Coverage with Evidence Development (PROPOSED)

VIA ELECTRONIC SUBMISSION
Coverage and Analysis Group, CMS
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244
August 21, 2023

RE: Coverage and Evidence Development Proposed Guidance Document

Dear Coverage and Analysis Group,

The Robert J. Margolis, MD Center for Health Policy at Duke University (“the Duke-Margolis Center” or “the Center”) appreciates the opportunity to comment on the Coverage and Evidence Development Proposed Guidance Document published on June 22, 2023.

The Duke-Margolis Center generates and analyzes evidence across the spectrum of health policy and supports the triple aim of better care, better health, and lower cost. A core mission of the Center is to focus on increasing the value of biomedical innovation to patients. Center experts are engaged in policy research and development efforts to improve the processes and infrastructure needed at the Centers for Medicare and Medicaid Services (CMS) to ensure efficient access to new and innovative technologies.

These comments describe opportunities to ensure that Coverage with Evidence Development (CED) studies that meet the proposed new requirements produce sufficient evidence to inform CMS’s assessment that a novel technology is reasonable and necessary for Medicare beneficiaries. These comments are informed by the Center’s independent analysis of the proposed guidance, participation in the recent Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) panel on the “Analysis of Coverage with Evidence Development (CED) Criteria,” and engagement with a diverse group of stakeholders, including manufacturers, real-world evidence experts, providers, researchers, and payers.

The Duke-Margolis Center is supportive of the CED proposed guidance. Separating existing compound requirements into distinct, thematic criteria allows for more specificity and clarity of study guidance, which will better inform study design and facilitate downstream assessments of study results. The revisions also reflect evolving evidence needs for novel technologies including “fit-for-purpose” (FFP) study designs and a greater reliance of real-world data (RWD) collection methods allowing CMS to reevaluate efficient and appropriate coverage of novel technologies for Medicare beneficiaries in a timely manner. In order to ensure the effectiveness and the impact of the CED guidance, Duke-Margolis recommends CMS:

Require interim results reporting as part of the proposed CED criteria 2: “Milestones”;

Clarify when there is scope for multi-stakeholder engagement to inform CED study objectives and designs;

Provide specific guidelines and examples on the types of data generation strategies, data sources, and study designs that support CMS Medicare coverage in the forthcoming FFP guidance;

Clarify how CMS will evaluate specific CED study designs relative to related guidance on clinically meaningful endpoints for that disease area and applicable data generation strategies, data sources provided from the forthcoming FFP guidance; and

Increase CMS resources and capacity to support Medicare coverage activities, including implementing the proposed revisions to the CED requirements and guiding evidence generation for new technologies.

Background

The CED policy was developed to provide access to novel technologies that did not have sufficient evidence to substantiate the Medicare’s coverage standard of reasonable and necessary. For a product to be reasonable and necessary, it must be: (1) safe and effective, (2) not experimental or investigational, and (3) appropriate for use in Medicare beneficiaries.¹ An item or service is “appropriate” in this context if it is furnished according to the medical practice standards for the diagnosis or treatment of a condition, in a setting of care that can meet patient needs, by a qualified provider, whether a product meets the medical needs of the patient, and whether it is as least as beneficial as an existing alternative.

The CED proposed guidance is part of broader initiatives of modernizing Medicare coverage processes to be more timely, transparent and predictable. Advances in biomedical innovation and the growth of expedited FDA regulatory processes have accelerated the pace at which novel technologies reach market authorization. Many of these novel new technologies, while promising, may have limited evidence on health outcomes for Medicare beneficiaries, long-term adverse events, and the treatment durability at the time of approval, which suggests greater reliance on CED as a means to provide access. Concurrent with the growing pace of medical innovation are the growing importance of RWD and real-world evidence (RWE) as a means to evaluate health outcomes for Medicare beneficiaries. Traditional clinical studies are not generally designed to evaluate the impact of novel technologies in real world settings with the variety of patients reflective of the diverse Medicare populations. As such, RWD sources and methods are becoming a more relevant means of generating the evidence that could substantiate the reasonable and necessary coverage. The CED proposed guidance presents an opportunity to further allow for greater use of RWD and RWE to support Medicare coverage. Another broad trend that has been driving the assessment and evaluation for novel technologies is the principle of FFP study methodologies as determined by both evidence questions and the endpoints and outcomes evaluated. The proposed CED guidance allows for these new methods to qualify and quantify the impact of novel technologies on Medicare beneficiaries.

Through the CED proposed guidance, CMS aims to provide a more transparent and predictable evidence generation framework to facilitate Medicare coverage; allow for broader range of FFP study designs; and accelerate beneficiary access to new items and services. The first part of this comment letter will evaluate how the proposed criteria support CMS’s aims. The second part of the comments will address how additional guidance could strengthen the overall CED processes.

Providing a more Predictable and Transparent Evidence Generation Framework

The CED proposed guidance provides more specificity regarding the evidentiary expectations and populations of interest than the previous guidance to create a more predictable and transparent framework for CED studies. For example, criteria 6: “Study Population,” explains a threshold for which factors sponsors must consider for reflecting the diversity among intended Medicare beneficiaries, namely attention to the racial and ethnic backgrounds, comorbidities, gender, age, and disabilities within the user population. Criteria 10: “Objective Success Criteria” does not define the objective thresholds for all studies to meet, but notes that sponsors will establish an evidentiary threshold for primary outcomes with CMS and AHRQ. This engagement will add an element of certainty that the primary outcomes for CED studies are the most appropriate and relevant for answering the CED research question. Additionally, criteria 14: “Reporting” lays out a timeline for when final results must be submitted to publication, as well as potential avenues for publication, which may help sponsors develop an appropriate publication plan and add to framework predictability. CED studies should also be registered with ClinicalTrials.gov for additional transparency, and the statistical analysis plans delivered to CMS, per criteria 3: “Study Protocol.” Publishing the study design and the study results will help inform providers and patients of the risks and benefits of a product or service, as well as indicators of treatment success to better inform decision-making.

The proposed guidance also addresses predictability of the overall CED process. Since the CED policy was first implemented, there have been 26 National Coverage Determinations (NCDs) requiring CEDs.² Per CMS’s analysis, only 3 CED NCD topics have had the CED requirement removed following an NCD reconsideration and have received national coverage. According to the most recent updates on the CMS website, there are four NCDs with CED requirements for which no studies have been approved. Accordingly, stakeholders have voiced concerns in the past over the lack of predictability around timing of CED reconsiderations and a lack of definitive ending of CED.^{3, 4, 5} A first step towards addressing these issues is defining key study milestones including interim results and study finalization. The proposed criteria 2: “Milestones” will require sponsors to give CMS a plan for key study milestones, which will include results reporting. This plan could include both start and end dates, as well as a final results reporting date. Interim results could help CMS better understand the state of the evidence and allow them to plan for the NCD reconsideration process. Final reporting should initiate a discussion for plan for NCD reconsideration. This will also allow sponsors to have a more precise timeline for long term Medicare coverage.

Recommendation: CMS should require interim results reporting as part of proposed CED criteria 2: “Milestones” to ensure timely reconsiderations and increase pathway predictability.

Allow for Broader Range of Fit-For-Purpose Studies

Past CED studies have utilized a number of different study designs, including both traditional clinical trials and fit-for-purpose designs that analyze secondary use of real-world data (RWD). More traditional studies have ranged from randomized, prospective, multi-blinded designs^{6, 7} to prospective, longitudinal, non-blinded designs,⁸ depending on the nature of the CED research question and the rigor required to show improvement in health outcomes. Other CED studies have utilized data collected in real-world settings through CMS-approved registry data^{9, 10, 11} and analyses of claims data.^{12, 13} Thus, CMS has been moving towards using FFP study designs and data sources to address CED questions.

The CED proposed guidance could encourage a broader range of FFP studies leveraging RWD sources. Depending on the research question, studies leveraging RWD may be an effective avenue for answering evidence questions for CED. This proposed CED guidance includes criteria that may make it easier to design studies that capitalize on existing data sources, such as Medicare claims or electronic health records. As cited by the AHRQ analysis of CED criteria,¹⁴ the Duke-Margolis framework for regulatory use of real-world evidence states that RWD must be valid, high-quality, reliable, and relevant and to be conclusive. To this end, proposed criteria 5: “Study Design” is flexible enough to allow for FFP studies that utilize any type of RWD to fill evidentiary gaps, so long as the study generates valid evidence to infer causal inference. The data also must meet the threshold for data quality as required by the CED research question (11: “Data Quality”). It will be important for CMS to work with study sponsors to clarify expectations for the various aspects of quality highlighted in the “Data Quality” criteria. Sponsors must show CMS how the data collected or gathered from existing sources will be valid and contribute to a better understanding of identified health outcomes of interest (12: “Construct Validity”). Finally, the proposed criteria that requires data to come from expected sites of care when applicable (8: “Care Setting”) will help contribute to the relevance of the RWD to Medicare intended users.

Accelerate Beneficiary Access to New Items and Services

The proposed guidance may help extend access to underserved populations, which supports CMS’s mission to advance health equity. While traditional trials may offer ideal conditions for determining causal inference, they often have smaller sample sizes, are shorter, and have strict enrollment criteria. RWD over a larger, more diverse cohort can provide key insights into what constitutes “appropriate” use of a product by allowing investigators to observe how a product performs in different patient populations, with different provider experience or site capacity. The proposed criteria requires study populations to reflect the demographics of the intended Medicare users (6: “Study Population”), and study sponsors will be required to consider and discuss the subpopulations and underrepresented groups in the study, how the enrollment criteria will affect trial diversity, and plans for population retention (7: “Subgroup Analyses). Both of these criteria will not only help CMS have confidence that the study data is generalizable to the intended users and help determine the proper context of care for the item or service, but also potentially expand item or service access to populations that may not otherwise be included.

The proposed criteria may likely increase the predictability and transparency of the CED process, which could accelerate beneficiary access to new items and services. Future guidance on the types of RWD and data collection methods that CMS finds most rigorous will further help inform CED study design and objectives, which will allow manufacturers to begin earlier planning for post-market studies that would support Medicare coverage. Efforts to accelerate beneficiary access to new items and services may benefit from early and sustained engagement between CMS, manufacturers, and other stakeholders engaged in evidence generation that can support CED. Sponsors may need additional CMS guidance on outcomes of interest, study duration, and data collection efforts to design an effective study that would address CED questions. Early engagement between CMS, sponsors, FDA, and other stakeholders may enable CMS to more efficiently identify the evidence gaps relevant to Medicare beneficiaries. This will then have an effect on criteria 4: “Study Context,” which requires that CED studies have rationales supported by available scientific evidence, which may be supplemented by engagement with providers, specialty societies, or data experts. Earlier multi-stakeholder engagement will also assist with developing primary health outcomes of interest and thresholds that can demonstrate clinically meaningful differences (9: “Health Outcomes;” 10: “Objective Success Criteria”). Finally, earlier engagement between FDA, sponsors, and CMS may help prevent overlaps and duplication in CED and post-market evidence collection efforts.

Recommendation: CMS should clarify when there is a scope for multi-stakeholder engagement to identify outcomes of interest or align on CED research questions and study design.

Future Directions for Supporting Proposed CED Guidance

CMS appears to be incrementally moving towards a CED framework that utilizes FFP study designs, reflecting the advancing methods for collecting and utilizing RWD and RWE. Accordingly, CMS has indicated that there is forthcoming guidance on FFP studies. CMS states that CED studies should be as rigorous as possible, employing a study design and using data sources appropriate to answer the research question, whether by developing a randomized controlled trial, utilizing advanced study designs to simulate randomization with an active comparator (for example, compare to current standard of care). CMS also notes that studies should minimize confounding and bias. While the CED proposed guidance may help investigators design FFP studies to answer CED research questions, additional specificity in forthcoming FFP study guidance could ensure that studies meet CMS’s standards for study rigor to increase the degree of confidence that CMS can derive from study results while capitalizing on secondary uses of RWD. Additional guidance on the types of FFP study designs, types of data, and data collection methods that CMS would find most rigorous, as well as the outcomes of interest in different disease areas will provide additional transparency and predictability to the framework.

The success of this proposed CED guidance document will also depend on the strength and thoroughness of Clinical Endpoints Guidance for specific disease areas. Concurrent with the CED proposed guidance, CMS published a proposed Clinical Endpoints guidance document which illustrates, using Knee Osteoarthritis as an example, how CMS evaluates clinically meaningful endpoints and their clinically meaningful differences in specific disease areas. CMS has indicated they will publish different clinical guidance documents for different diseases areas. The availability of clinical guidance would favorably impact the extent to which a study sponsor could design a CED study. In particular, the effectiveness of proposed criteria 4: “Study Context” and 9: “Health Outcomes” are going to be highly dependent on whether there is published CMS guidance on the current state of the evidence for a particular disease space and the endpoints that can fill evidentiary gaps within that space. Criteria 4 states that “The rationale for the study is supported by scientific evidence and study results are expected to fill the specified CMS-identified evidence deficiency and provide evidence sufficient to assess health outcomes.” Criteria 9 then outlines that health outcomes for the study must be “important to patients and their caregivers [and] clinically meaningful.” These CED proposed criteria are indicative of the interaction with the forthcoming Clinical Endpoints guidance documents.

Recommendations: CMS should provide specific guidelines and examples on the types of data generation strategies, data sources, and study designs that support CMS Medicare coverage in future fit-for-purpose guidance. Accordingly, CMS should clarify how CMS will evaluate specific CED study designs relative to related guidance on clinically meaningful endpoints for that disease area and applicable data generation strategies, data sources provided from the forthcoming FFP guidance.

The CED proposed guidance aims to provide more clarity around the process that will be needed to support predictable, timely, and productive interactions between CMS, manufacturers, and investigators to meet CED expectations. With the growing pace of novel technologies, the ratio of CED to total coverage decisions continues to increase¹⁵, and the number of interactions needed to reach consensus on the types of evidence that would support fit-for-purpose studies increases, CMS will need more resources to engage with sponsors and provide guidance on important outcomes of interest. Any new CED criteria will have the greatest impact if accompanied by steps to ensure adequate resources and capacity for CMS for implementation. CMS could leverage additional resources to work with other agencies and subject matter experts to discuss evidence needs and the types of trial designs that would most effectively and efficiently answer evidentiary questions for a given product. This would allow for an earlier understanding of the types of evidence infrastructures needed to develop evidence for coverage, making it easier and less costly to develop the necessary post-market evidence. We believe the resource requirements to support expedited coverage and the new CED criteria will be modest relative to their impact on innovation and Medicare patients’ health outcomes.

Recommendation: Increase CMS resources and capacity to support Medicare coverage activities including implementing the CED proposed guidance and guiding evidence generation for novel technologies.

Conclusion

The Duke-Margolis Center supports the CED proposed guidance and encourages CMS to consider the importance of additional elements that encourage transparent and predictable early engagement between stakeholder and encourage innovative study designs and CED approaches. Adequate resourcing will ensure CMS is equipped to support these changes and ensure the impact of the proposed guidance are all the more effective. The Duke-Margolis Center appreciates CMS’s consideration of our comments, and the Administration’s support for advancing high-value, affordable healthcare.

Sincerely,

Beena Bhuiyan Khan – Assistant Research Director, Duke-Margolis Center
Hannah Graunke – Senior Policy Analyst, Duke-Margolis Center
Mark McClellan – Director, Duke-Margolis Center

References
1 Centers for Medicaid & Medicare Services, “Medicare Program Integrity Manual, Ch 13” (CMS, February 12, 2019), https://www.cms.gov/regulations-and-guidance/guidance/manuals/downloads/pim83c13.pdf.
2 Centers for Medicare & Medicaid Services, “(Proposed) Coverage with Evidence Development,” Medicare Coverage Document (CMS, June 22, 2023), https://www.cms.gov/medicare-coverage-database/view/medicare-coverage-document.aspx?mcdid=33&docTypeId=1&status=&sortBy=title&bc=16.
3 “MEDCAC Meeting - Analysis of Coverage with Evidence Development (CED) Criteria,” Centers for Medicare & Medicaid Services, February 13, 2023, https://www.cms.gov/medicare-coverage-database/view/medcac-meeting.aspx?medcacid=79&year=all&sortBy=meetingdate&bc=15.
4 Centers for Medicare & Medicaid Services, “Transitional Coverage for Emerging Technologies Listening Session (Transcript),” March 31, 2022, https://www.cms.gov/files/document/transcripttransitionalcoverageofemergingtechnologylisteningsession03312022.pdf.
5 Centers for Medicare & Medicaid Services, “Webinar: Transitional Coverage of Emerging Technology (Transcript),” February 17, 2022, https://www.cms.gov/files/document/transcripttransitionalcoverageofemergingtechwebinar02172022.pdf.
6 VertiFlex, Incorporated, “A Prospective, Multi-Center, Randomized Controlled Double-Blind Trial Evaluating the VertiFlex® TotalisTM Direct Decompression System Versus a Sham Comparator Surgical Procedure in Patients With Lumbar Spinal Stenosis,” Clinical trial registration (clinicaltrials.gov, August 4, 2020), https://clinicaltrials.gov/study/NCT02079038.
7 LivaNova, “A Prospective, Multi-Center, Randomized Controlled Blinded Trial Demonstrating the Safety and Effectiveness of VNS Therapy® System as Adjunctive Therapy Versus a No Stimulation Control in Subjects With Treatment-Resistant Depression,” Clinical trial registration (clinicaltrials.gov, September 2, 2022), https://clinicaltrials.gov/study/NCT03887715.
8 Medical College of Wisconsin, “A Multi-Center Biologic Assignment Trial Comparing Allogeneic Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in Patients w/Intermediate-2 & High Risk Myelodysplastic Syndrome (BMTCTN1102),” Clinical trial registration (clinicaltrials.gov, March 1, 2023), https://clinicaltrials.gov/study/NCT02016781.
9 American College of Radiology Imaging Network, “The National Oncologic PET Registry,” Clinical trial registration (clinicaltrials.gov, August 21, 2020), https://clinicaltrials.gov/study/NCT00868582.
10 American College of Cardiology, “The Society of Thoracic Surgeons/ American College of Cardiology Transcatheter Valve Therapies Registry Mitral Module,” Clinical trial registration (clinicaltrials.gov, February 1, 2022), https://clinicaltrials.gov/study/NCT02245763.
11 “STS/ACC Transcatheter Valve Therapy Registry (TVT Registry) - NCT01737528,” ClinicalTrials.gov, August 25, 2022, https://clinicaltrials.gov/ct2/show/NCT01737528.
12 Vertos Medical, Inc., “MILD® Percutaneous Image-Guided Lumbar Decompression: A Medicare Claims Study,” Clinical trial registration (clinicaltrials.gov, August 14, 2023), https://clinicaltrials.gov/study/NCT03072927.
13 Reapplix, “Reapplix 3C Patch® System for the Treatment of Diabetic Foot Ulcers: A Medicare Claims Study,” Clinical trial registration (clinicaltrials.gov, February 21, 2022), https://clinicaltrials.gov/study/NCT03997526.
14 Effective Health Care Program, “Analysis of Requirements for Coverage with Evidence Development (CED) – Topic Refinement,” Agency for Healthcare Research and Quality, September 7, 2022, https://effectivehealthcare.ahrq.gov/products/coverage-evidence-development/draft-comment.
15 Emily Zeitler et al., “Coverage With Evidence Development: Where Are We Now?,” The American Journal of Managed Care, August 2022, 28, no. 8 (April 7, 2022), https://www.ajmc.com/view/coverage-with-evidence-development-where-are-we-now-.

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August 21, 2023

Joseph Chin, MD, MS
Acting Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Electronically Submitted: https://www.cms.gov/medicare-coverage-database/view/medicare-coverage-document.aspx?mcdid=35&docTypeId=-1&status=open&sortBy=title&bc=16

Re: Public Comment on Proposed Coverage with Evidence Development Guidance Document

Dear Dr. Chin:

The American College of Radiology (ACR) representing more than 41,000 diagnostic radiologists, radiation oncologists, interventional radiologists, nuclear medicine physicians, and medical physicists, appreciates the opportunity to submit public comments in response to the Centers for Medicare and Medicaid Services (CMS) proposed Coverage with Evidence Development (CED) guidance document. We strongly support updates to factors CMS considers in making National Coverage Determinations (NCDs) using the CED framework to provide more predictable and transparent evidence development. ACR participated in the February 2023 Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) public meeting to examine general requirements for clinical studies submitted for CMS coverage under CED.

We believe an NCD that requires CED as a condition of coverage should not last indefinitely and appropriate clinical end-points need to be included as part of the CED. CMS must ensure a clear pathway from CED to a coverage determination. CMS must also use reported CED results to inform new or revised coverage decisions. Once sufficient evidence is generated, the outcome should result in a coverage decision of either 1) sufficient evidence for a coverage NCD; 2) sufficient evidence for a non-coverage NCD; or 3) a decision to defer the coverage decision to a Medicare Administrative Contractor (MAC). Improving the predictability of the CED process by setting start and end dates with a specific and transparent timeline would address stakeholder concerns with the current CED criteria.

We fully understand that when the available evidence is insufficient to demonstrate that items and services are reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member, CED has been used to support evidence development that is likely to show benefit for the Medicare population. Over the years, many innovative technologies have reached the market with limited or developing evidence for coverage purposes. CMS relies heavily on health outcomes data before proposing an NCD. There is rarely sufficient clinical evidence for new technologies to support broad national coverage. We recommend that CMS establish appropriate outcome measures that better evaluate advanced imaging and specialty products (such as diagnostic radiopharmaceuticals) and their impact on patient management and clinical outcomes. ACR supports updates to the CED process to better reflect clinical practice using scientific rigor to ensure Medicare beneficiaries have access to care. Additionally, clarifying the process that will enable CMS and investigators to agree on the evidentiary threshold to discontinue the CED condition is important.

The CED process has been assessed over time and improvements are necessary to ensure coverage decisions are reached after sufficient evidence is generated. Notably, a recent study identified the “wide range of program duration for the 4 programs with retired data collection requirements (4 to 12 years) and the long duration of CED programs resulting in NCD revocation (10 and 13 years).” [1] Another article, discussing the CMS decision to cover FDA-approved monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease, noted the need for a “timeframe for CED completion and for a decision on whether coverage should be modified or withdrawn, based on the results, and mechanisms to ensure that results are published in the peer-reviewed literature.” [2] The ACR believes that for any technology or service provided coverage through CED, an endpoint should be established for when the process is complete.

We urge CMS to improve the current process by using the CED selectively to provide evidence-based coverage, establish specific and transparent timelines, and allow stakeholder input to incentivize innovation and afford timely access to services for Medicare beneficiaries. ACR has extensive experience with the CED process. The ACR is a professional organization committed to advancing the science and quality of radiological care for patients. As part of that commitment, the ACR Center for Research and Innovation is a prominent CED study sponsor and operation leader. In May 2006, the ACR launched the CED-approved National Oncologic PET Registry (NOPR), with collaboration from the Academy for Molecular Imaging, The American Society of Clinical Oncology, and the Society for Nuclear Medicine. Studies published in the Journal of Clinical Oncology the Journal of Nuclear Medicine and Cancer analyzed data from more than 41,000 NOPR cases and found that results of PET scans led to an intended change in cancer management of nearly 40 percent of patients. [3] Approximately 10 percent of all Medicare-covered PET scans in 2007 were performed under the auspices of the NOPR. In 2009, CMS duly expanded access and coverage of PET scans performed in both the initial and subsequent evaluation of patients with many types of cancer. This decision was based on significant clinical evidence regarding the effectiveness of PET for the management of patients with cancer gleaned from the NOPR.

Since Sept. 27, 2013, CMS has covered beta-amyloid PET imaging under CED. The ACR has worked with CMS over the last decade to generate the evidence necessary to expand coverage and access to this critical diagnostic tool for patients suffering from cognitive decline. The hallmark molecular biomarker of Alzheimer’s disease (AD), beta-amyloid protein, can be non-invasively detected by PET. The ACR serves as the sponsor and operating center for the Imaging Dementia – Evidence for Amyloid Scanning (IDEAS) Study and subsequent New IDEAS study. These studies were developed to address the CED requirements of CMS’s 2013 NCD 220.6.20. Building upon the momentum of the IDEAS Study, the research team launched the New IDEAS study in December 2020 to analyze the clinical utility of beta-amyloid PET imaging of the brain in a diverse cohort of individuals diagnosed with mild cognitive impairment (MCI) or dementia. Without the insights provided by a diverse cohort, the clinical utility and effectiveness of beta-amyloid PET are less likely to be fully understood. For example, genetic, medical, and lifestyle factors are known risks for dementia, although the evidence has been developed from mostly white cohorts. In contrast, racial adversity, vascular disease, education disparities, and inequitable health care access, all play important roles in the excess risk of AD in African Americans. [4] Hence, the inclusion of New IDEAS data is critical to ensure the representativeness of the subject population, effective clinical management, and advancement of health equity within the cohort. As of July 27, 2023, the study has enrolled a total of 4,414 participants, of whom over 3,539 have already received their beta-amyloid PET scan. The national site network for the study includes 146 dementia practices and 126 PET imaging facilities. New IDEAS is still active and accepting applications for participating PET imaging facilities and dementia practices. However, coverage was not expanded despite clinical evidence and publications until the Agency’s recent proposed decision to remove CED and allow local coverage decisions. The ACR’s experience in conducting CMS-approved CED studies allows for insight into real-world barriers faced by the physician community since 2013.

In addition to our CED activities, since 2009, the ACR has requested several times that CMS Coverage and Analysis Group (CAG) include CT Colonography (CTC) as a covered exam for colorectal cancer screening in Medicare beneficiaries. [5] A formal reconsideration request was submitted in 2022, presenting new supporting evidence and reflecting our ongoing concerns. CMS indicated that the additional evidence that was submitted was insufficient to support a reconsideration as it would not change the existing NCD. The ACR has provided ample evidence addressing the concerns raised by the coverage team over the past 14 years, but still, our formal reconsideration requests both past and present have not been accepted. CTC is the only American Cancer Society (ACS) and U.S. Preventive Services Task Force (USPSTF) that recommended colorectal screening exam not covered by Medicare. The ACR believes it is reasonable for CMS to conduct a National Coverage Analysis (NCA) to evaluate the available evidence for screening CTC and determine that a national coverage determination is warranted.

ACR supports this proposed CED guidance to provide a more transparent and evidence-based framework to facilitate Medicare coverage. CMS must remain flexible and work with sponsors/investigators to execute a written plan of agreed-upon key study milestones to ensure the timely completion of the CED process. Study design, protocols, outcome measures, and results should be made publicly available. Both AHRQ and CMS should meet regularly with the study sponsor to ensure sufficient evidence is generated and results are interpreted correctly. Investigators may need additional guidance from CMS on outcomes of interest and study duration to decide on an effective study methodology that would generate the types of evidence that CMS would need to make a coverage determination decision and end CED. The proposed requirements will support early engagement between CMS, sponsors, FDA, and other stakeholders, and ultimately allow CMS to efficiently identify evidence gaps, provide guidance on study design, and complete the process in a timely and predictable manner. It will be imperative that CMS has adequate resources to ensure it can engage with stakeholders and provide detailed guidance on CED studies.

In its analysis, CMS mentions that the NCD process, in general, is a transparent one, and that requesters may meet with CMS informally and frequently. A tracking sheet is posted on the CMS website for the public to monitor the progress of the review. ACR requests that CMS update the dashboard of CMS’ NCD requests that are either under review, requests that have been reviewed and not yet opened (referred to as the NCD Wait List), open with a national coverage analysis underway, or finalized within the past 12 months. The NCD Wait List is an alphabetical list of the complete, formal NCD requests that have been accepted by CMS that it intends to open in the future. This file was last updated in September 2020 so the public is not aware of future NCD requests. This dashboard should be updated with CED content quarterly to allow the public to monitor what is being considered. We encourage CMS to maintain information on ongoing CED research studies on its website, along with links to the ClinicalTrials.gov website.

We appreciate CMS recognizing the limitations of randomized controlled trials (RCTs) as it relates to items and services. There are ethical concerns about withholding treatment from the control group. CMS recognizes that not all studies can be single- or double-blinded. In cases where blinding is not possible or not used, CMS will closely examine the study design and analysis elements to mitigate the risk of bias. ACR would like to suggest that when looking at outcome measures for diagnostic technologies, CMS should focus on the impact on patient management. CMS should also consider the need for randomized controlled trials when prospective registries that can incorporate real-world evidence would suffice. Limiting evidence review to only randomized controlled trials can raise ethical issues and could lead to uneven coverage of beneficiaries. The proposed requirements would support innovation in real-world evidence-gathering strategies that support fit-for-purpose studies, allowing CMS to evaluate appropriate coverage in a predictable, transparent, and timely manner. We support the inclusion of real-world data when randomized control trials do not yield expected results. CMS may benefit more by moving towards more opportunities to incorporate real-world evidence through claims data, electronic health records, and other systems.

Thank you for your willingness to consider our comments on the clinical study standards for CED. ACR welcomes the opportunity to provide CMS with additional clinical or other information to assist CMS with its coverage policy decisions. If you have any questions or comments on our letter, please do not hesitate to contact Alicia Blakey MS, Principal Economic Policy Analyst, at ablakey@acr.org.

Respectfully submitted,

William T. Thorwarth, Jr. MD, FACR
Chief Executive Officer

References
1. https://www.ajmc.com/view/coverage-with-evidence-development-where-are-we-now-
2. https://www.healthaffairs.org/content/forefront/medicare-coverage-evidence-development-leaps-into-spotlight-cms-draft-national-coverage
3. Impact of Positron Emission Tomography/Computed Tomography and Positron Emission Tomography (PET) Alone on Expected Management of Patients With Cancer: Initial Results From the National Oncologic PET Registry. Bruce E. Hillner, Barry A. Siegel, et.al. Journal of Clinical Oncology 2008 26:13, 2155-2161.
4. Barnes LL. Alzheimer disease in African American individuals: increased incidence or not enough data? Nat Rev Neurol. 2022 Jan;18(1):56-62. doi: 10.1038/s41582-021-00589-3. Epub 2021 Dec 6. PMID: 34873310; PMCID: PMC8647782.
5. Screening Computed Tomography Colonography (CTC) for Colorectal Cancer.

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August 21, 2021

Chiquita Brooks-LaSure
Administrator
Centers for Medicare and Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Re: Proposed Coverage with Evidence Development Guidance Document

Dear Administrator Brooks-LaSure,

Medtronic is the world's leading medical technology company, specializing in implantable and interventional therapies that alleviate pain, restore health, and extend life. With our strong history of working with CMS to generate meaningful evidence under Coverage with Evidence Development (CED) we are pleased to submit these comments in response to the proposed CED guidance document.

Medtronic has participated in CED for technologies such as implantable cardioverter defibrillators, transcatheter aortic valve repair, and leadless pacemakers. Across these CED programs we have experienced different approaches to the design and execution of CED studies; it is with this experience that informs our comments on the proposed CED guidance document.

Overall, Medtronic is aligned with the CED principles and appreciates CMS’s focus on advancing transparency, predictability, and flexibility within the CED program. The proposed guidance document generally reflects the findings in the Agency for Healthcare Research and Quality’s (AHRQ’s) final report “The Analysis of Requirements for CED” and incorporates the discussions during the public meeting of the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) on CED requirements.

Medtronic’s more detailed comments on the proposed CED guidance document are outlined further in this letter. We appreciate CMS’s consideration of these comments and look forward to continuing to work closely with the Agency on the further development, advancement, and operationalization of CED.

- Ending CED. Medtronic supports the language within the guidance document that states CED-required data collection should have an established start and end date as part of the Evidence Development Plan. Incorporating stopping dates and interim analyses into the CED study designs improves predictability for all stakeholders. As discussed in TCET, CMS urges manufacturers to consider incorporating a continued access study in the evidence development plan (EDP) to maintain market access between the period with the primary EDP is complete and CMS conducts the evidence review and decision-making process. Similar emphasis should be reflected in the CED guidance to provide clarity that a continued access study would enable access when transitioning from an NCD with CED.

- CED Study Population and Fit-for-Purpose Study Designs. The guidance document states the CED study population should reflect the demographic and clinical diversity of the Medicare beneficiaries who are the intended population of the intervention. However, under CED, a technology/service is considered non-covered outside of CMS-approved CED study. Therefore, for a new technology/service to obtain broad patient access, every indicated Medicare beneficiary must be enrolled in a CED study. There are a variety of fit-for-purpose study designs, data sources, and methodological approaches that could yield evidence that is generalizable to the Medicare population without including the entirety of those clinically indicated.

As noted in TCET, a claims data study may be incorporated into an EDP to ensure continued access while transitioning from the proposed TCET coverage pathway. With CMS’s emphasis on flexibility and efficiency in an EDP, CMS should clarify whether CMS could extend coverage to an item/service beyond the specific population enrolled in the CED study or whether manufacturers should incorporate an ‘access study’ as opposed to a ‘continued access study’ to facilitate broad coverage at the time of an approved EDP while an additional study runs in parallel targeted to more specific evidence gaps outlined in the NCD.

- Comparator Groups. CMS states its preference for inclusion of contemporaneous comparison groups in CED studies to enable causal inference of treatment effects. While the guidance document stops short of making this a requirement through allowing study sponsors/investigators to provide justification for not including contemporaneous control groups, this appears to be a substantial change from previously approved CED studies. In the spirit of fit-for-purpose study designs, Medtronic believes there may be instances where a comparison group, contemporaneous or otherwise, may not be necessary. Medtronic urges CMS to consider the practicality and feasibility of including contemporaneous comparison groups when reviewing CED study designs. Additionally, CMS should consider the incorporation of indirect comparison methodological approaches that could yield comparative insights, where appropriate.

- Study Protocol and Supporting Materials. In effort to improve efficiency and consistency in the CED process, Medtronic recommends adjusting the timeline of CED study materials submitted to CMS. Specifically, we recommend CMS keep the language that a study protocol is registered at clinicaltrials.gov and submitted to CMS before study initiation, but does not require the statistical analysis plan to be submitted to CMS prior to study initiation. As outlined in Section V.A. of the FDA guidance document on Statistical Principles for Clinical Trials, the principal features of the eventual statistical analysis of the data should be described in the statistical section of the protocol. The guidance document further notes that the SAP may be written as a separate document to be completed after finalizing the protocol. The SAP may contain more technical and detailed elaboration of the principal features stated in the protocol and be amended based on review of the data, which is particularly important in studies using secondary data where data assumptions may need additional validation. Medtronic recommends, the SAP, along with the programming code, data, and results, are submitted to CMS as part of CED study result reviews outlined in the study protocol milestones.

Thank you for the opportunity to comment on CED proposed guidance. We appreciate CMS’s consideration of these comments and the Agency’s strong commitment to providing Medicare beneficiary access to medical technology. If you have questions or need further information related to these comments, please feel free to contact me at lindsay.bockstedt@medtronic.com.

Sincerely,

Lindsay Bockstedt, PhD
Vice President, Global Health Economics and Outcomes Research
Medtronic, Inc.

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We urge CMS to clarify how the CED requirements will apply to TCET. V-Wave believes that acceptance into TCET is an acknowledgement of the importance of the device for Medicare beneficiaries. We believe that CMS should be more flexible with respect to TCET fit-for-purpose study design than it might be for non-TCET CED, and this should be negotiated on a case by cases basis with manufacturers. V-Wave believes that when a manufacturer has conducted a successful randomized, highly powered clinical trial they should not have to rerun another similar trial to support the CED requirement, even if the original trial used a hierarchal composite endpoint with clinical and patient-reported outcome components to it. In fact, in some cases, V-Wave believes that CED may not be needed at all, particularly when the totality of data from pre-market studies is substantially positive demonstrating concordance of multiple clinical and patient-reported outcomes. All CED policies both through TCET and outside of TCET should have clear timeframes with a definite end date.

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PDF also submitted electronically to CAGInquiries@cms.hhs.gov

August 21, 2023

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

Re: Coverage with Evidence Development; Proposed Guidance Document

Johnson & Johnson (“J&J”) is pleased to submit the following comments and recommendations in response to the Centers for Medicare & Medicaid Services’ (CMS’) proposed guidance on Coverage with Evidence Development (CED). J&J is the world’s most comprehensive and broadly-based manufacturer of healthcare products for pharmaceutical, medical devices, and diagnostics markets. For nearly 130 years, we have led the way in innovation and are continuing this heritage today by bringing important new pharmaceutical products and MedTech innovations to market in a range of therapeutic areas on behalf of all our current and future patients, including Medicare, Medicaid, and Marketplace beneficiaries.

As the largest dual-sector healthcare company introducing innovative pharmaceutical products and medical devices in the US, J&J offers a unique perspective in navigating Medicare coverage and reimbursement. Our experience confirms the importance of a transparent process that includes public engagement and provides clarity and predictability for beneficiaries, providers, and manufacturers.

Below we offer comments on the proposed CED guidance and its potential use in guiding the development of clinical evidence development as part of the Medicare coverage process.

J&J Supports a CED Program where the Consideration of Clinical Evidence and Evidence Development is Predictable, Transparent and Allows for Meaningful Stakeholder Engagement
We understand the proposed guidance represents CMS’ current thinking on the factors CMS considers in developing National Coverage Determinations (NCDs) using the CED paradigm, and we support efforts to ensure consideration of clinical evidence and evidence development is predictable and transparent, with opportunities for meaningful stakeholder engagement. Below we offer comments on the draft guidance and its intended use.

J&J Supports Clear CED Principles That Expand Access to New Technologies and Treatments for Medicare Beneficiaries
CED should be used to expand coverage of and access to promising medical technologies and treatments, where additional evidence generation will resolve gaps in clinical evidence and support CMS’ statutory requirement that items and services improve outcomes for Medicare beneficiaries. It should not be used to restrict or limit access to new and novel treatments that are likely to predict benefit for the Medicare population.

CED offers the opportunity for Medicare beneficiaries to participate in clinical research and to have some coverage for promising treatments when CMS is not yet ready to assert a new or innovative treatment or device is “reasonable & necessary” for Medicare beneficiaries. J&J historically has been supportive of CED for promising technologies, particularly when the alternative option to CED is non-coverage under Medicare. As such, we support CMS’ statement of intent to “encourage innovation and accelerate beneficiary access to new items and services.”

J&J Values an Open and Transparent Coverage Determination Process That Expands Equitable Access to New Medical Technologies and Treatments.

Evidence generation under CED should be targeted and specific to address the relevant outstanding clinical questions being asked and should not duplicate evidence development conducted to satisfy FDA’s requirements for market authorization. CMS issued companion guidance document on National Coverage Analysis Evidence Review in which the Agency describes “fit for purpose” clinical studies that “should be sufficient to credibly answer the question(s) [the study] intends to answer.” We understand further guidance is forthcoming on the concept of “fit for purpose” studies and we look forward to gaining more clarity, as well as having the opportunity to comment.

Finally, in conducting evidence development under this paradigm, we urge CMS to consider equitable patient access to clinical trials as well as the impact of health disparities when a new technology may serve a population facing such disparities. We specifically recommend CMS advance recommendations on how a modernized CED program will achieve the health equity goals established by the Agency.

CMS Should Maintain a Flexible Approach to CED Study Design to Allow for Surrogate Endpoints

CMS states in the draft guidance that it relies heavily on health outcomes data before proposing an NCD and comments on the FDA’s use of surrogate endpoints to predict clinical benefit early in the product lifecycle. On page 4 of the draft guidance, CMS comments that the FDA “requires that surrogate endpoints be reasonably likely to predict clinical benefit for accelerated approval but requires validated surrogate endpoints for full approval” and that “surrogate outcomes are not direct measures of clinical benefit” such as mortality, disease progression or quality of life. CMS continues that “there is often little evidence at this point regarding health outcomes,” yet it is not clear what CMS is referring to with this assertion, given many surrogate endpoints have been validated to predict clinical benefit by a wealth of clinical data, including clinical and epidemiological studies.

CMS’ draft guidance document provides a set of general clinical study standards for CED studies and notes on page 9 [Health Outcomes] that primary health outcome(s) for the study should be important to patients and caregivers and should be clinically meaningful, but “a validated surrogate outcome that reliably predicts these outcomes may be appropriate for some questions.” This proposed standard also aligns with CMS’ statement on page 7 that the CED guidance is being updated to better allow for a broader range of fit-for-purpose study designs, particularly for items and services that show promise of benefit for the Medicare population.

Use of surrogate endpoints, including those reasonably likely to predict clinical benefit, has enabled efficient and expedited drug development programs for the benefit of Medicare beneficiaries. The accelerated approval pathway has afforded more timely patient access to new and novel treatments for serious and life-threatening conditions such as HIV and cancer where limited or no treatment options are available. CMS should maintain a flexible approach to CED study design to allow for surrogate endpoints as appropriate, including those reasonably likely to predict clinical benefit, per the proposed guidance document. We also request CMS clarify any concerns regarding the use of surrogate endpoints in predicting health clinical benefit.

