View Public Comments for Draft Guidance for the Public, Industry, and CMS Staff Coverage with Evidence Development in the context of coverage decisions

January 28, 2013

VIA electronic delivery

Ms. Marilyn Tavenner
Acting Administrator
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850

Dear Ms. Tavenner,

On behalf of the Personalized Medicine Coalition (the “PMC”), we are pleased to submit comments on the Draft Guidance for the Public, Industry, and Centers for Medicare & Medicaid Services (“CMS”) Staff - Coverage with Evidence Development (“CED”) in the Context of Coverage Decisions (“the Draft Guidance”).

Personalized medicine is the tailoring of medical treatments to the individual characteristics of each patient, and the ability to classify individuals into subpopulations based on their susceptibility to a particular disease or their responses to a specific treatment. Personalized medicine therefore has the potential to optimize delivery and dosing of treatments so patients can receive the most benefit with the least amount of risk, cutting out the difficulties of the current trial-and-error process many patients endure to find the correct diagnosis and treatment for their condition. Clinicians rely on research to help them assess and understand a given patient’s disease and provide information to guide treatment decision-making. Accordingly, PMC supports the agency’s efforts to improve access to new medical technologies through CED when additional information is necessary to answer specific clinical questions related to a Medicare coverage decision, with the caveat that application of CED should not negatively affect the ability of clinicians to provide the optimal treatment to each patient based on the patient’s individualized needs.

Representing more than 225 academic, industry, patient, provider, and payer organizations, PMC is an education and advocacy organization that promotes the understanding and adoption of personalized medicine to benefit patients and the health care system. Given the mission of PMC and the desires of the patient and provider communities we bring together, the Coalition has a keen interest in the agency’s Draft Guidance and the application of CED. Specifically, this letter comments on the following:

• CMS should adopt the principles included in the 2006 CED guidance document.



• CMS should ensure that review of evidence and decisions about evidence development are clearly explained and transparent.



• CMS should clarify the role of the Agency for Healthcare Research and Quality (“AHRQ”) in the application of CED.



• CMS should consider additional factors for CED.

These points are described more fully below:

1. CMS should adopt the principles included in the 2006 CED guidance document.

In its prior CED guidance, CMS included a list of eight principles to guide the application of CED. These principles provided a useful benchmark for all stakeholders and helped ensure that CED would be applied when appropriate and would not unnecessarily limit access to the optimal diagnostic and therapeutic items and services for patients. In the Draft Guidance, CMS does not provide these or any guiding principles, saying only that “some” of the 2006 principles are now moot. PMC strongly disagrees. We believe that these principles continue to be relevant and urge CMS to adopt them in the final CED guidance that it issues. PMC believes a number of the 2006 principles are particularly important to include in the final CED guidance, as discussed below.

1. CMS should consider alternative processes to foster collaboration in CED implementation.

PMC recognizes that CMS has gained valuable experience since the 2006 guidance document and recommends that CMS learn from prior CED efforts. Specifically, PMC believes that collaboration among stakeholders in the early stages of the CED process is essential to successful implementation. Stakeholder collaboration during the early stages of coverage decision-making and defining study designs and research protocols will provide valuable expertise to the CED process. CMS should consider establishing partnerships to allow innovators and other stakeholders to help advance the agency’s goals for CED. PMC believes that broad participation of innovators and stakeholders throughout the process will help maximize the likelihood of successful CED implementation. PMC believes this type of partnership will be particularly important in relation to personalized medicine, where science and clinical practice are rapidly evolving and gaining external expertise and input on appropriate research questions and study designs will be essential.

2. CMS should use CED infrequently and only to expand access for Medicare beneficiaries.

In the 2006 guidance document, CMS indicated that it expected to use CED infrequently and in general to expand access to technologies and treatments for Medicare beneficiaries. PMC is concerned that CMS’s intent to apply CED to older existing technologies and services, as well as to new ones, is evidence of an approach that departs substantially from these principles and indicates an interest in expanding the scope of CED in a manner that could impede access to care and restrict the ability of providers to make decisions in the best interest of the individual patient. PMC urges CMS to clarify that this is not the case by reaffirming all of the 2006 principles in the final CED guidance.

Further, the suggestion in the draft guidance that coverage for a product or service under CED could end during the interval between the end of the CED study and the completion of the agency’s review of the study data is inconsistent with the notion that CED is intended to improve the quality of patient care and should be rejected. If the item or service covered under CED was covered before and during the study, coverage should not be terminated at the end of the study until that agency determines, after completion of its review of the study data, that the evidence does not support continued coverage. If CED is appropriately applied, such instances should be extremely rare.

