(PROPOSED) Clinical Endpoints Guidance: Knee Osteoarthritis

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

RE: Proposed Clinical Endpoints Guidance: Knee Osteoarthritis

Dear Coverage and Analysis Group,

The Robert J. Margolis, MD Center for Health Policy at Duke University (“the Duke-Margolis Center” or “the Center”) appreciates the opportunity to comment on the Proposed Clinical Endpoints Guidance: Knee Osteoarthritis, published on June 22, 2023.

The Duke-Margolis Center generates and analyzes evidence across the spectrum of health policy and supports the triple aim of better care, better health, and lower cost. The Center focuses on transforming health care delivery and increasing the value of biomedical innovation through evidence-based solutions to the most pressing, relevant health care delivery and payment policy questions. Center experts are engaged in policy research and development efforts to improve both care delivery and the processes and infrastructure needed at the Centers for Medicare and Medicaid Services (CMS) to ensure efficient access to new and innovative technologies.

The comments below describe opportunities for strengthening the Clinical Endpoints Guidance: Knee Osteoarthritis to more closely align with CMS’s goals for the guidance to provide a framework for more predictable and transparent evidence development. These comments are informed by the Center’s independent analysis of the guidance document and engagement with a diverse group of stakeholders, including manufacturers, real-world evidence experts, providers, researchers, and payers. The Duke-Margolis Center is supportive of the direction of the Clinical Endpoints Guidance: Knee Osteoarthritis document. To further strengthen this guidance document and future guidance, the Center recommends that CMS:

• Clarify the circumstances under which CMS would facilitate broader stakeholder engagement for determining clinical endpoints of interest for emerging therapeutic areas;
• Include guidance on the types of data sources and data collection strategies that would generate data on the outcomes of interest identified; and
• Clarify how they will prioritize the selection of therapeutic areas in which to develop Clinical Endpoints Guidance and clarify if forthcoming guidance can inform evidence generation efforts for existing CED requirements; and
• Consider aligning the recommended outcome domains with existing performance and quality measures that CMS already collects to inform quality and performance metrics in the same therapeutic areas.

Background

Clinical evidence that supports a coverage determination must show that an item or service is reasonable and necessary for the Medicare beneficiary population. For a product to be “reasonable and necessary,” it must be: (1) safe and effective, (2) not experimental or investigational, and (3) appropriate for use in Medicare beneficiaries.¹ An item or service is “appropriate” in this context if it is furnished according to the medical practice standards for the diagnosis or treatment of a condition, in a setting of care that can meet patient needs, by a qualified provider, whether a product meets the medical needs of the patient, and whether it is as least as beneficial as an existing alternative. Medicare beneficiaries tend to be older, with multiple comorbidities, and are often underrepresented or not represented in many clinical studies. CMS thus looks to the evidence supporting FDA market authorization and product indications for evidence generalizable to the Medicare beneficiary population, data on improvement in health outcomes, and durability of those outcomes. In cases in which the evidence is promising, but does not necessarily show that an item or service is appropriate for the intended Medicare populations, CMS can offer Coverage with Evidence Development (CED) as sponsors collect supplementary data in the post-market setting. The benefit of these CED studies is they often offer a larger, more diverse cohort can provide key insights into what constitutes “appropriate” use of a product by allowing investigators to observe how a product performs in different patient populations, with different provider experience or site capacity.

The Clinical Endpoints Guidance not only reflects CMS’s current view on health outcomes for the treatment of Knee Osteoarthritis, but also illustrates the methodology that CMS uses to identify clinically meaningful endpoints within a disease area when determining a National Coverage Determination. This is the first of a series of guidance documents that will review the clinical outcomes for treatments in different disease areas. In turn, these are the types of endpoints that could be used in both investigational clinical trials and post-market studies, such as those designed to support Medicare coverage. Through this guidance, CMS is aiming to:

• Provide a framework for more predictable and transparent evidence development by demonstrating how CMS assesses health outcomes and clinically meaningful endpoints and evidence thresholds to support Reasonable and Necessary coverage; and to
• Illustrate the types of evidence CMS intends to review.

