T-cell therapy.”

In summary, CMS should ensure that the patient eligibility criteria in the final decision provide sufficient flexibility for future CAR T innovations. We recommend CMS do this by aligning all of the criteria, including the comorbid condition exclusions, with the FDA label or indications supported by one or more of the Medicare-approved compendia for each FDA-approved CAR T cell therapy.

Criteria for Sites Administering CAR T Cell Therapy

Celgene strongly supports CMS’s proposal to cover CAR T cell therapy in both inpatient and outpatient settings of care. We are conducting clinical trials to demonstrate that, depending upon the characteristics of the individual patient, his or her underlying disease, and the profile of the CAR T cell therapy itself, patients can safely and effectively receive CAR T cells as outpatients.¹⁰

Celgene agrees with CMS that important patient safeguards should be put in place for managing adverse events for CAR T cell therapies. Sites with which Celgene chooses to partner to deliver CAR T cell therapy will need to meet robust safety standards, including but not limited to FDA Risk Evaluation and Management System (REMS) requirements and additional infrastructure requirements for patient monitoring, quality management and procedures for a patient’s admission to an intensive care unit (ICU) when necessary.

Among the most important safety criteria that should be in place for the delivery of CAR T cell therapy is an integrated medical team of physicians, nurses, and care coordinators who will comprise the CAR T cell care management team. Consistent with CMS’s proposal, this CAR T cell care management team should have a documented protocol to ensure 24/7 communication and logistics for patient care coverage by members of the designated care team and provide continual oversight of the patient by the primary CAR T cell physician.

Aligned with our comments above, Celgene urges CMS to establish site requirements that can adapt to rapidly evolving scientific advances in CAR T cell therapy, including the development of therapies with different profiles than the currently approved CAR T cell therapies. In particular, Celgene urges CMS to not limit provision of CAR T cell therapies to “hospitals” in the final decision memo and use a more generic term such as “site.” Using “site” instead of “hospital” would allow Medicare to cover CAR T cell therapies in any appropriate site of care as these technologies and treatment regimens evolve. Celgene believes strongly that the safety criteria outlined in the PDM should drive the determination of appropriate sites where CAR T cell therapy is available, rather than the legal or billing distinction as a hospital. CMS should cover CAR T cell therapies in any setting of care that meets the proposed requirements of section B.3 of the Proposed NCD Manual language, regardless of whether that site meets CMS’s definition of hospital in this context.

The emerging safety profile of Celgene’s CAR T cell therapies suggests that some CAR T cell therapies, in certain patient populations, have low rates of CAR T cell side effects or late onset of side effects that make immediate hospitalization at time of infusion unnecessary. As experience with CAR T cells increases, and cell therapy evolves, we anticipate that toxicity management algorithms will become more established, and the side effect profiles of each therapy more defined, potentially allowing use in more settings of care.

We highlight the latest liso-cel investigational data below to demonstrate the substantial variation in safety profile that can occur across CAR T cell therapies. These data show that the majority of patients (57%), including those over age 65, do not experience cytokine release syndrome (CRS) or neurotoxicity. Notably, only 1% of liso-cel patients experienced grade 3 or 4 CRS. When these side effects occurred, patients typically experience them late in the first week or into the second week after treatment (median of 5 and 10 days, respectively).

		CORE Population11
	All Treated n=102	Total n=73	50x106 CAR T cells n=33,	100x106 CAR T cells (n=37),
CRS, any grade	37%	37%	42%	30%
CRS, grade 1-2	36%	36%	39%	30%
CRS, grade 3-4	1%	1%	3%	0%
NT, any grade	23%	25%	24%	24%
NT, grade 1-2	10%	10%	3%	16%
NT, grade 3-4	13%	15%	21%	8%
Any CRS or NT	43%	44%	45%	41%
Any sCRS or sNT	13%	15%	21%	8%

Celgene is currently conducting multiple studies in outpatient sites of care, including sites that do not bill as hospitals. The OUTREACH¹² study is designed to test the safety of liso-cel in outpatient sites of care in order to safely expand access of care to qualified oncology care sites that can support CAR T cell administration and management. PILOT¹³ is a study in second-line, transplant non-eligible patients. This patient population is treated predominantly at non-academic centers that also have a predominantly outpatient site of care model.

Both trials will contribute significantly to our experience and data around administering CAR T cells safely in the outpatient setting in sites that may or may not meet the definition of hospital intended by CMS in the PDM. These sites have several defining characteristics. First, they have demonstrated one of the following core capabilities: Transplant capability, phase 1 hematology/oncology trial experience, or CAR T experience with currently marketed CAR T cell therapies. Second, they work in a coordinated care model that includes cross functional CAR T cell therapy medical teams. Lastly, they are able to function seamlessly across the various disciplines and include oncologists, nurse coordinators, specialists such as neurologists and ICU physicians, apheresis centers, emergency room, infusion centers, and inpatient hospital staff to care for each patient.