CMS Should Ensure Flexibility in the Application of Clinical Study Standards or Characteristics for CED
CMS outlines standards or general conditions for clinical studies that were recommended by Agency for Healthcare Research and Quality (AHRQ) after a notice and comment process in 2022. We note these broad and general characteristics could raise questions when applied in practice on a case-by-case basis when CMS establishes NCDs with CED. Clarity is critical and given the wide and varied range of medical technologies and their intended uses, we urge CMS to consider the practical challenges associated with generating evidence, to consider all levels of valid scientific evidence and to maintain flexibility in the interpretation and application of these standards in reviewing and approving CED studies for Medicare coverage decision-making.

One recommendation is for CMS to advance the AHRQ analysis and develop a specific Request for Information (RFI) soliciting feedback on the modernized paradigm for post-market evidence specific to the Medicare population and its unique coverage standard. While flexibility, efficiency and burden are critical principles in establishing an evidence collection paradigm, a CED paradigm focused on the key patient characteristics, safety-related outcomes and evidence-related outcomes that are most critical to CMS in establishing a CED policy for the Medicare population will benefit all stakeholders.[1] A key component of this RFI could also offer stakeholders and evidence development experts another avenue to explore those circumstances by which clinical study data is not generalizable to the Medicare population; and to provide additional evidence and explanation of those circumstances by which CMS will require additional evidence and specificity on the goals of the additional evidence to achieve the coverage standard.

CMS Should Ensure Seamless Transition to Coverage When CED Ends
J&J agrees with CMS’ statement on page 12 that CED as a condition of coverage should not last indefinitely. The endpoint for CED-required data collection and related timelines should be defined in advance to avoid unnecessarily burdensome and potentially costly ongoing data collection and to streamline and expedite, where appropriate, more comprehensive beneficiary access. J&J supports transparency and a process that ensures that no gaps occur in coverage between the conclusion of a CED study and the issuance of a permanent NCD. We also support recommendations advanced by AHRQ to define termination or timely completion with a “pre-defined schedule for completion of key milestones to ensure timely completion of the CED process.” Moreover, commitments by the Agency to routinely meet with manufacturers, as well as the sponsors/investigators, on progress is warranted. For example, an improved CED process could include a formal assessment of the timely completion of key milestones for evidentiary standards, with clear stage gates for all parties, afford opportunities for beneficiary and patient caregiver input and provide transparency to all parties.

Further, if CMS determines that a study has met its outcomes and that a change in coverage status is warranted, based on the evidence review, the Agency should move to swiftly implement and announce to the public such change without undue delay. In the interest of transparency, sponsors could still be expected and obligated to fulfill reporting requirements associated with the program (e.g. submission in the public domain within a certain timeframe after conclusion of the trial); but, in the interest of timely conclusions of CEDs, a peer-reviewed publication process should neither be materially required nor have to temporally precede it. CMS’ requirements should be specified more clearly in the Guidance.

CMS Should Provide Greater NCD Transparency at all Stages of the Process
CMS notes on page 12 that “[t]he NCD process, in general, is a transparent one.” However, this transparency, in terms of informing stakeholders regarding proposed coverage determinations and providing opportunity to provide input, occurs only after a National Coverage Analysis (NCA) is opened. There is not transparency regarding the number of NCD applications CMS has received or is considering at any given time. In 2020, CMS posted an NCD “dashboard” to its website, providing a snapshot of NCDs current under consideration. While limited in scope, this dashboard did provide interesting and useful information regarding its NCD activity at the time. We urge CMS to update the dashboard on a regular basis, and would suggest at least annually, to provide the public with information on how CMS is prioritizing its NCD decision-making.

Specific Comments on the Proposed CED Guidance

On page 4, CMS claims that it is rare for new technologies to have sufficient clinical evidence to support broad national coverage. This broad and very general characterization does not take into consideration that many new technologies have developed substantial clinical evidence, including in the Medicare population. CMS should point to what evidence it is using to support its claims that most new FDA-approved technologies have insufficient clinical evidence. Further, CMS should soften the language on page 4 to read:

“For some new technologies, it is rare that there is sufficient there may be insufficient clinical evidence to support broad national coverage under 1862(a)(1)(A).”

On page 4, in the final paragraph, revise “there is often little” to “there may be less” so the sentence reads: “…and there may be less evidence at this point regarding health outcomes…”

* * *

Johnson & Johnson appreciates the opportunity to submit comments in response to the CMS’ proposed CED guidance. We look forward to working with CMS to modernize and update Medicare coverage programs, including CED, as more innovative technologies come to market that may challenge existing coverage paradigms in an effort to support beneficiary access under Medicare, Medicaid, and the Marketplace. Please contact the J&J Payment and Delivery Team if there is any further information we can provide or if the Agency has additional questions about the topics discussed in our comments.

Sincerely,

Jacqueline Roche

Jacqueline Roche, DrPH
Head Payment and Delivery Policy & Global Policy Institute
Johnson & Johnson Worldwide Government Affairs & Policy

Chandra N. Branham

Chandra N. Branham, JD
Sr. Director, Payment & Care Delivery, Health Policy
Johnson & Johnson Worldwide Government Affairs & Policy

Footnote [1]: Refer to the Alzheimer's Disease Monoclonal Antibodies with Traditional Approval May 31, 2023, report for additional recommendations https://healthpolicy.duke.edu/sites/default/files/2023-05/Alzheimers%20Disease%20mAb%20Traditional%20Approval.pdf

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August 21, 2023

Chiquita Brooks-LaSure
Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
7500 Security Blvd
Baltimore, MD 212441

RE: Coverage with Evidence Development Proposed Guidance Document

Dear Administrator Brooks-LaSure:

The ALS Association appreciates the opportunity to provide recommendations the Centers for Medicare and Medicaid Services’ (CMS’) on the proposed guidance on Coverage with Evidence Development (CED). We share the concern of the rare disease community that a balanced and transparent patient informed CED framework is necessary to ensure health equality and access to care.

The ALS Association:
Established in 1985, The ALS Association is the only national nonprofit organization fighting ALS on every front. By leading the way in global research, coordinating multidisciplinary care through certified clinical care centers, and fostering government partnerships, our mission is to build hope and enhance quality of life while aggressively searching for new treatments and a cure for ALS. The ALS Association is committed to ensuring all people with ALS have equitable access to health care services to enhance their health and wellbeing and improve the quality of their life. Until ALS is cured, our goal is to make ALS a livable disease for all.

Delivering effective treatments and a cure to people affected by ALS will take the commitment and compassion of all people and federal and state government partners collaborating with urgency across geographic, socio-economic, cultural, and ideological boundaries. Therefore, The ALS Association is dedicated to cultivating an inclusive environment in which patient and caregiver voices are raised and heard as we serve, engage, advocate for, and empower people with ALS to live full and active lives. We are committed to maintaining a community that resolves inequities that impede progress in the fight against ALS and ensures that our mission-driven work is informed by multiple perspectives and experiences.

About ALS:
Amyotrophic Lateral Sclerosis is a neurodegenerative disease that can affect anyone, at any time. ALS destroys nerve cells in the brain and spinal cord, causing the loss of muscle control throughout the body in which people with ALS become prisoners within their own bodies, unable to eat, breathe, or move on their own. Their minds, however, often remain sharp so they are aware of what is happening to them. There is no cure for ALS, and most people with the disease die within 2 – 5 years of diagnosis. Although the disease can strike at any age, symptoms most commonly develop between the ages of 55 and 75.

ALS often commences with muscle twitching and weakness. The weakness slowly spreads to both arms and both legs as the motor neurons slowly die and stop sending signals to the muscles which results in the loss of the use of a limb and slurred speech. Eventually, ALS affects major muscles essential to move, speak, eat, and breathe. As the disease progresses, a person with ALS requires more support for activities of daily living. In addition to multidisciplinary specialty services provided by physicians and clinicians, people living with ALS require skilled (nursing and allied health professional) and non-skilled (activities of daily living) care services provided by paid providers and family caregivers. A person living with ALS often requires access to durable medical equipment to manage their conditions such as complex power wheelchair systems, ventilators, speech generating devices, and other assistive communication technologies to assist people with ALS and their family member or caregiver to communicate.

Our comments center on the following recommendations:
1. CED should prioritize engagement with patient communities and must include patient-centered perspectives;
2. CMS should uphold safeguards to ensure that CED provides timely access to FDA approved treatments; and
3. CED should not consider evidence from discriminatory measures that devalue the lives of people living with ALS.

Concerns about the existing CED Pathway:
Under the current CED pathway, Medicare makes coverage determinations for items and services on the condition that they are supported by clinical studies and or the collection of additional clinical data. Unfortunately, the CED pathway has been subject to considerable criticism by the academic and the patient advocacy community because the CED has historically been utilized with minimal success. Of the 27 CED determinations from 2005 to 2022, only four CEDs led to an NCD for continued coverage, and two CEDs led to coverage revocation and deferral to local coverage decisions as reported by a recently published analysis by Johns Hopkins University’s Evidence-based Practice Center.

Inadequate and untimely CED pathways will not ensure timely access to care and therapies for people living with ALS. Significant improvements and resources will be needed to make the CED (and NCD) processes adequate to ensure health equality and timely access to care. We especially believe that CMS must prioritize improving the coverage determination process and ensure that the agency devotes additional resources to support improvements to the CED process.

1. CED should prioritize engagement with impacted patient communities and must include patient-centered perspectives in clinical evidence development.

CMS should prioritize stakeholder engagement early and often in CED determinations and consider patient perspectives in clinical evidence determinations. We hear from ALS advocates from across the country whether a treatment is reasonable and necessary or whether a therapy would improve their quality of life. Patients and caregivers would also hold strong opinions on whether a new therapy should be subject to a CED review and determination. Currently, patients do not have a way to directly engage with the agency on the choice to apply CED requirements. We advise that patient-centered data and evidence should be the backbone of the CED process. This essential element of patient-centered evidence could be established through open data collection activities with patients and people with disabilities. Enriching patient engagement opportunities should establish a predictable process for engagement throughout the CED process and provide meaningful roles for patients and people with disabilities to participate in during all stages of the CED process including deliberations, implementation, collection, and in conclusion of a CED.

2. CMS should uphold safeguards to ensure that CED provides timely access to FDA approved treatments, so they are not restricted or unnecessarily delayed.

It is important for CMS to consult stakeholders to identify and address impositions that the CED pathway might have on vulnerable patient populations such as restricting access to treatments, delaying treatments, reducing of quality of life, and or other prohibitive factors that affect a patient wellbeing. The use of a CED would affect timely delivery of therapies and services for people living with ALS. Therefore, as a condition of coverage, CEDs should be time-limited in their application and consideration of whether evidence is sufficient to support a permanent Medicare coverage determination under the reasonable and necessary standard. For the goal of making ALS livable, time is a critical factor.

3. CED should not consider evidence from discriminatory measures such as QALYs that devalue the lives of people living with ALS.

We are concerned that CMS may not effectively eliminate Quality-Adjusted Life Years (QALYs) from CED and NCD analysis. QALYs and the similarly flawed Equal Value of Life Years Gained (evLYG) are value assessments that discriminate and fail to accurately reflect cost and quality of life factors that matter to patients. The use of these measures in utilization management tools restricts patient access, thereby limiting the ability of patients and their providers to make decisions about the best treatment path. Unfortunately, the use of these measures increases risk of adverse health outcomes and out-of-pocket costs associated with their health care.

We request that CMS offer more clarity into exactly how the agency will exclude QALY-based metrics from analysis of clinical evidence. We also request that CMS publicly report when and how the agency removes QALY-based metrics from consideration in CED and NCA analysis. Greater transparency is needed in prohibiting the use of QALYs and or referencing other metrics or studies that included QALYs from clinical evidence reviews.

Conclusion:
In addition to these recommendations, we join with other coalitions such as the Independence Through Enhancement of Medicare and Medicaid (ITEM) Coalition, Partnership to Improve Patient Care (PIPC), and the National Health Council (NHC) and their recommendations for improvements to the CED pathway.

The ALS Association appreciates engaging with CMS to enhance care for people with ALS. Please feel free to contact Rich Brennan rich.brennan@als.org with any questions.

Sincerely,

Melanie Lendnal
Senior Vice President, Policy & Advocacy
The ALS Association

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August 21, 2023

Chiquita Brooks-LaSure
Administrator
Centers for Medicare & Medicaid Services
7500 Security Blvd
Baltimore MD 21244

Re: Proposed Coverage with Evidence Development; CMS National Coverage Analysis Evidence Review; and Clinical Endpoints Guidance: Knee Osteoarthritis Guidance Documents

Dear Administrator Brooks-LaSure,

The Advanced Medical Technology Association (AdvaMed) is pleased to offer comments on the Centers for Medicare & Medicaid Services’ (CMS) three proposed guidance documents released in conjunction with the Transitional Coverage for Emerging Technologies (TCET) notice:¹ Proposed Coverage with Evidence Development (CED); CMS National Coverage Analysis Evidence Review; and Clinical Endpoints Guidance: Knee Osteoarthritis Guidance Documents. AdvaMed has long supported both policy and process improvements that would result in a predictable pathway to national Medicare coverage for new medical devices and diagnostics.

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.

The medical device industry supports evidence-based coverage policy, and we appreciate the challenges faced by CMS in trying to improve the National Coverage Determination process. We believe that, to advance its health equity and other goals, CMS can and must play a role in advancing access to emerging innovations that improve health outcomes for a wide array of Medicare beneficiaries.

While additional evidence generation may be necessary in some cases, it is crucial the process involve collaboration between CMS and its stakeholders, such as medical device companies, in order to identify data collection objectives, appropriate study endpoints, methods, and duration of the data collection. In cases where CMS conditions coverage on the development of additional evidence, AdvaMed has advocated for policies that minimize administrative burden where possible.

We have stated repeatedly that when Medicare coverage is contingent on the collection of additional clinical or scientific evidence (beyond Food and Drug Administration (FDA) requirements for safety and efficacy), CMS should:

I. Proposed Coverage with Evidence Development (CED) Guidance

CED should be used to expand, and not restrict, coverage. AdvaMed has previously submitted comments to CMS regarding CED, including the Agency for Healthcare Research and Quality (AHRQ) draft report: Analysis of Requirements for CED2, and most recently provided public comments at the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) meeting on Analysis of CED³. We were pleased to see some of our recommendations made to AHRQ were incorporated into this proposed guidance.

Within the background section of the guidance document CMS states, “For new technologies, it is rare that there is sufficient clinical evidence to support broad national coverage under section 1862(a)(1)(A).” We respectfully disagree with this statement and believe that it is not always necessary to require CED for new and/or novel technologies. First, this statement does not take into account many technologies that have developed substantial clinical evidence in the Medicare population prior to seeking coverage, and therefore do not require CED. Second, there is also a category of new technologies that have a sufficient level of evidence to support a reasonable and necessary determination under limited circumstances, but real-world data is needed to inform long-term national coverage. Currently, CMS defers these products to local Medicare Administrative Contractors for coverage. CMS should provide additional guidance to manufacturers on this category of products, where CED is not needed, but some real-world data may be needed to bridge the data gap to obtain national coverage.

Recommendations:

AdvaMed recommends that this sentence be revised to reflect that sufficient evidence is generated by manufacturers of new technologies in some cases, such as: “For some new technologies, evidence may be insufficient to support broad national coverage under 1862(a)(1)(A)”

AdvaMed recommends CMS provide additional guidance to manufacturers on methods for achieving national coverage determination for products that meet the reasonable and necessary standard, but may need to provide some real world data outside of CED to bridge the data gap to obtain national coverage.

Clinical Study Standards for CED under Section 1862(a)(1)(E)

We recognize that this section has been significantly updated and expanded based on the work done by AHRQ and MEDCAC over the last two years, and we appreciate that many of comments submitted by AdvaMed on the standards language and requirements were incorporated into the guidance documents. We support efforts to impart more transparency and predictability into the processes for Medicare coverage, and we believe that these standards provide a step in the right direction to providing more clarity to manufacturers. However, we urge CMS to provide flexibility for manufacturers when these standards are operationalized into the CED process, especially given the wide and varied range of medical technologies and their intended uses. During this process, CMS should consider the practical challenges associated with generating evidence and consider all levels of valid scientific evidence.

Recommendation:

AdvaMed recommends that CMS exercise flexibility in the interpretation and application of these standards.

Ending CED

AdvaMed continues to believe that the termination date of a CED for the identified use of an item or service should be discussed and agreed upon in advance by CMS and the study sponsors. We support language within the guidance document that states CED-required data collection should have an established start and end dates as part of the Evidence Development Plan (EDP). We recognize flexibility will be important in this regard. As noted in the TCET notice, development of an EDP will involve CMS determining in advance the duration of the data collection, or the specific issues or questions CMS seeks to address through data collection. This will create “stopping rules” for data collection and avoid burdensome and costly data collection without a clear end point. We encourage CMS to ensure these are tenets of CED are applied broadly, whether inside or outside the TCET program. Additionally, between the end of the study and the Agency’s review of the scientific results, there is a potential under CED for a gap to occur in coverage. We urge CMS to ensure continuous coverage of an item or service after a study ends, to avoid disruption in coverage and continue to allow Medicare beneficiaries to benefit from important FDA-approved technologies and services until a new or revised coverage determination is issued.

Recommendations:

AdvaMed agrees with CMS that CED as a condition of coverage should not last indefinitely, and further agrees the EDP should include established start and end dates. Also, the EDP should include interim analysis check points to assess if sufficient data is being collected, or if all the data is available at this point, a revised NCD could be expedited once results are published.

CMS should ensure there are no gaps in coverage between the conclusion of a CED study and issuance of a permanent NCD.

Transparency of CED

In this section of the proposed guidance document, CMS states, “the NCD process, in general, is a transparent one.” However, this transparency, in terms of informing stakeholders regarding proposed coverage determinations and providing opportunity to provide input, occurs only after a National Coverage Analysis is opened. Besides what is posted in the Medicare Coverage Database, there is not much transparency from CMS regarding how the Agency manages NCD requests, prioritizes requests, or keeps track of requests in the queue for future review (the “waiting lists”). CMS at one point did publish an NCD waitlist dashboard on its website, but has not updated it since September 2020.⁴ This dashboard was a positive step towards greater transparency. We urge CMS to update this waitlist dashboard to include all NCDs in process, including those that are part of the TCET program.

Recommendation:

AdvaMed recommends CMS provide greater transparency into the coverage process. At a minimum, CMS should update the NCD waitlist dashboard to include all NCDs, CEDs, and TCET applications, including any NCD reconsiderations.

II. National Coverage Analysis Evidence Review Proposed Guidance Document

As stated previously, AdvaMed has long supported both policy and process improvements that would result in a predictable pathway to national Medicare coverage for new medical devices and diagnostics, and this new proposed guidance on National Coverage Analysis Evidence Review provides useful information to aid manufacturers in navigating this process.

Methodological Principles

Within this section, CMS describes methodological principles that the Agency considers when reviewing clinical evidence, and notes that each NCD has its unique methodological aspects. While we appreciate CMS acknowledging the uniqueness of each NCD, we are still concerned that some of these may not be feasible for medical device products. For example, the requirements of “use of randomization”, “large sample sizes”, and “masking” for the studies are problematic given the unique characteristics of medical devices. Unlike pharmaceutical products, it may not always be feasible to conduct a double-blinded. head-to-head comparison in a trial for medical devices due to issues such as ethical concerns or a low volume of the procedure in which the device is used. Therefore, we strongly suggest that CMS revise this language to appropriately differentiate between drugs and medical devices in the NCD evidence review requirements.

Additionally, at the end of this section CMS states it, “carefully considers the funding source and potential conflicts of interest for study investigators.” AdvaMed agrees with CMS that thorough assessment of individual studies generating evidence for Medicare coverage is critical to assess their methodological rigor. However, we urge CMS to not dismiss company-funded research as automatically presenting a conflict of interest, but to instead review whether steps were taken to manage any potential conflicts, including disclosure of funding relationships with the Principal Investigator.

Recommendations:

AdvaMed recommends CMS revise the methodological principles to appropriately differentiate drugs and medical devices in the NCD evidence review requirements.

CMS should not dismiss company-funded research automatically but instead review whether steps were taken to manage any potential conflicts.

Review of Individual Studies

We are encouraged that CMS endorses the concept that studies should be fit-for-purpose, where the study design, analysis plan, and data source(s) should be sufficient to credibly answer the question(s) it intends to answer. AdvaMed supports CMS’ willingness to incorporate robust fit-for-purpose evidence development into the TCET program, and we look forward to the Agency’s forthcoming guidance. These studies will be crucial to ensuring the TCET program can work to accelerate coverage and close evidence gaps in a timely manner. We urge that the guidance be released soon and allow opportunity for stakeholders to comment. Additionally, within this section CMS describes evidence they may consider, but leaves questions around what evidence is required and which data is captured during the review. More specifically, we seek clarity on whether CMS will accept unpublished evidence or prepublication manuscripts during the systematic review of findings.

Recommendations:

AdvaMed supports CMS’ efforts to incorporate fit-for-purpose studies, and encourages release the forthcoming guidance soon and allow opportunity for stakeholders to comment.

AdvaMed seeks clarity on exactly what evidence will be considered as part of the systematic review, such as unpublished evidence or prepublication manuscripts.

III. Proposed Clinical Endpoints Guidance: Knee Osteroarthritis

CMS issued this proposed guidance document to provide the public with the health outcomes of interest to CMS when reviewing technologies for the treatment of knee osteoarthritis when considering reasonable and necessary NCDs. CMS indicates that the overall objective for this guidance document, as well as the noted plans for subsequent endpoints guidance documents in other therapeutic areas, is to improve the transparency of the NCD process.

AdvaMed is supportive of both the efforts to increase transparency and to release additional endpoints guidance documents for other therapeutic areas. To facilitate this process, AdvaMed encourages CMS to publish on its website a list of therapeutic areas for which CMS plans to release guidance documents, including anticipated release dates. This will provide manufacturers transparency on timing for anticipated guidance documents. We also encourage CMS to provide an opportunity for stakeholders to comment on these documents before they are finalized.

Recommendations:

AdvaMed encourages CMS to publish on its website a list of therapeutic areas for which CMS plans to release guidance documents, including anticipated release dates.

CMS should allow public comment on any subsequent guidance documents in other therapeutic areas prior to finalizing the guidance.

We greatly appreciate the opportunity to comment on these three guidance documents. If you have questions regarding these comments or if you require additional information, please contact Tara Burke at tburke@advamed.org.

Sincerely,

/s/
Tara Burke, PhD
Vice President, Payment and Healthcare Delivery Policy
AdvaMed

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1 Federal Register, Vol. 88, No. 122, pp.41633-41644, June 27, 2023
2 https://effectivehealthcare.ahrq.gov/products/coverage-evidence-development/research-report
3 https://www.cms.gov/medicare-coverage-database/view/medcac-meeting.aspx?medcacid=79
4 https://www.cms.gov/files/document/ncd-wait-list.pdf

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Abbott welcomes the opportunity to comment on the Centers for Medicare & Medicaid Services’ (CMS) Medicare Coverage with Evidence Development Proposed Guidance Document (Proposed CED Guidance).

Abbott is a global healthcare leader that helps people live more fully at all stages of life. Our portfolio of life-changing technologies spans the spectrum of healthcare, with leading businesses and products in diagnostics, medical devices, nutritionals and branded generic medicines. Our 115,000 colleagues serve people in more than 160 countries.

As a leading medical technology manufacturer, we seek to ensure that Medicare policies promote beneficiary access to high-quality healthcare innovations that address unmet medical needs and improve health outcomes. We commend CMS for seeking to “encourage innovation and accelerate beneficiary access to new items and services” by providing “a framework for more predictable and transparent evidence development” for National Coverage Determinations (NCDs) that include a CED component. We would like to offer our comments on the following aspects of the Proposed CED Guidance:

We believe there are opportunities for CMS to provide additional clarity regarding the CED process. In particular, we recommend that CMS expedite the release of additional draft process guidelines, subject to public comment, detailing the timeline for key milestones throughout the CED process, from initial consultations between manufacturers and CMS through Medicare Administrative Contractor (MAC) implementation of NCDs. We also request that CMS explain any differences between the processes/timelines CMS envisions for (1) the NCD process with no evidence collection requirement, (2) the NCD process with a CED requirement, and (3) the NCD process under the proposed “Transitional Coverage for Emerging Technologies” (TCET) pathway.

Regarding the principles governing the application of CED, we agree that CMS should impose CED requirements only in those cases in which the available evidence for a technology does not demonstrate that the statutory reasonable and necessary standard is met. Any CED clinical study requirement should be narrowly tailored to address specific evidence deficiencies.

We request confirmation that data elements posted on the ClinicalTrials.gov site satisfy the CED requirement for a written plan describing the “schedule for completion of key study milestones, including results reporting.”

We recommend that CMS clarify that Medicare coverage will continue for patients after CED study enrollment has ended but before a revised NCD is issued to maintain patient access to care.

Our specific recommendations follow.

I. Timeline and Process for CED Development

According to CMS, the Proposed CED Guidance “represents CMS’ current thinking on the factors CMS considers in making NCDs using the [CED] paradigm.” We appreciate CMS providing additional information regarding the principles CMS intends to apply in establishing CED requirements and various clinical study standards. We believe that gaps remain, however, in transparency regarding key procedural steps and timelines for CMS development of NCDs with CED requirements.

The lack of guidance on the CED timeline and milestones contrasts with CMS’s proposed approach for the TCET pathway. The proposed TCET notice sets forth detailed CMS timeframes throughout the coverage development process, including acceptance into the TCET program, benefit category review, evidence preview, third-party finalized evidence development program, opening of the NCD process, and release of proposed and final TCET NCDs. On the other hand, there is no established timeline for CMS response to a formal request for an NCD, with or without a CED component; formal acceptance can take many months or even exceed a year. While CMS notes that the Agency for Healthcare Research and Quality (AHRQ) reviews all CEDs, the TCET notice observes that “CMS and AHRQ have made iterative refinements to the CED coverage pathway over time,” and there is not public visibility into the evolution of these requirements. The Proposed CED Guidance also is silent on the CMS timeline for consideration of individual CED study requests, either concurrently during the coverage analysis stage or after an NCD with a CED requirement is finalized. Likewise, after an NCD with or without CED is finalized, there is no established timeline for CMS to issue a transmittal to MACs with NCD implementation instructions, which can cause confusion for providers, beneficiaries, MACs, and Medicare Advantage plans in the interim.

To enhance the predictability and transparency of the CED process, we recommend that CMS expedite the release of draft process guidelines, subject to public comment, providing additional clarity throughout the entire CED process, from initial consultations between manufacturers and CMS through NCD implementation. We request that these draft guidelines include details regarding the timeline for at least the following steps in the CED process:

Pre-NCD meetings between potential requestors and CMS, including the recommended timeline for requestors to contact CMS relative to the timing of anticipated FDA market authorization for new technologies.

CMS acceptance of a formal request for an NCD, including a timeframe for any determination that a request is not a “complete, formal request” for an NCD and specification of what CMS considers to be lacking in the request. For instance, in the proposed TCET notice, CMS states that it will contact the manufacturer by email to confirm that a submitted nomination appears to be complete and is under review by CMS. Further, “CMS commits to making at least a preliminary decision to provisionally accept or decline a nomination within 30 business days following the date noted in CMS’ email to manufacturer.” Establishment of a similar timeline for NCDs outside of the TCET pathway would be helpful.

The evidence review process, including any evidence review activities that precede acceptance of the NCD, and the timing and triggers for AHRQ review and/or any other third-party evidence review.

The stage at which CMS determines that a technology does not meet the “reasonable and necessary” standard for Medicare coverage without additional evidence development through a CED, and how that determination impacts the external review process or any other aspects of the NCD timing.

The earliest point in the NCD/CED process at which specific study requests for a CED review will be considered.

Opportunities for the requestor to provide input during the national coverage analysis process, including during the evidence review process and development of study protocols.

Targets for CMS issuance of implementation instructions to the MACs following finalization of an NCD.

We recommend that the requested draft document highlight any differences between the processes/timelines CMS envisions for (1) the NCD process with no evidence collection requirement, (2) the NCD process with a CED requirement, and (3) the NCD process under the new TCET pathway. A side-by-side flow chart illustrating the timelines and procedural steps under each pathway would enhance clarity.

II. Principles Governing the Application of CED

The Proposed CED Guidance adds new language to CMS’s principles governing the application of CED to clarify that CED will generally expand access to medical technologies for beneficiaries “because the technologies would not otherwise meet the reasonable and necessary coverage standard under section 1862(a)(1)(A) of the Social Security Act.” The Proposed CED Guidance also clarifies that “the CED will require the generation of evidence that addresses specific evidentiary deficiencies identified in National Coverage Analyses” (rather than the current statement that “CED will lead to the production of evidence complementary to existing medical evidence” ).

We support both clarifications. We believe that CMS should impose CED requirements only in those cases in which the available evidence for a technology does not demonstrate that the statutory reasonable and necessary standard is met. Any clinical study requirement should be narrowly tailored to address specific evidence deficiencies. We likewise share CMS’s view that the “fit-for-purpose” concept is useful for considering the type of study design that is sufficient to answer the narrow research question posed by the CED.

III. Clinical Study Milestone Requirement

Section VI of the Proposed CED Guidance addresses “Clinical Study Standards for CED under Section 1862(a)(1)(E).” In this section, CMS proposes certain features for agreements a study sponsor would enter into with CMS to voluntarily participate in a CED trial under an NCD. Among other requirements, CMS proposes that the CED agreement with a sponsor or study site would address the following condition:

A written plan is in place that describes the schedule for completion of key study milestones, including results reporting, to ensure timely completion of the CED process.

We request confirmation that data elements posted on the ClinicalTrials.gov site are sufficient to satisfy the requirement for a written plan describing the “schedule for completion of key study milestones, including results reporting.” CMS states that it intends “to maintain information on ongoing CED research studies on its website along with links to the ClinicalTrials.gov website maintained by the National Library of Medicine.” CMS also notes that the ClinicalTrials.gov listing includes “a standardized set of data elements to describe the study design, eligible populations, outcome measures, and other parameters and results.”

To the extent CMS seeks any additional information to fulfill the “key study milestones” provision, we request that CMS define this term precisely. We also recommend that CMS specify that any information it seeks beyond what is reported on ClinicalTrials.gov may be provided confidentially to CMS, rather than posted publicly.

IV. Ending CED/Continued Patient Access During NCD Reconsideration

The Proposed CED Guidance states that a “CED cycle is considered completed when CMS completes a reconsideration of the CED coverage decision and removes the requirement for study participation as a condition of coverage.” CMS also affirms the need to “minimize delays in transitioning from a CED NCD to coverage without evidence development requirements.” CMS recommends that sponsors “build interim analyses into their study design and communicate these results to CMS,” which could support expediting a revised NCD once the study is completed and the results are published.”

The Proposed CED Guidance does not address coverage for patients after CED study enrollment has ended but before CMS completion of the NCD reconsideration. We request that CMS clarify that Medicare CED coverage will continue during the NCD reconsideration process, even after required CED study enrollment is completed, to maintain patient access to care. We also request that details regarding this continued access period, including any requirements for evidence collection beyond the CED study primary analysis population, be negotiated and agreed to by CMS prior to the end of primary study enrollment to ensure beneficiary access is not interrupted or delayed unnecessarily.

* * * * *

We appreciate your consideration of our comments. Please feel free to contact me if you have any questions or if you need additional information.

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August 21, 2023

The Honorable Chiquita Brooks-LaSure
Administrator
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Centers for Medicare and Medicaid Services; Proposed Coverage with Evidence Development Guidance

Dear Administrator Brooks-LaSure:

In service of the neuromuscular disease (NMD) patient community, the Muscular Dystrophy Association (MDA) thanks the Center for Medicare and Medicaid Services (CMS) for the guidance released on June 22nd, 2023, about the Proposed Coverage Evidence Development Guidance as required by Section 1862(l)(1) of the Social Security Act (the Act).

MDA is the #1 voluntary health organization in the United States for people living with muscular dystrophy, ALS, and related neuromuscular diseases. For over 70 years, MDA has led the way in accelerating research, advancing care, and advocating for the support of our families. MDA’s mission is to empower the people we serve to live longer, more independent lives.

Background:

For an item or service to be covered under Medicare, it must be “reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.” Social Security Act, 42 U.S.C. 1395y(1)(A). Under current policies, CMS determines whether specific devices and technologies are reasonable and necessary through various pathways (e.g., National Coverage Determinations (NCDs), local coverage determinations (“LCDs”), claim-by-claim adjudication, Coverage Evidence Determinations (CED), etc.). Given the NMD community’s reliance on the technologies considered by these practices, we ask that CMS continue to consider the unique perspective brought and challenges faced by those with rare neuromuscular diseases. To best support these communities, we offer the following recommendations:

CMS’ Consideration of Quality of Life Data in the CED Process:

Throughout its consideration of data points relevant to a CED process, CMS routinely refers to quality of life as a potentially relevant metric “when combined with physiologic or structural outcomes.” Centers for Medicare and Medicaid Services Coverage with Evidence Development Proposed Guidance Document Issued June 22, 2023. https://www.cms.gov/medicare-coverage-database/view/medicare-coverage-document.aspx?mcdid=35 While we appreciate CMS’ willingness to look at benefits that may not be present in statistical data, such as the freedom and autonomy provided to those who can now access seat elevation systems due to CMS’ recent coverage of those devices (MDA Comments on Seat Elevation Systems). This consideration does raise concerns that CMS may turn to flawed measures similar to Quality-Adjusted Life-Years (QALYs) and other harmful utilization management metrics. We would, therefore, ask that CMS consider these factors wholistically and not through a harmful metric such as those similar to QALYs. QALYs rely on an inherently ableist and utilitarian concept of quality of life and assumes outcomes for able-bodied patients in perfect health. Such ableist assumptions about what constitutes a “good” quality of life in determining treatment effectiveness for patients with disabilities fail to consider other factors such as emotional wellbeing, the personal wishes, and aspirations of the patient, the will to live, and the personal beliefs of the patient, among others. As such, we ask that CMS refrain from considering these and other similar harmful metrics when considering additional benefits of CEDs to patients.

Consideration of those Receiving Care in a Home and Community Based Setting:

In considering the CED standard that “When feasible and appropriate for answering the CED question, data for the study should come from beneficiaries in their expected sites of care,” we would urge CMS to consider those beneficiaries who receive care in Home and Community Based (HCBS) settings. HCBS is vital for many in the NMD community as it allows them to stay in their homes and communities as their disease progresses. These services present a unique set of challenges and benefits, such as the impact of a device or therapy on disease progression, the utility of a device in personal autonomy or safety in the home, or the benefit of a device to a caregiver in the home. As such, HCBS should be considered in CMS’ evidentiary determinations.

Surrogate Endpoints and Accelerated Approval:

Within this proposal, CMS expresses skepticism over the use of surrogate endpoints within the accelerated approval pathway to gain FDA approval. For example, CMS states, “Surrogate outcomes are not direct measures of clinical benefit, and there is often little evidence at this point regarding health outcomes”. Later, CMS expresses a greater openness to use of surrogate endpoints within the context of CEDs, saying, “The primary health outcome(s) for the study are those important to patients and their caregivers and that are clinically meaningful. A validated surrogate outcome that reliably predicts these outcomes may be appropriate for some questions.”

MDA encourages CMS to consider that an accelerated approval using a surrogate endpoint at times may be the only viable approval pathway for certain slowly progressive genetic diseases in which a statistically significant clinical benefit may be impossible to obtain over the standard duration of a clinical trial. Instead, if a treatment is able to restore the missing or malfunctioning protein that is causing the disease, this points to being an effective treatment.

Disregarding these realities will only lead CMS to disproportionately punish those with slowly progressive genetic conditions with adverse coverage determinations or onerous CED requirements.

Diversity in CEDs and Clinical Studies:

We share CMS’s goal to ensure the studies that contribute to CEDs are diverse and accurately reflect the populations that may receive the intervention upon coverage. For example, we contributed to efforts that led to clinical trial diversity legislation being enacted in 2022, and are engaged in further efforts in Congress and at the FDA to make clinical trials more diverse.

While we share these goals, challenges in making clinical studies diverse should not be a reason for requiring CED studies that limit access to therapies. Crafting well-run and representative rare disease clinical studies is incredibly difficult, and often the rarity of the disease may make it impossible to include many individuals over the age of 65. While this should be addressed with better trial design, it should not lead to limitations on coverage, particularly in rare diseases where sample sizes are miniscule to begin with.

Redundancy with FDA Requirements:

Within the guidance, CMS states, “CED will not duplicate or replace the FDA’s authority in assuring the safety and effectiveness of drugs, biological products, and devices”. We certainly concur with this goal, and ask CMS to expand on how requiring a CED of an innovative treatment that has been deemed safe and effective for the labeled population does not duplicate FDA’s authority. We fail to foresee a situation in which a treatment has obtained FDA approval for a particular population, and any CED created for that very same population is not duplicative of the studies already completed that provided the necessary data to prove safety and effectiveness.

CEDs as Voluntary

CMS states that “participation in CED studies is voluntary both for beneficiaries and trial sponsors and participating study sites.” While we hope this to be true and accurate, our understanding is that recent CED studies were required BEFORE certain FDA-approved treatments would be made available to the broader Medicare population, and the only way in which that FDA-approved treatment could be accessed at all was through the CED study.

This obviously in not voluntary for anyone involved. It is not voluntary for the Medicare beneficiaries who wish to access the FDA-approved treatment as participating in the CED study is the only way to obtain the treatment. It is not voluntary for the trial sponsor as conducting the CED study was the only way for the treatment to be accessible in the Medicare program, and the only way for the treatment to potentially become accessible for all beneficiaries later on.

We ask that CMS clarify how CED studies are voluntary in the situation described above.

Conclusion:

MDA is committed to ensuring that individuals with neuromuscular diseases have access to drugs and devices to promote safe and healthy lives. We encourage CMS to consider all relevant data for Coverage Evidence Determinations.

We appreciate this opportunity to provide comment on CMS’ Coverage with Evidence Determinations. For questions regarding MDA or the above comments, please contact advocacy@mdausa.org

Sincerely,

Paul Melmeyer, MPP
Vice President, Public Policy and Advocacy
Muscular Dystrophy Association

Joel Cartner, Esq.
Director, Access Policy
Muscular Dystrophy Association

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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Coverage with Evidence Development Proposed Guidance Document, June 22,2023
Coverage and Analysis Group, Centers for Medicare & Medicaid Services (CMS), Health and Human Services (HHS)
Maiistop: S3-02-01, 7500 Security Blvd.
Baltimore, MD 21244
RE: CIBMTR comments

The Center for International Blood and Marrow Transplant Research (CIBMTR) is a clinical research program dedicated to addressing important issues in the field of Hematopoietic Cell Transplantation (HCT) and Adoptive Cell Therapy (ACT). CIBMTR maintains a large outcomes registry of real-world data with information for >625,000 HCT/ACT patients in treatments centers in the United States (US) and globally and provides statistical support and scientific expertise for analyzing those data. The CIBMTR registry data is routinely used to fill in knowledge gaps where randomized trials were not feasible.

Many patients with specific diseases and/or at certain ages are denied access to cellular therapy in the US due lack of insurance coverage by the Centers for Medicare and Medicaid Services (Medicare). To help secure Medicare coverage for these patients, CIBMTR, the National Marrow Donor Program (NMDP) and The American Society of Transplant and Cellular Therapy (ASTCT), along with other organizations partnered with Medicare to launch HCT-relevant CED studies. These CED studies allow Medicare to provide coverage to patients enrolled on the clinical studies that inform policy decisions. Recognizing the importance of the Medicare CED process, CIBMTR has been engaged in Medicare CED studies since 2010 and is currently supporting 5 studies focused on myelodysplastic syndrome, myelofibrosis, and multiple myeloma for patients older than 65 and sickle cell disease for adolescents and adults; 7,295 patients have received transplants with Medicare reimbursement because of these studies.

Given CIBMTR's experience with the design, development, and implementation of Medicare CED studies, we recognize the thoughtful approach provided within the Proposed Guidance and respectfully provide the following comments:

We advocate for studies that are straightforward, transparent, and timely: Study design should support timely access to the population of interest, use of current technologies and clinical frameworks, and relevant and timely policy decisions. As proposed, a requirement for a written plan describing a schedule of completion and key study milestones should support timeliness as a cornerstone of the study design as well as completion. We continue to advocate for a straightforward approach to study design that supports access to the population of interest and with some consideration of current and future relevancy to the clinical field as well as to other stakeholders. Consideration of a mechanism for early dialogue about proposed CEO language that includes key stakeholders, such as CIBMTR, could be considered to help mitigate potential issues.

It is important to recognize that these studies may have no source of funding for "evidence development." Clinical studies are costly, and the lack of a funding mechanism represents a real limitation to their fulfillment. The Proposed Guidance assumes an avaiiabie funding source, or that evidence development will occur during the usual course of clinical care. That is not always the case and, if possible, funding mechanisms should be considered for each CED indication.