The first part of this comment letter will analyze how the process described in the guidance document supports these aims, as well as CMS’s overarching goals for Medicare coverage. The second portion of the comments will address opportunities for greater alignment with broader Medicare reforms, especially how these clinical endpoints could align with existing quality and performance measures.

Strengthening Guidance to Support CMS Goals

In the Clinical Endpoints Guidance, CMS outlines the framework that they use for determining clinical endpoints of interest through a systematic literature review imbedded in a Technology Assessment (TA). TAs involve a systematic evaluation of the available evidence on a given technology to determine the effect of a technology on patient health outcomes. The TA includes a systematic literature review with specific inclusion and exclusion criteria, including date and language of publication, reporting on appropriate outcome measures for managing knee osteoarthritis (KO), and methods for evaluating and developing consensus on outcomes of interest. The evidence was then appraised to assess its validity (credibility), usefulness (clinical applicability), and importance (magnitude of effect).

CMS also reviewed society consensus statements and core outcome sets, noting overlap between these sets of outcomes and endpoints commonly used in the existing literature. From this data, CMS was compiled a list of prioritized outcome domains for researchers to consider for future studies that would be particularly relevant and meaningful for evaluating medical technologies to treat KO. CMS does identify the most commonly used instruments in the literature for supporting the priority domain outcomes, but does not necessarily make recommendations about which instruments would be most valuable in trials. Rather, CMS recommends that clinical studies prioritize validated endpoints and instruments to ensure that CMS can more easily interpret study results.

CMS’s description of this methodology and its resulting recommendations do push CMS closer to meeting its goals of providing a predicable framework and illustrating the types of evidence CMS intends to review. Importantly, for emerging therapeutic areas where there are no existing frameworks for interventions, there may not be enough directionally aligned literature to determine or prioritize a list of relevant and meaningful clinical endpoints. In the event that there are not validated endpoints or instruments to measure outcomes for a given therapeutic area, a systematic literature review may not reveal clear outcome domains. CMS could call on the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) panel or engage with a variety of stakeholders, including patients, providers, and specialty societies to better prioritize and align on outcomes of interests.

Recommendation: CMS should clarify the circumstances under which CMS would host a MEDCAC and facilitate broader stakeholder engagement for determining clinical endpoints of interest for emerging therapeutic areas.

Prioritizing Therapeutic Areas

Knee Osteoarthritis was an illustrative disease area to develop a proposed clinical endpoints guidance. We note that while there may be ongoing medical innovations in this therapeutic space, KO has well established reimbursement structures that may preclude the need for formal coverage processes for new innovations. As CMS considers developing internal processes to develop clinical endpoints guidance documents, they should clarify how they will prioritize the selection of therapeutic areas. CMS could additionally clarify if they will develop clinical endpoints guidance for therapeutic areas with no pre-existing coverage policies, or if forthcoming guidance can support evidence generation efforts for existing NCDs with CED requirements.

Recommendations: CMS should clarify how they will prioritize the selection of therapeutic areas in which to develop Clinical Endpoints Guidance and clarify if forthcoming guidance can inform evidence generation efforts for existing CED requirements.

Another way that CMS can add additional transparency and predictability to the clinical endpoint guidance documents—and thus add further clarification to Medicare coverage pathways—is to include guidance on the types of data, potential data sources, and evidence generation strategies that would best support collection of the identified clinical endpoints throughout different stages of evidence development. Different types of data may be more effective for determining the clinically meaningful differences in outcomes over others. Guidance on data sources that are most rigorous, high-quality, and least burdensome need not limit studies, but guidance may help sponsors use existing data infrastructures or plan for new infrastructures when applicable. This will help support the updated CED guidance and timely access to novel technologies if manufacturers are able to more quickly and confidently develop evidence development plans or study designs.

Recommendation: CMS should include guidance on the types of data, data sources, and data collection strategies that would best support data collection for the identified clinical endpoints.

Alignment with Broader Medicare Measures

Although the clinical endpoints guidance documents are a summation of what CMS may be looking for when reviewing devices within a therapeutic area, there is an opportunity to align these guidance documents with broader Medicare performance or quality measures to provide greater consistency in reimbursement for Medicare items and services.