In addition to the emerging safety data that support greater utilization and administration of CAR T cell therapies in an outpatient setting of care, Medicare policies that blur the line between hospitals and non-hospital settings reinforce why coverage of CAR T cell therapies should be available across appropriate sites of care. In the PDM, CMS says the benefit categories for CAR T cell therapies include Social Security Act (SSA) §§ 1861(b) (“inpatient hospital services”) and 1861(s)(2)(B) (“hospital services (including drugs and biologicals which are not usually self-administered by the patient) incident to physicians’ services rendered to outpatients and partial hospitalization services incident to such services).” These benefit categories do not align neatly with either the statutory definition of a “hospital”¹⁴ or the definition of “covered outpatient department services.”¹⁵ A provider can be a “hospital” under one part of the statute but not have its services paid as hospital services under another part of the statute. Moreover, the safety requirements that CMS proposes for delivery of CAR T cell therapies can be fulfilled by a site regardless of whether it meets the statutory definition of a hospital or whether its services are payable as “covered outpatient department services”. In light of this fact, Celgene recommends that CMS remove the term “hospital” from the final decision and instead allow “sites” to administer CAR T cell therapy that meet the standards outlined in section B.3 of the proposed NCD Manual text.

Treatment Criteria

Celgene understands CMS’s desire for additional clinical data on CAR T cell therapy for the Medicare population, and we support the collection of these additional data which we believe will demonstrate the transformative potential of CAR T therapies in treating multiple forms of cancer. At the same time, we strongly believe that any evidence development requirements must be implemented in the least burdensome manner to ensure that the NCD achieves CMS’s goal of appropriately expanding access to CAR T cell therapies. As discussed above, Medicare’s coverage requirements for CAR T cell therapies also should be aligned with FDA-approved labeling or Medicare-approved compendia.

Additional Doses of CAR T Cell Therapies Should Be Covered Consistent with FDA label or Medicare-Approved Compendia

Celgene notes that the limitation outlined in the treatment criteria under section B.3.a. of the proposed NCD Manual language which limits a Medicare beneficiary’s coverage of CAR T cell treatment to a single dose of an FDA approved biological unless a new primary cancer diagnosis is made may not be consistent with the FDA approved labels or Medicare-approved compendia as CAR T cell treatment paradigms evolve. Celgene urges CMS to cover additional doses as described in the FDA label or the Medicare-approved compendia so that patients may receive coverage for additional doses as supported by the clinical evidence.

CMS Should Clarify How Registries Should Address the Proposed Questions

We appreciate the proposal that additional clinical data be collected via a registry mechanism because many sites administering CAR T cell therapy will be familiar with this approach, and it would limit hurdles for providers and patients. Several biopharmaceutical companies have already committed to the collection of long-term outcomes and safety data for CAR T cell therapies and are partnering with organizations like the Center for International Blood and Marrow Transplant Research (CIBMTR) that have experience with the collection of this type of data.

Celgene agrees with the questions posed of the CED registry and the types of data for collection as long-term real-world evidence is of utmost importance in a new and rapidly evolving treatment landscape. Celgene urges CMS to consider the following changes to maximize value of the evidence collected through the CED registry:

• Clarify the approach to CED questions that are not addressable through the data variables to be collected (i.e. efficacy relative to a standard of care control, outcomes relative to clinical trial results)
• Provide greater guidance and specificity regarding the data collection time points, specifically what constitutes “baseline” measurement for CAR T cell treatment (i.e. post apheresis, but pre-lymphodepletion). In the relapsed or refractory cancer setting, there is a time interval between when a patient’s disease progresses and when they receive CAR T cell therapy. During this time, a patient’s quality of life may rapidly change. Without clear guidance of what constitutes baseline, there may be inaccurate representation of the baseline for patients receiving therapy.

CMS Should Revise the Proposed Requirements for Collection of PRO Data

Celgene shares CMS’s interest in addressing the patient’s health related quality of life. PROs are important to understanding health-related quality of life (HRQOL) and symptom impacts associated with treatments such as CAR T cell therapy. Celgene has long had a commitment to assessing PROs in the context of clinical trials and in the real world. We believe this information should be collected regardless of whether the patient is treated in the inpatient or outpatient setting, and should be encouraged, but not required, for coverage of CAR T cell therapies.

In pivotal trials for both liso-cel and bb2121, Celgene is utilizing the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30), an integrated system for assessing the Health-Related Quality of Life (HRQOL) of patients with cancer, and EQ-5D-5L, a measure of patients’ well-being and perceived health status. In addition, the myeloma-specific subscale of the EORTC QLQ-C30 has been included in the bb2121 clinical program. Celgene intends to collect PROs for at least two years for liso-cel and up to five years for bb2121 after initial administration. Celgene is also conducting individual patient interviews in a subset of trials in order to capture additional patient experience data.