There is a need for additional clarity around the translation of study results into a National Coverage Determination (NCD), clarification of what evidence is needed to effect policy change and, using study results, a transition plan bridging the time between a study and a final NCD. While the Proposed Guidance speaks to timely publication of results and, when appropriate, inclusion of interim analyses supporting evidence it does not provide guidance specific to a decision of NCD. As noted below, gaps in coverage are life-threatening for certain popuiations.
A CED study plan will have both a start and end date, along with a defined popuiation type and enrollment necessary for its statisticai analysis plan. There are three time periods during which beneficiaries face a strong potential for lack of coverage during a Nationai Coverage Analysis invoiving a CED: 1) during the initial NCA process, which takes between 9-12 months, 2) during the time-period between reaching the study accrual target and either an extension or additional CED-compliant study being approved, and 3) during the 9-12 month reconsideration time-period at the end of a CED. The time periods cited above are the stated minimum based on federal response standards. However, the process often takes longer. For individuals needing HCT to treat their disease, for example, these gaps in coverage (and therefore access) are lifethreatening - patients that are candidates for HCT may have limited treatment options to bridge these time periods.

There is a need for communication toois to help centers and patients better understand billing and reimbursement under CED that is not addressed in the Proposed Guidance. CMS should develop better communication tools to help centers who treat patients under CED to better align billing codes to ensure appropriate reimbursement for care delivered under CED. Centers participating in CIBMTR CED studies and enrolling patients have had substantial difficulty navigating the biliing system and receiving reimbursement, which may limit access for patients in certain health systems if there is a lack of confidence in reimbursement despite CED.

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August 18, 2023

Dr. Joseph Chin, M.D.
Coverage and Analysis Group
Centers for Medicare and Medicaid Services
mailstop: S3-02-01, 7500 Security Blvd.
Baltimore, MD. 21244
CAGInquiries@cms.hhs.gov

Dear Dr. Chin:

The Partnership to Improve Patient Care (PIPC) appreciates this opportunity to comment on the Proposed Guidance Document for Coverage with Evidence Development (CED). We share the agency’s concerns that a framework is needed for more predictable and transparent evidence development. We hope our comments are useful in finalizing a framework that is centered on achieving outcomes that matter to patients and people with disabilities.

Since its founding, the Partnership to Improve Patient Care (PIPC) has been at the forefront of applying principles of patient-centeredness to the nation’s health care system – from the generation of comparative clinical effectiveness research at the Patient-Centered Outcomes Research Institute (PCORI), to the translation of evidence into patient care in a manner that achieves value to the patient. Having driven the concepts of patient-centeredness and patient engagement in the conduct of research, PIPC looks forward to bringing the voices of patients and people with disabilities to the discussion of how to advance patient-centered principles throughout an evolving health care system.

Our comments focus on the following concerns and recommendations:

CED guidance should promote early and consistent engagement of patients and people with disabilities.

Patient safeguards should promote health equity, not restrict access to care.

CED should focus on real world data collection.

CMS should establish standards for meeting evidence generation requirements.

CED should clearly acknowledge and abide by the laws barring use of QALYs and similar measures.

CED guidance should promote early and consistent engagement of patients and people with disabilities.

Patients and people with disabilities should be engaged in CED determinations beyond written notice and comment opportunities. This includes AHRQ’s prioritization of the needs and priorities of the Medicare program, determinations of whether evidence is “insufficient” to determine “reasonable and necessary,” and determinations of the CED measured outcomes that will address “specific evidentiary deficiencies.” Early stakeholder engagement, including impacted patient communities, should first seek to understand the patient perspective related to whether a treatment is reasonable and necessary and whether it should be subject to CED. Once a determination is made to subject a treatment to CED, patient stakeholders should be engaged in identifying the specific evidentiary deficiencies, with ongoing engagement to identify the data to be collected to address such specific deficiencies.

PIPC had limited experience with the TVT Registry Project for TAVR in its early stages, in which patients were engaged but the goals of data collection were not particularly clear, leading to concerns about burdensome data collection requirements for providers without a clear understanding as to what data was required to be collected to achieve the “reasonable and necessary” standard. While patients had a seat at the table in the later stages of data collection for the TAVR CED, it was not clear how patients were engaged early in the process of selecting specific deficiencies on which data was to be collected, which would have made it much easier to then determine how to collect data and what information was important to be reported.

By updating its guidance, CMS can incorporate what has been learned from past CEDs to provide an improved framework for patient engagement. We would encourage CMS to build on the engagement best practices of entities such as the Patient-Centered Outcomes Research Institute (PCORI).¹ Similar to PCORI, CMS and sponsors of data collection activities should engage patients and people with disabilities and establish a predictable process for engagement in the CED process. This includes meaningful roles for patients and people with disabilities throughout the process, including in Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) deliberations, in the implementation of data collection and the conclusion of a CED.

Patient safeguards should promote health equity, not restrict access to care.

We are concerned that CMS is advancing its goal of ensuring that systematic patient safeguards are in place by potentially advancing policies that encourage CED to restrict access to care for certain patients. Restricted access to care can have the unintended consequence of entrenching health disparities and work against the agency’s goals of health equity by making it harder for treatments to reach the populations most in need. Once FDA has approved a treatment, it is important to recognize that safety and effectiveness is already established. At that point, patients should be safeguarded against restricted access to a treatment that FDA has deemed to have evidence of effectiveness, particularly patients with few other options. Achieving broad knowledge of how a treatment impacts subgroups requires more, not less, access to the treatment on which data is being collected.

CED should focus on real world data collection and its use in shared decision-making.

We share concerns about representation in pivotal studies due to factors such as age and disability, and therefore strongly support subgroup analyses. For CED to generate real world evidence will require broad access to new treatments, consistent with the CMS principles seeking to expand access to medical technologies. Real world data collection will further support health equity by increasing the representation of subgroups in the evidence base and therefore expand information about a treatment’s clinical benefit for those subgroups.

With real world evidence, CMS will be in a stronger position to advance its program for shared decision-making authorized by the Affordable Care Act to support preference sensitive care.² A 2018 letter strongly encouraged CMS to advance shared decision-making fundamentals for healthcare organizations, establish a measurement framework for shared decision-making, and then implement the “Drivers of Change” outlined by the National Quality Partners Playbook: Shared Decision-Making in Healthcare.³ Advocacy organizations have recommended, “Providers whose reimbursement may be impacted by incentives to conduct shared decision-making should have appropriate guidance from CMS, and patients should have assurances that shared decision-making will empower them, not overwhelm them or steer them to a payer-preferred treatment.”⁴ While the Playbook is careful not to recommend shared decision-making as a requirement of CED, we urge CMS to recognize the significance of real world evidence to inform discussions between patients and providers and drive improved treatment decisions based on how treatments impact patients with similar needs, preferred outcomes and characteristics.⁵ Real world evidence can address the need articulated by advocates for “specialized training to develop providers’ person-centered communication capabilities, validation that patient decision aids meet the quality standards outlined in the Playbook and deference in coverage decisions to the outcome of a high-quality shared decision- making process.”⁶ CMS should focus its efforts on improving shared decision-making and supporting preference sensitive care, a core component of the statute establishing a Shared Decision-Making Program within CMS.

CMS should establish standards for meeting evidence generation requirements.

We are concerned that the standards for evidence generation to support coverage and data quality are not clearly defined, i.e. when evidence of health outcomes is determined to be sufficient. It is important to recognize that CMS sets the standard for some payers and that researchers will respond to CMS standards for high quality patient-centered evidence. For example, CMS indicates that some CEDs may require randomized clinical trials with placebo. Yet, upon FDA approval, we question whether a control group provided a placebo can be done ethically or morally when a treatment is already deemed safe and effective. Instead, we would urge generation of real-world evidence be the focus of CED, with the intent of extending more access to treatment, not less. In the draft guidance, it is also not clear how a CED is determined to have served its evidentiary purpose so that a treatment may go on to be fully covered. We are concerned that a CED could be misused to restrict access to certain treatments, particularly treatments for rare diseases and conditions or treatments for conditions that have few, if any, options. CMS should be clear in its guidance that CED is only intended to generate the evidence needed to meet the “reasonable and necessary” standard, with significant weight given to the patient and disability perspective as to whether that standard has been met.

CED should clearly acknowledge and abide by the laws barring use of QALYs and similar measures.

By law, CMS cannot reference measures of effectiveness that devalue disabled lives or discriminate to determine whether a treatment will be subject to CED.^7,8 We are concerned that the MEDCAC has referenced studies utilizing the quality-adjusted life year (QALY) in the past as part of its National Coverage Decision process, twice leading to a decision to subject a treatment to CED,^9,10 despite enactment of provisions in the Affordable Care Act (ACA) barring use of QALYs in Medicare coverage decisions.¹¹ In the final guidance, we urge CMS to acknowledge current nondiscrimination laws and the ban on using QALYs and similar measures to make Medicare decisions, including those related to coverage through CED.

In closing, we appreciate CMS’ efforts to provide clarification of its CED authority through updated guidance. We hope that the final guidance will reflect policies that are centered on the needs of patients and people with disabilities, especially those with few options for treatment that stand to benefit most from newly approved treatments by the FDA.

Sincerely,

Tony Coelho
Chairman
Partnership to Improve Patient Care

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1 PCORI, “Engagement Rubric for Applicants,” Patient-Centered Outcomes Research Institute, last modified June 6, 2016, https://www.pcori.org/sites/default/files/Engagement-Rubric.pdf.
2 Patient Protection and Affordable Care Act. Section 936 [42 u. S. C. 299b-36] program to facilitate shared decision making. 2010.
3 See http://www.pipcpatients.org/uploads/1/2/9/0/12902828/sdm-letter-to-cms-final.pdf
4 See http://www.pipcpatients.org/uploads/1/2/9/0/12902828/sdm_comment_on_interoperabiity_final.pdf
5 See http://www.pipcpatients.org/uploads/1/2/9/0/12902828/pipc_sdm_lung_cancer_ncd_final.pdf
6 See http://www.pipcpatients.org/uploads/1/2/9/0/12902828/sdm_comment_on_interoperabiity_final.pdf
7 29 USC Sec 794, 2017.
8 42 USC Sec 12131, 2017.
9 Tamra Syrek Jensen, et. al., “Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers,” Medicare Coverage Database, Centers for Medicare and Medicaid Services, August 7, 2019, https://www.cms.gov/medicare-coveragedatabase/view/ncacal-decision-memo.aspx?proposed=N&NCAId=291. (Reference to ICER report)
10 Tamra Syrek Jensen, et. al., “Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease,” Medicare Coverage Database, Centers for Medicare and Medicaid Services, January 11, 2022, https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=Y&NCAId=305. (Footnote to ICER report)
11 House of Representatives, Congress. 42 U.S.C. 1320e - Comparative clinical effectiveness research. U.S. Government Publishing Office, https://www.govinfo.gov/app/details/USCODE-2010-title42/USCODE-2010-title42-chap7-subchapXI-partD-sec1320e

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Coverage and Analysis Group
Center for Medicare & Medicaid Services
Department of Health and Human Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Comments on CMS’ Proposed Coverage with Evidence Guidance Document

Administrator Brooks-LaSure:

On behalf of the Alliance for Patient Access (AfPA), thank you for the opportunity to provide comment on the Center for Medicare and Medicaid Services (CMS) Coverage with Evidence Development (CED) Proposed Guidance Document. As CMS considers updates for National Coverage Determinations (NCD) using CED, we urge CMS to consider the challenges to appropriate access that CED poses to patients and providers.

About AfPA

Founded in 2006, AfPA is a national network of policy-minded health care providers who advocate for patient-centered care. AfPA supports health policies that reinforce clinical decision making, promote personalized care, and protect the physician-patient relationship. Motivated by these principles, AfPA members participate in clinician working groups, advocacy initiatives, stakeholder coalitions, and the creation of educational materials.

CED Impact on Access to Care and Lack of Transparency

CMS notes that CED is intended to expedite access to innovative therapies. However, in practice the CED requirement often serves the opposite role by placing restrictions on access to new FDA-approved treatments. Prior to approval, new treatments undergo rigorous review by the FDA for both safety and efficacy. When CMS restricts coverage by requiring further evidence development, these requirements for already-approved therapies are often burdensome for patients and providers and limit access to FDA-approved treatments.

CED has led to lengthy, complicated requirements for accessing treatment for patients and providers while yielding few results. A review of all CEDs issued, published by The American Journal of Managed Care (AJMC), found that there have only been four with retired evidence collection requirements and two redeterminations (1). Some CEDs have been in place for as many as thirteen years before reconsideration (2). CMS should establish and publish criteria for ending a CED cycle, including defined endpoints.

CMS should also add transparency requirements to ensure consistent CED application. Differing programmatic elements are required for each CED, making it difficult to set clear expectations when NCD with CED is issued. Unfortunately, the proposed CED guidance fails to address these inconsistencies and clarify any timeline or requirements for patients and providers.

AfPA urges CMS to clearly define its requirements and endpoints for the CED process in order to support providers and patients and ensure the best possible care. The proposed guidance should take steps to address current inefficiencies and ensure the process is not a deterrent for patient and provider participation.

Impact of CED on Health Equity

We are also concerned that any additional barriers from CED will continue to reinforce inequities for people of color, who are historically under-represented in such medical research. Despite the claim that FDA clinical trials “may not be generalizable to the Medicare population if Medicare beneficiaries are insufficiently represented,” CMS’s prior CED trials were often only accessible in large, metropolitan areas or near academic research centers (3). This left rural practices, private clinics, underserved communities, and smaller hospitals, that often lack the required infrastructure to participate in these programs, unable to meet the needs of their patients.

As stated previously, Black Americans are less likely to participate in clinical trial-like programs as a result of historic racism in clinical trials in the United States (4). One widely-cited study documented this, stating that “a number of barrier themes were identified in the study, including mistrust of researchers and the health care system, fear related to research participation, inadequate information about research and opportunities, [and] inconvenience…”(5). While we appreciate CMS’s goal of ensuring diverse clinical trials, continued use of CED will only serve to exacerbate the disparities that CMS seeks to ameliorate.

AfPA believes CMS should consider all barriers when designing or implementing CED. Requiring Medicare beneficiaries to participate in these burdensome programs contradicts the efforts to implement timely care and in fact, can limit access to innovative treatments.

Looking Forward

While developed with good intent, in practice CED has created challenging barriers and delays for patients, as well as burdensome requirements for providers. For Medicare beneficiaries, these delays can lead to disease progression, negative patient outcomes, and higher health care spending. For these reasons, CMS should limit the use of CED as much as possible and provide clear programmatic guidance in the Proposed Guidance document. Should CMS choose to institute CEDs, we would encourage you to place clear, structured parameters in place, as well as realistic duration timelines.

We appreciate the challenges that CMS faces and are pleased for this opportunity to provide insights on the impact of CED utilization. Please reach out to cmcpherson@allianceforpatientaccess.org or (202)951-7097 if AfPA can provide any further information.

Sincerely,
Josie Cooper
Executive Director
Alliance for Patient Access

(1) Zeitler EP, Gilstrap LG, Coylewright M, Slotwiner DJ, Colla CH, Al-Khatib SM. Coverage With Evidence Development: Where Are We Now?. Am J Manag Care. 2022;28(8):382-389. https://doi.org/10.37765/ajmc.2022.88870
(2) Ibid
(3) Ibid
(4) Scharff DP, Mathews KJ, Jackson P, Hoffsuemmer J, Martin E, Edwards D. More than Tuskegee: understanding mistrust about research participation. J Health Care Poor Underserved. 2010 Aug;21(3):879-97. doi: 10.1353/hpu.0.0323. PMID: 20693733; PMCID: PMC4354806
(5) Ibid

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August 21, 2023

Joseph Chin, M.D., M.S.
Acting Director
Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Attention: (Proposed) Coverage with Evidence Development
Mailstop: S3-02-01
7500 Security Blvd.
Baltimore, MD 21244

Re: Coverage with Evidence Development – Proposed Guidance Document

Dear Acting Director Chin,

Edwards Lifesciences (“Edwards”) appreciates the opportunity to comment on the proposed Coverage with Evidence Development (“CED”) guidance released by the Centers for Medicare & Medicaid Services (“CMS”) on June 22, 2023. In September 2022, Edwards submitted comments on the CED requirements as outlined in the Agency for Healthcare Research and Quality (“AHRQ”) draft report, “Analysis of Requirements for Coverage with Evidence Development – Topic Refinement.” Subsequently, in January 2023, Edwards commented in advance of the Medicare Evidence Development & Coverage Advisory Committee (“MEDCAC”) meetings on February 13, 2023, and February 14, 2023, to discuss the CED criteria. The comments in this letter regarding the proposed guidance build upon the previous submission.

Edwards is the global leader of patient-focused innovations for structural heart disease and critical care monitoring. Our technologies address patient populations in which there are significant unmet clinical needs, such as structural heart disease, heart valve disease and advanced monitoring of the critically ill. Many of our technologies are utilized in the care of Medicare patients undergoing higher-risk surgical procedures, especially in complex cases with severe comorbidities requiring specialized care. Because of this, we have a sincere interest in ensuring continuous improvement in the Medicare coverage landscape and also that patients have more timely and predictable access to life-saving medical technologies and services. Further, any changes to Medicare coverage policy must promote high quality care and ensure greater access to care for all beneficiaries.

Edwards supports and recognizes CMS’s authority to use CED. Section 1862(a)(1)(E) gives the agency coverage authority when conducting research using section 1142 when the items or services have not been deemed reasonable and necessary. The specific statutory reference follows:

"Section 1862(a)(1)(E) in the case of research conducted pursuant to section 1142, which is not reasonable and necessary to carry out the purpose of that section"[1]

Edwards believes in and invests in the evidence generation process for our technologies and supports the use of the National Coverage Determination (“NCD”) process, which utilizes CED in circumstances where additional clinical evidence is determined to be needed to demonstrate that the technologies meet the reasonable and necessary standard. NCD with CED requirements should only be used in those very specific circumstances in order to make a coverage determination. Edwards has been engaged with CMS and has committed to the CED pathway for more than a decade, first with the Transcatheter Aortic Valve Replacement (“TAVR”) CED and more recently with the Mitral Transcatheter Edge-to-Edge (TEER) CED. Given this, we offer the following principles and recommendations to improve the NCD with CED process. Our focus is on balancing the need for CMS to receive the additional evidence necessary to make coverage determinations, along with the desire to ensure broader and equitable

beneficiary access to new, ground-breaking FDA-cleared and approved products where there remains a significant unmet patient need.

NCD with appropriate CED requirements, when streamlined, efficient and time-limited, can be a powerful tool for CMS to ensure patients have timely and equitable access, while ensuring additional evidence is developed for promising technologies. In short, when properly utilized, it can offer benefits, including the following:

Allows patients in need to access innovative technologies sooner;

Addresses barriers to entry, helping smaller innovators bring competitive products to market; and

Decreases the cost and burden of product development by leveraging registry data.

I. Edwards CED Principles

As a member of the Advanced Medical Technology Association (“AdvaMed”), Edwards agrees with AdvaMed’s support for the NCD with CED pathway, and its recommendations of the following policy tenets, including (i) ensuring a timely and predictable process that is sensitive to patient needs, (ii) encouraging innovation, (iii) maintaining a transparent process, (iv) appreciating the practical challenges of evidence generation, and (v) supporting patient participation in clinical trials. We concur and offer the following additional principles that guide our recommendations for enhancing the NCD with CED pathway:

Patients’ timely access to FDA-approved and cleared innovative therapies for serious health conditions

Post-approval data collection of additional evidence where needed to:

- Address clinically relevant, unanswered or unresolved questions
- Provide patients, providers and regulators with meaningful information about outcomes
- Assess therapy performance in a real-world setting (beyond clinical trials)
- Improve quality through ongoing performance measurement
- Develop and improve upon innovations

Reduced administrative burden through “flexible coverage” that follows FDA-approved expanded indications within a therapy category

Time-limited with a clear endpoint for the CED defined based on when evidence gap is met.
These principles are critical to supporting patient access to innovation, while also producing the vital data necessary for CMS to make coverage determinations.

II. Feedback on Components of Proposed CED Guidance
Edwards appreciates the opportunity to provide feedback on the proposed CED guidance. As stated above, Edwards believes that CED, when properly utilized, can be a powerful tool for CMS to ensure additional evidence is developed while allowing patients to have early and broad access to promising new technologies. It is important, however, that the CED process is collaborative between CMS and the manufacturer and implemented in a least-burdensome way. From that perspective, Edwards offers feedback below on sections of the Proposed CED guidance which are shaped in part by the AHRQ report and findings from the MEDCAC meeting.

A. Clinical Study Standards
MILESTONE
In the proposed guidance, CMS states the following requirement for the study milestone (previously referred to as communication):

"A written plan is in place that describes the schedule for completion of key study milestones, including results reporting, to ensure timely completion of the CED process."

Edwards supports the submission of a written plan that outlines the targeted schedule of key study as well as defined evidence milestones, particularly to ensure a clear and final milestone that would signify the completion of the CED process. Patients, providers and innovators need to clearly identify the study objectives and the defined timelines in advance (including clear rules for sunsetting data collection requirements). This step is important for stakeholders to plan and invest accordingly and to guarantee CMS obtains the data required to evaluate products properly. As important, it is also critical so that innovators have a clear end goal and clear timeline to ensure that CED works as intended, i.e., driving the generation of evidence to revise and, where appropriate, improve coverage policies to increase access to patients over time.

PROTOCOL
CMS proposes the following requirement for the protocol of a study used for CED:

"The CED study is registered with ClinicalTrials.gov and a complete final protocol, including the statistical analysis plan, is delivered to CMS prior to study initiation."

Developing a study protocol requires a significant investment of time and resources by investigators and the study sponsor. A written protocol for a successful study design addresses many parameters including, but not limited to:

General information about the researchers and background information on the investigational product;

Detailed description of the trial objectives, purpose, and design;

Patient eligibility criteria;

Treatment of the subjects or the diagnostic protocol;

- Statistical methods for analyzing the evidence.
These protocols go through an iterative process in their development with updates as needed based on feedback or due to evolving circumstances. We agree with the CMS requirement that the CED study must be registered at https://clinicaltrials.gov/ and supports the confidential disclosure of the complete protocol to CMS. However, it is important to note that the protocol would contain information that is exempt from disclosure under the Freedom of Information Act Exemption 4, given the high likelihood that it would contain trade secrets and confidential commercial or financial information.

POPULATION
In the proposed guidance, CMS outlines the following requirement for the study population:

"The study population reflects the demographic and clinical diversity among the Medicare beneficiaries who are the intended population of the intervention. At a minimum, this includes attention to the intended population’s racial and ethnic backgrounds, gender, age, disabilities, important comorbidities, and dependent on data availability, relevant social determinants of health."

As stated in our prior comments, Edwards commends AHRQ for the incorporation of this requirement in the final AHRQ report and CMS for incorporating this requirement into the proposed guidance as Edwards strongly supports diversity in the populations for its clinical trials. To promote this goal, Edwards:
1. Seeks to include diverse Principal Investigators and study Leadership Committee participants (race, gender, age, etc.) in our clinical trials to ensure study design considerations are inclusive of diverse patient populations, and that patients seeking trial participation are able to find representative physicians to treat them.
2. Trains sites during the start-up and enrollment process on the importance of diverse patient participation and access to research for all patients, as well as unconscious biases and barriers to trial participation (i.e., childcare, mid-day appointments, multiple appointments, language, etc.). As research sites are the front line of inclusion or exclusion of diverse patient participation, Edwards asks each site to self-assess their catchment area for diversity rates, so they can understand and impact their own clinical trial diversity and inclusion (D&I) metrics.
3. Offers D&I stipends to any site who seeks the extra funding to enhance D&I recruitment activities.
4. Provides multi-cultural and multi-linguistic recruitment tools at no charge to all sites.
5. Actively participates on multiple initiatives and work groups (AdvaMed’s Women Heart Health, MedTech Color’s Collaborative Community on Diversity and Inclusion in Medical Device Product Development and Clinical Research, etc.) seeking to effect positive and meaningful change in clinical trial diversity and inclusion of all patients.

REPORTING
In the proposed guidance, CMS revises the final requirement on reporting from the AHRQ report and stated the following requirement:

"Final results must be provided to CMS and submitted for publication or reported in a publicly accessible manner within 12 months of the study’s primary completion date. Wherever possible, the study is submitted for peer review with the goal of publication using a reporting guideline appropriate for the study design and structured to enable replication. If peer-reviewed publication is not possible, results may also be published 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 incomplete results)."

In its prior comments, Edwards questioned the intent of requiring peer reviewed publication to satisfy the recommendation for public posting. We believe the existing CED reporting requirement allows for multiple options for publicly reporting results while still satisfying the need for transparency of the study design and methods. Limiting the reporting requirement to peer review publication would have been overly burdensome and would have jeopardized timely stakeholder access to evidence generated under CED and, potentially, patient access to technologies. We commend CMS for listening to the feedback from stakeholders and appropriately revising the requirement.

SHARING
CMS proposed the following requirement for sharing data and information specific to CED:

"The sponsors/investigators commit to sharing data, methods, analytic code, and analytical output with CMS or with a CMS-approved third party. The study should comply with all applicable laws regarding subject privacy, including section 165.514 of the Health Insurance Portability and Accountability Act of 1996 (HIPAA) and 42 CFR, Part 2: Confidentiality of Substance Use Disorder Patient Records."

As articulated in our prior comment letter, Edwards supports the sharing of aggregated study data and a detailed overview of the methodology used in the data analysis. We continue to be concerned that adding a de-identified data sharing requirement would create substantial administrative burden without CMS providing appropriate justification for its inclusion as a criterion. In a prior version of this requirement, it would have required a schedule of sharing incorporated into the study milestones. Edwards thanks CMS for removing that requirement because, as we previously noted, the timing for sharing can be difficult to determine and should be evaluated on a case-by-case basis.

HEALTH OUTCOMES
In the proposed guidance, CMS presents the following requirement for the health outcomes for the evidence development:

"The primary health outcome(s) for the study are those important to patients and their caregivers and that are clinically meaningful. A validated surrogate outcome that reliably predicts these outcomes may be appropriate for some questions."

Edwards agrees that in designing the study, sponsors and investigators should establish study outcome(s) that are important and relevant to the patient. In addition, we concur with the findings in the previously noted final AHRQ report that the focus should not be on patient-reported outcomes. Edwards had previously expressed concern with this requirement and that concern remains. Our concern in this requirement rests with the use of the phrase “clinically meaningful” as that term is rather vague and could lead to variability in the interpretation and application of this term. With this requirement, as with the other requirements, it is critical that CMS be clear and transparent in its expectations, and collaborative in the process of determining the appropriate primary outcomes relevant to the study and the intended population. That would allow sponsors and/or investigators to design and implement their study in a way that meets the Agency’s objectives without being unnecessarily burdensome.

B. Importance of Control Groups and Blinding in CED Studies
In this section of the proposed CED guidance, in addition to discussing the importance of control groups and blinding for studies, CMS also presents its thinking on fit-for-purpose (“FFP”) studies, expressing openness to FFP study designs and defines a FFP study as “one where the study design, analysis plan, and study data must be sufficient to credibly answer the question(s) posed by the CED.”

Edwards is encouraged by CMS’s position on incorporating robust FFP evidence development. Edwards commends CMS for its acknowledgment of the benefits of fit-for-purpose study designs and its willingness to consider FFP studies given that these studies, as articulated by CMS in the TCET proposed procedural notice, have the “potential to generate evidence that complements tightly controlled premarket traditional clinical trials by demonstrating external validity.”

As articulated in our comment letter in response to the proposed rule repealing the Medicare Coverage of Innovative Technology pathway (CMS-3372-P2)[2] and in our written testimony before the House Committee on Energy and Commerce[3], FFP evidence generation in the context of Medicare coverage determinations should:

be designed with patients and their needs in mind;

be limited to the essential data needed to address unanswered questions and demonstrate to CMS that the innovation is reasonable and necessary;

utilize, where appropriate, retrospective real-world data including payer claims and electronic clinical and patient data as an alternative to registry data collected prospectively; and

allow for the collection of data in the most efficient and least burdensome way for providers and the innovator company.
The process of identifying the essential data could involve CMS working with the FDA, manufacturers, patients, and specialty societies to outline data requirements and collection techniques to be used. Such an approach would ensure that coverage of the technology is directly linked to evidence of its benefit to the Medicare population as well as support the implementation of appropriate safeguards for patients.

We urge CMS to continue its efforts to further define FFP evidence development for breakthrough technologies and encourage CMS to do so with the approach outlined above in mind. We acknowledge that CMS, in the materials issued alongside the TCET notice, stated that it expects to publish more detailed fit-for-purpose guidance later this year. Edwards looks forward to reviewing this forthcoming guidance.

C. Ending CED
A key on-going concern with NCD with CED is the lack of clarity regarding when the CED period has ended. In the TCET proposed procedural notice, CMS discusses the end of CED signaled by the completion of the evidence development plan (“EDP”) and an evidentiary re-review by the contractor. In this proposed guidance, CMS states that it does not believe that “CED as a condition of coverage should last indefinitely.” Edwards strongly agrees with this position and supports requirements that clearly articulate (a) the outcomes that CMS is seeking to achieve in each particular CED, (b) how companies can demonstrate that those outcomes are met (e.g., peer-reviewed publication or findings published on clinicaltrials.gov), and (c) the specific triggers for initiating a reconsideration of the NCD once the CED is completed.

* * * * *

Edwards thanks you for your consideration of these comments on the proposed CED guidance, and we look forward to seeing the finalized guidance once published by CMS. If you have questions or would like additional information, please contact me at 949.250.0764 or at mary_coppage@edwards.com.

Sincerely,

Mary Coppage
Vice President, U.S. Healthcare Policy
Edwards Lifesciences

[1] https://www.ssa.gov/OP_Home/ssact/title18/1862.htm
[2] https://downloads.regulations.gov/CMS-2020-0098-0605/attachment_1.pdf
[3] https://d1dth6e84htgma.cloudfront.net/Todd_Brinton_Witness_Testimony_HE_Hearing_07_18_23_af9125a2a6.pdf

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August 21, 2023

Chiquita Brooks-LaSure
Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
7500 Security Blvd
Baltimore, MD 212441

RE: Coverage with Evidence Development Proposed Guidance Document

Dear Administrator Brooks-LaSure:

The National Health Council (NHC) appreciates the opportunity to provide input to the Centers for Medicare and Medicaid Services’ (CMS’) proposed guidance on coverage with evidence development (CED).

Created by and for patient organizations more than 100 years ago, the NHC brings diverse organizations together to forge consensus and drive patient-centered health policy. We promote increased access to affordable, high-value, sustainable, equitable health care. Made up of more than 150 national health-related organizations and businesses, the NHC’s core membership includes the nation’s leading patient organizations. Other members include health-related associations and nonprofit organizations including the provider, research, and family caregiver communities; and businesses representing biopharmaceutical, device, diagnostic, generic drug, and payer organizations.

Making sure that the coverage decision process works in favor of patients efficiently and safely having access to innovative treatments is a priority for the NHC, and we appreciate CMS’s attention to improving the process. We urge CMS to take a measured and balanced approach towards implementing CED in a way that enhances access to the greatest extent possible.

CED, which could be a useful tool in getting innovative products to patients more quickly, can also unnecessarily restrict access to treatments that would otherwise be covered by Medicare. The burden associated with access driven by CED studies can make it prohibitive or otherwise not pursued by treating physicians. It can also result in inequitable access to treatments. For instance, if CED studies are limited to academic institutions that are not geographically located in diverse areas, it may influence the demographics of the participants. The rigors of CED studies might also limit access for people from marginalized communities that may have economic or transportation barriers to participation. A 2021 study found that one of the top five barriers to increasing participation of patients from historically underrepresented racial and ethnic backgrounds in clinical trials was “time and resource constraints associated with participation.” We recommend that the CED pathway include an exception process in place for those patients in underserved communities that may not be able to access an approved study site or have other issues with access.

There is still a lack of predictability and understanding of when CED will be used, and the more clarity that CMS provides, the more patients and advocates will be able to partner with CMS to provide input to assure CED is used appropriately.

The Relationship Between FDA Approval and CED

Further clarity on the use of CED is particularly important because of the variety of paths that treatments and devices may take to enter the approval process. The relationship between FDA approval and the use of CED can be complicated. For drugs, there is a straightforward pathway to coverage after FDA approval. Once safety and efficacy have been approved by the FDA — and CMS has reviewed the reasonableness and necessity of the treatment — coverage should very rarely need further investigation. For some devices, the pathway is different, and CED may be used to gather needed data to meet more robust standards.

On one hand, the use of CED for FDA-approved medicines has raised concerns about delays in access to treatment and geographic variation in access to treatment. For example, CMS has implemented CED for novel amyloid beta-targeting therapies for Alzheimer’s disease even when these therapies are being used according to their FDA-approved label and accepted medical practice, and continued CED even once products have transitioned from accelerated approval to traditional approval. Use of CED in this manner threatens the FDA’s authority on the question of efficacy. Patients may end up not benefiting from the accelerated approval pathway, as originally intended, which was designed to speed access to new medicines. Therapies approved using the accelerated approval pathway are not considered experimental. They have been evaluated rigorously using a surrogate endpoint so that individuals facing serious or life-threatening conditions with great unmet needs can access them at the earliest possible moment. When CED is implemented for novel FDA-approved medicines, patient access suffers, as patients may only access these medicines through sites that are participating in the CMS-approved CED studies and themselves have no option but to consent to participation.

On the other hand, there are instances where the use of CED can help further needed evidence collection, particularly in cases where standards for FDA approval are less stringent. Medical devices that received FDA clearance through the 510k pathway are a good example of where these trials may be useful to establish additional data for efficacy in order to receive coverage. The 510k pathway allows medical device manufacturers to demonstrate that their technology works the same way as an existing technology to gain approval. If CMS would like more data to establish coverage for these devices, the CED process allows collaboration, so that the product manufacturer can gather the right data to meet CMS’s needs. In these instances, impacts to beneficiary access are less acute because by definition, an analogous device is already on the market. This is not true in the case of drugs that have a more robust FDA approval process to demonstrate safety and efficacy.

Patient Engagement

CMS currently seeks input on proposed coverage policies through the National Coverage Determination (NCD) process, but patients do not have a way to directly engage with the agency on the choice to apply CED requirements. As with all health care decisions that CMS and others in the health care ecosystem influence, the NHC recommends that CMS consult patients on how imposition of CED might impact:

Beneficiary access to treatment (e.g., geographic barriers);

Beneficiary health and outcomes (e.g., from delayed access to care); and

Beneficiary and caregiver experience (e.g., quality of life and other factors).

If CMS determines that it will utilize CED, it should also consult patients on study design protocols and outcomes of relevance to transitioning to full coverage for the product or service.

The need for patient engagement in trial design, choice of outcomes most important to patients, and other parts of the CED decision making process is not directly addressed in this guidance. In the past, the primary role of patients has been limited to their role as study subjects. Understanding their ability and willingness to participate in studies is critical. We need to make sure that study designs are as least burdensome as possible and support the patient’s successful participation in trials. If there are issues with participation, the patient perspective can also identify barriers that can be overcome. In both examples, engaging patients both in study design and implementation will result in better outcomes. In addition, when designing studies, identifying measures and outcomes that matter to patients is another key area of engagement. Over the past two decades, stakeholders have collaborated to develop best practices for identifying concepts important to patients and developing corresponding patient-centered outcome measures. The NHC urges CMS to make sure that all aspects of the CED process properly engage patients.

Reevaluation of CED

One other area of needed clarity is the protocol for reevaluation as treatments are in the CED process and how the transition to NCD may occur. In defining CED study protocols, CMS should be clear about the specific timing for evaluation of study data and reconsideration of CED and the criteria under which CMS will remove the CED requirement for coverage. In addition, when CMS determines that the data support removal of a CED requirement, CMS should issue a revised NCD that specifies full coverage for the product or service, as this is the best way to ensure consistent access for Medicare beneficiaries with no disruption in care.

Conclusion

Please do not hesitate to contact Eric Gascho, Senior Vice President of Policy and Government Affairs, if you or your staff would like to discuss these issues in greater detail. He is reachable via e-mail at egascho@nhcouncil.org.

Sincerely,
Randall L. Rutta
Chief Executive Officer

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August 21, 2023

BY ELECTONIC DELIVERY (CAGInquiries@cms.hhs.gov)

Joseph Chin, M.D.
Medical Officer for Coverage and Analysis
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Coverage with Evidence Development; Proposed Guidance Document

Dear Dr. Chin:

Eli Lilly and Company (Lilly) appreciates the opportunity to respond to the Center for Medicare & Medicaid Services (CMS) Coverage with Evidence Development (CED) Proposed Guidance Document (Proposed CED Guidance).¹ Lilly is one of the country’s leading innovation-driven, research-based pharmaceutical and biotechnology corporations. Our company is devoted to seeking answers for some of the world’s most urgent medical needs through the discovery and development of breakthrough medicines and technologies and through the health information we offer. Ultimately, our goal is to develop products that save and improve patients’ lives.

Lilly is the manufacturer of Amyvid® (florbetapir F18 injection), a beta amyloid positron emission tomography (AB PET) agent that has been subject to CED since 2013.² Lilly has discovered and is currently pursuing FDA approval of donanemab, an anti-amyloid monoclonal antibody designed to treat Alzheimer's disease. If approved, that product will also be immediately subject to a National Coverage Decision (NCD) mandating CED.³ Furthermore, Lilly innovates in other therapeutic areas with high unmet need and the potential for rapidly evolving innovation like additional neurodegenerative disease states as well as oncology, and immunology.

Based on these experiences and our pipeline, Lilly is uniquely positioned to comment the Proposed CED Guidance. In brief, our main recommendations include:

As explained at Section IV, below, Lilly continues to have significant concerns regarding CMS’s legal authority to implement CED in the manner contemplated by this Proposed CED Guidance. Nevertheless, Lilly is committed to workable solutions that advance access to critical medicines and we commend CMS for its willingness to engage with stakeholders.

In the Preamble to the Proposed CED Guidance, CMS sets out its commitment to transparency and to providing notice and comment opportunities for potentially impacted stakeholders. On, or about, the same day that CMS issued the Proposed CED Guidance (June 22, 2023), CMS also released three other documents advancing and expanding the CED construct:

A press release explaining some aspects of the CED “clinical registry” that CMS will be using for “traditionally” (non-accelerated approval) approved monoclonal antibodies for the treatment of Alzheimer’s;

A draft National Coverage Analysis Evidence Review,⁴ clarifying the CMS methodology for evidence review. Comments are also due August 21, 2023; and

In the device arena, a proposed “breakthrough device” coverage guidance called the Transitional Coverage for Emerging Technologies or TCET rule,⁵ which relies extensively on the CED process to provide some coverage for breakthrough devices. Comments on the proposed guidance are due 60 days following Federal Register publication.

While Lilly appreciates the opportunities to comment on these new sources of potential authority, this recent flurry of regulatory activity has the feel of a choreographed effort to expand CED. And, despite CMS’s stated commitment to transparency, stakeholders like Lilly are left scratching their heads as to the scope, scale and future intentions of CMS as it relates to the imposition of CED requirements, especially as those requirements might relate to drugs that are already subject to years of rigorous clinical evaluation by the Food & Drug Administration (FDA).

Notice and comment opportunities are only meaningful if stakeholders have a clear view of the context in which they are commenting. Therefore, while we may be able to reasonably infer CMS’s intentions (namely, to subject more FDA-approved drugs to CED requirements), we cannot guess at CMS’s “long game” based on the disclosures described to date. Accordingly, we urge CMS to issue a clear policy statement describing the agency’s current thinking on how it plans to use CED for drugs and biologics, how many drugs or biologics will be subject to CED in the future, and what, if anything, manufacturers or sponsors of clinical trials investigating those drugs or biologics should be doing differently in their Phase 2 or Phase 3 clinical development programs to ensure that those research and developments efforts can be temporally co-extensive with CMS’s own – and perhaps separate – requirements for clinical investigation.

II. CMS Should Acknowledge that CED Is Not Truly Voluntary (Section II, Purpose)

CMS asserts that “it is important to remind the public that beneficiary participation in a CED trial is completely voluntary, as is the choice for an entity to seek to sponsor an approved trial.”⁶ We understand, as a legal matter, why CMS endeavors to make this point, but in reality this is a cynical and questionable assertion and it is not in the long-term interests of the agency to perpetuate this inaccuracy.

First, for the beneficiaries who have spent their entire working lives contributing to the Medicare Trust Fund with the expectation of insurance coverage upon retirement or disability, CED has been demonstrated to be an added barrier and mandatory condition of coverage. The choice between participating in a CED trial or paying for an item or service out-of-pocket is illusory for many. Moreover, if that item or service is an FDA approved medicine that delays or treats a fatal disease, such as Alzheimer’s disease or cancer, the term “voluntary” seems particularly inapt. For beneficiaries, the nature of CED is not voluntary, as there is no “choice” when a patient needs treatment and can only receive coverage if they participate in a CMS required CED program.

