CMS National Coverage Analysis Evidence Review (PROPOSED)

August 21, 2021

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

Re: Proposed Evidence Preview 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. We are committed to the continual research and development necessary to produce high-quality products and to support innovative therapies that improve health outcomes for patients.

Medtronic appreciates CMS’s publication of the proposed guidance on National Coverage Analysis Evidence Review and its expressed goal of improving predictability and transparency of evidence assessment approaches when evaluating new items and services for national coverage. The proposed guidance reflects a pragmatic approach to evidence assessment that leverages existing frameworks, methodological principles, and best practices, while acknowledging the need for flexibility and inclusion of emerging methods. This is particularly important as advances in observational study designs, data sources, and statistical methods to mitigate risk of bias and improve causal inference are emerging faster than evidence assessment frameworks have adapted.

Medtronic’s specific comments on the proposed guidance are in the spirit of acknowledging and including the breadth of data and methods available to consider when conducting evidence reviews.

Methodological Principles. It is important to recognize that while high quality comparative studies allow for the assessment of relative outcome differences, there may be particular circumstances where single arm trials, registries, or other non-comparative studies provide sufficient evidence for determining whether an item or service is reasonable and necessary.

Review of Individual Studies. Medtronic supports incorporation of both a systematic review of findings reported in peer-reviewed literature and findings from other publicly reported results into the evidence assessment. However, Medtronic believes it is important to also consider results from studies under review during the evidence assessment. The peer-review process is lengthy and unpredictable, which could arbitrarily exclude important results that could inform CMS on the outcomes and generalizability of a particular item or service. Additionally, Medtronic believes CMS should also consider results that have been shared with CMS as part of CED study milestones. It is also worth noting that while it is important to ensure appropriate disclosures in funding and potential conflicts of interest, industry sponsored and/or conducted studies should not be assumed to be lower quality if there is reasonable assurances that there is transparency in study design and faithful study execution.

Risk of bias. Medtronic appreciates CMS’s thoughtful consideration of the risk of bias. Medtronic thinks the risk of bias section could benefit from further distinguishing between study types – interventional (e.g., RCTs) and observational (e.g., registries, secondary data studies) – and their associated methodological approaches to reducing the risk of bias. Currently, there is no mention of methodological approaches to addressing unobservable characteristics/confounding which may be appropriate for causal inference in observational nonrandomized studies (e.g., instrumental variables, regression discontinuity design, etc.). For example, matching and balancing only addresses observed characteristics/confounders in non-randomized studies. It is important to acknowledge the assumptions involved in estimating treatment effects and incorporate sensitivity analyses to evaluate potential impacts of unobservable characteristics/confounders.

Precision of Estimates. Medtronic agrees the precision of estimates should be considered when assessing the evidence. However, in comparative studies – particularly nonrandomized studies using real-world data - power analyses may not be appropriate given the variety of circumstances, data sources, and study designs. Medtronic recommends CMS defers to the best practices, many of which are still emerging, when evaluating the precision of treatment effect estimates.

Strength of Evidence Assessment. Medtronic acknowledges that CMS-approved CED studies may be more persuasive than other observational studies given the level of transparency and engagement during the study design process. Medtronic believes that other observational studies that are conducted using real-world evidence transparency best practices and frameworks should be considered to meet high standards of credibility.(1,2)

In addition, in reviewing the evidence base, Medtronic acknowledges that grading evidence according to the most important outcomes using the GRADE approach should be considered when robust pooled estimates are available. However, given the nature of medical technology development is often through rapid iterative innovation, formal evidence synthesis may not be feasible as studies report, measure or include disparate outcomes. Alternative methods for grading the certainty of evidence through structured narrative review and appraisal should be also considered by CMS.(3)

Thank you for the opportunity to comment on the CMS National Coverage Analysis Evidence Review 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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1. Jaska A, Wu J, Jonsson P, et al. Organized structure of real-world evidence best practices: moving from fragmented recommendations to comprehensive guidance. Journal of Comparative Effectiveness Research 2021; 10(9): 711-731
2. Wang S, Pinheiro S, Hua W. STaRT-RWE: structured template for planning and reporting on the implementation of real world evidence studies. British Medical Journal 2021; 372:m4856
3. Murad MH, Mustafa R, Shunemann H, et al. Rating the certainty in evidence in the absence of a single estimate of effect. Evidence Based Medicine 2017; 22(3): 85-87.

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Trial Design Issues
V-Wave recommends that CMS add a specific discussion of how CMS will consider — and whether or not it agrees to — RCTs with hierarchical composite endpoints that use statistical methodology like Finkel-Schoenfeld along with patient reported outcomes or surrogate or symptomatic endpoints. Such trial designs are very common and looked on favorably by the FDA. In addition, FDA looks favorably on the use of Bayesian Analysis and other alternative ways of analyzing data.
We also ask that CMS specifically discuss its view on use of claims data in TCET clinical trials – used as a control group, as an adjunct to other data collection, or as a sole means of data collection.

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

August 21, 2023

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

Re: National Coverage Analysis Evidence Review; 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’) National Coverage Analysis (NCA) Evidence Review proposed guidance document. 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 manufacturers, providers, and patients.

Below we offer comments on the proposed NCA Evidence Review Guidance and its potential use as a framework for more predictable and transparent evidence development, as stated by CMS in the preamble.

At the outset, J&J commends CMS for issuing draft guidance on this important topic and soliciting public input. As CMS states in the proposed guidance, the Agency is tasked with evaluating relevant clinical evidence to reach a determination as to whether an item or service is reasonable and necessary for Medicare beneficiaries under section 1862(a)(1)(A) of the Social Security Act. CMS describes its objective as determining whether the Agency is confident that the clinical questions being asked can be answered conclusively to support Medicare coverage.

To this end, CMS assesses the quality of the clinical studies, what conclusions can be drawn from the body of evidence (including an assessment of benefits and potential harms), and the generalizability of findings from relevant studies to the Medicare population.

The draft guidance document outlines a set of methodological principles and, notably, asserts that each National Coverage Determination (NCD) has its own unique methodological aspects. J&J agrees and generally supports a broad framework based on principles, rather than specific evidentiary criteria that may not fit every national coverage assessment.

CMS Should Not Discount Company-Led Research as a Conflict of Interest
CMS notes on page 4 that it “carefully considers the funding source and potential conflicts of interest for study investigators.” While J&J agrees that methodological rigor is instrumental and thorough assessment of individual studies that generate evidence for Medicare coverage is critical, CMS should use caution to not dismiss company-funded research as presenting a conflict of interest but should review whether steps were taken to manage any potential conflicts, such as fully disclosing potential conflicts to research participants or using informed consent in carrying out clinical research. Medical device and pharmaceutical companies employ clinicians, technical experts, experts in clinical trial design and others to ensure study results are unbiased and are in the best interest of the patients being studied.

CMS Should Further Clarify its Interpretation of “Fit-for-Purpose” Study Design
In the proposed guidance document, CMS endorses the concept that studies should be fit-for-purpose (FFP) and generally defines a FFP study as being “sufficient to credibly answer the question(s) it intends to answer.” We understand that CMS may be considering issuing additional guidance in the future on FFP studies, and we look forward to gaining additional clarity on this topic and having the opportunity to provide more detailed comments. J&J believes studies should be sufficient to answer the intended clinical questions being asked and should require the collection of the minimum data necessary to answer those questions.