Celgene believes collecting PRO data from patients receiving CAR T cell therapy is important. However, we know from direct experience that the data collection, analyses, and interpretation for PROs can be complex and logistically challenging. We are concerned that the PRO requirements in the PDM could create barriers to patient access in the near term as the infrastructure to collect PRO data from patients through registries is largely underdeveloped. As noted above, Celgene has experience with PROs both in a clinical trial setting and through the continued real-world collection of patient outcomes via Celgene Connect® Registries. As a result of this experience, Celgene urges CMS to consider the following changes to the way that the PRO collection is structured within the coverage decision:

• Implement a single measure, the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS®), with specific domains for assessment, to evaluate symptom impact, functional well-being, and HRQOL as PROMIS represents a comprehensive and robust patient reported outcome measure.
• Collect PRO data across inpatient and outpatient settings and adjust the time intervals for data collection to provide increased granularity around schedule of assessments and consider a single “baseline” assessment to maximize consistency and minimize patient burden.
• Rather than require providers to submit PRO data as a condition of coverage, allow providers to submit PRO data voluntarily until additional experience and insight is gained through CIBMTR’s electronic PRO (ePRO) pilot.

Providers Should Collect PRO Data Using a Single Tool

PRO data differ from objective clinical data, in that the data must be collected prospectively and directly from the patient, requiring the need for a tool that can be used in diverse circumstances that are convenient and efficient for the site, healthcare provider, and patient, while also ensuring that the data collected are accurate. As noted in our testimony at the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) meeting, collecting PROs in a real-world setting can present unique challenges for patients and providers, particularly if those PROs are expected to be collected two years post treatment administration.

Requiring institutions with limited experience with PRO measures to select between the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO CTCAE™) and PROMIS (as well as specific adverse events and symptom impact, functional well-being, and HRQOL, respectively) may lead to inconsistent assessments and a data set that is difficult to analyze. Celgene recommends that CMS limit the PRO collection to the PROMIS tool, which would address CMS’s objective of capturing “symptom function health-related quality of life changes over the course of their treatment”. PROMIS is the more appropriate tool as it measures functions, symptoms, behaviors, and feelings, while the focus of the PRO-CTCAE is the evaluation of symptomatic adverse events (frequency, severity and/or interference), which may be impacted by non-CAR T-cell treatments (e.g., lymphodepletion, treatments following progression).¹⁶ Celgene specifically recommends the Physical Function, Global Health, Pain Interference and Fatigue modules to best assess symptoms, function, and HRQoL in patients receiving CAR T cell therapy.

Providers Should Collect a Consistent Set of Data Across Settings of Care

Celgene also urges CMS to consider the collection of PRO data across both the inpatient and outpatient settings of care in order to maximize the value of evidence collected. We believe that PRO data could be informative and valuable for patients treated across settings of care. In addition, patients may initiate care in one setting and transition across multiple sites of care, thereby undermining CMS’ goal to collect HRQOL data for those beneficiaries treated as outpatients.

PRO Data Will Provide Additional Insights if Collected Soon After Treatment with CAR T cell Therapy

In addition, Celgene recommends considering the collection of data via PROMIS at one month after CAR T cell administration, in addition to collection of data at baseline, treatment, and follow-up at 3 months, 6 months, and 12 months. We believe that collecting data after one month will increase the credibility and validity of the data, as patients will be better positioned to report their recent post-CAR T cell infusion experience. Celgene also recommends CMS limit the follow-up period to one year and provide more flexibility around data collection time points (e.g., 3 months ± 2 weeks).

CMS Should Leverage the Ongoing CIBMTR Pilot Before Implementing a PRO Requirement

CIBMTR began a pilot program during the summer of 2018 using PROMIS as an ePRO. In addition, CIBMTR formed a multidisciplinary working group to devise a strategy for the collection of late effects of patients contributing to the CIBMTR registry. Given the unique challenges of PRO data collection in the real world, Celgene strongly recommends that PRO data collection not be a condition of coverage, and that such data collection be a recommendation rather than a requirement. Celgene urges CMS to allow the CIBMTR ePRO PROMIS pilot program to be completed, such that the learning and insights can be used to mitigate the unique challenges of collecting PRO evidence and position CMS, patients, and providers for success.

Nationally Non-Covered Indications

Celgene recommends that CMS make changes to section C of the proposed NCD Manual text. CMS should delete the second sentence of this section, which currently refers to the relapsed and refractory indications specified in the draft patient criteria section of the proposed NCD manual text. We note that the references to the sections of the NCD Manual in section C also do not appear to be correct and should be updated in the final decision.

Conclusion

Celgene is committed to developing CAR T cell therapies in areas of significant unmet medical need, and we are supportive of the framework for this coverage decision. We look forward to continuing to collaborate with CMS to ensure that Medicare beneficiaries can obtain access to these novel therapies as the science in this therapeutic class continues to rapidly evolve.

We appreciate CMS’ attention to and investment in CAR T cell therapies and the agency’s desire to ensure appropriate access for Medicare patients. To further that goal, we urge CMS to make targeted revisions to the PDM to ensure that Medicare’s final coverage policy for CAR T cell therapies can accommodate future evidence-based changes in where, how, and for whom these exciting medicines show promise.