Second, CMS states that entities are free to sponsor an approved trial. This may be technically correct, but it forces certain entities – such as biopharmaceutical manufacturers – into a Sophie’s choice: undertake the effort, expense, and uncertainty that one can ever satisfy CMS’s shifting CED goals to provide limited coverage for their FDA-approved medicines to the Medicare patient population or make the difficult decision not to sponsor a CED trial leaving it up to CMS to either develop its own evidence collection techniques and/or to await the agency’s “grace” in reopening a coverage determination and evaluating subsequent data to provide coverage. As discussed further below, this approach is especially fraught because to date the CED process on a given technology has traditionally taken over a decade to conclude, if they are even concluded at all.

Agency honesty is integral to building the enduring trust of stakeholders and credibility with the public. At a time when government institutions – particularly public health institutions – are subject to growing public skepticism, regulators must take extra care with their hard-earned reputations. Lilly has a deep and abiding respect for the professionalism of CMS and its employees. To maintain this trust, CMS should avoid glib characterizations of critical issues, such as the “complete voluntariness” of CED.

III. CMS Should Not Use CED To Second-Guess the FDA (Section III, Background)

In the “Background” section of the Proposed CED Guidance, CMS has announced a number of new and troubling positions related to the imposition of CED to FDA-approved drugs and biologics. Specifically, CMS appears to challenge the reliability of surrogate endpoints used in connection with Accelerated Approval drugs and biologics and states that pivotal trials “may not be generalizable to the Medicare population.”⁷ These statements strongly suggest that CMS will use CED to require manufacturers to re-do their clinical trials at times challenging the principle of equipoise. Aside from causing an unconscionable delay in broad Medicare access to proven therapies, this policy position has other unintended consequences, enumerated in greater detail below.

We are also discouraged by CMS’ stated goal of using CED to ensure that “patient safeguards…are in place to reduce the risks of new technologies...” as this undermines and duplicates FDA’s authority, wastes resources, and creates further roadblocks for patient access. FDA is the unique regulator of safety and effectiveness and, as such, is not only qualified and empowered by Congress for this role but is also resourced adequately to evaluate and monitor the safety of approved and marketed products. Drugs and biologicals must undergo years of rigorous clinical trials to ensure that the therapies can be safely and effectively used in human patients. Over the last two decades nearly 700 new prescription medicines have been approved for use by the FDA, at a potential cost to sponsors of over two billion dollars⁸ and taking on average 10.5 years.⁹ The data and results from such trials are carefully reviewed by the FDA prior to approval to ensure their rigor and reliability.¹⁰ Imposing additional post-approval CED requirements on therapeutics unnecessarily duplicates the careful and thorough work and analysis conducted by FDA.

A. CMS’s Proposed Application of CED is Contradictory to Advances in Science

If implemented, Lilly believes that the Proposed CED Guidance will hinder therapeutic advances made through the use of surrogate endpoints and biomarkers and contradict advances in regulatory policy setting us back decades. The accelerated approval program is a drug development pathway that offers a regulatory path to approval based on use of a surrogate or intermediate clinical endpoint in a clinical trial that is reasonably likely to predict clinical benefit and offers the advantage of being able to be measured at an earlier point in a trial than endpoints that may be used in a traditional approval. Accelerated approval allows patients with serious and life-threatening illnesses to benefit from earlier access to promising therapies without lowering the Agency’s evidentiary standard for safety and efficacy.^11,12 By permitting earlier access to novel therapies, the accelerated approval pathway has helped extend, and even save patients’ lives. One study published by leaders from the FDA Oncology Center of Excellence (FDA OCE) reported that cancer treatments approved under the pathway were available to patients an average of three to four years earlier than a traditional approval would have allowed.¹³ For example, the accelerated approval of Alimta® (pemetrexed) for treatment of patients with non-small cell lung cancer (NSCLC) that progressed or did not respond to prior therapy was among five medicines highlighted in a recent analysis, which found that the accelerated approval of this medicine allowed for earlier access by over a half million people.¹⁴

Since its initiation, more than 290 new drugs and biologics to treat serious or life-threatening illnesses have been approved through the accelerated approval program.¹⁵ Further, FDA may require sponsors to conduct post marketing confirmatory trials to verify and describe the anticipated effect on irreversible morbidity and mortality (IMM) or another clinical benefit for drugs and biologics approved under the accelerated approval pathway. Lilly is committed to expeditiously producing confirmatory trial data to support accelerated approvals; we work to align with the FDA on confirmatory study designs before accelerated approvals are granted, and we acknowledge and generally support both FDA’s authority to require and recommend that confirmatory trials be underway at the time of accelerated approval or within a specified time period after the date of the approval.^16,17 During that period, sponsors are already working closely with FDA to provide confirmatory evidence of clinical benefit for products that receive accelerated approval, and in that time, many of these drugs and biologics become standard of care for treating the diseases for which they are intended. CMS acknowledges in the CED Proposed Guidance Document that they have issued 26 NCDs requiring CEDs over the last two decades, and in that time only three CED NCD topics have had the CED requirement removed following an NCD reconsideration and received national coverage.¹⁸ In the 25 years since the initiation of the accelerated approval program, 93 accelerated approvals have been granted for the treatment of oncology indications; and in that time 51 have fulfilled their post marketing requirements and verified benefit, 37 indications have not yet completed confirmatory trials or verified benefit, and only five indications have ever been withdrawn from the market.¹⁹

B. CMS’s Narrow Reading of “Health Outcomes” Contradicts Science and Patient Priorities

CMS adopts a narrow and antiquated view of measuring patient benefit by disregarding the importance and meaningfulness of surrogate endpoints in drug development. Nowhere in 1862(a)(1)(A) does the statute require CMS to interpret the “Reasonable and Necessary” standard to mean impact on “health outcomes” exclusively and to ignore the impact of other endpoints deemed critically important to Medicare beneficiaries, the scientific community, or FDA. The term “health outcomes” as being the only endpoints CMS appears to consider is antiquated and not reflective of the science of innovative medicine development since the passage of FDASIA in 2010. Patient groups have demonstrated tolerance for uncertainty associated with surrogate endpoints and have overwhelmingly preferred earlier access to address significant areas of unmet need, as is enabled by the passage of FDASIA but negated by CMS with this guidance.

While we are appreciative that CMS states a desire to “encourage innovation and accelerate beneficiary access,” CMS takes the opposite approach with this Proposed CED Guidance. However, by disregarding clear evidence on surrogate endpoints and implying that they are somehow not important for patients and not sufficient for beneficiary access, CMS sets the science of drug development and patient access aims back decades. CMS should instead be encouraging the use of surrogate endpoints and contemplating how CMS can be partners in ensuring Medicare beneficiaries can have appropriate unrestricted access to such needed FDA approved medicines while the needed evidence to confirm clinical benefit is developed. Instead, CMS chooses to block and restrict access in the name of duplicative research through CEDs.

C. The CED Paradigm Worsens Disparities in Access to Care

Imposing CED compounds health inequities by unfairly restricting beneficiary access to needed care. As discussed, the application of CED generally means that Medicare beneficiary access is limited to the small number of patients fortunate enough to have reliable access to a CMS-approved trial or study. All other beneficiaries are de facto denied covered access to the therapy, again, even though the FDA has already approved the therapy and determined it is safe and effective. Moreover, CED restrictions on access disproportionately impact communities of color,²⁰ thereby exacerbating already significant issues of health inequity facing these communities.

Finally, the guidance is at odds with CMS’s health equity principles, contradicting the Administration’s commitment to health equity, which constitutes the first pillar of CMS’ Strategic Plan- a core function of CMS.²¹ As noted in recent guidance for the Part D Negotiation Program, CMS states it will formulate an initial offer to a manufacturer considering if it “meets an unmet medical need and the selected drug’s impact on specific populations.”²² Further, in revised guidance, CMS clarified that this includes underserved and underrepresented populations that may be experiencing disparities in health outcomes or access to the selected drug. Thus, taking the substantive evidence that CED aggravates disparities²³, the guidance is at odds with CMS’s previously stated positions on access to care for underserved populations.

IV. CMS’s Authority to Implement CED as Proposed Is Questionable (Section IV, Statutory Basis)

Lilly is concerned that CMS lacks the authority to institute CED in the manner suggested by the Proposed CED Guidance. There is nothing in the Medicare statute that authorizes or even mentions CED; it is a construct that CMS invented. In its Proposed CED Guidance, CMS claims that its statutory authority for CED stems from Sections 1862(a)(1)(A) and 1862(a)(1)(E) of the Social Security Act (SSA). But neither provision of the SSA authorizes CMS to establish any such program. Section 1862(a)(1)(A) requires that an item be reasonable and necessary to diagnose or treat illness or injury. It does not address what may be reasonable and necessary in the very different context of clinical trials or patient registries. Section 1862(a)(1)(E) does not authorize this outcome either. That provision applies in the context of AHRQ research— “in the case of research conducted pursuant to section 1320b–12 of this title.” The Proposed CED Guidance tellingly offers no explanation of how the clinical trials it contemplates would qualify as “research conducted pursuant to section 1320b-12.” Instead, the Proposed CED Guidance purports that CEDs are consistent with the requirement in section 1320b-12 that the Secretary “assure” that AHRQ priorities “reflect the needs and priorities” of the Medicare program. The Proposed Guidance states that AHRQ reviews all CED NCDs and “indicates its support” for the clinical trials. HHS’s own former General Counsel recognized that a mere note of approval from AHRQ on a CMS proposal to issue an NCD with CED does not suffice.²⁴ In short, the entire CED construct has no basis in law and CMS lacks statutory authority to impose it.

Even if CMS could point to some implicit statutory authority to create CEDs as an alternative coverage scheme for products or uses without FDA approval, CMS lacks any such authority when it comes to drugs that have been approved by FDA for use in the Medicare population and coverage is based on an on-label use. In such situations, a CED would conflict with FDA’s findings that a drug is safe and effective for on-label use and that the benefits outweigh any risks. See 21 U.S.C. § 355(d). Nor does the method of approval have any being as in FDA’s own words, “drugs granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval.”²⁵ The Proposed CED Guidance would have CMS – an agency without the clinical expertise or personnel capable of making these decisions – use its unauthorized CED structure to replace the FDA’s authority on safety and risks. In that situation, the risk that a CED determination will conflict with FDA’s prior safety and effectiveness findings is most acute.

We recognize that the statutory standard for coverage is phrased slightly differently from the statutory standard for marketing approval. But the Proposed CED Guidance reveals that CMS is choosing the CED pathway so it can evaluate the risks and benefits of any product—a determination reserved to FDA, and one that FDA has already made in many situations. It is implausible that Congress intended CMS to create a new paradigm for coverage, not mentioned in any statute, under circumstances where it would conflict with determinations already made by FDA. And the more implausible an agency’s assertion of authority, the clearer Congress must be in delegating the authority.²⁶ It therefore is insufficient that Congress did not explicitly forbid CMS from creating a CED construct; CMS would have to identify clear affirmative statutory authorization, and none remotely exists. As the D.C. Circuit has found, the statue “unambiguously authorizes the Secretary to make only a binary choice: either an item or service is reasonable and necessary, in which case it may be covered at the statutory rate, or it is unreasonable or unnecessary, in which case it may not be covered at all.”²⁷ There is no gap in that analysis into which CMS can shoehorn the CED framework.

If finalized, this Proposed CED Guidance would be a sharp departure from CMS’s prior policy in an additional important respect: CMS has not historically used CED to limit national coverage for an on-label use of a therapeutic drug or biologic already approved by FDA. In fact, the recent CED covering Monoclonal Antibodies Directed Against Amyloid (mAbs) for the treatment of Alzheimer’s disease represents the first such effort and would appear to be the impetus for CMS to create this Proposed Guidance. CMS did not acknowledge the unprecedented nature of its change in either the Proposed Guidance or the mAbs NCD. Even if CMS had some implicit statutory authority to create CED as an alternative coverage paradigm for products or uses not previously reviewed and approved as safe and effective by FDA, CMS lacks any such authority when it comes to a drug that has been approved by FDA for use in the Medicare population and is being considered for coverage for its on-label use and the agency has not explained why it needs to change its position at this time.

V. Additional Considerations for Principles Governing the Application of CED (Section V, Principles)

As part of the guidance, CMS sets forth seven principles to govern the application of specific CED criteria. These are:

CED NCDs will occur within the coverage determination process, which is transparent and open to public comment.

CED will not be used when less restrictive coverage is justified by the available evidence.

CED will generally expand access to medical technologies for beneficiaries because the technologies would not otherwise meet the reasonable and necessary coverage standard.

CED will require the generation of evidence that addresses specific evidentiary deficiencies identified in National Coverage Analyses.

CED will not duplicate or replace the FDA’s authority in assuring the safety and effectiveness of drugs, biological products, and devices.

CED will not duplicate or replace the NIH’s role in fostering, managing, or prioritizing clinical trials.

CED will be consistent with federal laws, regulations, and patient protections.

Lilly appreciates CMS’s attempt to establish principles, however it is unclear how CMS plans to operationalize them. We would appreciate additional clarity on the CED criteria and how CMS will ameliorate CED programs that end up inadvertently offending or running contrary to one of the principles above. Of those listed, we are particularly concerned with CMS’s application of the principle “CED will require the generation of evidence that addresses specific evidentiary deficiencies identified in National Coverage Analyses.”

CMS “Principles” for CED should reflect a clear commitment to protecting Medicare beneficiary access to safe and effective medicines and not unnecessarily limit access to FDA approved drugs and biologicals. CED has profoundly negative implications for Medicare beneficiaries by restricting access to a much narrower pool of patients than the FDA-approved indications, thus undermining efforts to meet unmet need and significantly delaying meaningful patient access. As noted, CED is particularly impactful for patients living with Alzheimer’s, with more than 6 million Americans suffering from this disease – a condition with a disproportionate impact on communities of color, CMS has proposed barrier after barrier in its coverage policy that will only worsen disparities in access to treatments. If these barriers persist, the number of patients with Alzheimer’s is expected to grow to nearly 13 million people by 2050 and impose more than $1.1 trillion in annual costs on our nation, not to mention the immeasurable impact on individuals, families, and communities.²⁸

Conversely, the removal of policy barriers like CED can yield tremendous patient and broader health system value. For example, a recent study highlighted the broader economic merit that can stem from therapies that delay progression of Alzheimer’s (and inherently patient access to these medicines).²⁹ Key findings included that a one-year delay in the transition from mild- moderate would have a value to the U.S. of $200 billion to $1.3 trillion over the next 10 years. This article notes that “Medicare coverage for new Alzheimer’s treatments could yield tremendous value for patients and their caregivers, taxpayers, and the health system at large. CMS should embrace these innovations and the potential relief they offer for this debilitating disease.”

There is growing awareness of the benefit of and thus support for the removal of unnecessary patient barriers like CED, not only from patients but policymakers and other significant stakeholders. The U.S. Senate Appropriations Committee recently approved FY 2024 Labor-HHS-Education spending bill report language advocating CMS provide full access for Medicare beneficiaries to FDA-approved Alzheimer’s treatments,

“The Committee remains disappointed about CMS’ decision to restrict coverage of an FDA-approved monoclonal antibody treatment for Alzheimer’s disease. That decision set a dangerous precedent that undermines FDA decision-making and may have far reaching consequences that extend well beyond Alzheimer’s treatments. Even now that FDA has granted traditional approval for such a treatment, the Committee is concerned that CMS continues to create barriers to care by requiring Medicare patients be enrolled in a qualifying registry. Given the substantial new clinical evidence published since the national coverage decision was issued and the FDA’s confirmation of clinical benefit in keeping with its traditional approval of a treatment in this class, the Committee expects CMS to reconsider the National Coverage Determination policy to provide full access for Medicare beneficiaries to these FDA-approved Alzheimer’s treatments.”³⁰

This concern for patient access and CED reform has been echoed by numerous advocacy organizations, professional societies, members of Congress and thought leaders. In a recent press release, the Alzheimer’s Association reinforced that while, “registries — an important tool to gather much-needed real-world evidence to transform and improve patient care — [they] should not be a requirement for coverage of a FDA-approved treatment.”³¹ Bipartisan members of Congress from both the U.S. House of Representatives and the U.S. Senate have also raised concerns about the impact of conditioning Medicare coverage on the development of additional evidence. For example, a June 2023 House letter signed by over 45 bipartisan members regarding the use of CED for amyloid-targeting Alzheimer’s therapies noted that the co-signers “remain deeply concerned about our constituents' lack of access to these FDA-approved therapies. Processes that may delay coverage decisions by months or years can impose significant access delays, resulting in irreversible disease progression for beneficiaries living with Alzheimer’s, and added burdens for their caregivers and loved ones.”³² These concerns are also shared by former Members of Congress, including former Finance Committee Chairman Senator Max Baucus who recently stated that “policies surrounding Alzheimer’s care need to be addressed in a comprehensive way that creates a path to care for all Americans (emphasis added).³³

VI. CMS Is Not Well Positioned to Oversee the Implementation of the Outlined Clinical Study Standards (Section VI, Clinical Study Standards)

The clinical study standards outlined in the guidance Proposed CED Guidance are consistent with generally accepted trial design approaches, and they underpin the drug development programs sponsors work with the FDA to plan and implement that support product approval. That said, there are many variables that must be considered in each clinical scenario that impact how these principles are applied in practice. This complexity is one of the main areas of focus during the numerous interactions that occur between sponsors and FDA during development. FDA dedicates significant resources to support these interactions in order to ensure there is alignment on the design decisions made by sponsors and confidence in the results. These resources are provided by a combination of appropriations and user fee dollars and are used to hire physicians, statisticians, and pharmacologists, among other specialties that contribute to the clinical plan. Without these resources, CMS is unlikely to be able to support the application of these clinical study standards in a consistent, timely, and predictable manner and, in turn, have confidence that the studies that are mandated lead to meaningful results.

As a manufacturer, we need certainty, clarity, and predictability as to how, when, and by whom clinical trials will be reviewed and approved; we do not support the establishment of parallel regulatory regimes, especially where one regulator has not established clear process and procedures designed to ensure procedural fairness. FDA, for example, has well-established meeting and review conventions. CMS should, itself, seek to avoid duplicative efforts and, unless it can commit to the same type of predictable, rigorous and responsive procedural safeguards that result in unambiguous commitments to predictable results (like FDA has created) CMS should not insert itself into the complex regime of clinical development and trial design.

VII. Use of Control Groups in CED Studies May Be Unethical (Section VII, Importance of Control Groups)

Medical ethics require clinical equipoise, a state of genuine uncertainty about the merits of the two arms included in a clinical study. The investigator must have no treatment preference between the study groups. Lilly has significant concerns about CMS’s potential disregard for this principle. Specifically, Lilly believes it may not always be ethical or appropriate to randomize patients to a control group where an approved therapeutic with demonstrated clinical benefit is available and is the standard of care. To the extent CMS finalizes or relies upon this Proposed CED Guidance and engages in broader CED requirements for drugs and biologics, the agency should pay close attention to input from physicians and entities that establish treatment guidelines. Where it is clear that it would be unethical to subject patients to the potential to receive inferior treatment, CMS should immediately suspend their CED requirements and ensure broad access to proven therapies.

VIII. CMS Needs to Establish Clearer Guidelines for Ending CED and Should Retain Flexibility Regarding the Need for Publication (Section VIII, Ending CED)

In the Proposed CED Guidance, CMS appears to condition removal of CED on publication of the CED results in a peer reviewed medical journal. This is odd and poses an unnecessary additional delay to ending CED. Specifically, if CMS believes that it has the clinical and medical experience and judgment necessary to approve and guide the design of clinical trials, why does CMS need the imprimatur of a medical journal editor or reviewer before it can weigh the results? Moreover, journals might not be interested in publishing the results of a CED study which means that sponsors – and Medicare beneficiaries – will be held in limbo based on the editorial whims of medical journal publishers. Instead, CMS should evaluate the data it has compelled the creation of and use that to make the final “reasonable and necessary” determination.

Our concerns about ending CED are not just theoretical—they are grounded in our direct experience with CED for Amyloid Positron Emission Tomography (PET) scans. Beginning in 2013, the Medicare program restricted access to Amyloid PET scans through CED.³⁴ Over the intervening decade, more than 40 studies in over 20,000 patients evaluated or utilized amyloid PET. These studies repeatedly and consistently demonstrated positive impact on patient care, which was buttressed by independent research from the Department of Veteran Affairs. Just last month, CMS proposed to remove the Amyloid PET CED and leave the ultimate coverage determination to the Medicare Administrative Contractors. In its decision, CMS summarized the mountain of studies demonstrating the effectiveness of Amyloid PET but did not itself make any determinations based on the data it required under the CED nor discuss how this data should or will be used going forward. Another compelling example is the CED for Transcatheter Aortic Valve Replacement (TAVR). After more than 10 years of CED, CMS appears no closer to making any conclusions about the procedure despite many practitioners concluding the CED study has outlived its usefulness.³⁵ At this point we think CMS would be hard-pressed say that TAVR is not reasonable and necessary for Medicare beneficiaries with heart valve disease who qualify of the TAVR procedure. In short, it appears to Lilly that these CEDs ere merely mechanisms for CMS to use to deny coverage to beneficial tools. Again, this is odd and inconsistent with the stated purpose of CED.

IX. Lilly Applauds CMS for Its Continued Commitment to Transparency and Engaging with Stakeholders (Section IX, Transparency of CED)

In general, while Lilly remains concerned that CMS lacks the authority to institute CED, we agree that any given CED process must be reasonably transparent and predictable, and we appreciate CMS’s efforts along these lines. We also thank CMS for its stated commitment to continuing to meet with stakeholders. We have found our interactions with CMS staff generally responsive to meeting requests, sincerely open to scientific and technical discussion, respectful of confidentiality and FOIA exemptions requests, and highly professional in their tone, conduct, and demeanor.

***

Lilly appreciates this opportunity to present our comments on the Proposed Guidance. We sincerely appreciate your thoughtful consideration of the issues presented above and look forward to working with you in the future. Please do not hesitate to contact Derek Asay at Asay_Derek_L@Lilly.com with any questions.

Sincerely,

Derek L. Asay
Senior Vice President, Government Strategy
Shawn O’Neail
Senior Vice President, Government Affairs

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1 CMS, Coverage with Evidence Development Proposed Guidance Document (June 22, 2023).
2 CMS, Decision Memo, Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N) (Sept. 27, 2013).
3 CMS, Decision Memo, Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N) (April 7, 2022).
4 The document can also be found on the CMS National Coverage Determination website at: https://www.cms.gov/medicare-coverage-database/view/medicare-coverage-document.aspx?mcdid=34
5 The CMS press release explaining the rule is available at: https://www.cms.gov/newsroom/fact-sheets/notice-comment-transitional-coverage-emerging-technologies-cms-3421-nc
6 Proposed CED Guidance at 3 (emphasis added).
7 Proposed CED Guidance at 4-5.
8 See, https://www.cbo.gov/publication/57126.
9 See, https://www.bio.org/blogs/how-long-does-it-take-get-drug-approved.
10 See generally BIO, Drug Development and Clinical Trial Process, https://www.bio.org/policy/human-health/drug-development-review-lifecycle-management.
11 Pharmaceutical Research and Manufacturers of America, see comment letter in response to FDA Draft Guidance on Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics submitted on May 26, 2023. Available at https://downloads.regulations.gov/FDA-2023-D-0110-0038/attachment_1.pdf.
12 Lilly notes that on page 4 of the current CED Proposed Guidance Document uses the term ‘full approval.’ We recommend that CMS refer to such FDA approvals as ‘traditional approvals’ in the proposed guidance document.
13 Beaver JA, Howie LJ, Pelosof L, Kim T, Liu J, Goldberg KB, Sridhara R, Blumenthal GM, Farrell AT, Keegan P, Pazdur R, Kluetz PG. A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review. JAMA Oncol. 2018 Jun 1;4(6):849-856.
14 Partnership for Health Analytic Research (PHAR), Issue Brief: Clinical Benefits of Accelerated Approval (July 26, 2022). Available at https://www.pharllc.com/wp-content/uploads/2022/07/Clinical-Benefits-of-Accelerated-Approval-Brief.pdf.
15 Beaver JA, et al. A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review. JAMA Oncol . Ibid.
16 Food and Drug Omnibus Reform Act of 2022 (FDORA).
17 Lilly, Lilly’s Principles on Accelerated Approval (June 2023). Available at Lilly’s Commitment on Accelerated Approval | Eli Lilly and Company.
18 Proposed CED Guidance at 5.
19 Beaver JA, et al. A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review. JAMA Oncol . Ibid.
20 See, e.g., Individualized Decisions for Endocrine Therapy Alone Study, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02400190 (CED IDEAS study participants self-reported as 88% non-Hispanic White/Caucasian. A New IDEAS study was subsequently launched with the specific objective of studying a more diversion population, but the study has had difficulty enrolling the targeted levels of diverse participants): IDEAS Study (Imaging Dementia Evidence for Amyloid Scanning): https://classic.clinicaltrials.gov/ct2/show/NCT02420756.
21 https://www.cms.gov/cms-strategic-plan
22 Fact Sheet: Medicare Drug Price Negotiation Program Initial Guidance (cms.gov)
23 Id.
24 HHS OIG, Advisory Opinion on Medicare Coverage with Evidence Development No. 21-03 (Jan. 14, 2021) (withdrawn).
25 FDA, “Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics” (May 2014), available at https://www.fda.gov/media/86377/download
26 See, e.g., Whitman v. Am. Trucking Associations, 531 U.S. 457, 468 (2001) (noting it would be “implausible that Congress would give” EPA power to consider costs in setting national air quality standards without a “clear” “textual commitment”).
27 Hays v. Sebelius, 589 F.3d 1279 (D.C. Cir. 2009).
28 Am J Manag Care. 2022;28(suppl 10):S188-S196. https://doi.org/10.37765/ajmc.2022.89236
29 Philipson, T., Ling, Y., Onogi, K., & Kataria, A. (n.d.). Evaluating the economic impact of CMS coverage delays https://bpb-us w2.wpmucdn.com/voices.uchicago.edu/dist/d/3128/files/2023/06/CMS_Alzheimers_Delays_June-6.pdf
30 Senate committee approves FY24 Labor, HHS, and education appropriations bill: United States Senate Committee on appropriations. Minority News Release | Minority News Releases | News | United States Senate Committee on Appropriations. (2023, July 27). https://www.appropriations.senate.gov/news/minority/senate-committee-approves-fy24-labor-hhs-and-education-appropriations-bill
31 Alzheimer’s Association. Alzheimer’s Association Welcomes Announcement of CMS Coverage for FDA-approved Treatments. July 6, 2023. Available at: https://www.alz.org/news/2023/medicare-medicaid-coverage-fda-approved-treatments.
32 https://lahood.house.gov/_cache/files/6/a/6a2983bf-36ad-4d38-82fb-8e86b3136824/0BE8E393A03AE489A9643C853B186AC9.house-of-reps-cms-alz-follow-up-letter-6.16.23.pdf
33 https://www.statnews.com/2023/08/03/alzheimers-drugs-lecanemab-donanemab-rural-states-medicare/
34 CMS, NCD Beta Amyloid Positron Tomography in Dementia and Neurodegenerative Disease (220.6.20). 35 https://www.medpagetoday.com/special-reports/exclusives/102144

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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Coverage with Evidence Development Proposed Guidance Document, June 22,2023
Coverage and Analysis Group, Centers for Medicare & Medicaid Services (CMS), Health and Human Services (HHS)
7500 Security Blvd.
Baltimore, MD 21244

RE: Doctors For America’s FDA Task Force Comment on CMS Coverage with Evidence Development Proposed Guidance Document

Thank you for the opportunity to comment on the Centers for Medicare and Medicaid (CMS)’ proposed guidance document for coverage with evidence development. Below we offer comments and recommendations for your consideration as you continue working on the final version of the guidance document.

The Doctors for America (DFA) Food and Drug Administration (FDA) Task Force educates, mobilizes, and empowers a multispecialty group of DFA members and clinicians to provide unbiased expertise in evaluating and responding to the FDA regulatory process in a way that maximizes meaningful clinical outcomes for our patients. We strive to support and strengthen an FDA that puts patients first. The Task Force cares deeply about the utilization of coverage with evidence developments (CEDs), as these policies have broad implications on patient safety and access to treatments. We are grateful that this forum is available and our coalition of practicing physician leaders are able to provide input on the tangible implications of this determination.

The FDA Task Force strongly supports CMS’ statutory authority to implement CED studies for drugs and therapeutics that have not yet proven to be reasonable and necessary under the standard described in section 1862(a)(1)(A) of the Social Security Act. While the proposed guidance provides necessary and helpful information on scope and function of CED studies, there are additional provisions we feel would provide clarification for physicians and patients.

CMS should issue clear guidelines on the CED process on approval and withdrawal of new and approved therapies.
Under Section VIII of the proposed guidance, Task Force members recommend CMS clarify the process of coverage withdrawal in the event that the CED study does not demonstrate clinical benefit or shows negative outcomes.

Clearly outlining the timeline and parameters for the cessation of coverage will help physicians better communicate these changes with patients and will reduce confusion amongst the general public. This is a necessary priority for both physicians and patients who look to agencies to clearly outline safety and efficacy standards and the protocol for protecting patients from harm.

CMS should, in coordination with FDA, clearly outline the role of randomized controlled trials (RCTs).
DFA’s FDA Task Force supports the promotion of RCTs as an effective measure for the collection of data as outlined by the agency in Section VII. We consider RCTs the ‘gold standard’ for evaluating a drug's effectiveness. As physician-scientists, we are glad to see that CMS placed value on control groups and blinding in CED studies though they are not always feasible. The Task Force recommends that CMS provide incentives for higher-quality studies and place significant value on RCTs where feasible. In order to further clarify the role of RCTs, we recommend clarification around the use and allowance of single-arm or open-label studies.

CMS must serve as the centralized repository of all data collected through the CED process, standardize access to and use of data, and prioritize transparency.
In order to aggregate and assess trends in patient outcomes, it is critical CMS is allowed access to all of data collected as part of CED studies. Physicians and patients need access to robust, accurate, timely data from CED studies. Data collected from CED studies should be published in peer-reviewed journals for public consumption and evaluation. Additionally, CMS should establish consistent baseline data collection requirements across all CED studies.

The DFA FDA Task Force thanks CMS for their commitment to ensuring patient safety while increasing access to innovative drugs and therapeutics. We urge CMS to consider the the recommendations outlined here and look forward to continued communication and collaboration.

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VIA ELECTRONIC DELIVERY TO: CAGInquiries@cms.hhs.gov

August 21, 2023

Coverage and Analysis Group
Centers for Medicare and Medicaid Services,
Mailstop: S3-02-01
7500 Security Blvd.
Baltimore, MD. 21244

Re: Coverage with Evidence Development Proposed Guidance Document

To the CMS Coverage and Analysis Group:

The Biotechnology Innovation Organization (BIO) appreciates the opportunity to comment on CMS’s, “Coverage with Evidence Development Proposed Guidance Document (hereinafter, “guidance”).ⁱ

BIO is the world’s largest trade association representing biotechnology companies, academic institutions, state biotechnology centers, and related organizations across the United States and in more than 30 other nations. BIO’s members develop medical products and technologies to treat patients afflicted with serious diseases, to delay the onset of these diseases, or to prevent them in the first place. In that way, our members’ novel therapeutics, vaccines, and diagnostics not only have improved health outcomes, but also have reduced healthcare expenditures due to fewer physician office visits, hospitalizations, and surgical interventions. BIO membership includes biologics and vaccine manufacturers and developers who have worked closely with stakeholders across the spectrum, including the public health and advocacy communities, to support policies that help ensure access to innovative and life-saving medicines and vaccines for all individuals.

According to the guidance, “to encourage innovation and accelerate beneficiary access to new items and services, CMS is proactively publishing this proposed guidance document to provide a framework for more predictable and transparent evidence development. This proposed guidance represents CMS' current thinking on the factors CMS considers in making NCDs using the coverage with evidence development (CED) paradigm.”

While BIO shares CMS’s goal to “to encourage innovation and accelerate beneficiary access to new items and services,” we believe that current CMS efforts to apply CED to FDA-approved treatments are against current law, unnecessarily duplicative, and ultimately thwart, rather than enhance, patient access to needed new therapies.

CMS’s principles for CED are not clear

As part of the guidance. CMS sets forth seven principles it says governs the application of specific CED criteria. These are:

• CED NCDs will occur within the coverage determination process, which is transparent and open to public comment.
• CED will not be used when less restrictive coverage is justified by the available evidence.
• CED will generally expand access to medical technologies for beneficiaries because the technologies would not otherwise meet the reasonable and necessary coverage standard.
• CED will require the generation of evidence that addresses specific evidentiary deficiencies identified in National Coverage Analyses.
• CED will not duplicate or replace the FDA’s authority in assuring the safety and effectiveness of drugs, biological products, and devices.
• CED will not duplicate or replace the NIH’s role in fostering, managing, or prioritizing clinical trials.
• CED will be consistent with federal laws, regulations, and patient protections.

While BIO appreciates CMS’s move toward transparency with the statement of these principles, it is not clear that the Agency is living up to them. In particular, we take issue with CMS’s application of the principle “CED will require the generation of evidence that addresses specific evidentiary deficiencies identified in National Coverage Analyses.” As we have stated to the Agency in comments before, we question the Agency’s application of CED, especially for products that have been previously judged by FDA as safe and effective.

The Agency has attempted to explain that the “reasonable and necessary” standard for Medicare coverage should not necessarily follow from the FDA’s judgement of “safe and effective” the Medicare “reasonable and necessary.” Nevertheless, the Medicare standard draws on FDA, defining “reasonable and necessary” as “safe and effective; not experimental or investigational; and appropriate for Medicare patients, including the duration and frequency that is considered appropriate for the item or service,”ⁱⁱ

It then follows that a treatment’s applicability to the Medicare population, as the Agency sees it, must be key to it approving coverage under Medicare. Indeed, in issuing a CED decision for monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease, CMS stated in April 2023, “there is not currently enough evidence of demonstrating improved health outcomes to say that it is reasonable and necessary for people with Medicare, which is a key consideration for CMS when making national coverage determinations” (emphasis added). Here we note the Agency’s judgement that the specific product, while judged safe and effective by FDA, did not generate sufficient evidence for “people with Medicare” where the Agency draws the line specifically for applicability to the Medicare population.

In the guidance, CMS further explains,

Taken together, such statements seem confusing given the diverse make-up of the Medicare program. Although the vast majority of the over-65 million Medicare beneficiaries are eligible by age, one-eighth of beneficiaries are below 65. Moreover, the program reflects the nation’s vast racial and ethnic diversity, as evidenced by the Agency’s publication of consumer information into 18 different languages.ⁱⁱⁱ Thus, it is not clear to us what is special or exclusive about the large and diverse Medicare program that renders evidence judged “safe and effective” by FDA to not meet standards for “people with Medicare.” At the very least, we question why CMS would not grant full coverage under Medicare for uses of a product consistent with patient need as indicated on product’s label. We invite the Agency’s explanation.

Moreover, the guidance may be seen to be at odds with CMS’s health equity principles, which make up the first pillar of the CMS Strategic Plan and a core function of CMS^iv. As noted in recent guidance for the Part D Negotiation Program, CMS says will formulate its initial offer to a manufacturer considering if it “meets an unmet medical need and the selected drug’s impact on specific populations.”^v Further, in revised guidance, CMS clarified that this includes underserved and underrepresented populations that may be experiencing disparities in health outcomes or access to the selected drug. As noted above, CMS will also consider the caregiver perspective to the extent that input reflects directly upon the experience or relevant health outcomes of the patient taking the selected drug. Thus, taking the Medicare population as a whole, as the CED guidance seems to do, puts this guidance at odds with CMS’s previously stated positions on access to care for underserved populations.

BIO continues to recommend that on-label uses of drugs and biologicals be excluded from CED restrictions. We believe use of CED for on-label uses drugs and biologicals is contrary to law, as well as the best available evidence and sound public policy.

CED is used for certain technologies where CMS does not believe there is sufficient evidence to conclude definitively that the item or service is “reasonable and necessary”^vi for the Medicare population. When CMS applies CED to a technology, it restricts Medicare coverage nationwide to only a narrow range of circumstances—e.g., coverage as part of clinical trials or registries meeting strict CMS criteria. Historically, CMS has limited use of CED to devices; other non-drug/biological technologies or procedures; or, in rare cases, to off-label uses of drugs or biologicals.^vii Earlier this year, however, in an unprecedented shift in policy, CMS issued a National Coverage Determination (NCD) that applied CED to the on-label use of an anti-amyloid product approved under a Biologics License Application (BLA).

BIO still contends application of CED to an on-label use of a drug or biological is contrary to the requirements of the Social Security Act (SSA).

CMS’s recent use of CED for an on-label use of a drug or biological is contrary to law. The SSA obligates CMS to cover drugs and biologicals in most settings of care,viii unless a particular therapy is not ““reasonable and necessary” for diagnosis, treatment, or to improve the functioning of a malformed body member.^ix As CMS itself has historically recognized, Food and Drug Administration (FDA) approval of a drug or biologic demonstrates the reasonableness and necessity of the therapy: “[A]s a matter of national policy,” CMS’s long-standing position has been that “drugs or biologicals approved for marketing by FDA are safe and effective when used for indications specified in their labeling.”^x

As such, application of CED to on-label uses of drugs and biologicals is fundamentally arbitrary. CED for on-label uses of drugs and biologicals also subverts the overarching regulatory structure, as it amounts to little more than second guessing the considered judgment of FDA about whether a drug or biological is, in fact, safe and effective for its indicated uses. CMS’s role is not to re-arbitrate the conclusive determinations of FDA.^xi Rather, CMS’s role is to defer to FDA’s judgment on issues of safety and effectiveness, and it is therefore inherently “arbitrary, capricious, . . . or otherwise unlawful” under statute for CED to be applied to restrict coverage to on-label uses of drugs and biologicals.^xii

Despite CMS’s stated CED principles, application of CED to on-label uses of drugs and biologicals is needlessly duplicative.

In the first place, applying CED to on-label uses of drugs and biologicals (or medically appropriate off-label uses) is needlessly duplicative and will impede beneficiary access to medicines that have already proven to be safe and effective. Drugs and biologicals are unique in that they must undergo years of rigorous clinical trials to ensure that the therapies can be safely and effectively used in human patients. Over the last two decades (between 2000 and 2020) nearly 700 new prescription medicines (new molecular entities (NMEs) and original biologic license applications (BLAs) have been approved for use by the U.S. Food and Drug Administration (FDA), at a potential cost of over two billion dollars^xiii and taking on average 10.5 years.^xiv Further, the data and results from such trials are carefully reviewed by FDA prior to approval to ensure their rigor and reliability.^xv Imposing additional post-approval CED requirements on on-label uses of drugs and biologicals unnecessarily duplicates the careful and thorough work and analysis conducted by FDA.

BIO emphasizes that CED also is duplicative of work already done by FDA for drugs and biologicals approved under the FDA’s Accelerated Approval Program. Accelerated approval is a special pathway created by Congress to allow for faster patient access to therapies treating serious conditions and unmet medical needs. Although the accelerated approval pathway involves the assessment of surrogate endpoints rather than clinical endpoints, accelerated approval is no less scientifically rigorous than traditional approvals.

The FDA conducts a thorough evaluation of proposed endpoints, all data is gathered under clinical trials demonstrating a drug’s safety and effectiveness, a rigorous confirmatory trial is required to assure anticipated clinical benefits, and the therapies must meet the same standards of safety and efficacy as traditional approvals. Further, drugs and biologicals approved under the Accelerated Approval Program are required by FDA to undergo Phase 4 confirmatory trials after approval. Additionally, according to the National Academies of Science, whether or not Phase IV trials are required by FDA, “all drugs are monitored to identify new or delayed toxicity—a process described as post-marketing surveillance.”^xvi Accordingly, imposing additional CED restrictions on accelerated approval therapies would be duplicative and wasteful, given that FDA already comprehensively regulates such therapies—including through post-approval studies.

Ultimately, CED simply would serve to impede patient access to these important therapies that otherwise could address the critical unmet medical needs of patients across the country as Congress intended when establishing the pathway.

Application of CED to on-label uses of drugs and biologicals restricts patient access, compounding existing inequities.

Imposing CED requirements to on-label uses of drugs and biologicals will compound health inequities by unfairly restricting beneficiary access to needed care. Imposition of CED generally means that Medicare beneficiary access is limited to the small number of patients fortunate enough to have reliable access to a CMS-approved trial or study. All other beneficiaries are de facto denied covered access to the therapy, even though FDA has already approved the therapy and determined it is safe and effective.