CMS Should Consider the Totality of the Evidence in its Evaluation and Review for National Coverage Decision Making
CMS states it will evaluate the body of evidence in its national coverage decision making, by applying several criteria for assessing risk of bias, consistency of findings, applicability or generalizability to the Medicare population and other factors. Overall, J&J is supportive directionally of these statements, but we are interested in how CMS will use this guidance in actual practice. Given the wide range of medical technologies and treatments, and their intended uses, we urge CMS to consider the practical challenges associated with generating and reviewing evidence, to consider all levels of valid scientific evidence and maintain flexibility in the interpretation and application of these standards.

Johnson & Johnson appreciates the opportunity to submit comments in response to the CMS’ NCA Evidence Review proposed 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
Senior Director, Payment & Care Delivery, Health Policy
Johnson & Johnson Worldwide Government Affairs & Policy

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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) National Coverage Analysis (NCA) Evidence Review Proposed Guidance Document (Proposed NCA 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” as part of the Medicare national coverage determination (NCD) process. We would like to offer our comments on the following aspects of the Proposed NCA Guidance:

We believe there are opportunities for CMS to provide additional clarity regarding the NCD 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 NCD 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 Coverage with Evidence Development (CED) requirement, and (3) the NCD process under the proposed “Transitional Coverage for Emerging Technologies” (TCET) pathway.

We share CMS’s view that the “fit-for-purpose” concept is useful for considering the type of study design that is sufficient to address questions related to evidence supporting Medicare coverage.

Regarding the “Strength of Evidence Assessment,” we agree that CMS should generally emphasize health outcomes important to patients and their caregivers.

Our specific recommendations follow.

I. NCD Timeline and Process

According to CMS, the Proposed NCA Guidance is intended to “provide a framework for more predictable and transparent evidence development” in order to “encourage innovation and accelerate beneficiary access to new items and services.” We appreciate CMS providing additional information regarding CMS standards for conducting NCAs to assess whether evidence is sufficient to support a finding that an item or service meets the Medicare “reasonable and necessary” coverage standard as part of the NCD development process.

We believe that gaps remain, however, in transparency regarding key procedural steps and timelines for CMS development of NCDs. The lack of guidance on NCD timelines 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; formal acceptance can take many months or even exceed a year. There is a lack of visibility into opportunities for requestor consultation with CMS or its third-party reviewers regarding clinical evidence throughout the NCD process. After an NCD 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, we recommend that CMS expedite the release of draft process guidelines, subject to public comment, providing additional clarity throughout the entire NCD 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:

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 NCA 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 process at which specific CED study requests will be considered.

Opportunities for the requestor to provide input, including during the evidence review process and development of any CED 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. Review of Individual Studies/Fit-For-Purpose Concept

In the Proposed NCA Guidance, CMS states that it “endorses the concept that studies should be fit-for-purpose (FFP).” CMS describes the FFP concept as meaning that “the study design, analysis plan, and data source(s) should be sufficient to credibly answer the question(s) it intends to answer.”

We 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 in an NCA. We likewise agree with CMS’s observation that CED observational studies also may “meet high standards of credibility through a review of study proposals with AHRQ and CMS before study execution, complete transparency, faithful execution, and clear public reporting.”

III. Strength of Evidence Assessment

The Proposed NCA Guidance notes that in developing making NCDs, “CMS considers the totality of the evidence across multiple dimensions, including study design and conduct.” CMS focuses on benefits that generally are “clinically meaningful and durable rather than marginal or short-lived.” CMS states that it “generally places greater emphasis on health outcomes important to patients and their caregivers, such as quality of life, functional status, duration of disability, morbidity, and mortality,” while placing “less emphasis on outcomes in which patients often have a less direct interest, such as intermediate outcomes, surrogate outcomes, and laboratory or radiographic responses.”

We agree with CMS’s prioritization of evidence that addresses meaningful health outcomes, particularly those impacting morbidity and mortality. We also believe CMS evidence review should be tailored to assess whether the available evidence related to a technology demonstrates that the statutory reasonable and necessary standard is met.

* * * * *

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

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

Re: CMS National Coverage Analysis Evidence Review – Proposed Guidance Document

Dear Acting Director Chin,

Edwards Lifesciences (“Edwards”) appreciates the opportunity to comment on the proposed National Coverage Analysis Evidence Review guidance released by the Centers for Medicare & Medicaid Services (“CMS”) on June 22, 2023.

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 to ensure 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 believes in and invests in the evidence generation process, and we commend CMS’s commitment to robust evidentiary review to ensure technologies benefiting Medicare patients are covered on the basis of scientifically sound clinical evidence. The proposed Evidence Review guidance document provides greater transparency into CMS’s expectations for evidence development and its framework for review. Edwards offers feedback on the Methodological Principles and Review of Individual Studies sections of the proposed guidance.

METHODOLOGICAL PRINCIPLES
Edwards appreciates CMS’s proposed methodological framework and its acknowledgement of the unique methodological aspects of each NCD. However, at the end of this section CMS states it, “carefully considers the funding source and potential conflicts of interest for study investigators.” Edwards agrees that thorough evaluation of individual studies generating evidence for Medicare coverage is critical to assess 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.

REVIEW OF INDIVIDUAL STUDIES
Edwards is encouraged by CMS’s openness to incorporating robust fit-for-purpose (FFP) evidence development. Edwards commends CMS for its acknowledgment of the benefits of FFP study designs and its willingness to consider FFP studies given that these studies have, as CMS states in the TCET notice, the “potential to generate evidence that complements tightly controlled premarket traditional clinical trials by demonstrating external validity.” As such, we look forward to the Agency’s forthcoming guidance on FFP.

Additionally, Edwards recommends that CMS acknowledge other elements of observational data when reviewing evidence for medical devices. Page five of the proposed guidance states, “In general, but not absolutely, the hierarchy of evidence dictates that randomized controlled trials (RCTs) represent the most credible evidence because they are the least subject to biased estimates of outcomes; even so, observational studies can be more representative of actual clinical practice and may answer questions that RCTs cannot answer.”

The proposed guidance document acknowledges that, while it is important to consider the quality and hierarchy of evidence, there is value in observational data to reflect outcomes in clinical practice. In the case of medical devices, observational studies may also add unique value by capturing the impact of device iteration and operator learning curve on outcomes. Observational studies may also provide evidence for outcomes in patient populations not included in or well represented by RCTs. For example, the FDA approved SAPIEN 3 for valve-in-valve procedures for aortic and mitral valve patients who were too sick for surgery based on data from the TVT Registry, and not an RCT. These other elements of observational data are critical to consider when reviewing evidence for medical devices.

Further, this section leaves questions around what evidence is required and which data is captured during the review. More specifically, Edwards seeks clarity on whether CMS will accept unpublished evidence or prepublication manuscripts during the systematic review of findings.

* * * * *

Edwards appreciates this opportunity to provide our comments and feedback on the proposed policy changes and clarifications in the proposed Evidence Review guidance document. Edwards thanks you for your consideration of this submission in support of beneficiary safety and access to clinically appropriate treatments and services. If you have any questions or would like additional information, please contact me at 949-240-0764 or mary_coppage@edwards.com.