Sincerely,

/s/
Richard H. Bagger
Executive Vice President, Corporate Affairs and Market Access
Celgene

1 Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N), Feb. 15, 2019, https://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=291&bc=ACAAAAAAQAAA&.
2 Efficacy and Safety Study of bb2121 in Subjects with Relapsed and Refractory Multiple Myeloma (KarMMa), available at https://clinicaltrials.gov/ct2/show/NCT03361748.
3 SEER, Cancer Stat Facts: Myeloma, available at https://seer.cancer.gov/statfacts/html/mulmy.html.
4 Celgene, Celgene Corporation and bluebird bio Announce bb2121 Anti-BCMA CAR-T Cell Therapy Has Been Granted Breakthrough Therapy Designation from FDA and Prime Eligibility from EMA for Relapsed and Refractory Multiple Myeloma (Nov. 16, 2017), available from http://ir.celgene.com/releasedetail.cfm?releaseid=1049014.
5 Study Evaluating the Safety and Pharmacokinetics of JCAR017 in B-cell Non-Hodgkin Lymphoma (TRANSCEND-NHL-001), available at https://clinicaltrials.gov/ct2/show/NCT02631044. Liso-cel is also referred to as JCAR017.
6 CMS proposes Coverage with Evidence Development for Chimeric Antigen Receptor (CAR) T-cell Therapy, Feb. 15, 2019, https://www.cms.gov/newsroom/press-releases/cms-proposes-coverage-evidence-development-chimeric-antigen-receptor-car-t-cell-therapy.
7 Clinicaltrials.gov: Study evaluating efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Participants With High-Risk Large B-Cell Lymphoma, available at https://clinicaltrials.gov/ct2/show/NCT03761056?term=NCT03761056&rank=1; A study evaluating EGFRvIII CAR T Cells for Newly-Diagnosed WHO Grade IV Malignant Glioma (ExCeL), available at https://clinicaltrials.gov/ct2/show/NCT02664363?term=NCT02664363&rank=1 ; A study evaluating Up-front CART-BCMA With or Without huCART19 in High-risk Multiple Myeloma, available at https://clinicaltrials.gov/ct2/show/NCT03549442?term=NCT03549442&rank=1
8 Id
9 Social Security Act (SSA) § 1861(s)(2). Medicare Benefit Policy Manual, ch. 12, § 50.4.5.
10 Clinicaltrials.gov: A Safety Trial of Lisocabtagene Maraleucel (JCAR017) for Relapsed and Refractory (R/R) B-cell Non-Hodgkin Lymphoma (NHL) in the Outpatient Setting, available at https://clinicaltrials.gov/ct2/results?cond=&term=NCT03744676&cntry=&state=&city=&dist=; Lisocabtagene Maraleucel (JCAR017) as Second-Line Therapy (TRANSCEND-NHL-006), available at https://clinicaltrials.gov/ct2/show/NCT03483103?term=NCT03483103&rank=1
11 All JCAR017 data presented in this section available at http://ir.celgene.com/releasedetail.cfm?ReleaseID=1069109 “Celgene Announces Updated Safety and Efficacy Data from the TRANSCEND Trial of liso-cel (JCAR017) in Patients with Relapsed or Refractory B-cell
12 Clinicaltrials.gov: A Safety Trial of Lisocabtagene Maraleucel (JCAR017) for Relapsed and Refractory (R/R) B-cell Non-Hodgkin Lymphoma (NHL) in the Outpatient Setting, available at https://clinicaltrials.gov/ct2/results?cond=&term=NCT03744676&cntry=&state=&city=&dist=
13 Clinicaltrials.gov: Lisocabtagene Maraleucel (JCAR017) as Second-Line Therapy (TRANSCEND-NHL-006), available at https://clinicaltrials.gov/ct2/show/NCT03483103?term=NCT03483103&rank=1
14 SSA § 1861(e).
15 SSA § 1833(t)(1)(B)(v).
16 National Cancer Institute, PRO-CTCAE available at https://healthcaredelivery.cancer.gov/pro-ctcae/; Health Measures, PROMIS, available at http://www.healthmeasures.net/explore-measurement-systems/promis.

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As a practicing transplant physician understanding the value of CAR T-cell therapy in the treatment of many current and future patients, it is critical that we have this option available for all appropriate patients. Simply put, make the policies in place that allow administration of this therapy to those who meet FDA approved indications. Also simply put, allow the treatment team and center to administer this therapy safely and effectively. For this to occur, adequate compensation is necessary.

Please do not close the options on this life-saving treatment early by establishing a National Coverage Determination that is inadequate and premature. If you do so, you would be going against the advice of professionals and those who truly have the patient's best interest at heart. It is an understandably expense therapy, but it has been demonstrated to be more cost effective than utilizing additional chemotherapies with inferior outcomes.