In practice, large clinical trials tend to be performed at academic medical centers (AMCs) or other major hospital systems in partnership with community organizations, because these are the facilities with the resources and expertise to conduct such trials. These AMCs are located in a relatively small number of geographic areas. As a consequence, beneficiaries may be restricted in accessing coverage through CED simply as a byproduct of geography. Further, in the past, CED restrictions on access often have proven disproportionately to impact communities of color,^xvii thereby exacerbating already significant issues of health inequity facing these communities.

Conclusion

BIO appreciates the Agency’s consideration of these comments. We strongly urge the Agency to recognize that on-label uses of drugs and biologicals should be categorically excluded from CED restrictions. We look forward to further engagement on these issues in the future.

Sincerely,

/s/
Crystal Kuntz
Senior Vice President
Healthcare Policy & Research
Biotechnology Innovation Organization /s/
Andy Cosgrove
Senior Director
Healthcare Policy & Research
Biotechnology Innovation Organization

---

i https://www.cms.gov/files/document/proposed-ced-guidance-6-22-2023.pdf
ii Federal Register, Vol. 86, No. 9, January 14, 2021, p. 2988. https://www.govinfo.gov/content/pkg/FR-2021-01-14/pdf/2021-00707.pdf
iii https://www.cms.gov/about-cms/agency-information/omh/resource-center/resources-by-language
iv https://www.cms.gov/cms-strategic-plan
v https://www.cms.gov/files/document/fact-sheet-medicare-drug-price-negotiation-program-initial-guidance.pdf
vi See Social Security Act (SSA) § 1862(a)(1)(A), (E).
vii See, e.g., CMS, Coverage with Evidence Development, https://www.cms.gov/Medicare/Coverage/Coverage-with-Evidence-Development (list of current CED NCDs) (last visited Sept. 16, 2022). Since 1999, CMS has issued only 29 NCAs related to drugs or biologicals out of nearly 300 total NCAs. Further, NCAs involving drugs or biologicals often address only off-label coverage or otherwise affirm availability of on-label coverage.
viii See, e.g., SSA § 1861(b) (inpatient hospital services includes drugs and biologicals), (s)(2)(A) (incident-to physicians’ services includes drugs and biologicals that are not usually self-administered furnished as an incident to a physician’s professional service), (s)(2)(B) (outpatient hospital services include drugs and biologicals not usually self-administered furnished as an incident to a physician’s professional service to an outpatient). Limited exceptions to the requirement to cover drugs and biologicals do apply—e.g., most self-administered drugs and biologicals furnished in Part B settings are not covered by Medicare fee-for-service. See, e.g., Decision Memo for Outpatient Intravenous Insulin Treatment (Therapy), CAG-00410N (Dec. 23, 2009); Decision Memo for Blood Brain Barrier Disruption Chemotherapy, CAG-00333N (Mar. 20, 2007); Decision Memo for Extracorporeal Photopheresis, CAG-00324R (Dec. 19, 2006) (first reconsideration).
ix Id. § 1862(a)(1)(A).
x See 54 Fed. Reg. 4,384, 4,306 (Jan. 30, 1989), accord Medicare Benefit Policy Manual, ch. 15, §§ 50.4.1 and 50.4.2.
xi See, e.g., Federal Food Drug and Cosmetic Act (FDCA) § 505.
xii 5 U.S.C. § 706(2)(A).
xiii See, https://www.cbo.gov/publication/57126
xiv See, https://www.bio.org/blogs/how-long-does-it-take-get-drug-approved
xv See generally BIO, Drug Development and Clinical Trial Process, https://www.bio.org/policy/human-health/drug-development-review-lifecycle-management (last visited Sept. 18, 2022).
xvi National Academies of Science, “.Medications in Single-Dose Vials: Implications of Discarded Drugs (2021),” http://nap.naptionalacademies.org/25911
xvii See, e.g., Individualized Decisions for Endocrine Therapy Alone Study, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02400190 (last updated Dec. 21, 2021) (CED IDEAS study participants self-reported as 88% non-Hispanic White/Caucasian. A New IDEAS study was subsequently launched with the specific objective of studying a more diversion population, but the study has had difficulty enrolling the targeted levels of diverse participants).

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August 21, 2023
Centers for Medicare & Medicaid Services
Department of Health and Human Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Coverage with Evidence Development: Proposed Guidance Document June 2023

Dear Administrator Brooks-LaSure:

Thank you for the opportunity to comment on the Coverage with Evidence Development Proposed Guidance. The undersigned organizations represent a diverse group of patient advocates, caregivers, and providers who are deeply committed to advancing the well-being of patients across diverse communities and ensuring equitable access to healthcare.

Medicare's mission is to provide coverage for items and services that are deemed "reasonable and necessary" for the populations it serves. The proposed guidance states that the agency will use the National Coverage Determination (NCD) using Coverage with Evidence Development (CED) process to expand coverage and gather data when the Agency lacks sufficient information from existing clinical research to make a positive coverage determination.

We wish to highlight the first and fundamental criteria put forward by the Medicare program to consider an item or service as reasonable and necessary—namely, its safety and effectiveness.[i] These very criteria align with those used by the Food and Drug Administration (FDA) in their rigorous approval process for medical interventions. We firmly believe that any medical intervention that has undergone such comprehensive evaluation and received FDA approval being safe and effective – including being indicated (or not contraindicated) for Medicare patients merits coverage and access under the program – should in nearly all circumstances fulfill the reasonable and necessary threshold requirement. At a minimum, the Centers for Medicare and Medicaid Services (CMS) should exercise deference to the FDA regarding the assessment of expected clinical benefit and to the Congressional intent related to accelerated approval.

We appreciate the opportunity to share our perspective on CMS’s proposed updated CED criteria, based on the program’s historical performance and the need for transparency and clarity in criteria and endpoints. It is essential that the agency address and cure these concerns in order to ensure the CED process efficiently develops additional data and expedites, rather than impedes, access to therapeutics. We sincerely appreciate the opportunity to provide our input and look forward to collaborating with CMS in developing policies that best serve the interests of patients nationwide.

CED Clinical Studies Are Not Voluntary for Patients Who Depend on the Medicare Program for Coverage

The proposed guidance document emphasizes and reemphasizes that participation in a CED clinical study is completely voluntary for both beneficiaries and sponsors. We disagree strongly with this characterization. Beneficiaries who depend on the Medicare program for coverage are unable to decide not to participate in a CMS-approved clinical study for FDA-approved treatments that have an NCD requiring CED and still have access to those treatments. We urge CMS to either remove reference to CED as “voluntary,” or to add language clarifying that FDA-approved treatments under an NCD requiring CED provided outside of CMS approved studies are nationally non-covered.

Older adults meet with their health care providers, often alongside family caregivers, to discuss the benefits and risks of treatment, according to their diagnosis and needs. It is against federal law for CMS to interfere with clinical care. Section 1801 of the Medicare law states, “Nothing in this title shall be construed to authorize any Federal officer or employee to exercise any supervision or control over the practice of medicine or the manner in which medical services are provided, or over the selection, tenure, or compensation of any officer or employee of any institution, agency, or person providing health services; or to exercise any supervision or control over the administration or operation of any such institution, agency, or person.” Section 1801 was included in the law to offset the criticism made by opponents of the proposal that Federal legislation would give Federal officials the opportunity and the right to interfere in the diagnosis and treatment of the individual. [ii]

A beneficiary’s decision to not participate in a CED clinical study does not necessarily reflect unwillingness, as there are often access barriers outside a patient’s control. These agency-directed restrictions may include, but are not limited to, care setting or provider eligibility criteria or limits on CED clinical study enrollment.

Post-market randomized control trial requirements (RCTs) may be unpalatable to beneficiaries and present ethical issues, as RCT study design in CED may require some Medicare beneficiaries to receive a placebo for a device, diagnostic, or prescription drug already found to be “safe and effective” by the FDA. Beneficiaries may be required to pay coinsurance for a placebo in order to maintain a blinded study. Some populations may experience mistrust based on historical experience or have legal concerns that create hesitancy to have personal health data collected in a clinical study. By creating barriers to patient access, denying that there are barriers, and placing the onus for shortcomings on sponsors and patients, CMS interferes with and restricts the medical autonomy of Medicare beneficiaries.

The proposed guidance also notes that a motivating factor for the use of CED is that many products that are early in their lifecycle have shown limited clinical evidence. CMS specifically implicates the Food and Drug Administration’s (FDA) Accelerated Approval Program (AAP) for not producing sufficient health outcomes data for the agency to determine that a therapeutic is reasonable and necessary. However, this position runs directly counter to the creation and intent of the pathway. Accelerated approval, and other expedited approval pathways, were created to allow for earlier approval of drugs that treat serious conditions and fill an unmet medical need. By issuing CED for those therapeutics, CMS ignores unmet medical need and works counter to the intent and nature of the pathway. The AAP allows for the initial approval of a drug that treats serious and life-threatening diseases based on a demonstration of effect on a surrogate endpoint—or an intermediate clinical endpoint—that is reasonably likely to predict a clinical benefit. Accelerated approval products are approved through the same statutory provision as non-accelerated approval drugs. [iii]

Conversely, CED is not mentioned in statute, and was originally developed by CMS in a 2006 guidance.[iv] The specific statutory basis cited in the proposed guidance makes no specific mention of a CED program or any CMS led evidence collection. Congress has not ratified CMS’ CED powers, or authorized CMS to conduct research studies into the effectiveness of medications or medical devices. In fact, Robert Charrow, former HHS General Counsel, previously issued an HHS Office of General Counsel Advisory Opinion explaining that CMS’ interpretation of its statutory authority to use CED as the basis for coverage of items and services is “unlawful […]” because CMS’s “broad reading of the term [support] is fundamentally inconsistent with” the legal definition of public health service support.[v][vi] For these reasons, we are concerned that this guidance provides pretext for Medicare to use CED to dismantle the Congressionally-mandated purpose of the accelerated approval pathway.

Overly Broad Criteria and Vague Endpoints

A major concern of the patient advocacy community is that the updated CED clinical study criteria outlined in this proposed guidance are overly broad with vague endpoints. Unfortunately, these shortcomings are not new and have repeatedly been flagged as key shortcomings of the current CED process. A seminal April 2022 article on CED published in the American Journal of Managed Care noted:

“Currently, data collection mechanisms for the CED program are designed and implemented without a specific and transparent timeline for coverage reconsideration by CMS. This is exemplified by the wide range of program duration ... thus, potential sponsors of CED registries or trials may be reluctant to fund these initiatives due to anxiety about the program’s duration, what constitutes “success,” and the possibility of “failure” that may eliminate any form of CMS coverage or even call FDA clearance or approval into question … a timeline for reevaluation could offer the predictability necessary for collaborators to confidently invest resources in data collection infrastructure. Moreover, from the perspective of CMS and Medicare beneficiaries, a stalled program means either a potentially beneficial therapy is being withheld or a potentially harmful therapy is being furnished to beneficiaries. Measures of ongoing success could be in the form of clinical trial or registry milestones such as protocol design, enrollment initiation, data analysis, and the like. Regardless of the specifics, measures of progress and an assessment timeline should be identified a priori with a plan to address delays on a regular basis.”[vii]

Several of our organizations publicly reiterated these concerns over the last year, including in a letter last September in response to the Agency for Healthcare Research and Quality (AHRQ) Draft Analysis of Requirements for CED[viii] and during the February 2023 Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) on Analysis of Coverage with CED criteria.[ix] In these forums, patients and advocates raised the need for CMS to provide clear standards to help ensure that clinical trials are designed so as to meet CMS’s reasonable and necessary criteria. Further, stakeholders shared the need for clear criteria and thresholds that will lead, if such results are attained, in the end of CED coverage restrictions for the affected products or procedures.

If CMS finalizes the proposed CED study criteria without addressing these key shortcomings, it will lead to an untenable situation in which CED will introduce even greater uncertainty than what exists under the status quo for patients, physicians, and sponsors.

Additionally, the criteria for clinical study standards under CED, as defined in section VI, are overly broad, lacking specific definitions for crucial terms and giving CMS officials open ended authority to enforce CED study criteria as they see fit, for example:

In section 6.4: The section “Evidence sufficient to assess health outcomes” fails to define such thresholds and remains entirely open to CMS’s interpretation.

In section 6.7: “Beneficiary subpopulations affected by the item or services under evaluation.” CMS highlights the need for expanded participation in trials while citing vague requirements for those subpopulations. CMS needs to provide a standard definition of what they consider to be representative in regard to clinical trial data. We encourage CMS to adopt a definition prioritizing representation that is reflective of the population in Medicare that experiences the disease. We also encourage CMS to avoid creating CED parameters that unintentionally prevent representative enrollment in CED trials.

In section 6.10: “Evidentiary threshold for the primary health outcome(s)” is a criterion that is meaningless post-FDA approval, after which a drug or therapeutic has demonstrated clinical efficacy or in the case of AAP, reasonable likelihood of clinical benefit to be confirmed via confirmatory trial.

In section 6.11: No terms that are descriptive of data quality are defined, including “provenance, bias, completeness, accuracy, sufficiency of duration of observation” or “sufficiency of sample size.”

In section 6.13: CMS must clarify the term “robustness of results.”
This ambiguity can be found throughout the guidance, in which CMS has allowed themselves undefined latitude in determining what type and amount of evidence is acceptable.

We are deeply concerned about unclear criteria for ending CED, and urge CMS to create a predefined trigger mechanism to end CED coverage if interim data reporting from CED trials show overwhelmingly positive outcomes in order to ensure timely access to innovative therapies. This approach would align with the FDA's practice of ending clinical trials early when a therapy proves so effective that it becomes unethical to keep the control group on a placebo.[x]

Ethics and Equity Considerations in CED Trials

In the pursuit of comprehensive data collection, CMS cites the underrepresentation of relevant subpopulations in clinical trials as a rationale for continued study and data collection through CED. While we affirm the importance of inclusivity in research, tying data collection to coverage restrictions will have unintended consequences and disproportionately restrict access to diverse and underrepresented communities, particularly people of color and especially women of color.

There is a troubling history of CMS allowing the policy objectives underlying equity standards as justification to limit coverage through CED. Unfortunately, these limitations have fallen disproportionately upon communities of color and rural areas. As a result, the use of CED has only exacerbated the inability of underrepresented communities to obtain timely access to the therapies that they need to treat their serious medical conditions.[xi] Moreover, by restricting coverage based on data collection requirements, CMS may inadvertently hinder the very data collection efforts it seeks to promote.

CMS must approach data collection and study design in a manner that respects patients' autonomy and prioritizes equitable access to approved treatments. Without a fundamental shift in approach to CED, access will be restricted for the very populations the agency aims to understand and serve.

Conclusion

CMS has failed to address the valid concerns raised by external stakeholders and members of the MEDCAC in the proposed CED guidance. This is unacceptable and CMS should reissue the guidance to address the concerns raised by our organizations.

We advocate in the strongest terms for broader access and data collection methods that facilitate inclusivity rather than imposing strict controls and cumbersome data registries. CMS must decouple the data collection process from coverage requirements to ensure that patients from all backgrounds have equitable access to innovative therapies and to foster a comprehensive research landscape. For additional questions about this letter, please reach out to Michael Ward, Vice President of Public Policy and Government Relations at the Alliance for Aging Research at mward@agingresearch.org and Adina Lasser, Public Policy Manager at the Alliance for Aging Research, at alasser@agingresarch.org.

Sincerely,

Alliance for Aging Research
Alliance for Health Innovation
Alliance for Patient Access
Alzheimer's Los Angeles
Alzheimer's New Jersey
Alzheimer's San Diego
Alzheimer's San Diego
Arthritis Foundation
Association of Black Cardiologists
Autoimmune Association
Caregiver Action Network
Chronic Care Policy Alliance
EveryLife Foundation for Rare Diseases
Family Caregiver Alliance
Global Coalition on Aging Alliance for Health Innovation
HealthyWomen
Infusion Access Foundation
Infusion Providers Alliance
LUNGevity
Lupus and Allied Diseases Association, Inc.
Melanoma Research Alliance
National Consumers League
National Minority Quality Forum
National Task Group on Intellectual Disabilities and Dementia Practices
Nevada Chronic Care Collaborative
NTM Info & Research
Parent Project Muscular Dystrophy
Partnership to Fight Chronic Disease
Society for Women's Health Research
The Global CEO Initiative on Alzheimer's Disease
The Mended Hearts, Inc.
UsAgainstAlzheimer's
Voices of Alzheimer's

__________________________________________

[i] Centers for Medicare & Medicaid Services. (n.d.). Internet-only manuals (IOMs). CMS. https://www.cms.gov/regulations-and-guidance/guidance/manuals/internet-only-manuals-ioms-items/cms019033.
[ii] Smith, J. A., & Johnson, B. R. (1985). Reflections on the enactment of Medicare and Medicaid. Health Care Financ Rev. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195078/
[iii] 21 U.S. Code § 356
[iv] Centers for Medicare & Medicaid Services. (2014, November 20). Guidance for the Public, Industry, and CMS Staff: Coverage with Evidence Development ("CED Guidance"). CMS. https://www.cms.gov/medicare-coveragedatabase/view/medicare-coveragedocument.aspx?MCDId=27
[v] Charrow, R. (2021, January 14). Advisory Opinion 21-03 on Medicare Coverage with Evidence Development, U.S. Dep't of Health & Human Servs., 2. (Rescinded). While this advisory opinion has since been withdrawn, Charrow’s legal interpretation remains valid.
[vi] Government Publishing Office. (2023). 42 CFR 93.221. https://www.ecfr.gov/current/title-42/chapter-I/subchapter-H/part-93/subpart-B/section-93.221
[vii] Zeitler, E. P., & Gilstrap, L. G. (2022). Coverage With Evidence Development: Where Are We Now? The American Journal of Managed Care, 28(8), 382-389. https://doi.org/10.37765/ajmc.2022.88870
[viii] Alliance for Aging Research. Comments on Draft Analysis of Requirements for Coverage with Evidence Development (CED). 28 Sep 2022. https://www.agingresearch.org/wp-content/uploads/2022/09/AAR-Draft-AHRQ-CED-Comments-FINAL-9.23-FINAL.pdf
[ix] Centers for Medicare & Medicaid Services. (n.d.). MedCAC meetings. CMS. https://www.cms.gov/medicare-coverage-database/view/medcac-meeting.aspx?medcacid=79&year=all&sortBy=meetingdate&bc=15
[x] Food and Drug Administration. (2006). Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees. https://www.fda.gov/media/75398/download. Sections 4.4.1.1 and 7.2.1
[xi] Peschin, S., Farber, D., & Trinh, J. Façade of Evidence: How Medicare’s Coverage with Evidence Development Rations Care and Exacerbates Inequity. (13 Feb 2023). https://www.agingresearch.org/wp-content/uploads/2023/02/Facade-of-Evidence-CED-2-13-2023.pdf

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August 21, 2023

Joseph Chin, M.D.
Medical Officer for Coverage and Analysis
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services, mailstop: S3-02-01
7500 Security Blvd.
Baltimore, MD 21244

Re: Proposed CMS Guidance for Coverage with Evidence Development (CED)

Dear Dr. Chin:

Thank you for the opportunity to comment on the Centers for Medicare and Medicaid Services (CMS)’s proposed Guidance for Coverage with Evidence Development (CED). Researchers at the University of Southern California (USC) Schaeffer Center for Health Policy & Economics have been studying how evidence can be used to define value in our healthcare system since 2009; our comments draw on our experiences and perspectives developed in that research(1). As part of the USC Schaeffer Center, we share a mission to measurably improve value in health through evidence-based policy solutions, research excellence, and private and public sector engagement.

CED is an important policy that CMS has implemented in various forms since its inception in 2006. The policy was designed to provide Medicare beneficiaries access to new technologies while facilitating ongoing data collection to prove reasonableness and necessity.

Since CED’s implementation, the healthcare community has learned more about its utility, and questions have been raised about its goals and whether those goals are being met(2). Unfortunately, CED is an example of a policy that may not have lived up to its promise, has diverged from its original purpose, and now presents real barriers to patient access. Below, we outline our perspectives on how CMS could improve its proposed guidance. We are grateful that CMS is seeking comment because CED is important for several reasons:

CMS serves as a model for other healthcare payers: CMS should consider the broad impact of its policies on the innovation of health technologies and their corresponding opportunity to improve public health. Private payers in the U.S. have frequently emulated CMS decisions(3), and CMS policy has been shown to affect provider behavior and patient treatment well outside of the traditional Medicare system(4). Improving CMS policy indirectly improves policy adopted by other payers(5), providing the opportunity to strengthen incentives for patient-focused innovation.

CED offers unrealized potential to drive meaningful(6) innovation, but improvements need to be made: In their current form, the criteria for invoking CED are vague and, as a result, could negatively impact innovation(7). Analysis of recent CMS National Coverage Decisions (NCDs) shows that CMS is increasingly implementing CED policies, which limit access to new therapies and add uncertainty, risk and data collection costs for drug and medical device developers – all of which impact incentives to innovate(8). This need not be the case. By setting forth objective criteria governing the use of CED, including concrete milestones that guide developers towards completing its requirements, CED could not just improve patient access to innovation but also promote and encourage more meaningful innovation.

Below are specific responses to points raised in CMS’s proposed guidance, with comments and suggestions for improvement, following the general flow of the proposed Guidance document:

1. Goals of Coverage with Evidence Development

CMS should be commended for outlining the specific goals of CED, against which all future policies and the Guidance document itself, should be measured. From a thorough review of the literature, CED policies throughout the world(9) share at least two important goals proposed by CMS:

“. . . expedite earlier beneficiary access to new items and services . . .” (10)

“. . . generate additional evidence that is appropriate for Medicare beneficiaries and that may demonstrate improved health outcomes . . .”(11) In addition, generating more evidence is a laudable goal for several other reasons. CED-generated evidence can:

• Inform and justify future coverage decisions (expanded or non-coverage)
• Facilitate ongoing value assessments
• Drive shared decision-making between providers and patients(12)
• Support safety surveillance or other safety-signal detection that may supplement the U.S. Food and Drug Administration (FDA) pre- or post-market requirements
• Provide clinically meaningful evaluation that could not otherwise be collected in a clinical trial (e.g., long-term safety)
• Assess whether clinical data generated for regulatory approval is generalizable to:
  -Real-world settings (i.e., outside the controlled environment of a clinical study)
  -The Medicare population, in cases where there is evidence an item or service may function differently in people 65-years-of-age or older(13)
• Identify differences in outcomes among subgroups/payer populations, including under-represented and underserved communities, that may not have been discoverable in a traditional clinical trial

However, we caution CMS against its potential focus on the evidence being “appropriate for Medicare beneficiaries.” CMS should be careful that its demand for sufficient representation of older Americans in clinical studies is based on legitimate scientific or clinical reasons as to why treatment effects might vary by age. Broadening the requirement risks denying Medicare patients access to effective therapies, without improving the evidence base for treating disease in this population group. There are practical and scientifically-sound reasons for excluding individuals with comorbidities from clinical studies, and there is a higher incidence of comorbidities in older people(14).

CMS should include promote meaningful innovation as a clear, primary goal. We are surprised that this was not called out as a specific goal in the proposed Guidance, as CED being the “driver of innovation” was explicitly mentioned in President Obama’s 2012 National Bioeconomy Blueprint and is one of the agency’s six strategic pillars in its 2023 strategic plan (15,16). In addition, CMS’s proposed Guidance for National Coverage Analysis Evidence Review refers to “encourage[ing] innovation” as a rationale for that Guidance(17). By providing patients access to items or services that meet certain criteria, the U.S. sends a clear signal to innovators about where to pursue treatment solutions for America’s seniors. CMS’s coverage policies should prioritize predictability for innovators which will reduce some of the risks inherent in drug and device development. The current uncertainty around CED policies is increasing the expected costs associated with innovation and reducing the number of projects that receive investment.

CMS should clarify its proposed goals of:

“. . . [assuring] that items and services are provided to clinically appropriate patients . . .”(18) While CMS has a legitimate interest in evaluating real-world evidence on medical necessity, there has been criticism that the Agency may have waded into FDA’s jurisdiction when determining what is clinically appropriate. There could also be concern that CMS could end up interfering with the practice of medicine by directing how and when clinicians should use a therapy(19). CMS should clarify how it would determine clinical appropriateness to avoid confusion and conflict with its stated principle of “not duplicating FDA authority.”

“. . . ensuring that systematic patient safeguards . . . are in place to reduce the risks inherent to new technologies . . .”(20) As stated above, CMS has a legitimate role in managing appropriate utilization of new technologies, particularly as their risk/benefit profile may be less understood in the early days of its introduction. With appropriate evidence generation, CED can help address uncertainty in the risk/benefit profile. That said, CMS should clarify how this goal does not conflict with its stated principle of “not duplicating FDA authority.” FDA has been uniquely empowered, qualified and resourced by the Congress to facilitate the benefit/risk trade-off decisions of safety and efficacy. A goal designed to “reduce the risks inherent in new technologies” could undermine FDA’s authority, create confusion and unpredictability in the market, and introduce significant market inefficiencies if this is not clarified.

One goal that was not mentioned, but which may have motivated recent applications of CED, is the desire by CMS to manage its budget. Recent attempts to use CED for high-cost drugs, such as the proposal to apply CED to CAR-T cell therapy(21) and its NCD on Aduhelm(22) may indicate a trend in this direction. We believe managing net program costs may be a legitimate public policy goal(23,24) but not appropriate as a motivator for use of CED at this time because:

It isn’t legal – the statute precludes CMS from making coverage decisions based on cost(25). Use of CED as a cost containment measure should be discontinued to the extent that it is occurring absent explicit Congressional authorization. Furthermore, without engaging in an appropriate public policymaking process (e.g., legislation or rulemaking), applying CED because CMS is concerned about budget implications undermines CMS’s credibility and public trust.

Cost-cutting may be counterproductive to other CED goals – Imposing CED on items or services that are expected to impose significant costs on the program may undermine an important CED goal: collecting evidence to address CMS’s concerns. In addition, addressing the costs of one item or service could have broader health implications for other Medicare costs (e.g., the opportunity costs of not treating the disease).

CMS isn’t equipped to conduct value assessment – Health technology assessment (HTA) is an important process that evaluates health technologies and guides coverage and pricing decisions. CMS has not established transparent, rigorous, and predictable rules to conduct a proper value assessment of new items or services. A report recently published by the USC Schaeffer Center and Aspen Institute introduced an approach to creating an HTA advisory board within HHS that could benefit CMS and CED(26).

2.Principles governing application of CED

We agree with many of CMS’s proposed principles, and we offer some additional suggestions for consideration:

Transparent and open to public comment (under an NCD process) – this is an important principle, but the guidance as written appears to undermine that principle, particularly since it ensures the CED requesting party can have continual, private dialogue with CMS. We agree open communication should be maintained, but with ALL stakeholders, not just the first individual or organization to request CMS’s opening of a CED-NCD. CMS should consider reforming its Medicare Evidence Development & Coverage Advisory Committee process to allow for greater public participation and flexibility. CMS could benefit from the experiences of Health Technology Assessment organizations around the world that have public mandates to involve the public and the impacted communities(27). In addition, CMS should consider a more formal process to notify the public, including publication in the Federal Register, media and news alerts, and community open forums for the public to ask questions. And CMS should provide Congress an annual report, reviewing the status of outstanding NCDs involving CED.

Limit evidence generation to that which addresses specific evidentiary deficiencies identified in the National Coverage Analysis process – this is an important principle which, unfortunately, has not been followed in past NCD/CED decisions. For example, the STS/ACC TVT Registry(28) that was established by the American College of Cardiologists and Society for Thoracic Surgeons collects more 276 fields for each patient(29). Such requirements can be costly and burdensome on an already taxed healthcare system(30). Required data collection should be limited to information that can help answer the original research question(s) posed by CED.

Don’t duplicate or replace FDA authority in assuring safety and effectiveness – we wholeheartedly agree with this principle. CMS and FDA evidence evaluation roles should be clearly delineated and respected. The current CED system could be construed as justification to second-guess the work of the FDA. Nowhere is this more apparent than in CMS’s National Coverage Decision concerning Aduhelm and all future monoclonal antibodies directed against amyloid that are approved by the FDA. That decision shows that CMS is concerned with the potential harms associated with this class of Alzheimer’s Disease drugs, which may include brain bleeds, falls, and other outcomes. In the decision, CMS indicated that the Agency “does not believe an item or service to be reasonable and necessary if the harms of the treatment outweigh the benefits.” Such a stance is difficult to distinguish from FDA’s adjudications regarding the safety and efficacy of an item or service. As previously stated, this undermines FDA’s authority, creates confusion and uncertainty in the market, increases costs, and impedes innovation. CMS should accept FDA’s determination that an item is safe and effective, limiting its review to whether the process is reasonable and necessary to treat or diagnose an injury or illness. Principles that we urge CMS to add to its proposed list include:

A patient-centered approach to decision-making that includes the patient voice and perspective

Minimally burdensome requirements on patients/beneficiaries (e.g., extensive travel to centers of excellence) and providers (e.g., costs, time) to facilitate data collection

Coverage constraints that are fit for the purpose of data collection (e.g., if a goal of CED is to collect real-world evidence, coverage should not be limited to “centers of excellence”)

Evidence generation grounded in good research principles (e.g., the evidence gaps cited are realistic and achievable)

Greater predictability and reduced uncertainty for providers through clear and objective application of timelines, standards and expectations

3.Factors to use when CMS considers implementation of CED

As previously stated, we recommend CMS add the important goal of promoting meaningful innovation. A principle to support that goal would be to reduce uncertainty for stakeholders through the development of clear expectations. CMS should adopt clear and predictable criteria for when CED should be considered, enabling patient groups, physicians, hospitals, and innovators to know when to expect the implementation of CED and plan accordingly.

The proposed draft indicates that there are two main criteria: 1) the “technology is likely to show benefit to the Medicare population,” but 2) the “available evidence is insufficient to demonstrate Reasonable and Necessary.” However, as written, the Guidance is unclear or even contradictory. For example:

Who determines whether the evidence is “insufficient?” What objective measure is used? The arbiters would seem to be CMS, the Agency for Healthcare Research and Quality (AHRQ) and sponsors/investigators(31), and it appears that CMS is indicating that the outcomes used should be those that matter most to patients(32). But it is not clear how the perspectives of these competing interests are balanced, and complaints of CMS’s unresponsiveness to patient organizations(33) suggest a lack of transparency on this point. Beyond the ability to comment through the public comment process, patients and patient advocacy organizations, which are most likely to understand the patient’s perspective, currently have no role in this decision.

What kind of outcomes does CMS consider “evidence” when evaluating the evidence’s sufficiency? CMS relies heavily on “health outcomes data,”(34) which don’t include surrogate endpoints because they are not direct measures of clinical benefit(35). However, when a validated surrogate endpoint is available(36), CMS should make use of data from this endpoint to support evidence generation(37).

Whose outcome is CMS considering? CMS appears to be concerned about the generalizability (e.g., “will this work for people treated outside the extremely controlled environment of a clinical trial?”) and representativeness of the data, both in terms of demographic diversity(38) and the Medicare population (people over 65 years of age)(39). Clearly articulating this goal is critical for generating clear and consistent decisions.

What is the measure of “insufficiency?” It appears from the proposed Guidance that CMS considers “insufficiency” to mean: any new technology(40), cases where the evidence lacks the sample size (typically a large enough clinical trial) to power sufficient statistical certainty(41), or when there is not enough data demonstrating long-term durability of the outcomes(42). Interestingly, the words “certainty/uncertainty” and “effect size”(43) are not mentioned, which are common concerns in CED policies globally(44). It again begs the question: is CMS considering whose standards will be used when setting these thresholds?

Who determines what is considered a benefit and its likelihood? Without more clarification on these points, stakeholders may be left to guess what CMS believes is a “benefit” and its “likelihood,” further weakening the Agency’s ability to influence better innovation investments.

All these questions can be answered. The statistical and economic sciences can help us create models to set objective measures for evaluation. More work will be needed to develop a specific methodological approach, but in the meantime, we recommend CMS adopt an alternative set of criteria to use when evaluating whether to apply CED. The following criteria illustrate one possible path forward:

A) An item or service promises (evidence published in a peer-review publication indicates more likely than not) to provide benefits that matter most to patients (as measured with scientifically rigorous methods for eliciting and quantifying patient preferences(45)) or the healthcare system, including four(46) or more of the following criteria:(47) The item or service:

Shows significant promise to improve healthcare or reduce costs

Is innovative or novel

Poses acceptable risk to patients intended to receive treatment

Is more closely aligned with patients’ preferences

Is a potential replacement for more complex methods/technologies

Alleviates high disease burden

Has no or few available alternatives

Reduces healthcare system resource utilization (e.g., hospital capacity, demands on labor)

Addresses unique challenges for underserved patient populations or patient subgroups that otherwise lack access to a covered treatment

AND

B)Significant (patient prioritized) questions (risks or uncertainties) exist about the value of items or services

Significant = high risk/likelihood of a negative outcome; or low risk/likelihood of a negative, but serious, outcome, as evaluated and measured through quantitative patient preference data

Uncertainty about relative risks/benefits remain, including any of the following:

Level of uncertainty for any of the risks of the item or service is outside of patient populations’ tolerance levels

Insufficient data to power confidence levels (as defined by the patient population) in any of the risk/benefit outcomes

High potential for confounding factors to influence predictability of outcomes (e.g., operator performance, context of delivery environment)

Unavailable data/information about outcomes that matter most to patients (e.g., long-term outcomes may be more important to younger patients, but less important to older patients)

4.Clinical research/study design standards

It is important that CMS be consistent in supporting its stated principle of only requiring “. . . the generation of evidence that addresses specific evidentiary deficiencies identified in National Coverage Analyses.” We recommend CMS also remain consistent with the additional principles we recommend, including:

Minimally burdensome requirements on patient/beneficiaries (e.g., travel to centers of excellence) and providers (e.g., costs, time) to facilitate data collection

Data collection grounded in good research principles (e.g., clear, achievable research questions)

Greater predictability and reduced uncertainty for providers through clear and objective application of timelines, standards and expectations.

Clinical Study Standards - We believe more work needs to be done with regard to CMS’s proposed clinical research/study standards to remain consistent with the goals and principles of CED. As some of us commented in our September 28, 2022 comments to AHRQ(48), we respectfully disagree with many of the study standards proposed. The AHRQ recommendations that CMS adopted as its CED study design requirements expanded rather than reduced the original thirteen requirements. CMS should consider prioritizing the requirements in order of importance, thus allowing sponsors of CED studies the ability to remain flexible on the less important criteria.

Study Design - We agree with CMS that “the study design, analysis plan, and data source(s) must be sufficient to credibly answer the question(s) posed by the CED.”(49) This “fit for purpose” study design is consistent with the goals and principles of CED, as adopted. But there are many questions that are raised when making this determination, the most important of which is: who determines if the study design is “fit for purpose?” CMS indicates a randomized control trial (RCT) may be appropriate where observational studies may not, but what are the objective criteria to ascertain “appropriateness?” It is difficult to imagine scenarios where an RCT would be appropriate in the context of a coverage decision. Typically, it would be inappropriate and unethical to randomize a beneficiary to a control arm. Why should one beneficiary have a 50% chance of receiving a potentially life-saving, FDA-approved treatment while another enjoys the benefits for which they both contributed to the Medicare Trust Fund through taxes? Other ethical questions remain, including: should a Medicare beneficiary be compelled to enroll in a science experiment not knowing if they will receive the benefit to which they’ve earned a right as a beneficiary? Or is it appropriate to conduct a “sham procedure” for a medical device implantation?

Other study designs may beg additional questions. If it is decided that a single-arm observational study (e.g., a registry) be utilized, what is a reasonable comparator? Should the comparator procedure or treatment option be included in registry data collection? Finally, there are legitimate cases where real-world studies improve external validity – e.g., interventions to improve medication adherence or influence patient behavior might produce artificial results in a controlled trial setting. In light of these questions and issues, we believe a consultative process with stakeholders, particularly patients and patient organizations, is the best approach to decision-making in this situation. At some point, researchers may propose a decision-making framework to help CMS and other payers make these kinds of determinations more consistently and objectively.

In addition, the research questions that CMS determines must be answered need to be designed to ensure that they can be answered with available data under realistic conditions (e.g., specific, measurable, achievable, realistic and time-specific).

Data Collection Methods - to maintain consistency with CED goals and principles, the least burdensome methods of data collection should be used to answer the questions posed by CED. Ideally, data could be gathered through “passive collection” techniques, such as administrative claims data or electronic health records. Additional considerations:

If CMS is to condition provider payment upon additional “active data collection” requirements, providers and/or data collection organizations should be compensated through increased payments to offset incremental expenses(50)

If data collection is to be conducted or managed by a third party, the data collected as a condition of coverage should be the property of CMS and made publicly available as discussed herein

Registries, if used, should follow best practices as outlined in “Recommendations for Advancing Safety and Public Health” - Medical Device Registry principles (by The Pew Charitable Trusts, Blue Cross Blue Shield Association, and the Medical Device Epidemiology Network)(51)

Patient consent to their data being collected and used for research should comply with the Common Rule(52)

Data analysis - CMS rightly proposes that information gathered under CED should be published(53) and publicly accessible to inform patients, caregivers and healthcare providers about the items or services under CED(54) so they can make good decisions(55). However, CMS’s internal capabilities to analyze data and evidence collected under CED is limited(56). To facilitate fair and balanced analysis of the data, we urge CMS to enlist the expert resources and capabilities of researchers with expertise in clinical effectiveness and outcomes research. We recommend early and real-time access to data in a phased approach, starting with expert resources providing reports to CMS, then opening the data to academic researchers, and ultimately to the public in an easily understandable format to facilitate patient decision making.

5.Ending CED

CMS has represented CED as a temporary condition, after which the Agency would make a National Coverage Determination to cover, not cover, or conditionally cover the item or service. However, many CEDs appear to never end, some lasting almost 20 years(57). These long or ambiguous timeframes create uncertainty that could chill innovation. It also results in less accountability; the science can be advanced when all stakeholders – including manufacturers of new therapies – have “skin in the game,” so they are motivated to help CMS design studies that provide the information needed to move the therapy to standard coverage. Without a predictable timeframe, providers face uncertainty about what requirements must be met to “graduate” from CED and what events may trigger failure. In the proposed Guidance, CMS continues to assert that CED should not last indefinitely(58), and coverage should be time-limited to allow for “sufficient evidence generation,”(59) but the Agency stops short of specific recommendations. CMS does recommend a stopping rule when sufficient evidence is gathered(60) or the study is completed and published(61).

Consistent with our proposed goals and principles of promoting innovation and the principles of transparency, predictability and minimally burdensome regulation, we would propose stopping rules similar to those proposed in CMS’s TCET Guidance:

A) Any announcement of CED should carry a presumption of coverage, meaning that at the expiration of the CED time limit, CMS is expected to announce an NCD granting the product coverage, unless generated evidence patently demonstrates that the item or service is not reasonable or necessary to diagnose or treat the indicated illness or injury and warrants non-coverage or coverage with conditions.
B) Before a CED decision is finalized, CMS works with stakeholders to develop objective, ex ante criteria for success or failure of the research questions, based on reasonable priorities and outcomes that matter most to patients
C) CED would apply for up to 3 years, or when the research questions are answered through sufficient data collection and objective analysis, whichever comes first, subject to the following conditions

“Sufficiency” of data type and amounts would be determined through processes and standards as outlined above in “Factors to use when CMS considers implementation of CED” and “Clinical research/study design standards”

An option to remove CED requirements earlier if significant new evidence arises

An option to extend CED longer than 3 years, not to exceed another 2 years, if significant new evidence arises that would have warranted the triggering of CED or a non-coverage decision. CED should not last more than five years under any circumstances.
D) After CED ends, CMS must finalize an NCD granting coverage, unless the evidence supports a non-coverage or limited/conditional coverage decision

6. Process

Broader and more sustained patient and public input are needed; CMS misses an opportunity to establish a more open and transparent approach to its coverage process in this proposed Guidance. The Agency indicates that “the public is afforded the opportunity to comment,”(62) which may have been the approach of federal agencies in the late 20th Century, but public engagement practices have advanced considerably in the last two decades. The Agency should learn from the experience of global Health Technology Assessment organizations, which over the years have developed processes to maximize opportunities for patient and public input in the assessment phase of new technologies(63). For example:

Long-range planning – Publish for public comment and input a forecast of potential disease areas of concern where CED may be warranted(64)

Near-range planning – Reach out proactively to patient organizations that represent the potential disease areas of concern to gather input and feedback on the patient experience to better inform CMS’s approach

Patient representatives – enlist the involvement of patients and carers with relevant disease experience at all stages of the process(65)

Qualitative and quantitative data analysis – identify or generate qualitative and quantitative data specifying patient perspectives and priorities

While the development of a CED policy itself may not be an “assessment” in the sense that CMS’s National Coverage Assessment is, the principle remains: a public payer has a responsibility to ensure it is representing the interests of the public it serves. Instead, the Agency has an opportunity for a “requestor” (“. . . any member of the public may request to reopen the NCD that requires CED”(66) ) to meet with CMS and frequent, informal contact is possible.”(67) This creates an aura of secrecy and “back room dealing” between the Agency and self-interested stakeholders.