Sincerely,

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

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August 21, 2023

The Honorable Chiquita Brooks-LaSure
Administrator
Centers for Medicare and Medicaid Services
U.S. Department of Health and Human Services
200 Independence Avenue, SW
Washington, DC 20201

Re: National Coverage Analysis Evidence Review Proposed Guidance

Dear Administrator Brooks-LaSure:

On behalf of the patients, family caregivers, and providers our organizations represent, we appreciate the opportunity to offer comments to the Centers for Medicare & Medicaid Services (CMS) regarding its “National Coverage Analysis Evidence Review” proposed guidance released June 22, 2023. The scope of this guidance is limited to CMS’ approach to National Coverage Analysis (NCA) evidence review, which is an important topic that we comment on below. However, our organizations strongly urge the agency to amend this guidance by adding process-related updates, including an explanation of how FDA-approved items and services will (or will not) be covered during the NCA process. Overall, the NCA/National Coverage Determination (NCD) process is opaque and challenging for beneficiaries and the general public to engage in. Additionally, Medicare beneficiary coverage and access to FDA-approved items and services during the NCA/NCD process is either unavailable or unclear. Our organizations provide several recommendations throughout our comments below for CMS to consider adding to this guidance in order to provide transparency and clarity to its NCA/NCD process.

Statement of Interest

Organizations listed here may present their own responses to CMS and will actively advocate for those positions. These comments are not intended to impact adversely the ability of individual organizations, alone or in combination, to pursue separate comments with respect to the proposed guidance on National Coverage Analysis Evidence Review.

NCDs and NCAs Should be Listed in the Federal Register

While the vast majority of Medicare coverage is provided on a local level, in certain cases, CMS decides to develop a National Coverage Determination (NCD) for an item or service to be applied on a national basis for all Medicare beneficiaries. CMS has a formal process for requesting an NCD, which is outlined on both the CMS website and in the Federal Register. The Federal Register (FR) provides a means for the government to announce to the public changes to government requirements, policies, and guidance.

Unfortunately, CMS does not post notice in the FR when the agency starts a new NCD process or reconsiders an existing NCD. Instead, the Agency posts a tracking sheet on its website and issues a National Coverage Analysis (NCA)—for which the public comment 30-day period starts the same day. Advocacy organizations and other external parties must either be aware that an NCD process is imminent and know how to navigate the CMS website (which is not consumer-friendly), or they must subscribe to the correct CMS email alerts. If not, they miss the opportunity to comment. This current process does not encourage equitable participation by stakeholders, but rather limits engagement to “those in the know.” Therefore, our organizations urge CMS to commit in this guidance to public notice and comment of all future national coverage analyses (NCAs) in the Federal Register, similar to the U.S. Food and Drug Administration. We also ask that CMS establish longer comment periods of at least 45 days to permit a larger group of stakeholders sufficient time to comment during the NCA process.

CMS Should Explain the Reasoning Behind its Evidence Review and Evidence Questions in Each NCA

There is currently no transparency about the rationale for how each NCA process is assessed. In the “Methodological Principles” section of this guidance notes that “The methodological principles described below represent a broad framework of the issues we consider when reviewing clinical evidence. However, it should be noted that each NCD has its unique methodological aspects.” The NCA serves as the agency’s justification for establishment of national Medicare coverage policy—which can include an NCD, an NCD requiring coverage with evidence development (CED), or non-coverage—that has significant implications for beneficiary access.

Additionally, it is difficult to comment on NCA methodological principles, study review, and strength of evidence when CMS' ultimate evidence targets for what constitutes “reasonable and necessary” are unclear. The list of vague, general methodological principles and evidence criteria in the NCA draft guidance affords CMS the ability to arbitrarily establish differing standards of evidence from medical development research, and then pose broad evidence questions based on those inconsistent standards, that also have no defined parameters for the answers. The proposed NCA guidance is missing important guidelines on what level of evidence is expected by the agency, including the level expected by type of coverage (i.e. NCD, NCD with conditions, CED, non-coverage) under the NCD program. Standards without clear definition are not sufficient nor transparent, and open up the agency to criticisms of potential bias or improper consideration of cost in deciding which items and services are subject to a NCA and coverage restrictions through the NCD process.

For example, in the proposed guidance CMS notes that in most situations randomized clinical trials (RCTs) represent the most credible source of evidence due to being least subject to a bias of outcomes. At the same time, CMS notes that in some cases observational studies can provide more accurate reflections of clinical practice and answer questions that a RCT is unable to answer. The agency also notes that “Coverage with Evidence Development (CED) observational studies may also meet high standards of credibility through a review of study proposals with AHRQ and CMS before study execution, complete transparency, faithful execution, and clear public reporting.” It is unclear which standard is preferred. If CMS’ answer is conditional, it is paramount to understand on what criteria those conditions are based upon. The current draft guidance provides no insight into how CMS specifically evaluates the evidence, which dilutes the usefulness of mentioning the criteria.

Further, CMS offers no clarity in the draft NCA guidance regarding evidence thresholds for CMS determining how it chooses an NCD versus an NCD requiring CED. Instead, the guidance generally states:
“In making NCDs, CMS considers the totality of the evidence across multiple dimensions, including study design and conduct. The evidence for some outcomes, populations, or clinical settings may be of higher quality than evidence for others. Additionally, when CMS reviews evidence for NCD reconsiderations, CMS-approved CED studies may generally be more persuasive than other observational studies because the study design, analysis plan, and data sources will generally be prespecified and posted on clinicaltrials.gov.”

Understanding CMS’ perspective on what types and quality of evidence differentiate an NCA evidence review that result in an NCD from one that results in an NCD requiring CED is critically important, since NCDs requiring CED impose further clinical study as a condition of coverage. While CMS maintains that CED study participation is “voluntary,” non-coverage is the only option for beneficiaries outside of study participation. It is also important to note that beneficiary preference is not the only factor that limits study participation, as eligibility criteria and often extensive data reporting requirements limit access to providers providing the item or service.

Beneficiaries may be subject to a CED requiring an RCT, as happened with CMS’ recent NCD on monoclonal antibody therapies targeting amyloid for early Alzheimer’s approved through the FDA’s Accelerated Approval Program. For the vast majority of highly innovative and novel drugs and devices approved by FDA, the premarket FDA clinical investigations have demonstrated superiority to a comparator. Post-market RCTs could present ethical issues because RCT study design in CED may require some Medicare beneficiaries to receive a placebo for a device, diagnostic, or prescription drug found to be “safe and effective” by the FDA. Further, beneficiaries may be required to pay coinsurance for a placebo in order to maintain a blinded study.

CMS also notes that RCTs (and presumably, the FDA approval that is based on the studies) may not be generalizable to Medicare due to insufficient enrollment of subpopulations, including by age, sex, race/ethnicity, the severity of disease, presence of co-morbidities, and disability status. We agree, but CMS does not provide a definition for what would be considered “representative” in clinical trial data, such as a percentage of trial participants equivalent to the percentage of Medicare beneficiaries living with the disease under study.

In terms of health equity, the restrictive eligibility criteria CMS has used in applying CED has historically produced counterproductive effects that disproportionately limit coverage to the very populations underrepresented in clinical trials. CED in particular has a tortured track record in advancing equity, as participating eligible hospitals are principally found in large, urban areas and connected to academic research centers. Rural and private clinics, along with smaller hospitals, are effectively shut out from participating in the CED trials. This has significant implications for underserved populations, who more often receive healthcare services from essential providers. In some cases, the criteria have resulted in beneficiaries in entire regions of the country not having access to the therapeutic covered under CED. As a result, many of CMS’s CED trials have included deeply unrepresentative patient populations, which has, in some cases provided continued justification of coverage restrictions.