If the recommendations of professionals and from data are not chosen to be used in making a decision and an NCD is prematurely made, please consider an NCD with a data collection requirement that leverages the registry reporting already occurring (instead of a Coverage with Evidence Development).

Please allow this therapy to patients who need it, and responsibly make decisions that allow the funding to support this therapy. The treatment requires reimbursement, a treatment that has proven to be more cost effective than alternatives. Please do the right thing for those who entrust their healthcare in you both now and in the future.

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Brad Gibson, CPA
Vice President and Treasurer
The University of Texas MD Anderson Cancer Center
PO Box 301429, Unit 1697
Houston, TX 77030
713-745-9585
bgibson@mdanderson.org

March 14, 2019

Ms. Seema Verma
Administrator
Centers for Medicare & Medicaid Services (CMS)
Department of Health and Human Services
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: CAG-00451N, Proposed National Coverage Determination for Chimeric Antigen Receptor T-cell (CAR T) Therapy for Cancer

Dear Administrator Verma:

On behalf of the University of Texas MD Anderson Cancer Center (MD Anderson), we appreciate the opportunity to comment on the Centers for Medicare & Medicaid Services’ (CMS) proposed National Coverage Determination (NCD) for Chimeric Antigen Receptor T-cell (CAR T) therapy for cancers.

MD Anderson is one of the world’s most respected centers devoted exclusively to cancer patient care, research, education and prevention. The institution pioneered a multidisciplinary approach to research-driven care and is at the forefront of innovative treatment options, such as immunotherapy and CAR T therapy. MD Anderson is committed to providing value-based care, and since 1944 more than 1.2 million patients have sought out MD Anderson’s expertise.

The MD Anderson CARTOX Program is a multi-disciplinary integrated team of physicians, nurses, pharm-Ds and mid-level providers that has been working together since 2016 to deliver high-quality care to patients receiving CAR T and other immune effectors. We were accredited by the Foundation for the Accreditation of Cellular Therapy (FACT) in April 2018 as the first stand-alone Immune Effector Cell Program to receive this accreditation. We also recently received the Blues Distinction Center Designation for Cellular Immunotherapy from Blue Cross Blue Shield. We have enrolled over 1200 patients on immune effector cell trials and infused CAR T and other immune effector cell therapies into over 260 patients, including more than 85 patients treated with Yescarta and Kymriah as the standard of care FDA approved cell therapy products.

We have serious concerns regarding the unnecessary restriction of the patient criteria, and the proposed administration of patient-reported outcome (PRO) assessment tools to report symptom function health-related quality of life changes in the outpatient hospital setting. Furthermore, we ask for clarification on the specific definition of a CAR T ‘outpatient hospital setting’ and ‘CMS-approved study’. Furthermore, we request careful consideration and clarity on the restriction of ‘specific CAR T products’ for repeat treatments.

Patient and Hospital Criteria

While we understand the restriction on ‘relapse and refractory cancer’, our recommendation is to remove this language and rely on the FDA-approved indication and approved compendia for covered indications. This change would eliminate the burdensome process necessary to amend when future CAR T indications are approved by the FDA or included in approved compendia and further support the agency’s focus on “Patients over Paperwork”.

As mentioned previously, The Foundation for the Accreditation of Cellular Therapy (FACT) establishes standards and implements accreditation programs for immune effector cells, which includes CAR T cell therapies. FACT accreditation is a rigorous process that recognizes cellular therapy programs that understand the unique needs of patients while being driven by quality management systems. The payor community adopts and recognizes FACT accreditation as a requirement for “center of excellence” status and coverage. Also, some clinical trial groups require FACT accreditation for participation. In support, we agree with the congruent requirement for hospital standards for medical team’s leadership, experience, integration, care areas, and guidelines.

Additionally, MD Anderson supports the use of national registries to promote consistent data collection while reducing provider burden. We request the Center for International Blood and Marrow Transplant Research (CIBMTR) be included in the decision documents as an example of an existing registry. CIBMTR currently collects and administers the Stem Cell Therapeutic Outcomes Database (SCTOD) for HPC transplantation and serves as the Cellular Immunotherapy Data Resource (CIDR) for Immuno-Oncology Transplantation Network (IOTN). CIBMTR is currently working with CAR T manufacturers to incorporate their requirements into their data forms, and manufactures have indicated they will use CIBMTR as their registry of choice. Moreover, CIBMTR is developing a PRO collection system to further increase efficiency but unlikely to be ready to collect PRO data by mid-May 2019. We would urge the agency to not finalize PRO data collection at this time.

Moreover, we do not understand the limitation of approved compendia to only the National Comprehensive Cancer Network (NCCN) compendia acceptance criteria. Our recommendation is to adopt the CMS NCD for Drugs and Biologics list of compendia which includes NCCN, DrugDex, Clinical Pharmacology, American Hospital Formulary Service (AHFS), and Lexi-Drugs.