For example, through the Quality Payment Program (QPP) CMS collects data on some of the recommended outcome domains identified in the proposed clinical endpoints guidance on KO. For example, Merit-Based Incentive Payment System (MIPS) measure #217: “Functional Status Change for Patients with Knee Impairments” captures a risk-adjusted change in functional status using a patient-reported measure of the FOTO Lower Extremity Physical Function (LEPF). Functional status is also further captured in MIPS measure #470: “Functional Status After Primary Total Knee Replacement” through either the Oxford Knee Score or the KOOS, JR. tool. In the Clinical Endpoints Guidance, there are recommended outcome domains of physical function and function/functional ability, though it is not immediately clear in the guidance how CMS is differentiating these domains, and how either may be different from the intended meaning of “functional status” in existing MIPS measures.

Additionally, although CMS states that this guidance document does not specifically endorse or recommend any particular instrument to measure outcome domains, only one instrument listed in the guidance document is also currently collected in CMS quality measures and in the Comprehensive Care for Joint Replacement model measures, namely the KOOS tool. CMS also noted that function/functional ability may be already captured in instruments that are used in other outcome domains, including the 12-item short-form health survey (SF-12), and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), both of which are surveys used to measure patient quality of life. The SF-12 focuses more on patient quality of life holistically through measuring physical functionality, bodily pain, general health, social functioning, and mental health,² while the WOMAC focuses more on joint pain, stiffness, and function.³ However, neither of these tools appear to be regularly collected by CMS. Thus, there are opportunities to foster alignment between what is regularly used in the literature in the KO space, what CMS will evaluate to determine appropriateness of a product or service, and what is collected by CMS to incentivize providers and health systems. Greater alignment in these related areas—data collection to support Medicare coverage and data collection to support quality and performance measures—could support CMS’s goals to minimize provider and patient burden of data collection. Aligning outcome domains and instruments to quality and performance measures would allow the clinical endpoints guidance document series to apply more holistically to disease spaces. This would in turn ensure that incentives across care delivery and evidence development for novel products are working in tandem, providing clear signals for technological innovation that can address CMS quality goals.

Recommendation: When prioritizing outcome domains of interest, CMS should consider aligning the recommended outcome domains with existing performance and quality measures (or vice versa) that CMS already collects to inform quality and performance metrics.

Conclusion

The Duke-Margolis Center supports CMS’s efforts to publish a series of guidance documents on clinical endpoints of interest for different disease areas. The Center encourages CMS to consider the importance of additional elements that encourage early stakeholder engagement, innovative study designs, and alignment across broader Medicare quality improvement efforts. The Duke-Margolis Center appreciates CMS’s consideration of our comments, and the Administration’s support for advancing high-value, affordable healthcare.

Sincerely,

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

References
1 Centers for Medicaid & Medicare Services, “Medicare Program Integrity Manual, Ch 13” (CMS, February 12, 2019), https://www.cms.gov/regulations-and-guidance/guidance/manuals/downloads/pim83c13.pdf.
2 Kate E. Webster and Julian A. Feller, “Comparison of the Short Form-12 (SF-12) Health Status Questionnaire with the SF-36 in Patients with Knee Osteoarthritis Who Have Replacement Surgery,” Knee Surgery, Sports Traumatology, Arthroscopy 24, no. 8 (August 1, 2016): 2620–26, https://doi.org/10.1007/s00167-015-3904-1.
3 “Western Ontario and McMaster Universities Osteoarthritis Index,” Shirley Ryan AbilityLab, July 26, 2016, https://www.sralab.org/rehabilitation-measures/western-ontario-and-mcmaster-universities-osteoarthritis-index.

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V-Wave understands that CMS intends to publish additional disease or condition specific guidance documents. We believe that disease specific guidance could be beneficial, but it is very important that CMS strikes the proper balance between additional helpful specificity and over-prescription. Guidance that is too specific and granular will put CMS and manufacturers into a bind because there will be insufficient flexibility to allow for novel trial designs. On the other hand, providing insufficiently specific guidance makes it more likely that manufacturers will design clinical trials that do not meet CMS needs and requirements.