CMS also offers no insight into how the agency develops its NCA evidence questions, which are sometimes carried into NCDs requiring CED. The NCA questions often refer to “sufficient” (i.e., is the evidence sufficient?), but do not describe the threshold of evidence that is meant by “sufficient.” This puts beneficiaries, providers, and sponsors in suspended states of unpredictability for coverage and access. The burden of rationale for the NCA questions is on CMS and should be explained by the agency in each NCA.

As a final point, CMS’ nod to evidence of outcomes important to patients and caregivers is incomplete and, in some cases, counter to what Medicare beneficiaries believe to be important. For example, for many patients and families facing life-threatening diseases where no treatment options currently exist, or where patients have run out of treatment options, recognition of surrogate endpoints reasonably likely to predict clinical benefit are both meaningful and vital. CMS’ dismissive stance toward surrogate endpoints, and the FDA’s Congressionally authorized Accelerated Approval Pathway, is deeply concerning for the patient advocacy community as well as federal lawmakers who authorized the program. In juxtaposition, CMS’s use of CED under NCD is often interpreted as having questionable grounding in the NCD statute.

It is for the reasons described above that our organizations urge CMS to require a clear explanation of the reasoning behind how the agency (uniquely) assesses the strength and rigor of evidence in each NCA, including how NCA evidence questions are derived and what type and amount of evidence will be sufficient to answer them. The NCA guidance should include a section on how the agency will accomplish this end.

CMS Should Provide Coverage Guidance in Each NCA

Medicare beneficiaries and clinicians should not have to wait months for coverage and access to FDA-approved products. The current NCA process lasts 9-12 months, and implementation can take months to years after that—patients are often left waiting without coverage in the interim. CMS currently provides no guidance in its NCA’s on the status of Medicare coverage (including non-coverage), either nationally or to its Medicare Administrative Contractors (MACs), and this needs to change. Our organizations urge CMS to clearly state coverage guidance in each NCA and not leave Medicare providers and beneficiaries hanging.

Conclusion

Thank you for considering our views. If you have questions, please contact Sue Peschin, President and CEO of the Alliance for Aging Research, at speschin@agingresearch.org or the Alliance's Vice President of Public Policy and Government Relations, Michael Ward, at mward@agingresearch.org.

Sincerely,

Alliance for Aging Research
Alliance for Health Innovation
Alzheimer's Los Angeles
Alzheimer's New Jersey
Alzheimer's San Diego
Arthritis Foundation
Association of Black Cardiologists
Asthma and Allergy Foundation of America
Caregiver Action Network
Chronic Care Policy Alliance
EveryLife Foundation for Rare Diseases
Family Caregiver Alliance
Global Alzheimer's Platform Foundation
Global Coalition on Aging Alliance for Health Innovation
HealthyWomen
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 Gerontological Society of America
The Global CEO Initiative on Alzheimer's Disease
The Mended Hearts, Inc.
UsAgainstAlzheimer's
Voices of Alzheimer's

_________________________________

i. Federal Register / Vol. 78, No. 152. https://www.cms.gov/medicare/coverage/determinationprocess/downloads/fr08072013.pdf.
ii. Vemulapalli, Sreekanth, et. al. Mitral Valve Surgical Volume and Transcatheter Mitral Valve Repair Outcomes: Impact of a Proposed Volume IRequirement on Geographic Access. Journal of the American Heart Association. Vol. 9, No. 11. 27 May 2020. https://www.ahajournals.org/doi/10.1161/JAHA.119.016140
Alliance for Aging Research. Façade of Evidence. Pages 18-25. February 2023. https://www.agingresearch.org/wp-content/uploads/2023/02/Facade-of-Evidence-CED-2-13-2023.pdf
iv. Health Subcommittee Legislative Hearing: “Lowering Unaffordable Costs: Legislative Solutions to Increase Transparency and Competition in Health Care.”https://energycommerce.house .gov/events/health-subcommittee-legislative-hearing-1.
v. These delays can occur as a result of the implementation of additional coverage requirements, such as the development of a RCT or data registry to support a NCD with CED.

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RE: CMS National Coverage Analysis Evidence Review Proposed Guidance Document

Dear Administrator Brooks-LaSure:

Boston Scientific Corporation appreciates the opportunity to provide comments in response to the Centers for Medicare and Medicaid Services’ (CMS) National Coverage Analysis Evidence Review Proposed Guidance Document.

As one of the world’s largest companies dedicated to developing, manufacturing, and marketing less-invasive therapies, Boston Scientific supplies medical devices and technologies that are used by the following medical specialty areas, all of which provide Medicare beneficiary care:

Cardiac Rhythm Management,

Electrophysiology,

Gastroenterology,

Interventional Bronchoscopy,

Interventional Cardiology,

Interventional Radiology,

Interventional Oncology,

Interventional Peripheral Vascular,

Neurologic & Movement Disorders,

Pain Management,

Urology, and

Women’s Health.

We applaud CMS’ efforts to work with stakeholders to improve the National Coverage Analysis Evidence Review process. We are encouraged by the many of the provisions included in this Proposed Guidance Documents that address the concerns raised by Boston Scientific and other interested parties.

However, we are still concerned, about the proposed requirements included under the Methodological Principal section of the document. 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 drugs and medical devices in the National Coverage Decision evidence review requirements.

Thank you for the opportunity to comment on the Proposed Guidance Documents. Please contact me at 571.228.3479 or Jenifer.Levinson@bsci.com if you have any questions.

Sincerely,
Jenifer Levinson
Vice President, Global Health Economics & Market Access
Boston Scientific Corporation

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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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August 21, 2023

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

Re: (PROPOSED) CMS National Coverage Analysis Evidence Review

Dear Coverage and Analysis Group,

In service of the neuromuscular disease (NMD) patient community, the Muscular Dystrophy Association (MDA) thanks the Centers for Medicare and Medicaid Services (CMS) for the opportunity to comment on the proposed guidance document entitled, “CMS National Coverage Analysis Evidence Review”. We are grateful for CMS’s efforts to articulate their expectations on the evidence necessary to successfully support a national coverage determination.

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.

Neuromuscular diseases are a group of rare, serious, progressive, mostly irreversible conditions that, while each unique, are collectively defined by progressive muscle weakening and degeneration leading to physical disabilities and, for many, early mortality. Clinical interventions for NMDs are particularly difficult to test within traditionally structured clinical trials for several reasons. First, each NMD is a rare disease, and most would be considered ultra-rare. Consequently, often there are simply not enough patients to power to a traditionally-run clinical study. The inherent heterogeneity of the diseases often confound results and endpoints are not only difficult to choose, but also challenged in measuring what’s truly impactful for the community.

With this in mind, it is incredibly important for decisionmakers to act with flexibility and understanding of these inherent challenges in rare neuromuscular disease clinical testing. Unfortunately, this draft guidance is incredibly rigid, and ignores the realities of clinical testing in rare diseases.