Lastly, the CMS-approved study requirement only adds unnecessary administrative and provider burden for treatments that are already FDA-approved and documented in accepted industry compendia as standard of care. This additional requirement for study participation presents an unnecessary and unwarranted burden to access for Medicare beneficiaries.

Patient Reported Outcomes (PRO) and Registry Data Collection

The proposed decision memo outlines PRO reporting requirements for CAR T administration in the outpatient hospital setting. While we support the use of PRO collection in quality measurement, we do not believe it would be appropriate to adopt PROs as a coverage requirement at this time. There are still administrative and operational challenges that would need to be defined in order to effectively implement this coverage policy. In congruent, we request clarification on the definition of ‘outpatient hospital setting administration’. If patients are infused in the outpatient hospital setting but require inpatient hospitalization within a short timeframe, are patients still considered an outpatient CAR T patient? If not, what would be the appropriate timeframe in which to consider a patient outpatient?

Additionally, we have serious concerns about the long-term, multi-center PRO follow-up collection. Oftentimes, patients come to CAR T providers for treatment and return back to their referring facility immediately after treatment completion. With immature PRO systems and processes across organizations, we have concerns this requirement will restrict access to only centers with infrastructure to develop and implement data collection processes. Long-term follow-up PRO collection is always a challenge. Given this, we would like to understand the implications for incomplete PRO data. If the PRO proposal were to finalize, our recommendation is to recognize institution PRO effort as sufficient for coverage rather than patient participation.

Furthermore, we request clarification on the definitions of ‘baseline’ versus ‘at treatment’ PRO administration. The proposed decision memo is requesting PRO administration at baseline, at treatment, and follow-up at 3 months, 6 months, 12 months, and 24 months after treatment administration. We suggest removing the ‘at treatment’ time point from the PRO requirement. We collect a baseline PRO and conduct a single baseline adjustment. We propose baseline, 30 or 45 days for PRO outcome assessment for CAR T providers. Lastly, without clear definitions, providers will be collecting inconsistent data further adding provider burden without the ability to draw meaningful conclusions.

Repeat Treatments

To conclude, we request clarification on what constitutes a “new primary cancer diagnosis” and “the use of more than one therapeutic dose of a specific CAR T product” for repeat treatment. There is a possibility that our patients could be diagnosed with a separate malignancy or new diagnosis of a previously treated cancer. Additionally, we request clarification on the definition of ‘CAR T product’. Does this policy reference a specific CAR T product manufactured at a point in time or the drug/manufacturer used? For example, if a patient fails Yescarta, would they be eligible for treatment with Kymriah? Furthermore, if a patient relapses 5 years after initial CAR T therapy, we would request this patient be allowed to receive a different CAR T treatment if the product meets all the approved FDA label requirements. As a result, we urge CMS to release an NCD that promotes new and innovative therapies and doesn’t limit access such as the proposed decision memo language released.

We appreciate the opportunity to submit this letter and further support the comments of the Alliance of Dedicated Cancer Centers (ADCC). If you have additional questions, please contact Michelle Ruben, Director of Clinical Revenue and Reimbursement (713-563-8850 or mruben@mdanderson.org). Thank you for your consideration.

Sincerely,
Brad L. Gibson, CPA
Vice President, Revenue Cycle and Treasurer

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Hello

I have been watching CMS’ policy development around CAR-T with much interest both as a health policy professional and a future Medicare beneficiary. I understand some of the nuances related to the high price of this therapy and the challenges that creates for payment by different payors including Medicare. I understand a Medicare Advantage plan requested CMS start a National Coverage Analysis for CAR-T since they are concerned about being able to pay for this therapy since payment for this has not been built into its per member per month rates. Naturally I can see that Medicare Advantage (MA) Plans are concerned about the outcome of this NCA. Wouldn’t it stand to benefit MA plans to have the NCD be as narrow as possible despite that not being good for patient access so that each time a new product comes to market, they can request a new NCD so that CMS has to embark on a new calculation of significant cost during which time the MA plan gets off the hook for paying for the therapy but CMS remains on the hook, again at least until MA payment rates are adjusted, presumably 2-3 years after the NCD effective date.

It seems like Yescarta and Kymriah will meet the significant cost determination criteria given the $373,000 price and once CMS adjusts the MA payments, then will all subsequent CAR-Ts under the policy be covered and no longer be considered “new” hence shutting down the need for future NCAs by MA plans?

From a financial perspective doesn’t it stand to reason that CMS should make the NCD broad enough to cover the current and future CAR-T products so that new FDA-approved CAR-T products can’t be considered “new” under the NCD. If CMS did this, Manufacturers would know this and wouldn’t this put pressure on them to introduce future CAR-T products at a cost less than $373,000 as this would be the only amount incorporated into the MA plan payments which is what the agency seems to want – manufacturers to lower drug prices and it seems like this is one indirect way that they would do that. This way there would not be a chance of re-opening the NCD to evaluate “significant cost” again and again.