3. CMS should not use CED when other forms of coverage are justified by the available evidence.

The two principles discussed above are related to another principle from the 2006 guidance document, that CED will not be used to determine coverage when it is justified by the other forms of evidence. PMC believes that, with regard to personalized medicine technologies, in most cases there will be no need for CED because of how these products and services are developed, approved and used.

Drugs and medical devices, for example, are reviewed and approved by the Food and Drug Administration (FDA) after a rigorous process based on supporting clinical validity data with a well-defined intended use in the patient population. Traditionally, CMS has found that the evidence necessary for FDA’s determination that a product is safe and effective is adequate to determine that a procedure, test or therapy is reasonable and necessary. Diagnostic tests performed in the clinical laboratory are reviewed using well-accepted processes for determining the analytical and clinical validity of a test and are subject to ongoing review by accreditation bodies and through statute. They are often included in prevention, screening and treatment guidelines of specific conditions that are developed by physician specialty societies, AHRQ and the United States Preventive Services Task Force (USPSTF). CED should not be used to reconsider the existing processes described above, which are firmly established in medical practice.

4. Application of CED should not duplicate the efforts of other federal agencies and entities that review and conduct research.

The 2006 guidance document also included principles providing that CED would not duplicate or replace the FDA’s authority in assuring the safety, efficacy, and security of drugs and would not assume the role of the National Institute of Health (NIH) in fostering, managing, or prioritizing clinical trials. Since the 2006 guidance was issued, the Patient-Centered Outcomes Research Institute (PCORI) has taken an active role in conducting research to provide information about the best available evidence to help patients and their health care providers make more informed decisions. CMS should ensure that its application of CED does not duplicate the efforts of any of these entities. This is necessary in order to make the best use of limited public and private resources available for research, to avoid redundancy, and to not impose overlapping and unnecessary burdens on patients and their caregivers.

5. CMS should apply CED only within the National Coverage Determination (NCD) process.

Finally, the 2006 guidance provided that CED would occur within the NCD process. CMS does not explicitly confirm this in the Draft Guidance, and statements included in its earlier solicitation for public comment on CED in fact included statements that suggested the agency intended to apply CED in other contexts. We are concerned that expanding CED to the local level could result in multiple or even conflicting data collection requirements, increasing burden and costs, as well as uncertainty regarding coverage and access to new technologies that are under a CED in one jurisdiction but not another. PMC urges CMS to adhere to this 2006 principle and to apply CED only within the NCD process. For CED to be effective and achieve its goal of producing evidence that will enable the agency to make informed coverage decisions, CMS will need to rely on input from knowledgeable stakeholders from all sectors, including industry, with regard to both review of the available literature, in design of the CED studies, and an appropriate timeline to produce the data the agency needs. The best way to accomplish this is to apply CED within the NCD process, which is well-known, transparent, and open to the public. Furthermore, it removes uncertainty regarding beneficiaries’ access to a technology in one coverage area while it is being investigated in another.

2. CMS should ensure that review of evidence and decisions about evidence development are clearly explained and transparent.

In addition to applying CED through the NCD process, CMS should make extra efforts to ensure that the analyses of evidence and decisions about evidence development methods leading to the initiation or end of CED are clearly explained and transparent. PMC appreciates the Draft Guidance CMS has provided on the application of CED and its efforts to update the existing guidance to reflect the agency’s experience with CED over the years. PMC believes that it is vitally important to the successful application of CED that the criteria CMS intends to use to analyze clinical data and evidence collection activities are clearly explained. The Draft Guidance takes steps in this direction by setting forth clearly when CMS expects CED to apply and its standards for scientific integrity. There is much more, however, that PMC believes CMS could do to ensure that stakeholders understand how the CED process will apply. For example, CMS does not provide guidance on how it plans to determine the evidentiary criteria for a particular application of CED or what the criteria might be. We suggest that evidentiary criteria will not be the same for each CED and suggest that CMS work with stakeholders at the beginning of the CED process to ensure that there is appropriate flexibility and that a single standard is not used for every research question. The Draft Guidance also does not explain how CMS will review data generated from CED studies to make coverage determinations, which leaves many concerned that an item or service could be caught in a perpetual CED cycle. Filling in the gaps in the Draft Guidance to ensure that all stakeholders know exactly the process CMS intends to follow when applying CED will minimize the uncertainty that can hinder patient access to the most appropriate treatment.