The Realities of Clinical Testing in Rare Diseases is Largely Ignored

CMS throughout this proposed guidance outlines the ideal mechanisms and features of evidence generation to justify a national coverage determination, and by focusing on the ideal, completely ignores the challenges associated with ultra-rare disease clinical testing.

Numerous examples exist. CMS states,

“In general, some of the methodological attributes of clinical studies that are associated with stronger evidence include the following:”

Use of randomization (in allocation of patients to either an intervention or a control group) to reduce bias.

Use of contemporaneous control groups (rather than historical controls) to ensure comparability between the intervention and control groups.

Prospective (rather than retrospective) studies to ensure comparability through a more thorough and systematic assessment of factors related to outcomes.

Larger sample sizes in studies to help ensure adequate numbers of patients are enrolled to demonstrate both statistically significant and clinically meaningful improvements in health outcomes.”

Concurrent controls are not always possible in ultra-rare disease clinical testing, and instead historical or other non-concurrent controls may be necessary. Moreover, larger sample sizes are impossible in diseases of only a handful individuals. How does CMS plan to consider evidence from studies that do not meet these expected methodological attributes?

CMS’s description of methods to maintain internal validity also bias against rare disease clinical studies. Participating in a clinical trial can be challenging for those with rare diseases for a number of reasons, including travel difficulties for those with chronic diseases and disabilities, few trial sites resulting in hundreds of miles of travel, and more. Consequently, selection and attrition biases can occur, but are manageable. Still, CMS must expect these difficulties within rare disease clinical trials to occur, and must not deter CMS from considering the evidence.

This proposal argues that “to interpret and generalize conclusions to the Medicare beneficiary population, studies may need to match or stratify their intervention and control groups by patient age, co-morbidities, disabling conditions, etc”. CMS also states that “Evidence that provides accurate information about a population or setting not well represented in the Medicare program might be considered, but their applicability may suffer from limited generalizability.” When only a handful of individuals are able to participate in a clinical study, and even fewer are within the standard Medicare beneficiary population, it may be impossible to stratify groups to satisfy this expectation. How will CMS consider evidence from an ultra-rare condition in which only a handful of the study participants are over 65 or otherwise qualify for Medicare?

Later, CMS suggests “Ensuring adequate sample size so that a study has sufficient power to detect clinically meaningful outcome differences between the treatment and control group, with acceptable precision”. At the risk of redundancy, this again ignores the inherent small samples sizes of rare disease, particularly ultra-rare disease, populations.

CMS continues, stating, “CMS can draw more confident conclusions about effectiveness when multiple studies report findings in the same direction for a particular health outcome.” Often only one study is difficult enough to conduct in rare diseases let alone two or more. This is at least in part why the Food and Drug Administration (FDA) considers the substantial evidence of effectiveness threshold to be met if one well-controlled trial plus confirmatory evidence is submitted to FDA for approval. Conducting multiple studies may not be possible in many ultra-rare diseases and could pose a barrier to evidence generation occurring at all if the evidentiary bar is too high.

Finally, CMS discourages studies to rely too heavily on academic medical centers, stating, “Trial participants in an academic medical center may receive more or different attention than is typically available in non-tertiary settings.” This again is likely unrealistic in rare neuromuscular diseases. Clinical trials are often run by the handful of clinical specialists in the field who are almost always housed at an academic medical center. Therefore most of rare disease clinical research inherently happens at these centers. CMS should not punish evidence generated from rare disease clinical studies due to it being collected at academic medical centers.

Randomized Clinical Trials Feature Unique Confounding Biases in NMDs

Many hold the belief that randomized controlled trials (RCTs) are the ideal method for collecting clinical data to serve as evidence for informed decisionmaking. Within this proposed guidance, CMS appears to agree, stating, “In general, but not absolutely, the hierarchy of evidence dictates that randomized controlled trials (RCTs) represent the most credible evidence because they are the least subject to biased estimates of outcomes; even so, observational studies can be more representative of actual clinical practice and may answer questions that RCTs cannot answer.”

We appreciate CMS’s acknowledgement that often observational studies can be more representative of actual clinical practice as not only can this be true within NMDs, but RCTs also carry their own confounding challenges in NMDs. For example, many RCTs in NMDs rely on subjective clinical outcome assessments that can confound results. The diseases are heterogenous and progressive, sometimes leading to an overperforming or underperforming placebo group, thus skewing results. RCTs within NMDs can fall victim to the same sampling challenges as other forms of trials.

In conclusion, RCTs in NMDs are not the panacea many would hope. Instead, they include the very same if not greater sampling, testing, validation, and other biases compared to other forms of clinical testing.

Benefits to NMD Population Are Hard to Capture

CMS also largely fails to recognize the difficulty of capturing the benefits or effectiveness of rare disease, particularly neuromuscular disease, treatments. For example, CMS says, “A wide confidence interval does not permit a confident conclusion regarding the effects of treatment.” While in an ideal world, this is indeed true, sometimes miniscule confidence intervals can be difficult to generate in small clinical trials of progressive, heterogenous diseases.

Moreover, CMS states,

“An intervention’s benefits should generally be clinically meaningful and durable rather than marginal or short-lived. When making NCDs, CMS generally places greater emphasis on health outcomes important to patients and their caregivers, such as quality of life, functional status, duration of disability, morbidity, and mortality, and less emphasis on outcomes in which patients often have a less direct interest, such as intermediate outcomes, surrogate outcomes, and laboratory or radiographic responses.”

CMS again is stating the ideal while ignoring the realities in rare diseases. Often short-lived benefits are still incredibly impactful to those with severe, often terminal, diseases such as amyotrophic lateral sclerosis (ALS). Often only clinical trials that use intermediate or surrogate outcomes are feasible with slowly progressive neuromuscular diseases. The benefit may not appears significant, perhaps only extending the life of an individual by a few months, or allowing an individual to walk or reach a cabinet for just a bit longer. But these benefits can be incredibly meaningful for those with neuromuscular diseases and should not be discounted.

In short, CMS must not be so careful with the benefit it perceives of certain interventions as to someone who is not living with the disease, they may not appear to be meaningful. While patient preference information can help emphasize what is important to different communities, such data may not always be available due to the rarity of the disease and the lack of investment into collecting such outcomes.

As we have asked throughout our comments, we request CMS to flexibly consider where these expectations may not be met for rare diseases and consider alternative approaches to coverage under national coverage determinations.

In conclusion, we are grateful for the opportunity to comment on CMS’s efforts to articulate the evidence necessary to justify a national coverage determination. For questions regarding MDA or the above comments, please contact us at 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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August 21, 2023

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

Dear CMS Review Team,

Thank you for sharing the information regarding the CMS National Coverage Analysis (NCA) Evidence Review Guidance. The Digital Therapeutics Alliance (DTA) appreciates the transparency and effort to provide a framework for evidence development that promotes predictability and transparency.

It is encouraging to see that CMS takes into account a range of factors, including clinical experience, medical, technical, and scientific evidence, as well as public comments, when assessing the reasonableness and necessity of specific items or services being provided under the Social Security Act.

The guidance outlines methodological principles that present a comprehensive approach to evaluating the quality and applicability of clinical evidence. The emphasis on factors such as randomization, contemporaneous control groups, prospective studies, larger sample sizes, masking, and thorough documentation ensures the robustness and reliability of evidence used for decision-making. However, requiring stronger evidence than medications which have substantial side-effects and contraindications, will continue to hinder innovation in healthcare.