For example, initial clinical trial results could require extended “negotiation” between CMS and manufacturers to agree upon fit for purpose studies as part of an NCD request. Extended negotiations would make it very unlikely that an NCD could be proposed and finalized anywhere close to the six-month timeline suggested by CMS in its TCET notice. In order to better support the goals of TCET, CMS, in our view, needs to explicitly say what sort of items, if any, are required versus those that are negotiable. Examples of negotiable items could include elements such as the percent of Medicare populations in a study, length of follow up, etc. Those elements may vary depending on the nature of the disease, the prevalence of the disease, the device, and other factors. We are concerned that the proposed guidance on knee osteoarthritis is inadequately clear to provide meaningful direction to manufacturers and therefore will not support development of trials that will produce results to meet CMS’ evidentiary needs.

In the case of knee osteoarthritis, CMS states the following:
“Generalizability to the Medicare population:
CMS may have difficulty drawing conclusions regarding potential benefits and harms associated with an item or service if Medicare eligible beneficiaries are insufficiently represented in clinical studies.

CMS recommends that investigators carefully consider the intended recipients of an item or service when designing clinical studies such that the findings may be credibly generalized to relevant Medicare beneficiaries, including important sub-populations.

CMS recommends that studies avoid poorly justified exclusions based on age or common comorbidities that may limit generalizability of findings.

CMS recommends that study investigators consider whether the context of care delivery within clinical studies may be reasonably generalized to the context where Medicare beneficiaries are expected to receive care.”

The statements about generalizability are too broad to be helpful to companies like VWave. If CMS is unable to be more specific with respect to a given disease, then CMS should explicitly state that the percentage of Medicare beneficiaries and subpopulations of Medicare beneficiaries it expects to be enrolled in a trial is not fixed and is subject to negotiation on a case-by-case basis. We believe that the percentage of Medicare beneficiaries enrolled in clinical trials should be roughly proportional to their representation in the disease state under investigation and at least adequate (i.e., large enough) to provide reasonable assurance of safety and effectiveness in subgroup analysis using interaction testing. In heart failure, where Medicare beneficiaries represent up to 70% to 80% of all patients in the US, we agree that studies should avoid poorly justified exclusions based on age or common comorbidities that may limit the generalizability of findings.

CMS also states:
“Traditionally, CMS relies heavily on health outcomes data to make NCDs. Where there is limited evidence on the health outcomes for individuals in the Medicare beneficiary population, there may not be sufficient evidence to support favorable national Medicare coverage under section 1862(a)(1)(A) of the Act.

CMS recommends that investigators consider the 11 prioritized outcome domains identified in Table 2 of this technology assessment when designing knee osteoarthritis clinical studies.

CMS does not recommend any specific clinical endpoint or instrument that was identified in this review, but generally recommends that clinical studies include a range of outcomes that reflect multiple attributes of an item or service within a clinical study.

When choosing among the available clinical endpoint options, CMS recommends that clinical studies prioritize validated endpoints / instruments and those with well-established/published minimal clinically important differences (MCID) values because study findings are more readily interpreted.”

These recommendations are more helpful than the recommendations on generalizability because they describe the endpoints most commonly used in clinical trials. However, most, if not all, manufacturers are already aware of them. Therefore, the guidance could be more helpful if CMS provided more information about how it perceives the endpoints. CMS should be more specific about which endpoints it considers to be validated, well-established, and clinically significant and tell manufacturers that if other endpoints are chosen, manufacturers will need to provide evidence in support of them, i.e., which endpoints CMS will accept. This would be similar to what FDA has done in its voluntary program to qualify medical device development tools (MDDTs) used for evaluating devices. In essence, the MDDT Program enhances the regulatory acceptability of endpoints meeting the requirements set forth in its Qualification of Medical Device Development Tools guidance document (https://www.fda.gov/media/87134/download), thus reducing the risk to study sponsors in using these tools as endpoints. For heart failure clinical trials, FDA has accepted the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Minnesota Living With Heart Failure (MLWHF) Questionnaire as MDDTs. Also, given the number of companies that use hierarchal endpoints with statistical methodologies like the well-validated Finkelstein Schoenfeld method, V-Wave suggests that CMS should accept them as sufficient for an NCD, when the components of the hierarchical endpoint are well-validated. For example, in contemporary heart failure trials (including both drug and device trials), such study endpoints often include, in the following hierarchical order, mortality, heart failure morbidity (heart failure hospitalization with or without other worsening heart failure events), and a patient-reported outcome such as the KCCQ or MLWHF Questionnaire.