Moreover, CMS should make the entire CED process transparent – from the decision to invoke CED, to the development of the study design, to the decision to end a study, and finally to the process for using the new evidence to make a coverage determination. We urge broad stakeholder engagement, including those from all sectors of personalized medicine. CMS discusses transparency in the Draft Guidance with regard to publication of the results of CED studies but by the time clinical literature is published, the opportunity for CMS to benefit from the knowledge and experience of stakeholders will have passed. The process must be transparent from the very beginning in order to ensure that CED is applied only for the most appropriate items and services, and in a manner that will not impede beneficiary access and will generate the data the agency needs to make coverage determinations.

3. CMS should clarify the role of AHRQ and the type of assistance it will provide.

CMS makes clear in the Draft Guidance that the sole basis for its authority to apply CED is the statutory authority to cover items and services that are reasonable and necessary to carry out research conducted pursuant to AHRQ’s authority under section 1142 of the Social Security Act. CMS describes the ways in which AHRQ’s authority and resources complement CMS’s interests in using CED, and CMS says that it believes that AHRQ’s role “will continue to develop.” Given that the statutory authority for CED is premised on research conducted or supported by AHRQ, PMC believes it is important for CMS to clarify the role of AHRQ in the application of CED. In particular, in light of the burdens of CED on all stakeholders, PMC hopes that CMS will provide more concrete guidance on the types of public/private partnerships AHRQ may establish to financially support CED studies. PMC also thinks it is important to ensure that AHRQ’s involvement in the CED process does not inhibit transparency, reduce opportunities for the involvement of knowledgeable stakeholders, or restrict access to non-government experts.

4. CMS should consider additional factors for CED.

PMC requests that the draft guidance be altered to ensure that Medicare beneficiaries have access to life saving technologies and that physicians have the flexibility to practice medicine in the way that is most suitable for the individual patient. PMC has long advocated for research that improves the evidence-base on which medical decisions are made. We urge CMS to recognize that the evidence threshold to invoke CED should include factors such as patient preferences and quality of life measures among others. Personalized medicine is a fast-moving field. We learn more each day about how to focus treatments on those who will benefit, saving time, expense and exposure for those who will not. We urge CMS to consider how to incorporate new evidence into CED decisions as new evidence may be published after a CED decision is made. Many personalized medicine technologies are new and evidence to support use of them may develop over time. We therefore ask that CMS allow all beneficiaries to have access to an item or service while it is under a CED. This will signal to patients and innovators that this policy is designed as intended: to improve patient care.

PMC appreciates the opportunity to provide comments on the Draft Guidance. If you have any questions about these comments, please contact Amy Miller at 202-589-1770, or via electronic mail to amiller@personalizedmedicinecoalition.org.

Sincerely yours,

Rosemarie Hakim, PhD
Centers for Medicare and Medicaid Services
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, Maryland 21244-1850

Dear Dr. Hakim:

Thank you for the opportunity to comment on the Centers for Medicare and Medicaid Services’ (CMS’s) Draft Guidance for the Public, Industry, and CMS Staff Coverage with Evidence Development in the context of coverage decisions. America’s Health Insurance Plans (AHIP) is the national association for the health insurance industry. Our members provide coverage to more than 200 million Americans, offering a broad range of health insurance products in the commercial market and demonstrating a strong commitment to participation in public programs.

General Comments

Expansion of the evidence base through rigorous research on the safety, effectiveness and value of new technologies, biologics and pharmacological products is critical to ensuring that patients receive the most effective and appropriate treatments. CMS’ CED policy was created to provide access to promising but unproven therapies within a framework designed to collect evidence and inform future coverage policy. In order to maximize the value of CED, we offer the following recommendations.

Recommendations to Maximize the Effectiveness of CED

Input of Private Payers on CED Applications

First, as the title suggests, the CED process CMS is proposing has implications for public programs such as state Medicaid programs and for the private sector. For that reason, in considering CED applications, it would be helpful to have input from both. We also emphasize that the CED process should be maintained as a national coverage decision and not based on local coverage decisions.

Need for Additional Clarity Regarding Evidentiary Threshold

To be effective, CED needs additional clarity in considering health services that are promising but lack evidentiary threshold for coverage. These services include treatments that are part of a well-designed clinical trial; treatments for illnesses for which no effective treatment exists when preliminary studies from at least two reports that the benefits of such treatments may exceed the potential harms; and treatments for other conditions that occur so infrequently that it is unlikely that a body of published evidence will be developed within a reasonable period of time. On occasion, there may also be specific situations where services may be considered for challenging conditions that pose significant disability and quality of life issues, e.g., treatment-resistant, severe, long-term depression.