While DTA acknowledges the significance of reducing bias, addressing confounding factors, and assessing the risk of bias in individual studies, we propose that CMS allow for progress without establishing criteria that are unattainable for many Digital Therapeutics (DTx) companies.

Currently, the evaluation of digital therapeutics products in the U.S. Food and Drug Administration (FDA) involves the consideration of various types of evidence. The FDA assesses the safety, effectiveness, and quality of these products based on a combination of clinical data, scientific evidence, and regulatory standards. The specific types of evidence used include:

-Clinical Trials: The goal of clinical trials is to provide critical evidence on DTx product's effectiveness, patient outcomes, and potential adverse effects. There are other acceptable trial designs that can accomplish this such as well-designed and well-executed single arm prospective studies and comparative effectiveness studies which are also recognized and accepted by FDA.
-Real-World Evidence: In addition to clinical trials, the FDA may consider real-world evidence (RWE) to assess the performance and impact of digital therapeutics in real-world settings. RWE includes data obtained from sources such as electronic health records, claims databases, patient registries, and observational studies. This evidence provides insights into the product's effectiveness and safety in broader patient populations and diverse healthcare settings.
-Patient-Reported Outcomes: Patient-reported outcome measures (PROMs) are used to capture the patient's perspective on the impact of digital therapeutics on their health and well-being. These measures assess subjective experiences, such as improvements in symptoms, quality of life, functional abilities, and treatment satisfaction. Patient-reported data is valuable in understanding the patient experience and assessing the overall effectiveness of the product.
-Technical Performance Data: Digital therapeutics often rely on software algorithms, user interfaces, and data analytics to deliver interventions and monitor patient progress. The FDA evaluates the technical performance data to ensure the reliability, functionality, and usability of the digital therapeutic. This includes assessing the product's ability to accurately deliver interventions, collect data, and provide appropriate feedback or recommendations.
-Risk Assessment: The FDA conducts a thorough risk assessment to identify and mitigate potential risks associated with the use of digital therapeutics products. This includes evaluating cybersecurity measures, data privacy, and any potential adverse events or patient harm that may arise from the product's use.
-Regulatory Standards: Digital therapeutics are subject to regulatory standards and requirements set by the FDA. The FDA considers compliance with these standards, such as the Quality System Regulation (QSR) for software, to ensure that the product meets the necessary quality and safety standards.

It is important to note that the specific evidence requirements and evaluation processes may vary depending on the intended use, risk classification, and regulatory pathway for each digital therapeutics product. The FDA's evaluation of digital therapeutics is an ongoing process, and the evidence requirements may evolve as the field continues to advance.

DTA commends the strength of evidence assessment outlined in the guidance. DTA supports the focus on clinically meaningful and durable outcomes and the consideration of health outcomes important to patients and caregivers that underscores CMS’ commitment to patient-centered care. However it is critical that the level of evidence required of DTx products aligns with intended use and clinical study parameters that are accepted by the FDA. Furthermore, it is important that this framework not hinder the innovation of needed Digital therapies in the future. While we appreciate the focus on innovative technologies in healthcare, it is imperative that CMS consider the following:

-It’s important for CMS to account for the cost of conducting each of these studies. These technologies are medical devices (SaMD or SiMD) and should be reviewed in line with evidence necessary to provide those products to patients. DTA agrees in the necessary rigor for data collection; however, the bar for evidence needs to follow realistic expectations for recruitment, population size, diversity, and outcomes. Given the nature of Digital therapeutics in terms of function and design we believe there should be allowances for cases where a prospective single-arm study can be used to demonstrate safety and effectiveness, which is often used by medical devices.
-DTA would ideally like both FDA and CMS to lean in more heavily on RWE, and for both to be aligned on the requirements.
Companies need sufficient lead time in order to design studies, recruit patients, conduct the study, analyze, and publish results. In an effort to provide the products to patients, while continuing to generate real world evidence, particularly in cases where there are no adverse events, CMS should take into account the full evidence generation plan while still allowing access for Medicare and Medicaid beneficiaries.
Once a framework is established, CMS needs to remain flexible to ensure that innovative technologies that offer quality healthcare solutions to patients can still find a pathway to market
-It is necessary to distinctly determine the purpose for which CMS plans to utilize this framework
-Lastly, it may be helpful to talk about how this framework will be used in the context of product evaluation and patient access in public programs

We appreciate the opportunity to provide feedback on the proposed National Coverage Analysis Evidence Review Guidance. We believe that the principles and considerations outlined in the guidance will hinder the evaluation of digital therapeutics and other innovative healthcare interventions. We are therefore requesting a meeting before these guidelines are finalized to discuss our concerns regarding evidence requirements for digital therapeutics.

Thank you for your dedication to improving the quality and accessibility of healthcare for Medicare beneficiaries.

Sincerely,

Andy Molnar
Chief Executive Officer

Sara Elalamy, MA
Director of US Government Affairs

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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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Thank you for the opportunity to submit this public comment to the Centers for Medicare & Medicaid Services (CMS) regarding its “National Coverage Analysis Evidence Review” proposed guidance released June 22, 2023.

UsAgainstAlzheimers (UsA2) is an organization founded by people whose families have been savaged by Alzheimer’s disease (AD) and who have created a national, patient-centric movement to end this disease. We speak to you with the voice of our own families as well as the millions of Alzheimer’s patients whose care and health outcomes will be directly affected by CMS’s decision.

We believe that patients should have access to medications that meet urgent, unmet medical needs as soon as they have been determined to be safe and effective, as long as there is no reason to believe that the safety and efficacy will not translate to people like themselves. They expect any insurer that intends to assess the reasonableness of a particular therapy to bring a depth of expertise in both the specific specialty and in evidence evaluation to the analysis. And those who volunteer to participate in medical research deserve the very best care and especially clear explanations of trial protocols, benefits, and risks.

If it were to finalize this guidance, CMS would be taking important steps away from these principles.

Until CMS has developed comprehensive guidance and expertise, it should not ignore the deep expertise within the FDA on the design of trials, the evaluation of evidence, and of many medical specialties and sub-specialties. It will not serve patients to have uncertainty, delay, or evaluation based on anything but the best scientific understanding and the clearest articulation of expectations. While there may occasionally be reason to believe that a therapy might have different performance in the Medicare population versus the trial population, difference should not be default assumption in the absence of evidence.

The draft guidance makes a broad assertion that “patients often have a less direct interest” in outcomes “such as intermediate outcomes, surrogate outcomes, and laboratory or radiographic responses.” In a document that is focused on evidence, we are unsure of the evidence for this statement. In our experience, patients with severe disease who have few options want access to therapies as soon as possible. Congress has recognized this as recently as last year in reaffirming the Accelerated Approval pathway, which could be vitiated for people on Medicare if this guidance is finalized. We also believe that patients clearly value outcomes such as the elimination of a malignant tumor, the reduction of hypertension, an improvement in hBA1C, and many other intermediate, surrogate, laboratory, or radiographic outcomes.