In other words, a broader NCD now would effectively serve as a mechanism to “cap” future CAR-T products from a Medicare pricing perspective. As new CAR-T products are introduced at lower prices, it would put pressure on current manufacturers to lower their prices too, assuming the products treat similar indications.

The flip side is that a “narrow” NCD now could mean that each future product is introduced at higher prices resulting in a new NCA request from an MA plan each time so that the MA plan is financially protected from the new CAR-T product cost?

If my line of reasoning is correct, the CMS should finalize an NCD that is broad for cell products to put pricing pressure on the industry.

Thanks for your attention, SKF

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Please eliminate the CED requirement and implement an NCD with data collection instead to avoid causing additional access problems for patients. Please also expand the indications that would be covered from patients with relapsed or refractory cancer to indications covered on the FDA approved label; list CIBMTR as an approved registry, and remove the requirement tying PROs to reimbursement for CAR-T.

The proposed changes would directly negatively impact our ability to deliver care to patients.

Michelle Hudspeth, MD
Associate Professor, Pediatrics
Daniel J. & Victoria P. Sullivan Chair in Pediatric Hematology/Oncology
Director, Pediatric Blood & Marrow Transplantation
Division Chief, Pediatric Hematology/Oncology
Medical University of South Carolina Children’s Hospital/ Hollings Cancer Center
A NCI Designated Cancer Center
135 Rutledge Avenue MSC 561
Charleston, SC 29425
FAX: 843-792-8912
PHONE: 843-792-0381

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Thank you for the opportunity to provide comments on the Centers for Medicare and Medicaid Services (CMS) Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-Cell Therapy for cancers.

AHIP is the national trade association whose members provide coverage for health care and related services to millions of Americans every day. 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.

CMS recognizes that this is a rapidly evolving field and that initial evidence appears promising, but inconclusive to determine whether CAR T-cell therapy improves health outcomes in the Medicare population. Therefore, CMS believes that further evidence on patients’ health outcomes, in defined circumstances, under a national, prospective, audited registry, may lead to additional evidence that physicians, patients, and their caregivers can use to make informed treatment decisions. Therefore, they propose to cover autologous CAR-T treatment through coverage with evidence development (CED), including a number of outlined criteria that must be met to qualify for CED.

We agree with CMS that there is currently limited evidence for CAR-T Therapies. To date, studies have consisted of single-arm trials performed in specialty-trained hospitals with small sample sizes; we agree that a CED will allow CMS to collect additional evidence.

We ask CMS to consider the following:

1. Evaluating long-term efficacy and safety to ensure quality care and improve health outcomes.
   While short-term efficacy endpoints are usually the standard outcomes for the FDA, we recommend that CMS collect data on long-term efficacy and safety through this CED. The optimal long-term efficacy endpoint, established through evidence-based principals, are critical as these therapies are burdened with high financial impact.

   Long-term follow-up is required in all age populations. Further, as part of this assessment, the long-term safety of CAR-T therapies should explore the impact of hypogammaglobulinemia which may require life-long immunoglobin treatments for patients, as well as the adverse reaction of secondary malignancies that can occur with chemotherapy or immunotherapy.

2. Evaluating non-medical costs associated with CAR-T.
   As a part of this CED, CMS may want to evaluate non-medical costs patients might incur as a result of CAR-T treatments (e.g., time off from work, travel expenses, etc.).


3. More clarity regarding patient registries.
   We recommend that CMS provide more clarity around who will be administering the patient registries required for patients who will receive CAR-T. The decision memo contains some information regarding how registries will be approved, reviewed and maintained. However, it is not clear how data will be collected across different registries. Further it is not clear if each institution will be creating their own registry, or if there will be a limited number of national registries established.


4. Study design.
   The CED explains that due to the registry-natured CED approach, pivotal trial results will be used as controls. If this is the desired route, then additional endpoints/outcomes need to be part of CED studies so proper comparative analyses can be conducted. The eventual CED recommendations need to acknowledge the epidemiological limitations from registry-designed studies. Another important situation that should be analyzed is the repeat administration of these therapies for the same or different oncological conditions.


5. Clarify language regarding comorbidities.
   As currently drafted, coverage for CAR-T through evidence development may be provided for patients with relapsed or refractory cancer that are not “experiencing any comorbidities that would otherwise preclude patient benefit.” This language is vague, and we recommend adding the following clarifications regarding patient eligibility for inclusion:
   1. Patient has an ECOG Performance Status of 0 or 1;
   2. Patients with CKD 3 and above should be excluded;
   3. Patients should have adequate cardiopulmonary function; and
   4. Patients with chronic liver disease should be excluded.

We thank you for the opportunity to provide feedback on this proposed decision memo. For questions, please email kberry@ahip.org.

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Coverage that is contingent on patient behavior up to 24 months after the therapy is very confusing. When patients feel better, indeed, may be fully healed from their cancer, they will likely complete follow-up visits with their primary care physician, but they may not want to see a medical oncologist or think about their terrible cancer again and may choose not to complete the registry or PROs at those later intervals. Will CMS subsequently deny and retract payment because the hospital cannot submit data on some patients at those intervals?