Finally, CMS states the following:
“Duration of follow-up:
CMS may have difficulty reaching conclusions regarding potential risks and harms associated with an item or service if studies lack sufficient follow-up to demonstrate the durability of improved health outcomes.

For osteoarthritis, CMS generally recommends that clinical studies include follow-up of at least one year for functional and/or patient reported outcomes.

CMS generally recommends that clinical studies include follow-up of at least two years to establish the durability of implanted devices, though shorter or longer follow-up may be reasonable in some circumstances.”

V-Wave finds this last set of guidelines to be useful in that it gives notice that the length of follow-up is negotiable. However, V-Wave understands that end points in trials can vary based on statistical models and study powering-sample sizes amongst other factors. The trial design and statistical plan should dictate the proper follow up period that is needed to properly reject the null hypothesis of a given trial.

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These comments were 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: Proposed Clinical Endpoints Guidance: Knee Osteoarthritis

Johnson & Johnson (“J&J”) is pleased to submit the following comments and recommendations in response to the Centers for Medicare & Medicaid Services’ (CMS’) proposed Clinical Endpoints Guidance for Knee Osteoarthritis. 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 technologies 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.

The proposed guidance document on Clinical Endpoints Guidance: Knee Osteoarthritis compiles a list of outcomes and instruments representing clinically meaningful outcomes that should be used to evaluate medical technologies that treat knee osteoarthritis (OA).

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

CMS Should Consider the Variability in Potential Technologies and Their Intended Use
The proposed guidance document is technology-agnostic as stated by CMS on page 3, noting that “specific technologies were not reviewed.” However, on page 17, CMS specifically mentions out implanted devices in its recommendation that “clinical studies include follow-up of at least two years to establish the durability of the implanted device…”. We are interested in how CMS will use this guidance in the future to account for various procedures (e.g., Total Knee Arthroplasty (TKA), Unicompartmental Knee Arthroplasty (UKA), Revision Total Knee Arthroplasty (rTKA). Furthermore, CMS notes that it generally recommends that clinical studies include follow-up of at least one year for functional and/or patient reported outcomes. However, if the intent of a given technology is to improve short term outcomes (i.e., faster return to full function/employment), then relevant follow-up duration would be shorter than one year and there may not be a validated instrument for capturing this information.

CMS Should Consider Inclusion of Commonly Used Patient Reported Outcome Measures (PROMs)
CMS provides Table 2. Prioritized Outcome Domains and Instruments (pg.10) based on the number of citations (e.g., met at least 50% of the highest cited instrument’s total citations within an outcome domain.). However, additional PROMs, commonly used in clinical practice and published in peer-reviewed literature, specific to the knee joint, should be considered for inclusion (e.g., Forgotten Joint Score, the Knee Society Score, and Oxford Knee Score). Given the wide range of medical technologies and treatments, and their intended uses, we urge CMS to consider all levels of valid scientific PROMs measurement tools and to maintain flexibility in the interpretation and application of these data.

Johnson & Johnson appreciates the opportunity to submit comments on the proposed guidance for Clinical Endpoints for Knee Osteoarthritis. We look forward to continued engagement with CMS on these and other important issues relating to evidence development and Medicare coverage. 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,

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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Thank you for the opportunity to review the CMS Proposed Clinical Endpoints Guidance on Knee Osteoarthritis. CMS has put together a comprehensive list of important outcomes that should be reported in studies evaluating technologies for knee osteoarthritis. A few specific comments:

1. Function/functional ability is included as a prioritized outcome domain in Life Impact, but instruments are not provided. It would be beneficial to include more clarity on what exactly is considered an instrument on function/functional ability. Is this specifically patient-reported activity level, return to work, return to sport etc.? Or is this more specific to the knee joint?