Finally, the draft guidance potentially creates substantial delay and other burdens in the system with its derogation of the nature of clinical trials. It suggests that, in clinical trials, “an investigator’s lengthy and detailed explanations of the potential benefits of the intervention, use of advanced testing, or access to specialty care may point to positive results that may not be consistently replicated in the community setting.” This is as it should be. We are sure that the writers of the guidance agree that volunteers in clinical trials are engaging in research for the benefit of all of us, and they deserve all of these protections. If the evidence that this work produces is somehow suspect because the care participants received was especially high-quality, CMS needs to consult with stakeholders each time on how additional evidence will be gathered, in what timeframe, with what restrictions on access, with what burden on providers.

Thank you for the opportunity to submit this public comment, and for diligently reviewing it. Please let me know if you have any questions or need further information about this public comment.

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August 21, 2023

RE: (PROPOSED) CMS National Coverage Analysis Evidence Review

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 reviews evidence within the context of 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.

We believe that one of the largest obstacles to improving health outcomes for our patient communities is the risk of unintended consequences due to applying policy priorities and initiatives designed to address the general population without considering the unique challenges associated with rare and ultra-rare conditions. A significant proportion of Haystack Project’s advocacy and education efforts focus on identifying and drawing attention to these unintended consequences.

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 could disproportionately harm patients with extremely rare conditions.

A one-size-fits-all approach to evidence review will disadvantage treatments for rare and ultra-rare conditions.

As you know, innovation in how we understand and address disease mechanisms has advanced at a pace that would have been unthinkable decades ago. Targeted cancer treatments, gene therapy and regenerative medicine, and immunologic approaches to rare, serious, and life-threatening conditions give renewed hope to the millions of Americans affected by a rare disease. However, exceedingly small populations, long diagnostic journeys, and a limited natural history knowledge base for many rare diseases 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.

Individuals without a disease-specific FDA approved treatment rely on off-label use of therapies approved for other conditions. These patients and their providers often face a labyrinth of claim denials, prior authorization requirements, reconsiderations, and appeals to access the care they need. Coverage policies and mechanisms, particularly NCAs, can present absolute, impenetrable, and persistent barriers to access if they are implemented without considering the treatment needs of rare disease patients. Any NCA granting coverage for on-label use of an FDA-approved treatment while foreclosing coverage for off-label indications could therefore have an unintended downstream impact on ultra-rare disease patients.

In addition to unintentionally limiting access for off-label use of treatments that might improve outcomes for ultra-rare disease patients, the evidentiary standards set forth in the proposed guidance appear to have been designed to capture “quality” evidence for relatively common conditions. As CMS noted in its proposed guidance, CMS’ evidentiary inquiry within an NCA is to “determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary.” Haystack Project and the over-130 patient advocacy organizations within its membership are concerned that CMS’ stated NCA objective of achieving confidence that “the specific assessment questions raised in an NCA can be answered conclusively” is an insurmountable challenge for new treatments addressing ultra-rare conditions. This is largely due to the fact that research and development on treatments for extremely rare diseases frequently rely on:

- FDA’s accelerated approval mechanism
- Use of surrogate endpoints
- Single-arm studies
- Evaluations of treatment impact over a relatively short period of time
- Enrollment of a small set of study participants

The FDA approval processes acknowledge the inappropriateness of a one-size-fits-all approach to evaluating whether the quality and quantity of evidence justifies a determination that a drug is safe and effective. Orphan Drug Act incentives, a dedicated orphan products division for review, the Patient Focused Drug Development Program, and the Rare Disease Endpoint Advancement Pilot Program were initiated to facilitate research and development of rare disease treatments. Haystack Project recently worked with Congress and the FDA on passage of the HEART Act to address informational and process gaps that have a disproportionate impact on product development in ultra-rare conditions. For example, as most rare diseases do not have a disease-specific treatment, much less a cure, patients are often willing to face a different risk-benefit balance than FDA typically sees. These patient perspectives are not included within clinical trial data but are crucial given that CMS’ definition of an intervention that is not reasonable and necessary is one for which the risk of harms outweighs the benefits. The bill encourages FDA consultation with experts in the science of small population studies. This is critical since the small populations for rare and ultra-rare disorders complicate clinical trial design and data analysis by, for example, adding a rescue arm or using historic comparators.

Put simply, the nature of ultra-rare diseases and their patient populations generally forecloses research efforts that would meet CMS’ standards of sufficient quality and quantity to justify coverage. Even if CMS would rarely or even never review an FDA-approved treatment that might be used in an ultra-rare condition, the concern that it could do so and would find the evidence insufficient may be enough to deter researchers and their investors.

CMS’ Evidentiary Inquiries Should be Driven by Context

The NCA process is an evidence-driven inquiry to determine whether a particular treatment is reasonable and necessary. The level of inquiry should acknowledge and be driven by the evidentiary showing required to obtain market authorization from FDA. For example, coverage decisions involving 510(k) cleared medical devices might afford CMS multiple relevant inquiries, including determining what benefit category the device falls under, and whether the scientific data meets the burden of proof needed to establish that the “reasonable and necessary” standard is met. Drugs and biologicals that FDA approves as safe and effective generally already fall within a benefit category. Although CMS has stated that its medical necessity standard is distinct from FDA’s “safe and effective” determination, it has not articulated what, if any, daylight separates a medically accepted use from a reasonable and necessary one. We assume that CMS would require sufficient evidence of patient harm or lack of patient benefit to determine that a safe and effective drug for any medically accepted use was not medically necessary.

Section 1860D-2(e)(4) of the Act defines “medically-accepted” use, in part by reference to section 1927(k)(6) of the Act, to any use of a covered Part D drug which is approved under the Federal Food, Drug, and Cosmetic Act, or the use of which is supported by one or more citations included or approved for inclusion in any of the compendia described in section 1927(g)(1)(B)(i) of the Act. The definition of medically accepted indication also includes drugs used in an anticancer chemotherapeutic regimen for a medically accepted indication by reference to section 1861(t)(2)(B) of the Act. This Part D definition has been applied to Part B drugs within the context of the Medicare Drug Negotiation Program [citation(s)], and we are unaware of any scientific rationale for applying different standards based upon how a treatment is dispensed and administered.

Medicaid programs must justify coverage limitations on medically accepted uses of covered drugs with scientific and clinical evidence. Part D plans and Medicare Advantage organizations must similarly base their utilization management tools and coverage restrictions on evidence, including clinical guidelines. We acknowledge the potential that evidence of harms associated with a drug used for a medically accepted indication may emerge over time and justify CMS’ NCA review process. Absent such evidence, however, we urge CMS to decline NCA review of medically accepted uses and to limit any NCA associated with FDA-approved drugs to indications for which there is evidence that harms outweigh benefits. The latter is particularly important for the rare and ultra-rare disease patients still awaiting disease-specific treatments and relying on off-label use to alleviate the disease burden.

Conclusion

Haystack Project appreciates the opportunity to submit feedback on the proposed guidance. If you have any questions, please contact our policy consultant M Kay Scanlan, JD at 410.504.2324.

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 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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To the Centers for Medicare and Medicaid Services (CMS):

Thank you for publishing the proposed guidance document, “CMS National Coverage Analysis Evidence Review” (the “Proposed Guidance”). Aetion appreciates CMS’s commitment to advancing the use of real-world data (RWD) and real-world evidence (RWE) in healthcare decision-making. Integrating RWE into healthcare decision-making will facilitate more efficient product access and enhance understanding of product safety and effectiveness. CMS’s work to provide robust, actionable guidance will help to better ensure that evidence submitted in support of National Coverage Determinations (NCDs) meet CMS’s expectations.