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It is not clear if CMS will be publishing a list of CMS-approved CAR-T hospitals. Will I also be required to submit a certified letter to CMS that our cell therapy program meets all the requirements including a team and quality manager and a designated patient care area with isolation precautions, and written guidelines about transfer to ICU? What is the process to be approved because patients may have had cells collected, but not yet infused until after May 17, 2019 when the NCD is final will that patient’s therapy be covered? I don’t want to risk non-coverage so I want to be able to assure CMS approval on May 17, 2019. I assume there is routine coverage of CAR-T where the patient meets the label requirements up until this date, correct?

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Hospitals don't have the resources to do the data analysis as described in the section 3.a.iii. It reads “The furnishing hospital shall address the CED questions on all registry patients by tracking the following clinical data elements at baseline, at treatment, and at follow-up 3 months, 6 months, 12 months, and 24 months after the treatment is administered.” There will be too few patients for any meaningful analysis by each individual hospital because each hospitals may only have two or 3 Medicare patients in a 6 or 8 month period and this low number of Medicare patients makes it inappropriate to answer the questions asked in this section. Perhaps this section is not written as CMS intends and these questions are to be answered by the registry.

Currently, the registries pay or reimburse fees for each form that a site completes and submits to the registry. These fees are actually paid by the manufacturers because the registry requirement is mandated as part of the FDA approval. If this same registry is CMS-approved, does that make these payments that are indirectly from the manufacturers improper according to the anti-kickback statute or Stark?

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I don’t understand why CMS is stating relapsed or refractory and expressing at least one chimeric antigen, I thought this is part of what FDA does with labeling the drugs and is part of the FDA approval process. Why is CMS not accepting the FDA label for coverage? CMS has other policies that cover off-label use of anti-cancer drugs. CMS usually does not limit more than FDA. Why isn’t the NCD just for FDA labeled indications and then data submission like other NCDs are on devices? This therapy helps very sick patients to live, why would CMS limit or non-cover life-saving therapy less than what FDA has approved? CMS, please change coverage to be matching whatever the FDA approves on its label for these products.

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To Whom It May Concern-

Thank you for your careful consideration of the matter of CAR T-cell therapy for cancers. While these therapies provide renewed hope for many patients, there is much we still do not know about their long-term efficacy and safety. The proposed coverage with evidence development (CED) takes an important step toward developing our collective knowledge in this regard. The following are comments on the proposed criteria:

The proposed CED criteria effectively address several key considerations

1. Coverage only of FDA-approved CAR T-cell products for labeled indications
2. Re-treatment with the same CAR T-cell product for the original cancer
3. Ensure treated members are enrolled in a respected patient registry

Data from the CED will facilitate understanding of several critical elements

1. Comparative efficacy of real-world experience to the pivotal clinical trials
2. Comparative efficacy between available CAR T-cell products which share a common clinical indication
3. Comparative efficacy of available CAR T-cell products to current standards of care for their respective clinical indication

Criteria can be improved

1. Repeat treatment is a concerning area with little to no data regarding safety and efficacy. Criteria 3a addresses one aspect of repeat treatment by requiring a new primary cancer diagnosis in order to receive repeat treatment with the same biological product. Not addressed, however, is treatment with a different CAR T-cell product for the original primary cancer.
   1. There is little to no evidence to support the safety or efficacy of re-treatment of the same primary cancer with the same CAR T-cell product
   2. There is even less (none) evidence to support the safety or efficacy of receiving treatment with two different CAR T-cell products for the same primary cancer. CMS should address this scenario in criteria 3a by including "Repeat treatment…using the same or an alternative CAR T-cell product…"

Thank you again for your careful consideration of the criteria for coverage of CAR T-cell therapies, and for your condensation of the above-mentioned points.

Sincerely,
Cody Gillenwater, MD
Medical Director
Cambia Health Solutions

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I do not know exactly what the CMS is looking for in these comments, however, I do know that a very large majority of Americans are not able to pay hundreds of thousands of dollars for medical treatment. Allowing Medicare to fund CAR-T therapy would be a significant step towards the ultimate goal of affordable access to proper health care for every American. The fact that [PHI Redacted] faces a potential medical bill of almost half of a million dollars is, respectfully, absurd. I sincerely hope that these comments are taken into strong consideration when making policy decisions regarding Medicare coverage and the decision to include CAR-T therapy.

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I am in full agreement with the proposed coverage. I would love to see it expanded to include TIL (Tumor Infiltrating Lymphocytes) the cousin to CAR T that treats solid tumors. [PHI Redacted] is a recipient of TIL and six months out has no detectable disease. He had stage III mucosal melanoma at the time of his TIL treatment. These adoptive t-cell treatments are changing the lives and outcomes for so many lucky individuals who have access and are early enough in their disease process to tolerate the treatment. I am grateful for CMS willingness to move forward and hopefully the private sector will follow. Thank you,

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