2. Range of motion should be considered as an instrument to measure the outcome domain of stiffness. I think this is important to include as this has significant implications on a patient's pain, function, activity level and satisfaction.

3. Radiographic imaging is a broad term to use as an instrument for joint structure. What specifically is being looked at in radiographic imaging? For nonoperative treatments is it progression of disease? More details regarding this instrument are important to include.

4. In the resource use and economical impact domain there is no discussion of cost or accessibility of treatment. While many studies may not have included such outcomes, I think it's worth noting that these are important to include in future studies. All patients may not have access to certain technologies to treat knee osteoarthritis. In addition, cost is an important consideration that should be reported in studies evaluating technologies for treatment of knee osteoarthritis.

5. For duration of follow-up, two years should be the minimum follow-up for clinical studies evaluating the durability of implanted devices (e.g. joint replacements). Long-term studies (e.g. 10+ years) are even more critical especially as the number of younger patients undergoing joint replacement is rapidly increasing over time.

6. Several of the included studies included heterogeneous patient populations, such as patients with rheumatoid arthritis or other musculoskeletal conditions in addition to OA. This inserts significant heterogeneity into the data and makes it difficult to ascertain any conclusions. For future clinical endpoint guidance documents, it would be best to include only those studies that include the target population.

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August 21, 2023

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

RE: Response to CMS Proposed Clinical Endpoints Guidance: Knee Osteoarthritis

Dear Dr. Chin,

Thank you for the opportunity to provide public comment. We appreciate CMS’ efforts to encourage innovation and accelerate beneficiary access to new items and services by publishing this, and future, Clinical Endpoints Guidance. The Clinical Endpoints Guidance is intended to demonstrate what types of evidence CMS will review when making national coverage determinations, and to improve the transparency of the NCD process.

For more than 20 years, Stanford Biodesign has been training innovators in a proven, repeatable process for identifying and screening important unmet health-related needs, inventing new solutions to address them, and developing implementation plans to advance those technologies into patient care. We have trained more than 200 full-time Innovation Fellows and over 2,500 students, resulting in more than 50 companies based on technologies invented during this training – and those technologies helping millions of people. Our comments are based on an analysis of the guidance, Stanford Biodesign’s experience teaching and training medical technology innovators, the accumulated real-world experience of Stanford Biodesign faculty, and recent work assessing time to Medicare coverage for novel technologies.[1]

The stated intent of the Clinical Evidence Guidance to provide clarity on the types of evidence that CMS will review during coverage decisions is an important one. Innovators and investors have described the process for establishing coding, coverage and payment for a new technology with words like “opaque”, “complex” and “challenging.”[2] The complexity arises, in part, from the late nature of coverage decision-making compared to the collection of clinical evidence about a new technology. The use of Clinical Evidence Guidance could provide a valuable mechanism to ensure that future clinical studies supporting a new technology will align to evaluation criteria.

Recommendation Summary:

To maximize the utility of the Clinical Evidence Guidance in guiding evidence collection for new technology and future coverage decisions, we recommend CMS:
1. Publish the list of topics CMS intends to evaluate and solicit public comment to ensure areas of need for Medicare beneficiaries are appropriately prioritized.
2. Direct contractors performing health technology assessment to recommend patient satisfaction or similar patient-reported outcome measures among outcomes recommended for clinical study.
3. Ensure that Clinical Evidence Guidance includes patient satisfaction, or a similar patient-reported outcome measure.
4. Consider a long-term goal to express a “least burdensome” approach to evidence generation for a novel treatment modality to meet technology assessment requirements and achieve coverage through an NCD or NCD with CED.

Recommendation Details:

1) Publish the list of topics CMS intends to evaluate and solicit public comment to ensure areas of need for Medicare beneficiaries are appropriately prioritized.