Aetion welcomes and appreciates the opportunity to comment on the Proposed Guidance. As a health technology company that specializes in the generation of RWE capable of supporting healthcare decision-making, we confront the matters addressed in the guidance on a daily basis. Our technology product, the Aetion Evidence Platform® (AEP), was originally created by two academia-based pharmacoepidemiologists to address a widely recognized need: scalable, transparent, and scientifically rigorous analyses of RWD to evaluate the safety and effectiveness of clinical interventions. A key feature of AEP is data fluency, meaning that it enables users to run analyses against different data sources in their near-native formats, with minimal transformations required prior to analysis.

Aetion shares CMS’s commitment to fostering high-quality analyses of fit-for-purpose RWD that can provide evidence for decisions across the product life cycle, including CMS’s review of safety and effectiveness in the context of NCDs. Greater alignment on principles and best practices, and greater public visibility regarding CMS’s expectations, will enable sponsors and other researchers to implement RWD analyses in a transparent, auditable, reproducible, and scientifically valid manner.

General Comments

We strongly agree that RWE studies should be robustly designed and use reliable, relevant, and fit-for-purpose RWD, to ensure confounding and other sources of bias are mitigated. We also agree with the Proposed Guidance’s stated approach of encouraging the pre-definition of essential elements in protocols and where relevant, statistical analysis plans (SAPs), which is critical for transparency and reproducibility. Conducting studies using these principles helps to ensure that RWE studies will produce interpretable and trustworthy results.

Taxonomy of Bias

We note that CMS characterized reporting bias as an issue of internal validity in an non-interventional study. We disagree with this characterization, as reporting bias stems from the fact that studies showing an effect tend to be published more often than studies showing no effect — both because researchers tend to not submit null findings and journals tend to not accept them for publication. Accordingly, while reporting bias matters when one is evaluating a body of evidence to make a conclusion about whether a treatment has an effect, it is not an internal validity issue, which pertains to whether the finding of a single study is itself interpretable given the methods. We recommend deleting the last bullet point from the list on top of page 4 (Systematic differences between published versus unpublished study findings (reporting bias)”) and inserting the following language before the final paragraph in that same section:

Additionally, when the findings of multiple published studies are used to make a conclusion about the causal relationship between an intervention and outcome, the potential of systematic differences between published versus unpublished study findings (reporting bias) should be considered.

Uniform Application of the Principles in the Proposed Guidance

The Proposed Guidance represents a strong acknowledgement of the role of RWE in CMS processes and approaches, and it will be a useful tool for stakeholders seeking to develop evidence that may support CMS in making NCDs. We strongly encourage CMS to apply the principles contained in the Proposed Guidance consistently across all its programs that may use RWE to support decision-making. Consistent principles across CMS programs will help to ensure a consistent quality of evidence generation, particularly because a given study may be relevant to CMS reviews in multiple contexts.

We especially encourage CMS to apply the principles articulated in the Proposed Guidance to RWE offered by stakeholders in the context of establishing maximum fair prices under sections 11001 and 11002 of the Inflation Reduction Act. In particular, we request that CMS ensure (1) appropriate coordination between the Coverage and Analysis Group and the Medicare Drug Rebate and Negotiations Group, and (2) alignment of the principles articulated in the the program guidance, “Medicare Drug Price Negotiation Program: Revised Guidance, Implementation of Sections 1191 – 1198 of the Social Security Act for Initial Price Applicability Year 2026,” as well as any subsequent guidance or rulemaking for future applicability years, with those principles articulated in the Proposed Guidance.

* * *

Aetion looks forward to collaborating with the Centers to support the successful use of RWD and RWE in healthcare decision-making. Please contact Lowell Schiller at Lowell.Schiller@Aetion.com with any questions regarding these comments or other issues related to RWE policy and development.

Sincerely,

Lowell Schiller
Chief Legal and Regulatory Officer, Aetion
Nicolle Gatto
Chief Science Officer, Aetion

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The National Center for Health Research (NCHR) appreciates the opportunity to express our views regarding the Centers for Medicare and Medicaid Services (CMS) National Coverage Analysis Evidence Review Proposed Guidance.

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.

According to CMS, the Proposed National Coverage Analysis (NCA) Guidance is intended to “provide a framework for more predictable and transparent evidence development.” We appreciate CMS providing additional information regarding their standards for conducting NCAs to assess whether evidence is sufficient to support a finding that a product or service meets the “reasonable and necessary” coverage standard as part of the NCD development process.

We support the methodological attributes of clinical studies that are described in the guidance. Specifically, the “use of randomization”, “large sample sizes”, and “blinding” are essential methods to determine solid scientific evidence and reduce bias. In addition, we appreciate that CMS carefully considers both the funding source and potential conflicts of interest for study investigators when evaluating the methodological rigor of a study.

The proposed NCA guidance notes that in making NCDs, “CMS considers the totality of the evidence across multiple dimensions, including study design and conduct.” CMS focuses on benefits that generally are “clinically meaningful and durable rather than marginal or short-lived.” CMS states that it typically places greater emphasis on health outcomes that are important to patients and their caregivers. These include quality of life, functional status, duration of disability, morbidity, and mortality, while placing “less emphasis on outcomes in which patients often have a less direct interest, such as intermediate outcomes, surrogate outcomes, and laboratory or radiographic responses.” We strongly agree with CMS’s priorities that emphasize evidence of meaningful health outcomes, particularly morbidity and mortality, since those can be evaluated more objectively.

This guidance also discusses the importance of the generalizability of findings from relevant studies to the Medicare beneficiary population. We agree that in order to interpret and generalize conclusions to the Medicare beneficiary population, studies “may need to match or stratify their intervention and control groups by patient age, co-morbidities, disabling conditions, etc.” Later in the guidance these criteria are expanded to include sex, race/ethnicity, and the severity of the disease, which is essential; unfortunately, too many studies have results that are not generalizable to Medicare beneficiaries because of the lack of people of color and patients under the age of 65, often with few if any patients over 70 or 75. As is often the case, research typically focuses on the youngest, healthiest sick patients, in order to reduce the confounding impact of co-morbidities and maximize the chances that the results will indicate benefits rather than harm. To ensure that medical interventions will benefit Medicare beneficiaries, data need to include enough patients to conduct subgroup analyses to determine if the benefits outweigh the risks for those types of patients.

Finally, regarding the strength of evidence assessments, we agree that CMS-approved CED studies may generally be more persuasive than observational studies because the study design, analysis plan, and data sources are generally prespecified and posted on ClinicalTrials.gov, to ensure that the study design, implementation, and analyses are not changed post hoc. Registration with ClinicalTrials.gov helps to ensure that Medicare beneficiaries and healthcare professionals are aware of studies that are underway, will soon be completed, and are supposed to already be completed; this will facilitate better informed decision making. Information about the study’s pre-specified primary endpoints and analyses help ensure transparency about how the study was meant to be implemented. It is unfortunate that the results of clinical trials are often not reported in a timely or comprehensive manner on ClinicalTrials.gov, because study results are not always published in medical journals. Moreover, studies that are reported in press releases and journals sometimes deviate from the study design and planned analyses, which raises questions about the integrity of the data. We urge CMS to continue to promote transparency in the studies that formulate their NCD and CED determinations.

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