7.Coverage – the “C” of CED

While evidence development is a worthwhile goal, perhaps the more controversial aspect of CED is the use of seemingly arbitrary coverage constraints to limit patient access during this “temporary phase” until sufficient evidence is developed to justify an NCD. While CMS technically can constrain access to new technologies under any circumstance, we believe a coverage decision that is invoked for the primary purpose of generating evidence should be fit to that purpose. Coverage restrictions should be guided by specific evidence that a technology or service is not suitable for a category of patients. Broadly limiting patient access to new items or services under CED is counter to the goal of evidence development, particularly if better understanding of the generalizability of the results of clinical studies is a goal. How can we learn if an item or service has similar results in the “real world” (outside of the controlled environment of a clinical trial) if coverage is limited to sites or individuals like those in a clinical trial?

We recognize there may be other goals or principles CMS may be trying to achieve with this policy, including reducing utilization. If evidence generation tools are working properly, CMS and other stakeholders will gain a better understanding about appropriate utilization as data is reported on a regular, real-time basis. If an item or service is being inappropriately used, properly designed data-collection strategies will demonstrate this fact and enable CMS to take corrective action.

We recommend CMS consider the development of a clear, transparent, and predictable decision-making framework to guide it through the use of coverage constraints to ensure they are fit for purpose.

Conclusion

CMS’s CED policy could be a valuable tool to promote and support innovation, expedite earlier beneficiary access to new items and services, generate additional evidence to evaluate these items and services, and ensure appropriate resource utilization. CMS has an opportunity, through its proposed Guidance, to improve the process, increase transparency, reduce uncertainty, stimulate meaningful innovation and build public support and confidence in the Agency’s decision-making. As we outlined in this comment, there are several improvements that need to be made in order for that to happen, including:

Limiting use of CED to those scenarios where real-world evidence is needed and will be informative rather than using it to effectively revaluate an approval decision

Limiting constraints on coverage to the purpose of generating evidence; real-world evidence depends on real-world utilization

Building clear and predictable decision-making tools to guide stakeholders (including CMS) on how and when to use CED, including specific guidance about when CED will be triggered (when there are significant research questions)

Right-sizing CED to narrowly address the questions or concerns identified, and removing it as soon as those questions are answered or after a set period of time

Involving patients and the patient community as primary stakeholders in the decision-making throughout the process

We look forward to working with CMS as it pursues continued improvement in its coverage process. Please let us know what we can do to further support CMS’s goals.

Sincerely,

Alice Chen, PhD
Senior Fellow, USC Schaeffer Center
Associate Professor and Vice Dean for Research, USC Sol Price School of Public Policy

Joseph Grogan, JD
Nonresident Senior Fellow, USC Schaeffer Center
Former Assistant, U.S. President
Former Director, Domestic Policy Council (DPC)

Mireille Jacobson, PhD
Co-director, Aging and Cognition Program, USC Schaeffer Center
Associate Professor, USC Leonard Davis School of Gerontology

Geoffrey Joyce, PhD
Senior Fellow, USC Schaeffer Center
Associate Professor and Chair of the Department of Pharmaceutical and Health Economics, USC Mann School of Pharmacy & Pharmaceutical Sciences

Darius N. Lakdawalla, PhD
Director of Research, USC Schaeffer Center
Professor, USC Alfred E. Mann School of Pharmacy & Pharmaceutical Sciences and Sol Price School of Public Policy

Barry Liden, JD
Director of Public Policy, USC Schaeffer Center

Eugene Lin, MD
Clinical and Resident Fellow, USC Schaeffer Center
Assistant Professor, Department of Internal Medicine, Keck School of Medicine of USC

Karen Van Nuys, PhD
Executive Director, Value of Life Sciences Innovation Program, USC Schaeffer Center

William Padula, PhD
Fellow, USC Schaeffer Center
Assistant Professor, Department of Pharmaceutical & Health Economics, USC Mann School of Pharmacy & Pharmaceutical Sciences

Alison Sexton Ward
Research Scientist, Value of Life Sciences Innovation Program, USC Schaeffer Center

Julie Zissimopoulos, PhD
Co-director, Aging and Cognition Program, USC Schaeffer Center
Professor, Sol Price School of Public Policy

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1. The views expressed in this letter are those of the authors and do not necessarily reflect the views of the USC Schaeffer Center or the University of Southern California (USC).
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6. CMS may wish to consider that “meaningful” innovations could be defined as those that combine the creation of value at four levels: “users, organizations, ecosystems, and society.” den Ouden, E. Meaningful Innovation. Innovation Design. 2011. Springer, London. https://doi.org/10.1007/978-1-4471-2268-5_4
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18. Guidance page 5
19. 42 U.S. Code § 1395 - Prohibition against any Federal interference. Available from: https://www.law.cornell.edu/uscode/text/42/1395
20. Guidance page 5
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22. National Coverage Determination for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease; CMS CAG-00460N (April 7, 2022)
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24. “Operationally, coverage determinations are reserved for those services that are likely to have a major impact on cost or quality of care or when safety concerns arise.” [emphasis added] Tunis S., Berenson R. Improving the Quality and Efficiency of the Medicare Program Through Coverage Policy. The Urban Institute. August 2011
25. Daval CJR, Kesselheim AS. Authority of Medicare to Limit Coverage of FDA-Approved Products: Legal and Policy Considerations. JAMA Intern Med. Published online July 28, 2023. doi:10.1001/jamainternmed.2023.3961
26. Lakdawalla DN, Neumann PJ… Wilensky GR. Health Technology Assessment for the US–A Vision for the Future. USC Schaeffer Center and Aspen Institute Advisory Panel on Health Technology Assessment in the US February 9, 2021.
27. Abelson, J., Wagner, F., Dejean, D., Boesveld, S., Gauvin, F.-P., Bean, S., Axler, R., Petersen, S., Baidoobonso, S., Pron, G., Giacomini, M., Lavis, J., 2016. Public and Patient Involvement in Health Technology Assessment: A Framework for Action. International Journal of Technology Assessment in Health Care 32, 256–264.. https://doi.org/10.1017/s0266462316000362
28. STS/ACC TVT Registry [Internet]. 2023 [cited 2023 Aug 15]. Available from: https://www.sts.org/registries/stsacc-tvt-registry
29. Simonato M, Vemulapalli S, Ben-Yehuda O, Wu C, Wood L, Popma J, et al. Minimum Core Data Elements for Evaluation of TAVR: A Scientific Statement by PASSION CV, HVC, and TVT Registry. The Annals of Thoracic Surgery. 2022 May 1;113(5):1730–42.
30. Clinical Registries: Getting Necessary & Costly [Internet]. 2012 [accessed 2023 Aug 11]. Available from: https://cardiovascularbusiness.com/topics/patient-care/clinical-registries-getting-necessary-costly
31. “In consultation with CMS and AHRQ, sponsors/investigators establish an evidentiary threshold for the primary health outcome(s)” [Guidance page 9]
32. “The primary health outcome(s) for the study are those important to patients and their caregivers and that are clinically meaningful.” [Guidance page 9]
33. Analysis of Coverage with Evidence Development (CED) Criteria [Transcript]. Baltimore, MD: CMS; [cited 2023 Aug 15]. Available from: https://www.cms.gov/Regulations-and-Guidance/Guidance/FACA/downloads/id79b.pdf
34. “In general, CMS relies heavily on health outcomes data before proposing an NCD.” Guidance page 4
35. “Surrogate endpoints are not direct measures of clinical benefit.” Guidance page 4
36. “A validated surrogate outcome that reliably predicts these outcomes may be appropriate for some questions.” Guidance page 9
37. FDA-NIH Biomarker Working Group. Validated Surrogate Endpoint, in “BEST (Biomarkers, EndpointS, and other Tools)”. Food and Drug Administration (US); 2020 [cited 2023 Aug 9]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK453484/
38. “traditionally underrepresented groups in clinical studies, how the inclusion and exclusion requirements effect enrollment of these populations.” Guidance page 9]
39. “. . . generalizable to the Medicare population . . .” Guidance page 5
40. “For new technologies, it is rare that there is sufficient clinical evidence to support broad national coverage under section 1862(a)(1)(A).” Guidance page 4
41. “sufficiency of sample size as required by the question” Guidance page 9
42. “sufficiency of duration of observation to demonstrate durability of health outcomes” Guidance page 9
43. Sullivan GM, Feinn R. Using Effect Size—or Why the P Value Is Not Enough. Journal of Graduate Medical Education. 2012 Sep 1;4(3):279–82.
44. Drummond M, Federici C, Reckers-Droog V, Torbica A, Blankart CR, Ciani O, et al. Coverage with Evidence Development for Medical Devices in Europe: Can Practice Meet Theory? Health Economics. 2022;31(S1):179–94.
45. Patient Preference Information (PPI) in Medical Device Decision Making [Internet]. U.S. FDA CDRH; 2023 [cited 2023 Aug 15]. Available from: https://www.fda.gov/about-fda/cdrh-patient-science-and-engagement-program/patient-preference-information-ppi-medical-device-decision-making
46. This could be more or less than four, but should be more than one and not all.
47. Federici C, Reckers-Droog V, Ciani O, Dams F, Grigore B, Kaló Z, Kovács S, Shatrov K, Brouwer W, Drummond M. Coverage with Evidence Development Schemes for Medical Devices in Europe: Characteristics and Challenges. Eur J Health Econ. 2021 Nov;22(8):1253-1273. doi: 10.1007/s10198-021-01334-9. Epub 2021 Jun 12. PMID: 34117987; PMCID: PMC8526454.
48. Comments on AHRQ Analysis of Requirements for Coverage with Evidence Development [Internet]. 2022. Available from: https://healthpolicy.usc.edu/wp-content/uploads/2022/10/USC-Schaeffer-re-AHRQ-Requirement-for-CED.pdf
49. Guidance page 11
50. “. . . [D]ata are often manually collected by human abstractors, which contributes to this time lag, can result in transcription errors, and adds significant expense to the collection process.” Maddox TM, Albert NM, Borden WB, Curtis LH, Ferguson TB, Kao DP, et al. The Learning Healthcare System and Cardiovascular Care: A Scientific Statement From the American Heart Association. Circulation. 2017 Apr 4;135(14):e826–57.
51. Recommendations for Advancing Safety and Public Health” - Medical Device Registry Principles [Internet]. The Pew Charitable Trusts; 2014 [cited 2023 Aug 17]. Available from: https://www.pewtrusts.org/-/media/assets/2014/09/device-registry-conference-report.pdf
52. https://www.hhs.gov/ohrp/regulations-and-policy/regulations/finalized-revisions-common-rule/index.html
53. “results of all CED approved studies under 1862(a)(1)(E) will be analyzed and published in the public domain, preferably in peer-review journals.” [Guidance page 12]
54. “publication of clinical studies is necessary to inform patients, their caregivers, and their healthcare providers about the risks and benefits of available health care options” [Guidance page 12]
55. “sufficient evidence to inform patient and clinician decision making” [Guidance page 12]
56. cite inability to publish anything from Zeitler.
57. Zeitler EP, Gilstrap LG, Coylewright M, Slotwiner DJ, Colla CH, Al-Khatib SM. Coverage with Evidence Development: Where Are We Now? Am J Manag Care. 2022 Aug;28(8):382-389. doi: 10.37765/ajmc.2022.88870. PMID: 35981123.
58. “CMS does not believe that an NCD that requires CED as a condition of coverage should last indefinitely” Guidance page 12
59. “coverage should be time-limited to facilitate the timely generation of sufficient evidence” [Guidance page 12]
60. “sufficiency of sample size as required by the question” [Guidance page 9]
61. “a revised NCD could be expedited once the study is completed and the results are published. CMS would also accept a manuscript that has been peer-reviewed and accepted for publication or studies that are otherwise published in the public domain” [Guidance page 12]
62. Guidance page 2
63. Abelson, J., Wagner, F., Dejean, D., Boesveld, S., Gauvin, F.-P., Bean, S., Axler, R., Petersen, S., Baidoobonso, S., Pron, G., Giacomini, M., Lavis, J., 2016. Public and Patient Involvement in Health Technology Assessment: A
64. Framework for Action. International Journal of Technology Assessment in Health Care 32, 256–264.. https://doi.org/10.1017/s0266462316000362
65. Nabarette H, Chastenay MH, Dupont JCK, Ganache I, Single ANV. Patient and Citizen Participation at the Organizational Level in Health Technology Assessment: An Exploratory Study in Five Jurisdictions. International Journal of Technology Assessment in Health Care. 2023 Jan;39(1):e51.
66. Guidance page 12
67. Guidance page 12

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August 21, 2023
Chiquita Brooks-LaSure
Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
7500 Security Blvd.
Baltimore, MD 21244-1850

Re: CMS National Coverage Analysis Evidence Review and Coverage with Evidence Development

Dear Administrator Brooks-LaSure,

On behalf of the more than 25 million Americans living with one of the over 7,000 known rare diseases, the National Organization for Rare Disorders (NORD) thanks the Centers for Medicare and Medicaid Services (CMS) for the opportunity to provide comments on the draft guidance documents “CMS National Coverage Analysis Evidence Review” and “Coverage with Evidence Development.”

NORD is a unique federation of non-profits and health organizations dedicated to improving the health and well-being of people with rare diseases by driving advances in care, research, and policy. NORD was founded 40 years ago, after the passage of the Orphan Drug Act (ODA), to formalize the coalition of patient advocacy groups that were instrumental in passing that landmark law. Since that time, NORD has been advancing rare disease research and funding to support the development of effective treatments and cures; raising awareness and addressing key knowledge gaps; and advocating for policies that support the availability of and access to safe and effective therapies.

At NORD, we believe all patients should have access to quality, accessible, and affordable health care coverage that is best suited to meet their medical needs. As the draft guidance indicates, the NCD process can help rare disease patients gain more timely and affordable access to new and innovative medical products that have been shown to be reasonable and necessary and should therefore be covered by the Medicare program. Such timely and affordable access is vital to our community. Approximately 11.5% of individuals enrolled in Medicare are rare disease patients, according to 2019 data.¹ Furthermore, rare disease patients often rely on both orphan and non-orphan products as a part of their treatment regimen.² Among Medicare beneficiaries, those with rare diseases spend on average approximately $28,185 more in direct medical costs under Medicare each year compared to those without rare diseases.³ This is true even though as many as 95% of the more than 7,000 known rare diseases have no FDA-approved therapy for that specific condition.

Because timely, data-driven, and transparent evidence generation and coverage decisions are critical to the rare disease community, NORD supports CMS’s intent to increase the transparency and predictability of National Coverage Determinations (NCDs) and the coverage with evidence development (CED) paradigm, and to use pre-market studies and other available data sources to the extent possible when making coverage decisions. However, the challenges of rare disease drug development result in unique issues and data limitations that must be considered in the NCD framework and CED process. Without appropriately accounting for these realities, rare disease patients will be at greater risk for wrongful coverage denials, resulting in negative health outcomes, increased out-of-pocket costs, and ultimately greater overall costs for the healthcare system.⁴ Informed by our 40 years of experience working constructively with all key stakeholders to help ensure the availability of and access to life-altering therapies to the rare-disease community, NORD is pleased to offer the specific recommendations below to make the draft guidance more applicable to the unique realities of rare disease patients.

Recommendation 1: Strengthen the alignment between CMS and FDA to ensure timely, consistent, and data-driven FDA approval or licensure, and predictable and transparent coverage decisions

Recommendation 1a: Collaborate closely with FDA to ensure Medicare populations are appropriately represented in pivotal trials for medical products. NORD appreciates that FDA and CMS operate under distinct Congressional mandates and statutory standards,⁵ and that in certain situations, CEDs can play a key role in determining that a therapy is reasonable and necessary for Medicare patients. However, the limited patient populations and overall scarcity of data for most rare diseases make greater standardization and alignment across FDA and CMS data collection efforts imperative to maximize efficiencies, avoid duplication of effort, and allow for timely approval and coverage decisions.

NORD agrees with CMS that such alignment is hampered by data limitations. Many clinical trials still lack appropriate representation of diverse patient populations, including those that are Medicare eligible. Although people over 65 years of age constitute a significant fraction of the patient population for many acute and chronic diseases, they are often underrepresented in clinical trials. Similarly, individuals with disabilities or specific chronic diseases that make them Medicare-eligible are often underrepresented in clinical research.^6,7 This lack of clinical trial diversity has several root causes - and it negatively impacts both FDA’s and CMS’s ability to fulfill their respective mandates.⁸

In recent years, FDA has increasingly tried to encourage sponsors to increase the diversity in clinical trials underpinning FDA approvals or licensures. Some of these strategies, including clinical trial diversity plans and FDA diversity reporting mandates, were codified through the Food and Drug Omnibus Reform Act (FDORA) of 2022, enshrining an ever-greater emphasis on diversity and representation into law.^9,10 Yet, successful implementation of these new mandates will require new approaches for trial recruitment and retention. Given CMS’s long history of successful outreach to and engagement with Medicare populations, NORD urges CMS to work closely with FDA to help identify practical strategies and best practices to increase recruitment and retention of diverse populations, including Medicare-eligible patients, and ensure more adequate representation of Medicare populations moving forward.

As one tangible example of strategies to increase equitable trial recruitment and retention, FDA recently released a draft guidance for industry on conducting decentralized trials and how these trials can help increase trial diversity through strategies such as remote trial participation in the patient’s own home.¹¹ As the experience with decentralized clinical trial adoption during the COVID-19 pandemic demonstrates, this can be a useful tool to increase equitable trial participation. However, ensuring these trials adequately account for and meet the unique needs of older adults and other Medicare populations will be key to their success. Depending on the implementation, strategies such as innovative remote or digital health technologies, increasing use of local healthcare facilities, and use of telehealth can work to either increase or decrease trial accessibility for Medicare populations. CMS should work closely with FDA to ensure decentralized trials in fact positively impact access and representation for Medicare populations.

Recommendation 1b: Work closely with FDA to align evidence generation for accelerated approval products to ensure efficient CEDs, adequate access, and timely conversion to traditional approval. The accelerated approval pathway has been and continues to be vital for rare disease patients.¹² For example, among 252 FDA-approved new orphan drugs and indications approved from 2008 to 2021, about a quarter were approved through accelerated approval. ¹³ As a 2011 study of oncology drugs demonstrates, drugs receiving accelerated approval are available to patients’ years earlier than they otherwise would – at a median 3.9 years faster than oncology drugs with immediate traditional approval.¹⁴

Products approved through accelerated approval rely on surrogate or intermediate clinical endpoints such as CD4 T-cell counts for HIV/AIDS products, tumor size for oncology products, or blood pressure for cardiovascular products. Sponsors must have demonstrated that the surrogate or intermediate clinical endpoint is reasonably likely to predict clinical benefit, but the final validation of this correlation within the specific context of use has not yet been completed. At the time of accelerated approval, FDA specifies which confirmatory trials are required for conversion to traditional approval, and in what time frame. Nearly all accelerated approval drugs are ultimately able to confirm clinical benefit and are eventually converted to traditional approvals. For instance, more than three out of four drugs that received accelerated approval from 1992 to 2016 have already been successfully converted to traditional approvals.¹⁵ Only about 10 percent of the 278 accelerated approval drugs approved from 1992 to now are currently past their original confirmatory trial completion date.¹⁶ Among them, more than half are less than a year past their confirmatory trial date and only four drugs are five or more years late.¹⁷

As these data show, most sponsors meet FDA’s requirements for post-market evidence generation, and most accelerated approval drugs are swiftly converted to traditional approval. Delays in confirmatory trial enrollment are one of the key reasons confirmatory trial dates are missed.^18,19 These enrollment challenges can have several distinct root causes, which each may warrant their own solutions.²⁰ For instance, transitioning confirmatory trials into earlier disease stages or population subgroups that do not have ready access to the approved drug can help overcome enrollment challenges that stem from a lack of incentives to participate in a confirmatory trial once a drug is approved and available outside of the confines of the trial; however, this approach may not always be feasible, and it may not be the only – or at times most appropriate – approach. For instance, efforts to modernize and decentralize trials can reduce the burden for patients and hence minimize the disincentives weighing against participation in confirmatory trials.

At the same time, patients face increasing barriers to coverage and reimbursement of drugs approved through accelerated approval.^21,22 This makes life-saving drugs essentially unaffordable for too many patients and threatens to undermine the integrity and intent of the accelerated approval pathway. NORD urges CMS to work with FDA to maximize alignment of the relevant evidence generation frameworks, and to find creative solutions to close any remaining post-market data gaps. This will help ensure the product’s clinical benefit specifically for Medicare populations is appropriately demonstrated, and the same evidence generated through post-market trials can be used to meet both FDA’s and CMS’ data needs. If done effectively, such approaches will benefit both confirmatory trial enrollment and NCDs simultaneously, helping ensure patients have and retain timely access to the therapies they need while protecting the intent of accelerated approval.

Recommendation 2: Reduce the burden for rare disease patients participating in NCDs with CED

CEDs can allow Medicare beneficiaries access to FDA-approved therapies while additional data are collected and before NCDs are completed, although they can be burdensome and unduly hinder patient access to needed therapies.²³ Based on a recent review of 27 CED programs, requirements among therapies have been highly variable. Only a few CED data collection requirements have been successfully retired because adequate evidence was collected to support - or revoke – coverage decisions.²⁴ To date, the majority of CEDs have relied on one, or often more than one, clinical trials for evidence generation, and some CEDs rely on registries in addition to - or rarely in lieu of - clinical trials. CED programs have varied in duration from 1 to 16 years, potentially creating burdensome and potentially protracted data collection efforts and ultimately delaying access to therapies.²⁵

Many rare disease patients are geographically dispersed, medically complex, and struggle with the logistics of trial or registry participation.²⁶ According to some estimates, more than 25% of rare disease trials that were terminated between 2016 and 2020 were halted due to insufficient patient participation rates.²⁷ Participation in CED trials can be quite burdensome for patients, particularly for rare disease patients and patients from historically underrepresented populations.²⁸ Randomized controlled trials for CEDs are difficult to scale and can create barriers to equitable patient access.²⁹ These studies are typically conducted in academic medical centers or large hospitals centered in densely populated areas, which can complicate access for rural and historically underserved populations.³⁰

Alternative trial methods, such as decentralized trials, can be useful levers in increasing trial participation in patient populations who would otherwise be unable to participate in the CED.³¹ Strategies such as greater reliance on registries to support CEDs may also help ease the burden on participants and increase equitable recruitment and retention, in particular if the data collection efforts are targeted specifically to the most impactful open questions regarding clinical benefit and the studies are designed with the unique needs and access barriers of the impacted populations in mind.³² Collaboration with patient advocacy groups and the patient community is vital to minimize patient burden and determine appropriate endpoints that can help strengthen the participation and utility of the data.³³

As these data show, CED requirements must be carefully balanced to ensure equitable access to novel therapies. Reducing the burden for participants is particularly important as barriers to equitable patient participation and the inherent limited patient populations for most rare diseases also hamper the ability of CEDs to timely generate robust and relevant evidence supporting clinical benefit. This is particularly important if medium or long-term outcomes require extended periods of follow-up. Proactive, intentional outreach to the relevant patient population for the product under CED will allow for a diverse range of impacted patients to participate in the CED process in a way that will help inform evaluators perspective of use of the product outside of a clinical trial setting.

Recommendation 3: Provide sufficient flexibility in the evidence generation framework to adequately account for the unique challenges in evidence generation for rare diseases

As stated in the guidance, CMS intends to rely on the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology in assessing NCD evidence for key study characteristics including risk of bias, precision, consistency, and directness.³⁴ NORD strongly supports the use of rigorous, consistent, and transparent criteria to evaluate whether strong evidence supports that a therapy is necessary and reasonable for Medicare patients. This will ultimately increase the timeliness and predictability of coverage decisions. However, although the GRADE approach has been widely adopted, it may not be suitable without adaptations in all circumstances, including for some rare diseases.³⁵

As the scientific literature demonstrates, overall paucity of peer-reviewed studies, including scarcity of large randomized controlled trials, lack of replicate studies, and patients that receive multiple (and varying) therapies simultaneously to manage their complex medical needs, are well-known challenges when applying the GRADE methodology to rare diseases.³⁶ Similarly, the common phenotypic and/or genotypic heterogeneity in rare diseases, and the limited precision of effect estimates based on small sample sizes in rare disease studies make application of GRADE to rare diseases uniquely challenging.³⁷

The unique challenges associated with rare disease research complicate both traditional randomized, double-blinded, placebo-controlled trials as well as alternative research approaches including observational studies, single-arm trials, and studies with external control arms. Real-world data including post-market data collected through investigational or observational studies can provide vital additional insights into safety, effectiveness, and optimal use and should not be discounted.38

Because the evidence available for rare diseases is often qualitatively and quantitatively different from that for more common diseases, more pragmatic approaches for recommendation generation may be needed. NORD urges CMS to consult the relevant literature that has explored the application of GRADE and other evidence generation approaches to rare diseases.^{39,40,41,42,43} An overly rigid application of the GRADE framework would limit the feasibility and applicability of the NCD framework for rare diseases.

NORD again thanks CMS for the opportunity to provide comments on this important draft guidance, and we look forward to continuing the dialogue around NCDs, as well as other strategies to make rare disease drugs on the market accessible and affordable to patients. For questions regarding NORD or the above comments, please contact Mason Barrett, Policy Analyst, at mbarrett@rarediseases.org or Hayley Mason, Policy Analyst, at hmason@rarediseases.org.

Citations:
1 Yang, G., Cintina, I., Pariser, A. et al. The national economic burden of rare disease in the United States in 2019. Orphanet J Rare Dis 17, 163 (2022). https://doi.org/10.1186/s13023-022-02299-5.
2 Depping, M. K., Uhlenbusch, N., von Kodolitsch, Y., Klose, H. F. E., Mautner, V. F., & Löwe, B. (2021). Supportive care needs of patients with rare chronic diseases: multi-method, cross-sectional study. Orphanet journal of rare diseases, 16(1), 44. https://doi.org/10.1186/s13023-020-01660-w
3 Yang, G., Cintina, I., Pariser, A. et al. The national economic burden of rare disease in the United States in 2019. Orphanet J Rare Dis 17, 163 (2022). https://doi.org/10.1186/s13023-022-02299-5.
4 U.S. Department of Health and Human Services. (2021, October 22). NIH study suggests people with rare diseases face significantly higher health care costs. National Institutes of Health. https://www.nih.gov/news-events/news-releases/nih-study-suggests-people-rarediseases- face-significantly-higher-health-care-costs
5 Press release CMS statement: Response to alzheimer’s Association’s request to reconsider the final national coverage determination. CMS. (2023, February 22). https://www.cms.gov/newsroom/press-releases/cms-statement-response-alzheimers-associations-requestreconsider-final-national-coverage
6 Beatty, L. (2023, August 16). The definition of clinical trial diversity must include disabled people. STAT. https://www.statnews.com/2023/08/17/clinical-trials-diversity-disabledpeople/#:~:text=Despite%20constituting%20the%20largest%20minority,heavily%20excluded%20from%20the%20process.
7 Csaba P Kovesdy, Clinical trials in end-stage renal disease—priorities and challenges, Nephrology Dialysis Transplantation, Volume 34, Issue 7, July 2019, Pages 1084–1089, https://doi.org/10.1093/ndt/gfz088
8 Beatty, L. (2023, August 16). The definition of clinical trial diversity must include disabled people. STAT. https://www.statnews.com/2023/08/17/clinical-trials-diversity-disabledpeople/#:~:text=Despite%20constituting%20the%20largest%20minority,heavily%20excluded%20from%20the%20process.
9 Center for Drug Evaluation and Research. (2023). Guidance Recap Podcast | Podcast for Patients — Enhancing the Diversity of Clinical Trial Populations—Eligibility Criteria, Enrollment Practices, and Trial Designs. U.S. Food and Drug Administration. https://www.fda.gov/drugs/guidances-drugs/guidance-recap-podcast-podcast-patients-enhancing-diversity-clinical-trial-populationseligibility#:~: text=To%20enroll%20participants%20from%20diverse,populations%20receive%20their%20health%20care.
10 Siddiqui, F., & Livornese, D. L. (2023, January 24). Under FDORA, FDA to require most drug and device trials to submit Diversity Action Plans. FDA Law Blog. https://www.thefdalawblog.com/2023/01/under-fdora-fda-to-require-most-drug-and-device-trials-to-submitdiversity- action-plans/
11 U.S. Department of Health and Human Services. (2023, April 24). Diversity and inclusion in clinical trials. National Institute of Minority Health and Health Disparities. https://www.nimhd.nih.gov/resources/understanding-health-disparities/diversity-and-inclusion-inclinical- trials.html#:~:text=People%20may%20experience%20the%20same,can%20benefit%20from%20scientific%20advances.
12 NORD, Temkin, E. & Trihn, J. FDA’s Accelerated Approval Pathway: A Rare Disease Perspective. https://rarediseases.org/wpcontent/ uploads/2022/10/NRD-2182-Policy-Report_Accelerated-Approval_FNL.pdf
13 Monge AN, Sigelman DW, Temple RJ, Chahal HS. Use of US Food and Drug Administration Expedited Drug Development and Review Programs by Orphan and Nonorphan Novel Drugs Approved From 2008 to 2021. JAMA Netw Open. 2022;5(11):e2239336. doi:10.1001/jamanetworkopen.2022.39336
14 Johnson, J., Ning, Y., Farrell, A. , Justice, R., Keegan, P., Pazdur, R.,, Accelerated Approval of Oncology Products: The Food and Drug Administration Experience, JNCI: Journal of the National Cancer Institute, Volume 103, Issue 8, 20 April 2011, Pages 636– 644, https://doi.org/10.1093/jnci/djr062
15 NORD, Temkin, E. & Trihn, J. FDA’s Accelerated Approval Pathway: A Rare Disease Perspective. https://rarediseases.org/wpcontent/ uploads/2022/10/NRD-2182-Policy-Report_Accelerated-Approval_FNL.pdf
16 Health and Human Services (2022, September 29). Delays in Confirmatory Trials for Drug Applications Granted FDA's Accelerated Approval Raise Concerns. Office of Inspector General. Retrieved May 15, 2023, from https://oig.hhs.gov/oei/reports/OEI-01-21-00401.asp
17 Id.
18 Health and Human Services (2022, September 29). Delays in Confirmatory Trials for Drug Applications Granted FDA's Accelerated Approval Raise Concerns. Office of Inspector General. Retrieved May 15, 2023, from https://oig.hhs.gov/oei/reports/OEI-01-21-00401.asp
19 NORD, Temkin, E. & Trihn, J. FDA’s Accelerated Approval Pathway: A Rare Disease Perspective. https://rarediseases.org/wpcontent/uploads/2022/10/NRD-2182-Policy-Report_Accelerated-Approval_FNL.pdf
20 Id.
21 Oregon Health Authority, 2022-2027 Medicaid 1115 Demonstration Application, (February 18, 2022), https://www.oregon.gov/oha/HSD/Medicaid-Policy/Documents/2022-2027-Waiver-Application-Final.pdf
22 Centers for Medicare & Medicaid Services, Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N), (January 11, 2022), https://www.cms.gov/medicare-coverage-database/view/ncacaldecisionmemo.aspx?proposed=Y&NCAId=305
23 Buch, L., & Von Eisenburg, M. (2022, June 24). NCDs, part I: Overview of ncds, CED, and potential access barriers. Avalere. https://avalere.com/podcasts/ncds-part-i-overview-of-ncds-ced-and-potential-access-barriers-2
24 Zeitler, E. P., & Gilstrap, L. G. (2022, April 7). Coverage with evidence development: Where are we now?. AJMC. https://www.ajmc.com/view/coverage-with-evidence-development-where-are-we-now-
25 Id.
26 Rath, A., Salamon, V., Peixoto, S. et al. A systematic literature review of evidence-based clinical practice for rare diseases: what are the perceived and real barriers for improving the evidence and how can they be overcome?. Trials 18, 556 (2017). https://doi.org/10.1186/s13063-017-2287-7
27 Ben Adams. (2021). More than a quarter of rare disease trials are culled due to low patient rates: report. Fierce Biotech. https://www.fiercebiotech.com/cro/more-than-a-quarter-rare-disease-trials-are-culled-due-to-low-patient-rates-report
28 Alliance report: Medicare using “coverage with evidence development” to ration patient access to FDA-approved treatments. Alliance for Aging Research. (2023, February 14). https://www.agingresearch.org/news/alliance-report-medicare-using-coverage-with-evidencedevelopment-to-ration-patient-access-to-fda-approved-treatments/
29 Von Eisenburg, M., & Harrington, S. (2022, June 24). NCDs, part II: Evidence development to fulfill CED requirements. Avalere. https://avalere.com/podcasts/ncds-part-ii-evidence-development-to-fulfill-ced-requirements-2
30 Alliance report: Medicare using “coverage with evidence development” to ration patient access to FDA-approved treatments. Alliance for Aging Research. (2023, February 14). https://www.agingresearch.org/news/alliance-report-medicare-using-coverage-with-evidencedevelopment-to-ration-patient-access-to-fda-approved-treatments/
31 Moore, J., Goodson, N., Wicks, P. et al. What role can decentralized trial designs play to improve rare disease studies?. Orphanet J Rare Dis 17, 240 (2022). https://doi.org/10.1186/s13023-022-02388-5
32 Von Eisenburg, M., & Harrington, S. (2022, June 24). NCDs, part II: Evidence development to fulfill CED requirements. Avalere. https://avalere.com/podcasts/ncds-part-ii-evidence-development-to-fulfill-ced-requirements-2
33 Rath, A., Salamon, V., Peixoto, S. et al. A systematic literature review of evidence-based clinical practice for rare diseases: what are the perceived and real barriers for improving the evidence and how can they be overcome?. Trials 18, 556 (2017). https://doi.org/10.1186/s13063-017-2287-7
34 Department of Health and Human Services. CMS National Coverage Evidence Review. June 2023.
35 Pai M, Iorio A, Meerpohl J, Taruscio D, Laricchiuta P, Mincarone P, Morciano C, Leo CG, Sabina S, Akl E, Treweek S, Djulbegovic B, Schunemann H; Consortium for the RARE-Bestpractices. Developing methodology for the creation of clinical practice guidelines for rare diseases: A report from RARE-Bestpractices. Rare Dis. 2015 Sep 29;3(1):e1058463. doi: 10.1080/21675511.2015.1058463. PMCID: PMC4590012.
36 Id,
37 Id.
38 Center for Drug Evaluation and Research. (n.d.). Postmarket requirements and commitments. U.S. Food and Drug Administration. https://www.fda.gov/drugs/drug-approvals-and-databases/postmarket-requirements-andcommitments#:~:text=The%20phrase%20postmarket%20requirements%20and,%2C%20efficacy%2C%20or%20optimal%20use.
39 Pai M, Iorio A, Meerpohl J, Taruscio D, Laricchiuta P, Mincarone P, Morciano C, Leo CG, Sabina S, Akl E, Treweek S, Djulbegovic B, Schunemann H; Consortium for the RARE-Bestpractices. Developing methodology for the creation of clinical practice guidelines for rare diseases: A report from RARE-Bestpractices. Rare Dis. 2015 Sep 29;3(1):e1058463. doi: 10.1080/21675511.2015.1058463. PMCID: PMC4590012.
40 Tingley, K., Coyle, D., Graham, I.D. et al. Stakeholder perspectives on clinical research related to therapies for rare diseases: therapeutic misconception and the value of research. Orphanet J Rare Dis 16, 26 (2021). https://doi.org/10.1186/s13023-020-01624-0
41 Pai, M., Yeung, C.H.T., Akl, E.A. et al. Strategies for eliciting and synthesizing evidence for guidelines in rare diseases. BMC Med Res Methodol 19, 67 (2019). https://doi.org/10.1186/s12874-019-0713-0
42 Scharpf J. The Challenge of Guideline Development When Evidence Is Sparse. Otolaryngol Head Neck Surg. 2017 Sep;157(3):383-384. doi: 10.1177/0194599817717676. Epub 2017 Jul 4. PMID: 28675089.
43 Annemans, L., Makady, A. TRUST4RD: tool for reducing uncertainties in the evidence generation for specialised treatments for rare diseases. Orphanet J Rare Dis 15, 127 (2020). https://doi.org/10.1186/s13023-020-01370-3

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Submitted by:
Maryam Mooghali MD, MSc
Osman Moneer, BA
Nikhil Chaudhry, BA
Reshma Ramachandran, MD, MPP, MHS
Yale Collaboration for Regulatory Rigor, Integrity, and Transparency (CRRIT)
Yale School of Medicine

INTRODUCTION
Thank you for the opportunity to comment on the proposed guidance document for coverage with evidence development (CED). We are members of the Yale Collaboration for Regulatory Rigor, Integrity, and Transparency (CRRIT), an interdisciplinary initiative aligning research on medical product evaluation, approval, and coverage toward advancing policies that improve patient outcomes. On behalf of CRRIT, we commend CMS for developing the proposed guidance document, which comprehensively details the several factors CMS considers in making National Coverage Determinations (NCDs) using the CED paradigm. We found many points of agreement with the proposed guidance document, particularly in its emphasis on leveraging CED to expand patient access to promising technologies that would not otherwise meet the “reasonable and necessary” coverage standard, while requiring the generation of evidence that addresses specific areas of uncertainty identified in National Coverage Analyses. In our comments below, we offer suggestions to further clarify and strengthen the CED process in order to achieve its intended goal of ensuring robust data collection critical to patients and clinicians as well as CMS in determining whether coverage should be broadened for medical products when residual uncertainty is present at the time of FDA approval.

Section II – Purpose of this Proposed Guidance Document: Section V: Principles governing the application of CED

Section VI: Clinical Study Standards for CED under Section 1862(a)(1)(E)
CMS has proposed that it will expect sponsors or study sites to sign an agreement for voluntarily participating in a specific CED study under the NCD. We believe that these agreements between the agency and the stakeholders should be publicly available on CMS’s website. As a part of the signed agreement, sponsors and study sites should also submit publicly available annual reports regarding the status of the CED study. If the sponsor or study fails to make these reports available, CMS should consider ending the CED and, thus, rescinding coverage of the medical product. Should sponsors or study sites wish to make changes to the protocol after the commencement of the CED study, the agreement should stipulate that they will publicly notify the CMS about the changes.

Milestones
CMS has proposed a written plan that describes the schedule for the completion of key study milestones, including results reporting. We believe that other key milestones, including study initiation, enrollment progress, and interim results reporting, should also be clearly described in the written plan. We recommend that sponsors or study sites provide updates and report outs of the status of the CED studies annually. Moreover, should sponsors or study sites wish to make changes to the schedule after the commencement of the CED study, CMS should ensure that the new timeline will be appropriate for fulfilling the NCD, and the change should be publicly announced within no more than 30 days of the CMS’s decision.

Study design
CMS has proposed certain flexibility in terms of study designs. We believe that this flexibility could create challenges for conducting comparative analyses of key clinical outcomes across studies. Therefore, to ensure robust data collection across all CED studies, CMS could provide more guidance around the CED study design standards, as included in the Proposed CMS National Coverage Analysis Evidence Review,3 and delineate the occasional situations where lower-quality study designs (such as observational or single-arm studies) may be allowed. For example, CMS has suggested that certain studies may not include contemporaneous comparison groups. In these cases, the agency should clarify how sponsors should leverage alternative data sources (e.g., historical controls) to conduct appropriate comparative efficacy and/or safety analyses and why these designs ensure sufficient rigor to determine benefits and harms in Medicare beneficiaries. In addition, there should be a detailed description of approaches that aim to minimize bias in both interventional and observational study designs. Moreover, given that a considerable portion of CED-approved studies are registries, CMS could clarify certain situations where registries are appropriate and identify specific criteria that could improve the quality of the evidence generated by registries. Moreover, should sponsors or study sites wish to make changes to the study design after the initial agreement, CMS should ensure that the new study design will be appropriate for fulfilling the NCD, and the change should be publicly announced within no more than 30 days of the CMS’s decision.

Study population
To facilitate recruiting more generalizable study samples, CMS has proposed that study populations should reflect the demographic and clinical diversity, in terms of several factors including “relevant social determinants of health”, among the Medicare beneficiaries. We believe that more clarity around “relevant social determinants of health” is needed. In addition to considering factors of racial and ethnic background, gender, age, disabilities, and comorbidities among the Medicare population, CMS could consider the diversity of geographic location (i.e., urban, rural, suburban) among beneficiaries. CMS often has certain criteria for CED studies, in terms of the eligible facilities or personnel providing the covered item or service to beneficiaries, which may create additional barriers to care access for patients not living in areas with those eligible facilities or appropriate personnel and thus, could impede representative enrollment for the CED study. We recommend that sponsors and study sites provide plans for enrolling representative populations, including patients living in rural locations, as a part of the study agreement. CMS also could provide further guidance and assistance to define and ensure adequate representation within these studies.