Providing a schedule for upcoming Clinical Endpoint Guidances could signal to the innovation community which clinical areas are important to CMS and could warrant an NCD. Product development and FDA authorization processes can stretch six to ten years before a technology and the treatment or diagnosis it facilitates reach sufficient maturity to request an NCD. Thus, the guidance will influence clinical evidence collection for technology already in development and may even catalyze new product innovation. The announcement of a guidance would be an important signal of which clinical areas CMS determines to be of highest need for beneficiaries and a signal of future coverage clarity for innovators and investors alike.

Solicitation of input from Medicare beneficiaries, their physicians as well as stakeholders in the medical technology innovation ecosystem would provide CMS with context on areas of unmet need where Clinical Endpoint Guidance would be helpful and influential. A process that solicits input on selection criteria could provide CMS with a framework for topic selection that balances clinical outcomes, cost effectiveness, patient satisfaction, and the number of beneficiaries impacted. We believe that evaluation and selection from a wide cross-section of unmet needs yields opportunities for significant patient impact, and encourage CMS to consider such an approach for topic development.

2) Direct contractors performing health technology assessment to recommend patient-reported outcome measures among outcomes recommended for clinical study.

Disruptive new technology often challenges conventional treatment for a disease state by moving treatment to a lower acuity setting and improving patient quality of life, satisfaction or recovery time. The Knee Osteoarthritis guidance includes patient satisfaction under the LIFE IMPACT outcomes measures recommended by CMS, but it was noted that a VAS or Likert scale has not been validated as an outcome measure among OA patients and a minimal clinically important difference (MCID) has not been established. Patient satisfaction is the only unvalidated outcome measure in the prioritized outcome measures. It is heartening to see this measure included in the guidance as it is in line with the trend to include patient reported outcome measures (PROMs) and patient input in health technology assessments; however, it appears that the prioritization of the LIFE IMPACT outcomes measures was made at the discretion of the contractor preparing the Technology Assessment. Patient reported outcomes are significant in clinical decision-making, and it is our strong suggestion that inclusion of patient-centric outcomes and PROMs be formally supported by CMS as a requirement in the solicitation of a Technology Assessment.

3) Ensure that Clinical Evidence Guidance includes patient satisfaction or a similar patient-reported outcome measure.

CMS uses the Technology Assessment to proposed conclusions in the final section of the guidance. These recommendations demonstrate 1) that clinical results be generalizable to the Medicare population by including Medicare beneficiaries in clinical studies, 2) recommends that investigators choose among the clinical outcomes measures prioritized in the technology assessment and include outcome domains that have well established MCID values, and 3) recommends the length of follow-up for functional outcomes and implanted devices. It is an important indicator to investigators that CMS has defined conclusions from the technology assessment. Unfortunately, CMS did not include patient satisfaction among the recommended clinical endpoints, and perhaps minimized its importance by recommending outcomes that have defined MCID. Specific inclusion of at least one PROM among the CMS conclusions will ensure that outcome measures meaningful to patients are systematically collected during evidence generation for a new technology.

4) Consider a long-term goal to express a “least burdensome” approach to evidence generation for a novel treatment modality or diagnostic to meet technology assessment requirements and achieve coverage through an NCD or NCD with CED.

A majority of novel medical technologies are pioneered by small entities whose sources of financial support are limited. Appreciating this limitation, in an effort to help these technologies advance into patient care, FDA has defined a “least burdensome” approach towards their processes and evidence generation. We are hopeful that CMS would consider adopting a similar “least burdensome” principle in CMS’ Clinical Endpoint Guidance documents.

We welcome the opportunity to further engage around these topics and others as they pertain to the advancement of medical technology innovation for patient care.

Thank you for your consideration of these public comments.

Sincerely,
Josh Makower, MD
Professor of Medicine and Bioengineering
Director and Co-Founder, Stanford Byers Center for Biodesign
Stanford University

References

1. Sexton ZA, Perl JR, Saul HR, et al. Time From Authorization by the US Food and Drug Administration to Medicare Coverage for Novel Technologies. JAMA Health Forum. 2023;4(8):e232260. doi:10.1001/jamahealthforum.2023.2260
2. Ruggles SW, Perl JR, Sexton ZA, et al. The Need for Accelerated Medicare Coverage of Innovative Technologies: Impact on Patient Access and the Innovation Ecosystem. Health Management, Policy and Innovation. 7(1). www.HMPI.org