As is true for other health services, those covered under CED must be:

• Supported by available clinical evidence;
• Appropriate for the unique patient needing the treatment;
• Cost-effective when compared to alternative treatments (or to no treatment, if no treatment is available).

Most health plans use a hierarchy of evidence (from strong to weak) that starts with statistically robust, well-designed randomized controlled trials if available, followed by statistically robust, well-designed cohort studies, followed by large multi-site observational series, and then single-site observational series. In the absence of incontrovertible scientific evidence, coverage for a service may be considered based upon national consensus statements by recognized authorities.

Without a clear and transparent evidentiary standard by which items and services will be judged eligible for CED, there is a risk that new technologies with only very preliminary evidence of effectiveness may be considered for coverage under CED’s Coverage with Study Participation (CSP) track. The establishment of clear and rigorous criteria for when CED should be used will result in research with more useful, definitive results. Our members also suggest CMS consider new criteria that include cost-benefit analysis for such services.Further, we suggest there be coordination of data sharing among those entities providing coverage during a CED trial.

One such approach would be a national registry of qualified studies to easily determine whether and when studies are underway. As with all registries, safeguards must be in place to protect identifiable patient information.

Reliance on CMS Clinical Trial Policy

We recommend that CED rely on qualified clinical trials, as defined in CMS’ Clinical Trial Policy, when it determines that an item or service be covered as long as it is provided within a research setting where additional data can be collected in the context of clinical care. Qualified clinical trials have the scientific rigor and control that better enable them to generate the evidence necessary to make definitive judgments as to whether an item or service meets the evidentiary standards for reasonable and necessary. These trials should be focused on addressing safety and efficacy so that usable information is collected and applied to the coverage determination process.

Clear Pathway for Reassessment of Coverage Decisions Upon Completion of CED

Finally, we recommend that CMS provide a clearer pathway for the reassessment of coverage decisions upon completion of CED. Timeframes, procedures and evidentiary thresholds should be specified so that the process for evaluating and incorporating the data collected into coverage determinations is clear and transparent. We concur with the overarching principle that there needs to be a timeframe for when CED ends. We also recommend that a non-biased, clinically-based, evidentiary review body assess the data and make the decisions about the results of the CED studies. We recommend that the resulting decisions be disseminated along with information on the evidence, or lack thereof, that led to these decisions.

Conclusion

Our members believe that the goal of CED, like the goal of all benefit coverage decisions, must be better health, better care, lower cost. Access to promising but unproven treatments is consistent with that goal only when the clinical evidence base is defined with rigor, and the execution of such a program clearly demonstrates within a defined period of time which health services work, and which do not. We thank you for the opportunity to comment on this important issue.

Sincerely,

January 28, 2013

Louis Jacques, MD
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mail Stop S3-02-0 1
7500 Security Boulevard
Baltimore, MD 21244

Dear Dr. Jacques:

St. Jude Medical, Inc. has prepared the following comments on the Draft Coverage with Evidence Development (CED) Guidance Document that was posted by the Centers for Medicare and Medicaid Services (CMS) on November 29, 2012. This draft guidance document is a revision of a guidance document on the same topic that was fmalized on July 12, 2006, after considerable public input. We appreciate the opportunity to share our views on this very important matter.

St. Jude Medical develops medical technology and services that focus on putting more control into the hands of those who treat cardiac, neurological and chronic pain patients worldwide. The company is dedicated to advancing the practice of medicine by reducing risk wherever possible and contributing to successful outcomes for every patient.

St. Jude Medical supp01is the continued use of CED as a means to provide Medicare beneficiaries with access to promising medical services and procedures while evidence is generated to inform national coverage decision-making. Through CED, CMS can cover promising new technologies on a conditional basis- providing beneficiaries with access to cutting-edge medical interventions in return for collection of information that can address the questions CMS has concerning new medical interventions.

In the years since this program began, CMS has identified a wide range of diagnostic and therapeutic technologies and procedures where the available evidence was considered to be insufficient for national Medicare coverage, and where CED could be used to generate the needed information. A number of study designs have been considered and used to generate evidence through the CED program. We view the variety of medical procedures that have been considered for CEO studies, as well as the differing study approaches that have been used, to be a strength of the program.