Health outcomes
CMS has proposed that a validated surrogate outcome may be appropriate for some questions. We believe that CMS should clarify (1) the level of evidence sufficient for CMS to consider the surrogate outcome to be validated and whether this would be consistent with the FDA definition and (2) the specific indications in which surrogate outcomes are allowed to be used. Furthermore, we believe that the primary outcome(s) of the study should be pre-specified to ensure that the study fulfills the intent of the CED in determining whether the product is reasonable and necessary. CMS should also encourage sponsors to avoid changing the outcomes later in the process and, as noted above, if the sponsor proposes changing the outcomes, this should only be done with CMS’s approval to ensure that the proposed new outcome will be appropriate for fulfilling the NCD. Finally, specific health outcomes collected as a part of the CED study should be paired with claims data to enable longitudinal assessments as well as objective measures of outcomes, such as hospitalizations, nursing home admissions, or deaths.

Objective Success Criteria
CMS has proposed that sponsors/investigators will establish an evidentiary threshold for the primary health outcome(s) in consultation with CMS and AHRQ. We believe that this evidentiary threshold for the primary health outcome(s) should be pre-specified. CMS should also encourage sponsors or study sites to not change the evidentiary threshold later in the process. Instead, sponsors or study sites should provide advance notice to the agency so that CMS can provide the necessary guidance that the proposed new outcome will be appropriate for fulfilling the NCD.

Sensitivity Analyses
CMS explicitly states that sensitivity testing needs to be “pre-specified”. We believe that this requirement could be applied across the protocol, particularly to the health outcomes collected in the CED studies.

Reporting
CMS has required manufacturers to provide final results within 12 months of the primary completion date. We believe that this requirement could be further strengthened by requiring the submission of participant-level data in addition to the summary-level data as a condition of coverage under CED. Moreover, sponsors and study sites should also report annual results, in addition to final results, to the CMS. Moreover, the submitted data should be independently verified annually or at the time CMS revisits an NCD.

Sharing
CMS has proposed that the sponsors/investigators commit to sharing data, methods, analytic code, and analytical output with CMS or with a CMS-approved third party. We believe that CMS should have access to beneficiary-level data from all CED studies as part of the agreements with sponsors.

Section VII: Importance of Control Groups and Blinding in CED Studies

Section VIII: Ending CED
CMS has provided guidance regarding ending CED when the evidence generated through CED studies supports a favorable coverage decision. We believe that further guidance is necessary for situations where the results of studies could not confirm the expected benefits (e.g., if the outcomes are negative or if sponsors do not report the interim results according to the agreement). In these cases, CMS’s authority for ending the coverage of these products should be clearly stated. Moreover, CMS has proposed that the NCDs will be revised once the study results are published. Since there could be a significant lag from study completion to peer-reviewed publication of the results, we believe that CMS should instead consider revisiting their coverage decisions in a more timely manner, based on the data submitted by the manufacturers upon study completion. Additionally, the evidence generated through CED may raise additional questions about harms and benefits that were unanticipated when the CED decision was initially made (i.e., at an early stage of familiarity with a given item or service). CMS should acknowledge that CED may need to be modified or extended to address these new open questions.

Section IX: Transparency of CED
CMS has proposed several efforts to improve the transparency of CED, including that the results of all CED studies will be published in the public domain, preferably in peer-reviewed journals. We believe that in cases where sponsors do not publish their results upon study completion, CMS should publicly publish their evaluation of any submitted data for re-evaluation of the coverage decision. Moreover, there is a need for a more comprehensive publicly available database where all the items and services covered under the CED program are listed, even after CED coverage is removed. Thus, the current CMS’s CED webpage could be improved by including a separate section listing the products that have previously been covered under the CED program. The database should include all updated decision memos and CED-approved studies to enhance transparency and facilitate data gathering and analysis for research purposes.

References
1. Dhruva SS, Ramachandran R, Ross JS. Medicare’s National Coverage Determination for Aducanumab — A One-Off or a Pragmatic Path Forward? New England Journal of Medicine. 2022;387(17):1539-1541. doi:10.1056/NEJMp2210198
2. Food and Drug Administration. Medical Device Coverage Initiatives: Connecting with Payors via the Payor Communication Task Force. Accessed August 19, 2023. https://www.fda.gov/about-fda/cdrh-innovation/medical-device-coverage-initiatives-connecting-payors-payor-communication-task-force#:~:text=In%202011%2C%20the%20FDA%20and,the%20subsequent%20CMS%20national%20coverage
3. Centers for Medicare and Medicaid Services. (PROPOSED) CMS National Coverage Analysis Evidence Review. Accessed August 15, 2023. https://www.cms.gov/medicare-coverage-database/view/medicare-coverage-document.aspx?mcdid=34
4. Karanicolas PJ, Farrokhyar F, Bhandari M. Practical tips for surgical research: blinding: who, what, when, why, how? Can J Surg. Oct 2010;53(5):345-8.
5. Castro M. Placebo versus best-available-therapy control group in clinical trials for pharmacologic therapies: which is better? Proc Am Thorac Soc. Oct 1 2007;4(7):570-3. doi:10.1513/pats.200706-073JK

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600 Massachusetts Ave. NW, Suite 300
Washington, DC 20001
Phone: (202) 296-7272
Fax: (202) 296-7290

August 21, 2023

Centers for Medicare & Medicaid Services
Coverage and Analysis Group
7500 Security Blvd.
Baltimore, Maryland 21244

Sent via electronic delivery

Re: Comments on Proposed Changes to Coverage with Evidence Development (CED) Guidance

Genentech appreciates this opportunity to provide comments on the Proposed Guidance Document regarding Coverage with Evidence Development (CED) (the “Proposed Guidance”). Genentech is a leading biotechnology company dedicated to pursuing groundbreaking science to discover and develop medicines for people with serious and life-threatening illnesses. We are committed to improving patients’ lives through new innovations. To this end, in 2021 we, under the Roche umbrella, invested $15 billion globally in research and development – more than any other health care company in the world. In the past ten years, we have delivered to patients 20 new medicines that treat devastating diseases like cancer, multiple sclerosis, and hemophilia. In addition to our over 40 approved medicines, we have 70 potential new medicines in clinical or preclinical development and have been granted 39 FDA Breakthrough Therapy Designations for medicines with the potential to provide substantial improvement over currently available treatments.

Access to clinically appropriate treatment is essential to improving health and health equity for Medicare beneficiaries. To this end, we provide the following comments and recommendations to ensure that access to FDA-approved drugs and biologicals remains broad and inclusive, while maintaining existing standards to ensure safety, efficacy, and appropriateness.

Generally, current Medicare coverage policy for drugs and biologicals affords Medicare beneficiaries broad access to new treatments, with great clinical benefits and associated reductions in medical expenditures.
CED National Coverage Determinations (NCDs) can be a mechanism to broaden access for certain new technologies; however, given Medicare’s long-standing coverage standards for prescription drugs, CED NCDs restrict Medicare coverage for drugs and biologicals.
CED NCDs—as recently implemented for monoclonal antibodies directed against amyloid for the treatment of Alzheimer's Disease, and contemplated by CMS in this draft guidance for broader use among drugs and biologicals—would disproportionately limit certain beneficiaries’ access to therapies, potentially worsening health outcomes and deepening health inequities.
Application of CED to Drugs and Biologicals Puts Beneficiary Access at Risk

CMS, through its longstanding interpretation of the statutory “reasonable and necessary” standard, has established and—until recently—uniformly applied a standard whereby FDA approval of a drug or biological provides a sufficient basis for CMS coverage. Under this standard, CMS has rightly relied on FDA’s scientific expertise in assessing the safety and efficacy of novel therapies, based on rigorous clinical studies and, in the case of products approved through the Accelerated Approval Program (AAP), scientifically validated surrogate endpoints. Notably absent from this interpretation is any requirement that pivotal studies be fully representative of the Medicare population.

Medicare beneficiaries have undoubtedly benefited from this coverage standard, which results in quick and reliable access to new medicines and, in turn, improved health outcomes and quality of life. However, in the Proposed Guidance, CMS suggests the agency is considering upending this standard. As proposed, CMS would rely more heavily on the use of CED NCDs to “expedite earlier beneficiary access” to medicines. This purpose aligns closely with one of CMS’s governing principles of CED application, which is to “generally expand access to medical technologies for beneficiaries.” However, in CMS’s own words, the CED standard is best applied for those technologies that “would not otherwise meet the reasonable and necessary coverage standard.” This is not true for drugs and biologicals. To the contrary, Medicare beneficiaries can typically access Part B medicines upon FDA approval without further restrictions or criteria. Any added coverage requirements thus represent an access restriction, cutting against CMS’s stated goals of the proposed policy. Application of CED to condition coverage on additional criteria beyond the current interpretation of “reasonable and necessary” for drugs and biologicals is unnecessarily restrictive and harmful to patient access.

We are also very concerned that in the Proposed Guidance, CMS seems to specifically target products approved under the AAP, noting that “it is rare that there is sufficient clinical evidence to support broad national coverage.” The AAP was created to encourage development of treatments for serious diseases and conditions with great unmet medical need, and has been proven successful by making critical and innovative therapies available to patients years earlier than under traditional approval, resulting in improved access and clinical outcomes. In fact, when examining real-world clinical effectiveness of Accelerated Approval (AA) drugs relative to current standard of care at the time, AA drugs have delivered more patient benefits, and the early time to market has led to notable overall gains in life years at the population level. Under this program, FDA’s standard for effectiveness requires substantial evidence based on adequate and well-controlled clinical investigations, and validation of a proposed surrogate endpoint. For drugs approved under this pathway, manufacturers then have an obligation to conduct post-approval studies to confirm the link between the surrogate/intermediate endpoint and clinical benefit, where possible; failure to confirm benefit can result in withdrawal of approval for the drug. Congress recently strengthened aspects of the AAP in an effort to ensure confirmatory trials are completed expeditiously, among other goals. However, in recognition of the value of the program to patients, Congress was careful not to change the standard for approval. CMS should likewise not implement policies that would undermine the successes of this program.

Application of CED to Drugs and Biologicals Could Exacerbate Health Inequities

Beyond our general concern that application of CED to drugs and biologicals will restrict beneficiary access to safe and effective therapies, we are especially concerned that those most likely to be negatively affected will be historically disadvantaged minority groups and other underserved populations. As a result, CED could inadvertently exacerbate inequities, in stark contrast to CMS’s stated policy aims.

As we noted in our response to the proposed NCD for monoclonal antibodies directed against amyloid for the treatment of Alzheimer's Disease, CED NCDs that require participation in a randomized controlled trial (RCT) would severely limit the participation of individuals who live in rural communities, where access to providers participating in this type of research is limited. Those without the means to travel long distances—disproportionately minority groups—would be effectively excluded from participating in a CED study, and therefore denied access to this class of therapies. And while we acknowledge that RCTs have not been the only type of study permitted under existing and historical CED policies, other forms of CED studies (e.g., registries) may be equally exclusionary if providers are unable or unwilling to participate in the study. Such providers are more likely to be under-resourced and caring for minority and other underserved populations, meaning those individuals are more likely to be denied access to a therapy subject to CED.

Adding to the enrollment and participation challenges related to a provider’s ability to satisfy CED requirements, substantial research has revealed that patients face many other barriers to participating in medical research, such as financial costs, logistical challenges, mistrust, restrictive protocol designs and processes, and the lack of educational resources for individuals, clinicians, and caregivers. These studies have also shown that factors common among medically disenfranchised or other minority groups—such as having low income, being uninsured, and facing language barriers—contribute to these groups’ underrepresentation in medical research. If CED were to be used more broadly for drugs and biologicals, these individual-level barriers to participation in medical research will undoubtedly result in similar access issues, with certain populations effectively made ineligible for treatment with an otherwise safe and effective product for an FDA-approved indication.

Rather than directly addressing the challenges around participation in clinical research, as FDA has begun to do and as Congress has done with the passage of the Consolidated Appropriations Act of 2023, CMS would effectively condition access to therapies on a patient's participation in ongoing research. Considering what is at stake if a patient does not have access to a life-saving medicine, participation in CED is hardly a “voluntary concept,” despite the many legitimate reasons why a Medicare beneficiary may not want or be able to participate in medical research.

We also note that the challenges described above would make it very difficult, if not impossible, for CED studies to include a diverse population that is representative of the national population diagnosed with a particular disease or condition. One of CMS’s key interests in applying CED more broadly appears to be generating data from a fully representative patient population. Yet under the CED, there could actually be significant delays in study recruitment and completion, which would also lengthen the time for which the access disparities under the CED persist. At the same time, CED studies—particularly those requiring RCTs—may actually serve to de-value the participation of individuals in clinical research altogether (including those from underrepresented groups), which could further compound the mistrust that is often a barrier to minority patients’ willingness to participate in clinical trials. If different RCTs were to be required for FDA approval, post-approval confirmatory requirements, and/or Medicare coverage, the value of the time, cost, and patient participation in each of those trials would be diminished.

* * * * *

Considering the implications of restricted drug access on beneficiary health and equity, we urge CMS to refrain from applying CED to drugs and biologicals, instead relying on its current standards to ensure broad access to FDA-approved therapies.

Thank you for the opportunity to provide our feedback on the Proposed Guidance. Please do not hesitate to contact Dan Neves, Director of Federal Policy, at nevesd2@gene.com should you have any follow-up questions.

Sincerely,
David Burt
Executive Director, Federal Government Affairs
Genentech, Inc.

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August 21, 2023

Re: Proposed Coverage with Evidence Development Guidance Document

The Pharmaceutical Research and Manufacturers of America (PhRMA) is pleased to submit these comments in response to the Centers for Medicare & Medicaid Services’ (CMS’) proposed Coverage with Evidence Development (CED) guidance document. PhRMA represents the country’s leading innovative biopharmaceutical research companies, which are devoted to discovering and developing medicines that enable patients to live longer, healthier, and more productive lives. Over the last decade, PhRMA member companies have more than doubled their annual investment in the search for new treatments and cures, including nearly $101 billion in 2022 alone.

PhRMA is a longstanding supporter of the ongoing generation of rigorous evidence following approval of a drug or biologic by the Food and Drug Administration (FDA). Evidence developed and deployed consistent with relevant PhRMA principles can provide useful information to payers, providers and patients. However, PhRMA does not believe that evidence generation, including in the context of CED, should be used by CMS to restrict coverage of FDA-approved medicines in Medicare Part B.

Furthermore, experience with the CED paradigm to date underscores why CED is likely to delay and restrict timely beneficiary access to important new treatment options. As noted in the proposed guidance document, CMS has issued more than twenty National Coverage Determinations (NCDs) containing a CED paradigm over the past twenty years. This time has afforded stakeholders significant experience with CED as framework for Medicare Part B coverage. As a collective of stakeholder groups recently noted, there is persistent concern that “CED has been ineffective in both enabling beneficiary access and generating the data CMS seeks.” PhRMA, along with a range of other stakeholders, shares this concern. Thus, we strongly urge CMS to refrain from relying on CED, as laid out in the proposed guidance document or otherwise, as a framework for coverage for FDA-approved medicines in Medicare Part B.

While PhRMA and other organizations have expressed long-standing opposition to CMS’ application of the CED concept to FDA-approved medicines in Part B, our concerns have been amplified by the agency’s flawed decision in 2022 to finalize an NCD that imposed restrictive CED requirements for anti-amyloid monoclonal antibodies (mAbs) for the treatment of Alzheimer’s Disease. This was the first time CMS had finalized a CED-based coverage restriction for an entire class of medicines for an FDA-approved indication, and illustrates that potential for CED to restrict access to medically appropriate treatment options. During the development of the NCD and since its finalization, numerous patient groups, provider organizations and academics have expressed concern about the NCD, and encouraged CMS to reconsider its decision.

Accordingly, PhRMA recommends several changes to the proposed guidance document in support of beneficiary access to medically necessary, FDA-approved medicines:

CMS should clarify the basis for its statutory authority to issue NCDs that condition coverage on ongoing evidence development via a CED requirement.

CMS should refrain from using CED to restrict coverage of FDA-approved medicines, including drugs approved via accelerated approval, in Medicare Part B.

CMS should ensure that reliance on CED does not undermine access to care for vulnerable and underserved populations.

CMS should either clarify or delete references in the proposed guidance to CED being “voluntary.”

We offer additional detail on each of these recommendations below.

I. CMS should clarify the basis for its statutory authority to issue NCDs that condition coverage on ongoing evidence development via a CED requirement.
As it does in its current CED guidance, CMS states in the proposed CED guidance document that the agency has the authority to adopt CED policies under section 1862(a)(1)(E) of the Social Security Act (SSA). We address this issue as a threshold matter given the importance of CMS adhering to the Medicare statute when making determinations about the coverage available to program beneficiaries. Any restrictions on Medicare beneficiaries’ coverage must always strictly adhere to applicable law; however, such restrictions take on particular importance in connection with therapies for serious diseases with few alternative treatment options.

Unless an exception applies, items and services are covered under Medicare Parts A or B if they fall within a benefit category and are “reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.” CMS has stated that in instances where “the item or service was promising but the evidence was insufficient to conclude that the item or service is reasonable and necessary,” it may cover the product – but only for those beneficiaries who participate in clinical trials or other specified evidence collection mechanisms – under SSA § 1862(a)(1)(E). In relevant part, SSA § 1862(a)(1)(E) permits coverage of an item or service:

“in the case of research conducted pursuant to section 1142, which is . . . reasonable and necessary to carry out the purposes of that section.”

SSA § 1142, in turn, permits the Director of the Agency for Healthcare Research and Quality (AHRQ) to “conduct and support research” for certain purposes. In relevant part, SSA § 1142 states that the Secretary, acting through AHRQ, shall:

“conduct and support research with respect to the outcomes, effectiveness, and appropriateness of health care services and procedures in order to identify the manner in which diseases, disorders, and other health conditions can most effectively and appropriately be prevented, diagnosed, treated, and managed clinically….”

In the proposed CED guidance, CMS states that AHRQ satisfies the requirement that it “support” research involving items and services covered by Medicare under CED policies because AHRQ “indicates its support for clinical research studies that CMS determines to address the CED questions and meet the general standards for CED studies.”

However, in a 2021 Advisory Opinion, then-General Counsel of the Department of Health and Human Services (HHS) Robert Charrow examined this issue and concluded that “AHRQ’s endorsement of the research” does not constitute “support” within the meaning of SSA § 1142, because “AHRQ is neither conducting the research, nor actively supporting the research through funding or other means.” The Advisory Opinion explains that “support” is “commonly understood to mean funding, whether by grant or otherwise,” citing Public Health Service Act (PHSA) §§ 301(a)(3), 306(e), and 405(b)(2) and 42 C.F.R. § 93.221. In order for AHRQ to “support” a CED study under SSA § 1142, the Advisory Opinion reasoned that AHRQ must provide funding for the study and do more than “merely endors[e] the clinical study.” Accordingly, the Advisory Opinion concluded that “this [‘endorsement’] interpretation of ‘support’ leads to Medicare payment that is unlawful under Section 1862, because AHRQ has not been ‘supporting’ the clinical trials and research required as part of an NCD using CED.”

CMS’ proposed guidance does not address the 2021 Advisory Opinion (nor has CMS addressed the Advisory Opinion elsewhere). The status of the 2021 Advisory Opinion is unclear, because the Advisory Opinion no longer appears on HHS’ website, and HHS has not explained why it was removed from the website. By contrast, in another case around the same time where HHS removed an HHS General Counsel’s Advisory Opinion from the HHS website, HHS issued a notice of withdrawal explaining the reason for the withdrawal. This suggests that HHS’ protocol at the time may have been to issue a public notice explaining HHS’ reasoning if HHS was withdrawing an Advisory Opinion. Because HHS has not issued a notice explaining why the 2021 Advisory Opinion was removed from the HHS website, it is unclear why the Advisory Opinion was removed, how CMS views the Advisory Opinion’s interpretation of SSA § 1142, and whether the Advisory Opinion has ramifications for CMS’ purported authority to use CED.

Therefore, PhRMA requests that CMS clarify the status of the 2021 Advisory Opinion and the agency’s position on what constitutes “support” under section 1142 – in particular, whether AHRQ “support” for a study under section 1142 requires funding. Additionally, PhRMA requests that CMS disclose whether AHRQ currently is funding any CED studies, and if so, to provide information on such funding, including how the funds were appropriated to AHRQ. We note that Congress authorized appropriations for AHRQ’s activities under SSA § 1142(i) for fiscal years 1990 to 1994, but there have been no specific amounts authorized under this section for the nearly 30 years since.

II. CMS should refrain from using CED to restrict coverage of FDA-approved medicines, including drugs approved via accelerated approval, in Medicare Part B.

As previously noted, PhRMA supports the development of evidence following approval of a drug or biologic by the FDA, and manufacturers typically support significant ongoing research to better understand the role and clinical impact of a medicine after its initial FDA approval. However, PhRMA does not believe that requirements for participation in evidence generation mechanisms (i.e., CED policies), should impede patient access to medically necessary treatments that should be covered by Medicare Part B without such requirements. Therefore, we strongly recommend that CMS refrain from using CED, as outlined in the proposed guidance document or otherwise, as a tool to restrict coverage for FDA-approved medicines. Below we outline our rationale supporting this recommendation.

Given the FDA’s rigorous standards for approval, CMS should not use CED to restrict access to FDA-approved medicines in Medicare Part B; instead, clinical decision making should be left to patients, caregivers, and physicians.

While CMS has often applied CED policies to medical devices, diagnostics and surgical procedures, it has rarely applied this paradigm to drugs. It is widely assumed that this is in part due to the significantly higher evidentiary standards that drugs are held to compared to other types of interventions – for example, fewer than one percent of medical devices undergo the phases of human clinical trials that the FDA requires of drugs.

Historically, CMS has generally recognized that FDA approval of a medicine – grounded in prospective clinical trials evaluating the potential risks and benefits of the treatment – provides a basis for finding the drug to be “reasonable and necessary” for at least some patients and thus ensuring it is covered and available to Medicare beneficiaries when the drug falls within a Part B benefit category. This approach of providing timely coverage of FDA-approved medicines has served patients well in ensuring access to medically appropriate, evidence-based treatment options; supporting significant improvements in patient outcomes; and affording patients the ability to make important treatment decisions in consultation with their treating physicians.

Conversely, if CMS uses CED to restrict coverage of medicines it would be a significant deviation from this pathway, and could jeopardize patient access and health outcomes. In the proposed guidance document, CMS states that CED is appropriate where “the evidence is not yet adequate for Medicare coverage...” As PhRMA has stated in past comments to CMS, we believe that, given the rigorous standards that the FDA applies in approving drugs and biologics, FDA-approved drugs and biologics meet the standard of being “reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.” This is in part because FDA’s drug review program is the global gold standard for regulatory review and approval, involving a rigorous, science-based evaluation of safety and effectiveness before any new drug or biologic can be introduced.

Moreover, Medicare coverage of FDA-approved medicines that fall within a Part B benefit category is particularly important because clinical decision making should remain primarily in the hands of patients, caregivers and physicians to optimize outcomes. As a legal matter, CMS must cover drugs that fall within a Part B benefit category that meet the reasonable and necessary standard. CMS’ historical approach recognizes that, following FDA approval of a medicine, patients and their caregivers and physicians can and will evaluate their available options and make decisions about the treatment approach that is best for them. The relationship between patients, their caregivers, and their care team allows for nuanced, individualized decision making regarding treatment plans based on a patients’ individual needs and preferences. CMS’ reliance on CED-based NCDs to impose access restrictions on FDA-approved medicines is disruptive and interferes with this relationship, as well as the clinical decision-making process. We strongly urge CMS to refrain from using CED to deprive patients, caregivers and patients of their ability to make the choice that is right for each individual.

CMS has historically failed to execute CED in a manner that facilitates timely access to treatments and interventions.

Furthermore, CMS’ record with CED to date serves to reinforce concerns expressed by PhRMA and other stakeholders that the policy results in unnecessary and inappropriate barriers and delays to beneficiary coverage and access. CMS states in the proposed guidance document that “CMS does not believe that an NCD that requires CED as a condition of coverage should last indefinitely.” However, CMS’ execution of CED over the past twenty years does not align with this statement. Researchers and stakeholders have looked back at previous CEDs and concluded that CMS often fails to publish results from CEDs or reconsider them to determine whether the CED requirements remain necessary following the generation of evidence to support coverage of an intervention. For example, a report published by a patient advocacy group noted that “Once CMS places a treatment in CED, it is extraordinarily difficult for the coverage restriction to be lifted.” The report notes that of the NCDs CMS has issued requiring CED, only four have been retired by the Agency. The report also notes that “under its current paradigm, CMS has enabled 22 CEDs to continue in perpetuity.”

Even CEDs that CMS has eventually reconsidered or retired frequently endure for lengthy periods of time. An analysis of CMS’ CED programs shows that the average time from the start of a CED until Medicare retires a CED is 11 and a half years. Research published in the American Journal of Managed Care noted that some CED programs have lasted up to 16 years. In practice, this means that burdensome access restrictions are likely to remain in place for more than a decade, under the guise of evidence generation. Whether and why those CED policies have continued for such an extended period of time (including if the interventions failed to achieve CMS’ standard of “reasonable and necessary”) is unknown due to a lack of transparency around CMS’ CED process.

When patients need treatment, they very often cannot wait more than ten years for CMS to reconsider a CED to access that treatment. Based on the average length of time it has taken CMS to reconsider CEDs previously, it is likely that that patients’ conditions will worsen or progress to the point where a treatment no longer is useful, or in some instances, such as Alzheimer’s Disease, they may die before CMS revisits the CED. Given the manner in which CMS has historically executed CEDs, it should refrain from using CED to limit patient access to medicines that have already met the rigorous standards for FDA approval.

CMS should refrain from restricting access to medicines approved via accelerated approval, which was created to expedite patient access to innovative therapies.
PhRMA is concerned about the implications of CMS’ statements in the proposed guidance document for medicines approved via accelerated approval (AA). The proposed guidance document states that “surrogate outcomes are not direct measures of clinical benefit, and there is often little evidence at this point regarding health outcomes (for example, mortality, disease progression, quality of life).” PhRMA interprets this statement to mean that CMS believes that drugs approved based on evidence regarding surrogate outcomes, such as medicines approved via AA, may offer “little evidence regarding health outcomes” and therefore may be optimal candidates for CED-based coverage. This appears to be the position CMS took in its recent decision to restrict coverage of anti-amyloid mAbs for the treatment of Alzheimer’s Disease approved via AA to beneficiaries participating in FDA-approved randomized controlled trials or studies supported by the National Institutes of Health.

Assertions that medicines with accelerated approval have “little evidence regarding health outcomes” are based on a flawed understanding of accelerated approval. Medicines approved via AA must adhere to the same standards for establishing safety and effectiveness as medicines receiving a traditional FDA approval. AA does not alter the statutory standard for new drug approval, and therefore still requires medicines to demonstrate “substantial evidence” of clinical benefit.

AA is based on a surrogate or an intermediate clinical endpoint, and the FDA has procedures in place to ensure the benefit of surrogate endpoints. As required by law, FDA publishes all surrogate endpoints that served as the basis of approval. FDA bases its decision on whether to accept a proposed surrogate endpoint or intermediate clinical endpoint on the available scientific data for that endpoint. Further, FDA has stated that if a surrogate endpoint was previously used to support AA but subsequent confirmatory trials failed to demonstrate the expected clinical benefit, the surrogate endpoint will no longer be accepted for that use by the FDA. CMS’ statement in the proposed guidance document on surrogate outcomes fails to acknowledge both FDA’s expertise and process for ensuring that surrogate outcomes and endpoints represent clinical benefit to patients.

The proposed guidance document and its implications for AA drugs also fail to acknowledge the importance of AA drugs to patients. In fact, the AA program was established at the urging of patients, to speed patient access to desperately needed treatments that address an unmet medical need for serious or life-threatening disease or conditions such as HIV and cancer. From its inception, the very purpose of AA has been to break down barriers for patients most in need, especially those suffering from a serious or life-threatening illness that lacked any alternative and viable treatment options. Over 250 new drugs and biologics to treat serious or life-threatening illnesses have been approved through AA to date. If CMS were to use CED again to restrict access to AA drugs, as it has done for treatments for Alzheimer’s patients, it would not only contravene the intent of AA but deprive patients of timely access to innovative medicines.

III. CMS should ensure that reliance on CED does not undermine access to care for vulnerable and underserved populations.

In 2021, the Administration outlined goals to mitigate “potential barriers that underserved communities and individuals may face” in access to health care in an Executive Order on equity. However, as detailed below, proposing and deploying a research-based framework for Medicare Part B coverage, including rigid study design criteria, inherently and systematically undervalues the preferences, priorities and health care needs of diverse populations across the United States. Given our concerns about the disproportionate impact that CED will have on health equity, PhRMA strongly recommends that CMS address in the final guidance how it intends to mitigate the harm CED could have on underserved and vulnerable populations.

It is widely acknowledged that although underrepresented populations may be equally willing as the general population to participate in clinical research, there are still challenges in recruitment of a diverse trial population. These challenges come in a number of forms. For example, clinical research often excludes patients with comorbidities, such as chronic conditions, which disproportionately impact communities of color. Additionally, any restriction on coverage to clinical trial sites (as outlined in the CED requirements for anti-amyloid mAbs approved via AA) will acutely impact disadvantaged and socioeconomically deprived communities, as identification, enrollment and participation in a clinical trial will likely require significant resources.

We encourage CMS to work directly with stakeholders representing underserved and vulnerable communities to ensure that their concerns are recognized and addressed to mitigate the impact of CED on access in any cases where CED policies are within CMS’ legal authority.

PhRMA also strongly disagrees with CMS’ characterization in the proposed guidance of participation in clinical studies as a condition of coverage as “voluntary.” CMS explicitly states that “it is important to remind the public that beneficiary participation in a CED trial is completely voluntary.” PhRMA disagrees with this statement. When a beneficiary must participate in clinical research in order to access a medically necessary treatment, and failure to do so would compromise their health, their participation in clinical research is not in fact voluntary. The ability to access health care absent Medicare coverage is a privilege that few of America’s seniors can afford, particularly in communities that are already underserved and vulnerable. CMS should remove this statement from the proposed guidance document.

* * *

PhRMA appreciates the opportunity to comment on the proposed Coverage with Evidence Development guidance document. Please do not hesitate to contact us if we can provide additional information or answer any questions related to our comments.

—s—
Lauren Neves
Deputy Vice President, Policy and Research
PhRMA

—s—
Corbin Santo
Assistant General Counsel
PhRMA

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August 21, 2023

Chiquita Brooks-LaSure
Administrator
Centers for Medicare & Medicaid Services
7500 Security Blvd
Baltimore MD 21244

Re: Proposed Coverage with Evidence Development; CMS National Coverage Analysis Evidence Review; and Clinical Endpoints Guidance: Knee Osteoarthritis Guidance Documents

Dear Administrator Brooks-LaSure,

AppliedVR appreciates the opportunity to offer comments on the Centers for Medicare & Medicaid Services’ (CMS) three proposed guidance documents released in conjunction with the Transitional Coverage for Emerging Technologies (TCET) notice: Proposed Coverage with Evidence Development (CED); CMS National Coverage Analysis Evidence Review; and Clinical Endpoints Guidance: Knee Osteoarthritis Guidance Documents. AppliedVR is a medical device startup in early stages of marketing the first Food and Drug Administration (FDA) authorized Immersive Virtual Reality (VR) program indicated for chronic low back pain. Given the critical importance of predictable pathways to CMS coding, coverage and payment, we strongly support both policy and process improvements that would result in a predictable pathway to national Medicare coverage for new medical devices and diagnostics.

AppliedVR understands the need for evidence in determining appropriateness for Medicare beneficiaries, and we appreciate the challenges faced by CMS in trying to improve the National Coverage Determination process. We believe that to advance its health equity and other goals, CMS can and must continuously improve and modernize processes that advance access to emerging innovations that improve health outcomes for a wide array of Medicare beneficiaries.

By their very nature, new technologies are likely to require additional evidence generation. As the manufacturer is responsible for producing the evidence necessary for FDA evaluation to obtain premarket clearance or approval, it is unrealistic to expect an independently generated body of evidence as a new technology is entering the market. It is, therefore, crucial that the process involves collaboration between CMS and its stakeholders, such as medical device companies, in order to identify additional data collection objectives, appropriate study endpoints, methods, and duration of the data collection. In cases where CMS conditions coverage on the development of additional evidence, policies should minimize administrative burden and provide clarity on timelines and objectives.

When Medicare coverage is contingent on the collection of additional clinical or scientific evidence (beyond FDA requirements for safety and efficacy), CMS should:
1) collaborate with stakeholders to clearly identify the data collection objectives;
2) consider the minimum data and least burdensome method necessary to achieve those objectives (i.e., ensure data collection is “fit for purpose”);
3) clearly identify, with input from interested stakeholders, scientifically supported study endpoints, methods, and the duration of data collection in advance (including clear stopping rules for data collection under CED);
4) identify an appropriate mechanism to ensure continuous coverage of an item or service after a study ends, to avoid disruption in coverage and continue to allow Medicare beneficiaries to benefit from important FDA-approved technologies and services until a new or revised coverage determination is issued; and
5) provide transparency in the performance of these processes to be accountable for timely decision-making and implementation.

I. Proposed Coverage with Evidence Development (CED) Guidance
CED should be used to expand, and not restrict coverage. AppliedVR’s industry trade organization, AdvaMed, has previously submitted comments to CMS regarding CED, including the Agency for Healthcare Research and Quality (AHRQ) draft report: Analysis of Requirements for CED , and most recently provided public comments at the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) meeting on Analysis of CED . AppliedVR was pleased to see some of the industry recommendations made to AHRQ were incorporated into this proposed guidance.

Within the background section of the guidance document CMS states, “For new technologies, it is rare that there is sufficient clinical evidence to support broad national coverage under section 1862(a)(1)(A).” We respectfully disagree with this statement and believe that it is not always necessary to require CED for new and/or novel technologies. First, this statement does not take into account many technologies that have developed substantial clinical evidence in the Medicare population prior to seeking coverage, and therefore do not require CED. Second, there is also a category of new technologies that have a sufficient level of evidence to support a reasonable and necessary determination under limited circumstances, but real world data is needed to inform long-term national coverage. Currently, CMS defers these products to local Medicare Administrative Contractors for coverage. CMS should provide additional guidance to manufacturers on these categories of products, where CED is not needed, but some real world data may be needed to bridge the data gap to obtain national coverage.

Recommendations

? AppliedVR recommends that the above quoted sentence be revised to reflect that sufficient evidence is generated by manufacturers of new technologies in some cases, such as:
“For some new technologies, evidence may be insufficient to support broad national coverage under 1862(a)(1)(A)”
? AppliedVR recommends CMS provide additional guidance to manufacturers on methods for achieving national or local coverage determination for products that meet the reasonable and necessary standard, but may need to provide some real world data outside of CED to bridge the data gap to obtain national coverage.
Clinical Study Standards for CED under Section 1862(a)(1)(E)
We recognize that this section has been significantly updated and expanded based on the work done by AHRQ and MEDCAC over the last two years, and we appreciate that many of the comments submitted by AdvaMed on behalf of the industry on the standards language and requirements were incorporated into the guidance documents. We support efforts to impart more transparency and predictability into the processes for Medicare coverage, and we believe that these standards provide a step in the right direction to providing more clarity to manufacturers. However, we urge CMS to provide flexibility for manufacturers when these standards are operationalized into the CED process, especially given the wide and varied range of medical technologies and their intended uses. During this process, CMS should consider the practical challenges associated with generating evidence and consider all levels of valid scientific evidence.
Recommendation:
? AppliedVR recommends that CMS exercise flexibility in the interpretation and application of these standards appropriate for the technology in question.

Ending CED
AppliedVR believes that the termination date of a CED for the identified use of an item or service should be discussed and agreed upon in advance by CMS and the study sponsors. We support language within the guidance document that includes establishing appropriate timelines for CED-required data collection as part of the Evidence Development Plan (EDP). As noted in the TCET notice, development of an EDP will involve CMS determining in advance the duration of the data collection, or the specific issues or questions CMS seeks to address through data collection. This will create “stopping rules” for data collection and avoid burdensome and costly data collection without a clear end point. We encourage CMS to ensure these tenets of CED are applied broadly, whether inside or outside the TCET program. Additionally, between the end of the study and the Agency’s review of the scientific results, there is a potential under CED for a gap to occur in coverage. We urge CMS to ensure continuous coverage of an item or service after a study ends, to avoid disruption in coverage and continue to allow Medicare beneficiaries to benefit from important FDA-approved technologies and services until a new or revised coverage determination is issued.

Recommendations:

? AppliedVR agrees with CMS that CED as a condition of coverage should not last indefinitely, and further agrees the EDP should include established start and end dates.
? Where appropriate, interim analyses may suggest data collection timelines should be modified, and processes should be included in the EDP for this purpose.
? CMS should ensure there are no gaps in coverage between the conclusion of a CED study and issuance of a permanent NCD.

Transparency of CED
In this section of the proposed guidance document, CMS states, “the NCD process, in general, is a transparent one.” However, this transparency, in terms of informing stakeholders regarding proposed coverage determinations and providing opportunity to provide input, occurs only after a National Coverage Analysis is opened. There is not much transparency from CMS regarding how the Agency manages NCD requests, prioritizes requests, or keeps track of requests in the queue for future review (the “waiting lists”). CMS has not published new NCD waitlist dashboards on its website, and has not updated this information since September 2020. This dashboard was a positive step towards greater transparency. We urge CMS to update this waitlist dashboard to include appropriate dates for all NCDs received and in process, including those that are part of the TCET program.

Recommendation:

? AppliedVR recommends CMS provide greater transparency into the coverage process. At a minimum, CMS should update the NCD waitlist dashboard to include all NCDs, CEDs, and TCET applications, including action dates and any NCD reconsiderations.

II. National Coverage Analysis Evidence Review Proposed Guidance Document

AppliedVR supports both policy and process improvements leading to a predictable pathway to national Medicare coverage for new medical devices and diagnostics. This new proposed guidance on National Coverage Analysis Evidence Review provides useful information to aid manufacturers in navigating this process.

Methodological Principles

Within this section, CMS describes methodological principles that the Agency considers when reviewing clinical evidence, and notes that each NCD has its unique methodological aspects. While we appreciate CMS acknowledging the uniqueness of each NCD, we are still concerned that some of these may not be feasible for medical device products. For example, the requirements of “use of randomization”, “large sample sizes”, and “masking” for the studies are problematic given the unique characteristics of medical devices. Unlike pharmaceutical products, it may not always be feasible to conduct a double-blind, head-to-head comparison in a trial for medical devices due to issues such as ethical concerns, inability to blind the test case, or a low volume of the procedure in which the device is used. Therefore, we strongly suggest that CMS revise this language to appropriately differentiate drugs and medical devices in the NCD evidence review requirements.

Additionally, at the end of this section CMS states it, “carefully considers the funding source and potential conflicts of interest for study investigators.” AdvaMed agrees with CMS that thorough assessment of individual studies generating evidence for Medicare coverage is critical to assess their methodological rigor. However, new technologies are developed and commercialized by companies, and we urge CMS to not dismiss company-funded research as automatically presenting a conflict of interest, but to instead review whether steps were taken to manage any potential conflicts, including disclosure of funding relationships with investigators.

Recommendations:

? AppliedVR recommends CMS revise the methodological principles to appropriately differentiate drugs and medical devices in the NCD evidence review requirements.
? CMS should be realistic in recognizing that early research on new technologies is company-funded and often focused on FDA processes, and not dismiss company-funded research automatically but to instead review whether steps were taken to manage potential conflicts.

Review of Individual Studies

We are encouraged that CMS endorses the concept that studies should be fit-for-purpose, where the study design, analysis plan, and data source(s) should be sufficient to credibly answer the question(s) it intends to answer. AppliedVR supports CMS’ willingness to incorporate robust fit-for-purpose evidence development into the TCET program, and we look forward to the Agency’s forthcoming guidance. These studies will be crucial to ensuring the TCET program can work to accelerate coverage and close evidence gaps in a timely manner. We urge that the guidance be released soon and allow opportunity for stakeholders to comment. Additionally, within this section CMS describes evidence they may consider, but leaves questions around what evidence is required and which data is captured during the review. More specifically, we seek clarity on whether CMS will accept unpublished evidence or prepublication manuscripts during the systematic review of findings.

Recommendation:
? AppliedVR supports CMS’ efforts to incorporate fit-for-purpose studies, and encourages release of the forthcoming guidance soon and allow opportunity for stakeholders to comment.
? AppliedVR seeks clarity on exactly what evidence will be considered as part of the systematic review, such as unpublished evidence or prepublication manuscripts.

III. Proposed Clinical Endpoints Guidance: Knee Osteoarthritis

CMS issued this proposed guidance document to provide the public with the health outcomes of interest to CMS when reviewing technologies for the treatment of knee osteoarthritis when considering reasonable and necessary NCDs. CMS indicates that the overall objective for this guidance document, as well as the noted plans for subsequent endpoints guidance documents in other therapeutic areas, is to improve the transparency of the NCD process.