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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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Instability is not a symptom of Osteoarthritis until it is end-stage where TKA is the only feasible treatment. Referencing McHugh M et al., 2020 as a reason for including instability in knee orthosis coverage is misleading, as this study focuses on ligamentous injuries, not OA. When creating criteria for addressing coverage of conservative treatment such as bracing and surgical treatments, such as TKA, then you must stage it appropriately. Conservative treatment is best used in early stages of the disease, when quality of life and pain reduction has the best chance of improving. Surgery should be withheld until later stages in the disease when conservative treatment is not as effective. The current bracing guidelines prevent beneficiaries from receiving bracing until the end-stage of the disease (due to the instability requirement), which is when it is the least effective. Removing studies like the one above, that are discussing instability as a measure for ligamentous injuries, would allow for the bracing guidelines for OA bracing to be aligned with the actual disease progression and allow for bracing to be used when it is most effective for the patient. Allowing access to bracing at the earlier stages of OA will allow the beneficiary to push surgery to a later time when the disease is more advanced. Preventing access to OA bracing at early stages allows the progression to happen at a faster rate and Medicare is therefore paying for surgery earlier and likely more frequently than they otherwise would (due to age vs mortality).

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MDMA applauds the Centers for Medicare & Medicaid Services (CMS) for releasing the three proposed guidance documents on National Coverage Analysis (NCA) Evidence Review, Coverage with Evidence Development (CED), and Proposed Clinical Endpoints for Knee Osteoarthritis. As the agency notes, “Section 1862(l)(1) of the Social Security Act (SSA) requires that the Secretary of Health and Human Services make available to the public the factors that are considered in making national coverage determinations (NCDs) of whether an item or service is reasonable and necessary.” Although CMS released its Procedure for Producing Guidance Documents Describing Medicare’s Coverage Process in September 2004 [69 Fed. Reg. 57,325], the agency has issued only a few guidance documents since then. MDMA and other stakeholders have encouraged CMS to update existing guidance documents and propose additional ones as we believe more predictability and transparency in the coverage process will help bring more innovations to market and accelerate Medicare beneficiary access to them.

The Proposed Clinical Endpoints for Knee Osteoarthritis guidance appears to represent the first of what CMS officials have previously referred to as “Medicare Evidence Development and Coverage Advisories,” which are intended to “provide more guidance to manufacturers about the clinical outcomes the agency will be looking for when reviewing studies, as well as the clinical differences that will be considered meaningful.” [Fleisher LA and Blum JD. A Vision of Medicare Coverage for New and Emerging Technologies—A Consistent Process to Forster Innovation and Promote Value. JAMA Internal Medicine. Oct. 12, 2022 (online). doi:10.1001/jamainternmed.2022.5085.] Guidance documents that review health outcomes and their clinically meaningful differences within therapeutic areas could be extremely helpful for manufacturers to identify and collect the clinical evidence and other information relevant to determinations regarding coverage by CMS and the Medicare Administrative Contractors seek when making coverage determinations. MDMA agrees that such advisories or guidances provide a framework for more predictable and transparent evidence development, encouraging innovation and accelerating beneficiary access to new items and services.

As we intend to outline in our separate comment letter on the TCET Federal Register Notice, we believe that the proposed guidance on Clinical Evidence on Knee Osteoarthritis is a good model for the Evidence Preview (EP) in the TCET coverage process. Such guidance—whether produced in response to the acceptance of a novel technology into the TCET process, or developed independent of the TCET process as was done with the Knee Osteoarthritis draft—provides insight into the outcomes of interest to CMS, associated endpoints, and clinically meaningful differences for the target disease or condition. Such insight can then provide the basis of discussions between CMS and the manufacturer regarding evidence gaps associated with a specific technology, and whether those gaps warrant the collection of addition clinical evidence under either CED or separate TCET temporary coverage.

With regard to clinical endpoint guidance documents that will be develop independent of the TCET process, we encourage CMS to obtain stakeholder input on which therapeutic areas could most benefit from the issuance of guidance.

Thank you for the opportunity to provide these comments.

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