We are supportive of both the efforts to increase transparency and to release additional endpoints guidance documents for other therapeutic areas. To facilitate this process, we encourage CMS to publish on its website a list of therapeutic areas for which CMS plans to release guidance documents, including anticipated release dates. This will provide manufacturers transparency on timing for anticipated guidance documents. We also encourage CMS to provide an opportunity for stakeholders to comment on these documents before they are finalized.

Recommendations:
? AppliedVR encourages CMS to publish on its website a list of therapeutic areas for which CMS plans to release guidance documents, including anticipated release dates.
? CMS should allow public comment on any subsequent guidance documents in other therapeutic areas prior to finalizing the guidance.

Respectfully Submitted,

AppliedVR, Inc.

By
/s/ Liesl M Oldstone
Liesl M Oldstone, PhD
VP, Health Economics and Market Access AppliedVR, Inc 16760 Stagg Street, Unit 216 Van Nuys, CA 91406

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We appreciate CMS' development of this proposed guidance document on its considerations of the Coverage with Evidence Development (CED) paradigm. We believe that many of the provisions outlined in this proposed guidance enable CMS to meet its mandate of covering reasonable and necessary treatment for its beneficiaries. Rigorous evidence generation in CED is critical to best serving Medicare beneficiaries, and we write to support CMS’ guidance and provide suggestions for ways in which the current guidance can be strengthened to further protect beneficiaries.

First, we applaud CMS for its commitment to a strong CED process that respects the distinct roles and mandates of CMS and the FDA. As the proposed guidance document rightly notes on page 4, “it is rare that there is sufficient clinical evidence to support broad national coverage under section 1862(a)(1)(A)” for new technologies approved by the FDA. Our research has shown that this is particularly true for FDA-approved medical devices: in multiple studies, we have shown that the majority of studies relied upon for FDA approval were not randomized, not blinded, and used surrogate end points for most primary outcomes (Zheng et al 2017, Dhruva et al 2009). While the FDA is tasked with determining the safety and effectiveness of a drug or medical device, CMS separately must determine whether this treatment is reasonable and necessary for Medicare beneficiaries, which requires strong clinical evidence that is generalizable to the CMS beneficiary population. As it stands, the participants studied in research used to support FDA approvals are not representative of Medicare beneficiaries, as Medicare beneficiaries are often older, are more often women, and are more often racially and ethnically diverse (Dhruva & Redberg 2008, Dhruva et al 2011). While the proposed guidance for CED studies requires subgroup analyses, the guidance should also specify that these subgroup analyses should show reasonableness and necessity for each subgroup of Medicare beneficiaries.

Crucial components of strong clinical evidence that demonstrates reasonableness and necessity are the use of control groups and blinding, and CMS correctly notes the importance of the use of control groups and blinding in studies used to generate evidence under CED. These aspects of study design are crucial for determining the true effect of a treatment for beneficiaries, and there should be a very high bar for not incorporating these elements into CED studies. In addition, as CMS notes on page 11, “Without an appropriately created (typically contemporaneous) comparison group, it is often impossible to convincingly isolate and measure the treatment effect of interest.” While sponsors/investigators must justify the lack of a contemporaneous comparison group, we believe that there must be a strict standard by which to judge this justification. We suggest that CMS clarifies when studies without control groups, blinding, or contemporaneous comparison groups are permitted for CED. As it is impossible to know if the new treatment is better than currently available treatment without a control group and blinding, such exceptions should be rare or non-existent. This is true for both drugs and medical devices—medical device procedures have been shown to have a substantial placebo effect that must be addressed through use of randomized controlled trials (Redberg 2014).

Similarly, we agree with CMS that primary health outcomes should be clinically meaningful, that “[s]urrogate outcomes are not direct measures of clinical benefit,” and that only validated surrogate outcomes "may be appropriate for some questions.” The lack of specificity on when validated surrogate outcomes are appropriate as well as when surrogate outcomes are validated, however, must be addressed. For surrogate outcomes to be appropriate, “they must be shown to predict meaningful clinical outcomes, which rarely happens” (Zheng et al 2017, Kim et al 2015). We urge CMS to outline requirements for the use of surrogate outcomes, as well as the process by which a surrogate outcome is considered validated, so that beneficiaries only receive care that has been proven to provide clinically meaningful benefit.

Rita F. Redberg, MD, MSc
Madris Kinard, MBA
Sarah Bitter, MA
UCSF Team for High-Value Care

References

Dhruva SS, Bero LA, Redberg RF. Strength of Study Evidence Examined by the FDA in Premarket Approval of Cardiovascular Devices. JAMA. 2009;302(24):2679–2685. doi:10.1001/jama.2009.1899
Zheng SY, Dhruva SS, Redberg RF. Characteristics of Clinical Studies Used for US Food and Drug Administration Approval of High-Risk Medical Device Supplements. JAMA. 2017;318(7):619–625. doi:10.1001/jama.2017.9414
Dhruva SS, Redberg RF. Variations Between Clinical Trial Participants and Medicare Beneficiaries in Evidence Used for Medicare National Coverage Decisions. Arch Intern Med. 2008;168(2):136–140. doi:10.1001/archinternmed.2007.56
Dhruva SS, Bero LA and Redberg RF. Gender bias in studies for Food and Drug Administration premarket approval of cardiovascular devices. Circulation: Cardiovascular Quality and Outcomes. 2011;4(2):165-171.
Redberg RF. Sham controls in medical device trials. N Engl J Med. 2014;371(10):892-893.
Kim C, Prasad V. Cancer Drugs Approved on the Basis of a Surrogate End Point and Subsequent Overall Survival: An Analysis of 5 Years of US Food and Drug Administration Approvals. JAMA Intern Med. 2015;175(12):1992–1994. doi:10.1001/jamainternmed.2015.5868

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SUBMITTED ELECTRONICALLY
August 21, 2023
RE: Proposed Guidance Document: Coverage with Evidence Development

Haystack Project appreciates the opportunity to provide comments on the Centers for Medicare & Medicaid Services’ (CMS’) proposed guidance document articulating its current thinking on how the Agency intends to utilize the Coverage with Evidence Development (CED) mechanism within a National Coverage Analysis (NCA).

Haystack Project is a 501(c)(3) non-profit organization enabling our membership of 140+ rare and ultra-rare disease patient advocacy organizations to coordinate and focus efforts that highlight and address systemic reimbursement obstacles to patient access. Our core mission is to evolve health care payment and delivery systems with an eye toward spurring innovation and quality in care toward effective, accessible treatment options for all Americans. We strive to amplify the patient and caregiver voice in these disease states where unmet need is high and treatment delays and inadequacies can be catastrophic.

Because the evidentiary review standards set forth in the proposed guidance on Evidence Review would tend to drive CMS to initiate CED if an NCA were pursued for an ultra-rare disease treatment, we have attached our previous comments to that proposed guidance. As we outlined in those comments, a significant proportion of Haystack Project’s advocacy and education efforts focus on unintended consequences our patient communities face when reimbursement paradigms designed for more common conditions are applied to rare and ultra-rare disease treatments. Haystack Project has also engaged with CMS, AHRQ and the MedCAC on coverage decision trends and refinements with potential to impact our patient communities’ access to treatments. We have repeatedly expressed our concerns about the potential for increasing CEDs for FDA-approved drugs, heightened scrutiny over accelerated approval treatments, and process gaps in ensuring that CED participations receive all research subject protections that are ordinarily afforded within clinical studies.

CMS notes that CED is used “when the available evidence is insufficient to demonstrate that the items and services are reasonable and necessary.” Our comments to the proposed guidance document highlight the challenges associated with developing and accessing rare disease treatments and urge CMS to consider and address the significant potential that NCAs for rare and ultra-rare disease treatments will disproportionately relegate our patient communities to limited treatment access and clinical trial requirements extending beyond FDA approval.

Background

Scientific advances in understanding and addressing disease mechanisms has advanced at a pace that would have been unthinkable decades ago. Targeted treatments, gene therapy and regenerative medicine, and immunologic approaches to rare, serious, and life-threatening conditions have offered renewed hope to individuals affected by a rare disease. However, exceedingly small populations, long diagnostic journeys, and a limited natural history knowledge base can make the treatment development and regulatory processes particularly challenging.

Of the approximately 7,000 rare diseases identified to date, 95% have no FDA-approved treatment option

80% of rare diseases are genetic in origin, and present throughout a person’s life, even if symptoms are not immediately apparent

Approximately half of identified rare diseases do not have a disease-specific advocacy network or organization supporting research and development.

Most rare disease patients have no available treatment beyond off-label use of therapies approved for other conditions. Coverage policies and mechanisms, particularly those within Medicare National Coverage Determinations, can present absolute, impenetrable, and persistent access barriers if they are implemented without considering the treatment needs of rare disease patients. Haystack Project remains concerned that CED mechanisms, including CMS’ study criteria, have been ill-suited to drive coverage for treatments labeled for, or used off-label in, managing very rare diseases.

Research and development on treatments for extremely rare diseases frequently relies on FDA’s accelerated approval mechanisms, use of surrogate endpoints, single-arm studies, and clinical trials evaluating treatment impact over a relatively short period of time in a small set of study participants. Therapies targeted to rare conditions also tend to be costly. We have expressed our concern that CMS can, in theory, single out any, or even all, accelerated-approval treatments, subject them to the critical lens of an NCA, predictably find that the evidence is insufficient to justify “national coverage,” and offer CED to give patients a chance at the access its self-initiated NCA process foreclosed.

Most individuals living with a very rare condition rely on off-label treatments to reduce disease burden and/or slow disease progression. NCAs for treatments can fully obstruct off-label use in rare diseases unless CED mechanisms and study criteria expressly provide for or exempt off-label uses supported by evidence in very rare conditions.

Individuals living with a very rare condition who fit within CMS’ aged and disabled Medicare population (and their treating physicians) have a substantial need for certainty with respect to treatment received. This severely complicates CED study requirements that condition coverage on participation in blinded, randomized clinical studies.

The unique challenges associated with research and development in rare diseases that are likely to drive increased scrutiny and create a perception of evidentiary uncertainty likely to trigger CED also create ethical issues complicating initiation of CED. This is particularly problematic when patients have limited treatment alternatives.

CED initiation should not be broadened beyond the relatively narrow statutory language authorizing its use.

As CMS has articulated in each CED NCD, its statutory authority for conditioning coverage on study participation is found in section 1862(a)(1)(E) of the Act, which provides that:

a) Notwithstanding any other provision of this title, no payment may be made under part A or part B for any expenses incurred for items or services—
. . .
(1)(E) in the case of research conducted pursuant to section 1142, which is not reasonable and necessary to carry out the purposes of that section.

Under Section 1142, AHRQ may conduct and support research on outcomes, effectiveness, and appropriateness of services and procedures to identify the most effective and appropriate means to prevent, diagnose, treat, and manage diseases, disorders, and other health conditions. While the Act requires that AHRQ research priorities reflect the needs and priorities of the Medicare program, it does not substitute CMS’ judgment for AHRQ’s research priorities. Similarly, neither the Act nor the Department of Health and Human Services have delegated broad authority to CMS to leverage the NCD process as a substitute for AHRQ-determined research priorities permitting the Agency to condition coverage on research participation when scientific evidence fails to clear the unreasonably high bar of confidence that it is conclusive.

Haystack Project understands that CMS likely receives requests to initiate a National Coverage Decision for technologies that are not supported by a sufficiently robust body of evidence to gain national coverage. Haystack is concerned, however, that when CMS initiates an NCA directed at FDA-approved drugs, CED becomes an inflexible utilization management tool, beneficiaries become research subjects, and treatment “decisions” are subjected to randomization and even “blinding” on the precise intervention. In this context, CED does not simply enable access to promising treatments; it conditions access to safe and effective treatments on beneficiary willingness to place their care into the hands of researchers rather than the clinicians managing their condition(s) as well as factors beyond the patients’ control (clinical trial availability, eligibility, and randomization.

CMS and AHRQ should prioritize ethical research, patient protections, equitable access, and meaningful informed consent.

We have previously urged AHRQ to ensure that its research priorities, and support for research, under Section 1142 prioritize access to care for patients covered by the Medicare program. We now urge CMS to avoid initiating the CED mechanism within the context of medically accepted uses of safe and effective treatments. Use of CED in these instances:

- Impermissibly substitutes CMS’ analysis of clinical evidence and conclusions for decisions delegated to and made by FDA or appropriately left to shared decision making between patient and clinician

- Perpetuates and exacerbates health inequities associated with race, ethnicity, and socioeconomic status

- Raises significant ethical concerns by conditioning coverage for on-label use and medically accepted off-label use of FDA-approved treatments on participation in CMS-directed, potentially randomized clinical trials

- Introduces logistic impediments that deny patient access to treatments that are medically necessary for their condition

- Creates considerable tension between an access-enabling view of CED facilitating innovation versus a real-world mechanism that leverages Medicare’s beneficiaries as research subjects to satisfy an amorphous bar of certainty on whether an intervention is reasonable and necessary

Institutional Review Board Review, Approval, and Oversight
Finally, Haystack Project is disappointed that CMS continues to assert that Institutional Review Board review, approval, and oversight over each individual CED study serves as a sufficient protection of patient rights within the context of research studies. Each NCA initiating CED, by necessity, a great deal of granularity on clinical study requirements and the research questions that those studies must resolve. Any entity, including CMS, engaged initiating, directing, reviewing and evaluating one or more clinical studies with a goal of utilizing data to evaluate the impact of an intervention on health outcomes is conducting research. CMS and AHRQ review and approve study protocols, gather and review data on patient outcomes, and assess study results. Including a requirement that each CED study be reviewed by an IRB is important, but it does not sufficiently protect the Medicare beneficiary population. We expect that the ethical considerations associated with conditioning coverage on clinical trial participation may vary based on the disease state, availability of alternative treatment options, assessed safety and efficacy of the intervention, and other factors.

The Federal Policy for the Protection of Human Subjects (the "Common Rule"), has been codified with respect to the U.S. Department of Health and Human Resources (HHS) at subpart A of 45 CFR part 46. It requires that U.S. institutions engaged in cooperative research must rely on a single institutional review board (IRB) to review and approve the portion of the research conducted at domestic sites. See 45 CFR 46.114(b). In order to be exempt from this rule, research must meet one of the criteria found at 45 CFR 46.104(d). Of the eight categories of exempt research, the only exemption that could possibly apply to CED research is 46.104(d)(5) which exempts from the Common Rule:

Research and demonstration projects that are conducted or supported by a Federal department or agency, or otherwise subject to the approval of department or agency heads (or the approval of the heads of bureaus or other subordinate agencies that have been delegated authority to conduct the research and demonstration projects), and that are designed to study, evaluate, improve, or otherwise examine public benefit or service programs, including procedures for obtaining benefits or services under those programs, possible changes in or alternatives to those programs or procedures, or possible changes in methods or levels of payment for benefits or services under those programs. Such projects include, but are not limited to, internal studies by Federal employees, and studies under contracts or consulting arrangements, cooperative agreements, or grants. Exempt projects also include waivers of otherwise mandatory requirements using authorities such as sections 1115 and 1115A of the Social Security Act, as amended.

It is highly unlikely that the clinical studies required under a CED NCD meet the standard for exemption from the Common Rule. In fact, HHS published a flow chart to illustrate applicability of exemption 45 CFR 46.104(d)(5) for Public Benefit or Service Programs. The chart emphasizes that the key factor is whether the research is designed to evaluate procedures, changes or alternatives to procedures, or methods or levels of payment. Although CED studies ultimately determine whether or not payment will be made, the clear intent of the exemption is to allow government agencies to broadly examine the effectiveness of their policies and programs – not to conduct randomized, controlled clinical trials examining the impact that a particular, and potentially FDA-approved, intervention has on Medicare beneficiary health outcomes.

Moreover, even if CMS were to fully consider this issue and conclude that there is no requirement that it must seek ethical review of its CED framework as applied to particular interventions and research questions, we strongly believe that as steward of the Medicare program it should do so. We urge CMS to obtain a clear and specific assessment of the ethical and patient protection concerns associated with each CED NCD and submit the CED study questions and requirements for IRB review and approval prior to finalizing any NCD requiring CED. In addition, the study criteria should include a requirement that investigators submit their protocols and other relevant information to the central IRB. We believe this is particularly important when the subject intervention is a medically accepted use of an FDA-approved treatment, and critical when such treatment addresses a life-limiting, progressive, and/or potentially fatal condition and access will be conditioned on study participation.

Finally, Haystack Project strongly believes that IRB and any other ethical review of CED NCDs should be made within the context of the Medicare population as a whole – individuals unable or unwilling to participate in clinical trials are denied access and, therefore, constitute an additional, albeit unintentional and non-consenting, “control” population.

Informed Consent
Haystack Project disagrees with CMS’ apparent belief that the “voluntary” nature of CED participation negates the potential for coercive influence on the decision to participate in a study. While CMS may be correct within the context of 510(k) cleared devices offered as one of many treatment options, patients unable to access coverage for the only, or a substantially superior, treatment option will feel all but compelled to enroll in a study if one is available to them. Depending on the patient’s condition and available treatment options, their choices could be limited to trial participation or paying out-of-pocket – a luxury that few Medicare beneficiaries can afford.
Haystack Project urges CMS to ensure that each CED study is subject to informed consent requirements that protect beneficiaries as patients, including informing potential participants:

That any FDA-approved treatment is NOT experimental or investigational

Existence of alternative mechanisms available for individuals to obtain access to treatment outside participation in clinical trials of FDA-approved treatments, including commercial availability for patients wishing to pay for the treatment. While this may appear to “favor” individuals with financial means, withholding the information is contrary to meaningful informed consent

Whether research subjects will be able to access treatment outside the clinical trial once their participation has concluded, including any longitudinal studies if the clinical trial results demonstrate improved patient outcomes

Whether research subjects (or their treating providers) will be informed on whether they are in the active treatment or control arm of the clinical trial

Costs, including copayment amounts, that patients will be required to pay within the clinical trial. This must include disclosure on whether subjects randomized to the control arm will be responsible for copayments associated with the FDA-approved therapy in the treatment arm

Disclosure of research subject responsibilities, including any invasive and non-invasive tests and imaging studies, that are associated with data collection rather than connected to treatment monitoring

Procedures available to appeal the CED NCA and/or its applicability to their medical condition

Any mechanisms permitting access for individuals seeking treatment for a medically accepted use but unable to meet inclusion criteria of a particular study or to find a study site within a reasonable distance from their residence

CED is likely to perpetuate and exacerbate health inequities despite implementation of a requirement that “[t]he study population reflects the demographic and clinical diversity among the Medicare beneficiaries who are the intended users of the intervention.”

Haystack Project understands that research sponsors and investigators face challenges in enrolling racially and ethnically diverse populations in clinical trials, and that lack of participant diversity increases uncertainties on the subpopulation-specific benefits and risks of emerging treatments. Systemic racism has impacted Black, Latinx, and other people of color with respect to income potential, reliable access to quality health care, representation in clinical trial populations, prevalence of significant comorbidities, and poor health outcomes. There are no easy solutions to “fix” these economic and healthcare inequities.

Currently, Black patients make up just 5% of clinical trial populations. People of color are more likely to have significant comorbidities that preclude clinical trial enrollment and can face substantial economic challenges associated with transportation to clinical trial sites. Just as importantly, however, people of color have a longstanding and legitimate basis for medical mistrust, particularly with respect to any appearance or perception that participation in research is forced. As we noted in Haystack Project’s comments to AHRQ and MedCAC, any government-initiated paradigm conditioning coverage for safe and effective treatments on participation in randomized, controlled studies is likely to further, rather than reduce, medical mistrust. More importantly, however, it negates the critical element of informed consent that researchers have historically denied to Black patient populations; lack of independent ethical review and central IRBs lend a measure of credibility to perceptions and fears that the government is using health care coverage to experiment on patients.

We are similarly concerned about the impact that CED requirements have on low-income individuals. Patients with adequate financial resources have always been able to access treatments that individuals relying on insurance coverage are unable to afford. Rare disease patients and their families are, however, often forced to decide whether they can afford a non-covered but potentially promising on- or off-label treatment regimen, and too often face the crushing reality that evolving standards of care are financially out of reach. Higher participation in Medicare Advantage plans among people of color will further complicate CED study enrollment.

Finally, we remain concerned that despite our expressed concerns, there has been little, if any, discussion on the implications associated with CED studies that (1) contain burdensome study requirements and are (2) for interventions within the financial reach of some, but not all Medicare beneficiaries. We have repeatedly articulated our concern that some CED requirements, applied to some interventions, could create the appearance of a two-tiered system of access where economically advantaged patients achieve early access to care based on physician/patient decision making. Patients without financial resources, in contrast, would be perceived as serving as research subjects for whom treatment is determined through randomization.

Additional recommendations to protect patients participating in CED studies

Haystack Project urges CMS to adopt additional CED process safeguards and clinical study requirements to protect Medicare beneficiaries participating in CED studies, including:

Requiring that CMS implement a monitoring function over all studies to ensure that randomization of research subjects ceases when likely clinical benefit is shown (through a CMS-initiated CED study or other evidence).

CMS creation of an alternative coverage pathway for Medicare beneficiaries who are unable (due to distance from a study site or enrollment restrictions) to participate in a CMS-approved clinical trial but seek coverage for a medically-accepted use of the intervention.

Ensuring that CED requirements do not disrupt treatment access for Medicare beneficiaries who are receiving (or have received) the intervention (through previous clinical trial participation, coverage by another payer, or other means) and have, according to their treating provider, experienced clinically meaningful benefits. Given that clinical studies generally limit enrollment to treatment-naïve individuals to preserve scientific integrity, patients would have to initiate direct appeals of the NCD to continue their treatment.

Conclusion

Haystack Project appreciates the opportunity to communicate its concerns and recommendations on the Proposed Guidance for Coverage with Evidence Development. Patients with rare conditions rely on the hope that research and development efforts will bring treatment innovations that reduce their disease burden and/or slow its progression. We urge CMS to prioritize beneficiary access and to implement patient protections that meet or exceed those extended to individuals participating in scientific research studies that are outside CMS’ CED mechanism.

Please contact Haystack Project’s policy consultant, Kay Scanlan, at 410-504-2324 with any questions.

Sincerely,

Alpha-1 Foundation
Association for Creatine Deficiencies
Biomarker Collaborative
Casey’s Cure Foundation
Choroideremia Research Foundation
CLL Society
CSNK2A1 Foundation
Cutaneous Lymphoma Foundation
Dup15q Alliance
Exon 20 Group
FACES: The National Craniofacial Association
Galactosemia
GO2 for Lung Cancer
HealthTree Foundation
Histiocytosis Association
International Cancer Advocacy Network
International Fibrodysplasia Ossificans Progressiva (FOP) Association
International Foundation for CDKL5 Research
International Pemphigus Pemphigoid Foundation
MET Crusaders
MLD Foundation
Myasthenia Gravis Foundation of America
NTM Info & Research
Organic Acidemia Association
PD-L1 Amplified
Sturge-Weber Foundation
SYNGAP1 Foundation
TSC Alliance
cureCADASIL
SADS Foundation (Sudden Arrhythmia Death Syndromes)

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The Alzheimer’s Association appreciates the opportunity to comment on the Centers for Medicare & Medicaid Services (CMS) proposed changes to the agency’s guidance on the Coverage with Evidence Development (CED) process (the “Proposed Guidance”). We share CMS’ efforts to expand access to innovative technologies through CED. However, the use of CED in NCDs for FDA-approved drugs and biologicals—as with the National Coverage Determination (NCD) for monoclonal antibodies (mAbs) directed against amyloid for the treatment of Alzheimer's Disease (AD)—can result in meaningful reductions and delays in coverage that can harm Medicare beneficiaries and impede efforts to advance health equity.

We therefore strongly urge CMS to continue its longstanding policy of providing coverage for all FDA-approved drugs and biologicals in order to provide Medicare beneficiaries with equitable and timely access to safe and effective treatments.

Applying CED to Drugs and Biologicals Breaks with CMS Precedent and Reduces Beneficiary Access
Throughout CMS’ use of the CED process, the agency has virtually never applied the procedure to FDA-approved drugs and biologics. Prior to the agency’s decision to apply CED to mAbs to treat AD, CMS had a longstanding precedent of providing coverage for a drug or biologic upon FDA approval—considering that approval a sufficient basis for Medicare coverage. Notably, this coverage standard has applied regardless of regulatory pathway, affording timely access to dozens of drugs and biologicals approved through FDA’s accelerated approval program, which allows for earlier approval of drugs that treat serious conditions and fill an unmet medical need based on a surrogate endpoint.

We appreciate CMS reiterating several important guidelines for the use of CED in line with this precedent in the Proposed Guidance, including the principle that “CED will not duplicate or replace the FDA’s authority in assuring the safety and effectiveness of drugs, biological products, and devices,” and that “CED will generally expand access to medical technologies for beneficiaries because the technologies would not otherwise meet the reasonable and necessary coverage standard.”

However, we are concerned that the Proposed Guidance contemplates broader use of CED as a tool for determining coverage of innovative technologies, which, in the context of drugs and biologicals, would result in narrower and slower coverage than Medicare beneficiaries have enjoyed for such products in the past. In the Proposed Guidance, CMS states that “coverage under CED can expedite earlier beneficiary access to new items and services while ensuring that systematic patient safeguards, including assurance that items and services are provided to clinically appropriate patients, are in place to reduce the risks inherent to new technologies or to new applications of older technologies.”

But, in the context of drugs and biologicals, coverage under CED has already resulted in dramatic restrictions and significant delays in beneficiary access to the two products to which CMS has recently applied CED: two mAbs for the treatment of AD. As CMS states in its general CED principles, the goal of CED is to “generally expand access to medical technologies for beneficiaries because the technologies would not otherwise meet the reasonable and necessary coverage standard.” While we recognize that the reasonable and necessary standard is not generally identical to the FDA’s standards, in the context of drugs and biologics, CMS has historically provided coverage for all FDA-approved drugs and biologics. Therefore, any expanded use of CED in this context will be working to restrict, rather than expand, beneficiary access. In disease areas with significant unmet need, such as AD, our health care system has traditionally deferred to patients and their providers to assess the relative benefits and risks of FDA-approved drugs and biologics.

This is for good reason in the case of diseases with unmet need and especially in the case of degenerative diseases, including but not limited to AD and dementia. Delays in Medicare coverage to FDA-approved drugs and biologicals can have a tangible negative clinical impact on beneficiaries. AD is a devastating progressive condition. For patients who do not receive access to safe and effective FDA-approved drugs or see this access delayed due to CED requirements or decision-making processes, as neurology researchers stated in urging rapid reconsideration of CMS’ CED policy for anti-amyloid mABs, “every day of delay” in access for Medicare beneficiaries “may result in treatable patients progressing beyond the window of therapeutic opportunity.”

Applying CED to Drugs and Biologics May Undermine Health Equity Efforts
In addition to the concerns expressed above about CED impact on beneficiary access to drugs and biologics, we are also concerned that CED restrictions will pose the greatest barriers for underserved populations, including racial and ethnic minorities and rural populations. CMS has rightly made health equity a priority for the agency as a whole and for the treatment of AD in particular, and expanded use of CED for drugs and biologics could undermine these efforts.

As we noted in our request for reconsideration of the NCD for monoclonal antibodies for the treatment of AD, the limitations on access imposed by CED requirements represent particular barriers for historically underserved and disproportionately affected populations (e.g., Black/African Americans, Hispanic/Latinos). Any new burdens on access for Medicare beneficiaries, including those that inevitably come with CED provisions, first exclude those with the greatest difficulty accessing the health care system. This burden is likely to fall the heaviest on rural and disproportionately underserved racial and ethnic populations and is essentially, denial of coverage and threat to health equity for those populations in greatest need.

Finally, it is important to note that the use of CED may actually undercut the general principle of medical research that research participation ought to be voluntary for the patient, because CED conditions access to a treatment on participation in research. We have been pleased to see that both FDA and Congress have taken steps to promote the participation of diverse populations within clinical trials, and we encourage CMS and HHS more broadly to continue considering creative policy options that can promote this goal and advance health equity.

As discussed above, the application of CED to FDA-approved drugs and biologicals can restrict beneficiary access to safe and effective treatments and undermine efforts to promote health equity. We strongly encourage CMS to continue its historical precedent of refraining from use of CED for drugs and biologicals, and instead provide coverage for all FDA-approved drugs and biologicals in order to provide Medicare beneficiaries with equitable and timely access to safe and effective treatments.

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The Academy of Managed Care Pharmacy (AMCP) thanks the Centers for Medicare & Medicaid Services (CMS) for the opportunity to provide comments in response to the proposed guidance titled “Coverage with Evidence Development” (Proposed Guidance) issued on June 22, 2023.

AMCP is the nation’s leading professional association dedicated to increasing patient access to affordable medicines, improving health outcomes, and ensuring the wise use of healthcare dollars. Through evidence and value-based strategies and practices, AMCP’s nearly 8,000 pharmacists, physicians, nurses, and other practitioners manage medication therapies for the 270 million Americans served by health plans, pharmacy benefit management firms, emerging care models, and government health programs.

AMCP supports providing patients with timely access to valuable and potentially lifesaving treatments. The use of the Coverage with Evidence Development (CED) pathway encourages evidence development, permits coverage of innovative drugs for people with Medicare who are participating in controlled trials. This pathway provides Medicare beneficiaries with vital access to promising treatments that would not otherwise be covered.

Clinical Study Standards for CED – Study Population

The Proposed Guidance includes the following clinical study standard: "The study population reflects the demographic and clinical diversity among the Medicare beneficiaries who are the intended population of the intervention. At a minimum, this includes attention to the intended population’s racial and ethnic backgrounds, gender, age, disabilities, important comorbidities, and dependent on data availability, relevant social determinants of health." (Proposed Guidance at p. 8).

AMCP is committed to addressing health disparities in medication use and access (see, e.g., AMCP’s strategic priorities at https://www.amcp.org/about/about-amcp/amcp-strategic-priorities). Clinical trials need to include people from diverse backgrounds given that people of different ages, races, and ethnicities may have different outcomes from medical treatment (see, e.g., https://www.fda.gov/consumers/minority-health-and-health-equity/clinical-trial-diversity). Without greater diversity in these trials, valuable evidence about potentially divergent outcomes is not being captured. Despite the growing awareness of the need for inclusivity in clinical trials, people from racial and ethnic minority and other diverse groups remain underrepresented in clinical research (https://www.fda.gov/media/168662/download?attachment).

While AMCP applauds CMS for addressing diversity in clinical trials, AMCP urges CMS to consider more stringent standards for health equity in CED clinical trials. CED clinical trials should take more concrete action to address the root causes of the lack of diversity, such as robust data collection, careful consideration of the potential biases inherent in the selected inclusion or exclusion criteria for the trial, countering mistrust in clinical trials due to historical atrocities, or considering how best to assist participants struggling with economic barriers to participation such as lack of transportation (See, e.g., https://www.nimhd.nih.gov/resources/understanding-health-disparities/diversity-and-inclusion-in-clinical-trials.html#:~:text=Historically%2C%20clinical%20trials%20did%20not,on%20White%20male%20study%20participants). AMCP believes that requiring concrete action would increase the likelihood of ensuring that the study population reflects the diversity of Medicare beneficiaries.

Conclusion

AMCP appreciates your consideration of the concerns outlined above and looks forward to continuing work on these issues with CMS. If you have any questions regarding AMCP's comments or would like further information, please contact AMCP’s Director of Regulatory Affairs, Geni Tunstall, at etunstall@amcp.org or (703) 705-9358.

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August 21, 2023

Coverage with Evidence Development Proposed Guidance Document, June 22,2023
Coverage and Analysis Group, Centers for Medicare & Medicaid Services (CMS), Health and Human Services (HHS)
Mailstop: S3-02-01, 7500 Security Blvd.
Baltimore, MD 21244
Re: College of American Pathologists comments

As the world's largest organization of board-certified pathologists and leading provider of laboratory accreditation and proficiency testing programs, the College of American Pathologists (CAP) serves patients, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide.

The CAP has been active in working to improve both local and national coverage processes to ensure equal access to quality care for Medicare beneficiaries. Part of this work includes ensuring appropriate conditional coverage through an effective coverage with evidence development (CED) process. As the Centers for Medicare & Medicaid Services (CMS) notes in their updated guidance document, CED has been used to support evidence development for certain items and services that are likely to show benefit for the Medicare population. The CAP has previously urged CMS to improve the current process by using establishing specific and transparent timelines and endpoints, and generally increasing transparency, flexibility, and stakeholder input to incentivize innovation and afford timely access to services for patients.

The CAP supports CMS’ proposed guidance on the factors it considers in making NCDs using the CED paradigm. Specifically, we agree with the additional details around milestones and study population, and we support any efforts that increase transparency and stakeholder input. Although the proposed guidance does not substantively alter the process for national coverage using the CED paradigm, it does reflect CMS’ commitment to ensuring access to promising treatments for Medicare beneficiaries by providing a framework for more predictable and transparent evidence development, ensuring populations studied represent the diversity in the Medicare beneficiary population, and providing for the timely completion of the CED process. However, while not discussed in this guidance document, the CAP also maintains that CED must be selectively utilized and intended only to provide for evidence-based coverage that will accelerate and expand access to services and items for patients, rather than restrict their use by physicians and other providers.

Transparency
As CMS notes, CED occurs within the existing national coverage determination (NCD) process which is transparent and open to public comment. We agree with CMS that the CED process should be conducted transparently to facilitate effective information exchange and afford the opportunity for relevant stakeholder input and engagement, including patient groups, professional societies, regulators, and others. The CAP also agrees with CMS’ proposal to publish its findings of data from clinical studies regardless of whether a study is completed or generates favorable evidence, as a way to inform patients and providers about the benefits and risks of available health care options and to further promote transparency. Additionally, as a way of increasing transparency and availability of study results, we support any added flexibility around the publishing of results outside of peer-reviewed publications when peer-reviewed publication is not possible, while ensuring appropriate standards and safeguards. Finally, the proposed guidance specifies that the CED study be registered with ClinicalTrials.gov, which CMS hopes will help ensure that Medicare beneficiaries and their treating health care professionals have pertinent information about CED studies. And the guidance also specifies that the study be conducted by sponsors/investigators with the resources to complete it successfully. However, we remain concerned about the lack of transparency around the funding and maintenance of data collection and the CAP urges CMS to also make this information available to the public.

Study population
As is noted in the guidance document, CED has been a pathway whereby Medicare covers items and services on the condition that they are furnished in the context of approved clinical studies or with the collection of additional clinical data. For these studies and data to be relevant, it is imperative that CMS improve the criteria around study population. The CAP believes addressing barriers to entry for underrepresented diverse populations in clinical trials will improve clinical research, patient safety, and ensure high-quality care in disease diagnosis and management. We applaud CMS for recognizing the importance of a study population that reflects the demographic and clinical diversity among the Medicare beneficiaries who are the intended users of the intervention and for requiring a plan for the retention and reporting of the populations in a clinical trial. A carefully and accurately defined study population will enhance the completed study’s relevancy and help assure the overall validity of the study results.

Timeline for completing the CED process
The CAP agrees with CMS that an NCD that requires CED as a condition of coverage should not last indefinitely, and in fact, we continue to believe that for any technology or service provided coverage through CED, an endpoint should be established for when the process is complete. We are hopeful that the inclusion of a written plan that describes the schedule for completion of key study milestones, including results reporting, will help ensure timely completion of the CED process. However, any further standards that improve the predictability of the CED process through set start and end dates and/or a specific and transparent timeline and endpoint would address additional issues.

Additionally, during the premarket stage of the Transitional Coverage for Emerging Technologies (TCET) pathway, a study approved by CMS as part of an Evidence Development Plan (EDP) must have established start and end dates. However, for studies transitioning to post TCET coverage that require additional CED to generate sufficient evidence to support a national coverage determination, the proposed CED guidance does not define “sufficient evidence” or specify a time limitation or outcome criterion for generating such evidence. The CAP recommends CMS define “sufficient evidence” to meet the threshold for national coverage and specify a time limitation or outcome criterion to meet that threshold.

Transition to Medicare coverage determination
The proposed CED guidance suggests that when transitioning from a CED NCD to coverage without evidence development requirements, sponsors should build interim analyses into their study design and communicate these results to CMS. Although this may increase the burdens on the trial sponsor, the CAP believes that interim analyses have the potential to modify the conduct of a study by allowing for decisions and changes to be made in the population sample or study protocol during the evidence gathering stage, thus potentially saving time in operations and coverage decision-making processes. As we outlined in our comments in response to the TCET proposed procedural notice, the CAP supports expedited coverage that ensures Medicare beneficiaries have more timely and predictable access to new and innovative medical technologies.

Thank you for your willingness to consider our comments on the general requirements for clinical studies submitted for CMS coverage requiring CED. The CAP welcomes the opportunity to provide CMS with additional clinical or other information to assist CMS with its coverage policy decisions and we look forward to continuing our work to improve access to care for all patients. Please direct questions to Nonda Wilson at nwilson@cap.org or (202) 354-7116.

Sincerely,

College of American Pathologists

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The National Center for Health Research (NCHR) appreciated the opportunity to express our views regarding the Centers for Medicare and Medicaid Services (CMS) Coverage with Evidence Development Proposed Guidance Document.

NCHR is a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, with a particular focus on which prevention strategies and treatments are most effective for which patients and consumers. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.

We appreciate the changes that were made to the guidance document in response to the February 13-14 Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) public meeting, which was convened to examine the general requirements for clinical studies submitted for CMS coverage under CED. We support the refinements to the proposed new criteria regarding the need for proper control groups and blinding in CED studies. However, we have minor suggestions that would strengthen these changes.

The updated CED guidance discusses the importance of blinding but also discusses exceptions for “cases where blinding is not possible or not used.” This should be amended to eliminate “or not used.” Blinding should be required in CED clinical studies, with exceptions only when it is not possible to do so.

The guidance also states that: “In some cases, an identified evidence deficiency may only be addressed through use of a randomized controlled clinical trial (RCT). In other cases, observational studies that employ advanced designs and analytic methods may be sufficient.” We urge this to be amended to recommend the use of RCTs unless it is not possible to do so. Even in the case that an observation study may be “sufficient”, if a RCT is achievable, it should be the chosen study design.

We also wish to emphasize testimony made by NCHR’s president, Dr. Diana Zuckerman, at the February MEDCAC public meeting. We urge you to incorporate her recommendations into the Clinical Study Standards for CED under Section 1862(a)(1)(E) in the final version of the CED guidance.

1. Health Outcome

We strongly agree that the primary outcomes for a study must be clinically meaningful and important to patients and their caregivers. We also agree that only “a validated surrogate outcome that reliably predicts these outcomes may be appropriate for some questions.” However, the interpretation of the definition of “reliably predicts” varies considerably. For example, we agree with the many experts who point out that the amount of amyloid beta plaque on the brain does not reliably predict cognitive impairment; however, some people argue that the biomarker is reliable enough. Surrogate outcomes should only replace clinically meaningful outcomes when the predictive value of the surrogate endpoint is consistent and conclusive.

2. Care Setting

The recommendation that beneficiaries should be studied “in their usual sites of care” is very important. But it is weakened with the words: “When feasible and appropriate for answering the CED question, data for the study should come from beneficiaries in their usual sites of care…” It is always appropriate and it is essential that it be feasible, so we urge CMS to strengthen that wording.

3. Context

This proposed guidance states that study results are expected to provide "evidence sufficient to assess health outcomes." However, there is no mention of the need for a net benefit, which was included in the standard discussed during the February 2023 MEDCAC meeting. “Evidence sufficient to assess health outcomes” does not specify that the evidence must indicate meaningful benefits, and even if it did specify meaningful benefits, that would not be sufficient because what is essential is that the benefits outweigh the risks. This should be clearly stated. We are also concerned about the deletion of the need to "establish an evidentiary threshold for the primary outcome(s) so as to demonstrate clinically meaningful differences with sufficient precision," as was included in the February MEDCAC meeting. We strongly urge that these prior requirements be restored because they are essential to ensure the safety of Medicare beneficiaries.

In summary, we agree that blinding is not always possible (for example, if the most appropriate control group does not require surgery or an injection) but when it is possible, it should be required. Too often, wording that is intended to provide reasonable flexibility instead creates huge loopholes that are harmful to Medicare beneficiaries and to the Medicare program as a whole. Similarly, there are surrogate endpoints that reliably predict meaningful clinical outcomes that are important to patients, but many do not; moreover, some reliably predict outcomes only for a subgroup of patients that might not be generalizable to all Medicare beneficiaries. In addition, when evaluating a clinical study for CED, having statistically significant results is necessary but not sufficient. Studying patients who are diverse in terms of race, ethnicity, gender and age is necessary but not sufficient. The data generated must be relevant to Medicare beneficiaries and must be valid and reliable, so that the results are proven to be clinically meaningful.

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