We are pleased that CMS undertook a comprehensive review of the CED program in light of the experience it has had with CED over the past several years. We are also pleased that CMS sought the views of the Medicare Evidence Development and Coverage Advisory Committee (MedCAC) on the use of CED to generate evidence, and that it has solicited comments on CED from the public. Although we were disappointed that the draft Guidance Document that was posted on November 29, 2012, did not provide the detail we had anticipated, we hope that the public comments that are submitted will spur CMS to develop a CED Guidance Document that gives stakeholders a better understanding of the national coverage decision-making process, promotes innovation, and results in aCED program that improves patient outcomes.

We commend CMS for proposing to focus its CED effmts on "coverage with study participation," situations where the evidence is considered to be insufficient to support Medicare coverage and where additional research is needed. We agree with the position taken by CMS in the draft guidance that the "coverage with appropriateness determination" form of CED designed to ensure that Medicare-covered items and services are used appropriately- should not be the focus of future CED efforts.

Stakeholders-including beneficiaries, clinicians, and technology manufacturers-should have a clear understanding of the circumstances when CED will be considered for use and the factors CMS will consider in determining the merits of a CED evidence generation effort. The draft guidance document that was posted on November 29, 2012, does not accomplish this and the document should be revised to provide the specificity stakeholders need in these areas.

• The CED Guidance Document Should Clarify That CED Will Remain a National Coverage Matter. The draft guidance document (at Section VII) makes reference to Medicare Administrative Contractors (MACs) and coverage of items. and services in clinical research. The draft document states that this listing "is not an exhaustive list of potential MAC activities in this regard." Our view is that CED should only be used in the context of national Medicru·e coverage decision-making and that MACs should not make use of CED in local coverage decision-making. We ask that this be made clear in the CEO guidance document.



• The CED Guidance Document Should Include Principles Guiding CED Use. CMS has not included in this draft guidance document a listing of Principles goveming the application of CED. Such a listing of Principles appeared in Section II of the 2006 CED Guidance Document. The principles in the 2006 CED Guidance Document, which CMS says are now "moot," include a number of matters that were the subject of extensive public comment when the guidance was being developed in 2005-2006. The 2006 CED Guidance Document included principles that inform stakeholders when CED will be used ("within the NCD processes" which are transparent and open to public comment; to "expand access to teclmologies and treatments"), that state how often CED will be used ("infrequently"), and that make clear that CED "will not duplicate or replace" FDA regulatory authority or "assume the NIH's role in fostering, managing, or prioritizing clinical trials." In our view, these principles are sound, and the principles should be retained. In any event, CMS should explain to stakeholders why it has deleted these 2006 principles, and the new guidance document should provide the principles that will guide CMS actions in the future.




• The CED Guidance Document Should Identify Where CED Will Be Used and the Criteria That Will Guide These Decisions. While the draft guidance document suggests that CED will be used more frequently than in the past, it does not provide information on the specific circumstances where CMS is considering its use. By comparison, the 2006 CED Guidance Document stated that CED would be used "infrequently," even though about one in five national coverage detetminations have resulted in a requirement for additional data through CED. Because one of the stated pmposes of the CED program is to reduce the barriers for technology innovation, it seems reasonable to expect this CED guidance document to provide stakeholders with realistic and specific information on the circumstances in which CMS anticipates that it will make use of CED.

  At a minimum, the guidance document should provide infmmation on the criteria that will be used in selecting candidate technologies, and it should make clear that CED will only be used where the value of the evidence generated exceeds the costs of data collection. A careful examination of the available evidence on almost any new item or service being considered for national Medicare coverage can be expected to raise additional questions concerning the impact of the medical intervention. Even in cases where the benefits of a new medical procedure or service can be judged to outweigh the risks involved, some matters will typically remain unanswered by the available evidence. We do not think CED should be used in these instances. CED should be reserved as a means to generate the information that is essential for making a positive coverage determination.



• The CED Guidance Document Should Make Clear That Evidence Generation Efforts Will Have Clear Stopping Rules. CMS should make clear in the guidance document that CED studies are not ongoing data collection exercises. The guidance document should make clear that the CED program permits the coverage of promising technologies in distinct studies designed to address specific clinical questions, and that the results of these studies are intended to inform national coverage detetminations. Each CED study must have specific study endpoints, and each must have pre-set stopping rules.



• Beneficiaries Should Not Be Denied Access To Technologies Covered Under Existing Coverage Policies During CED Evidence Gathering. CMS states in the draft guidance document that it intends to use CED to reexamine the evidence base for medical interventions that have already been covered by Medicare where "new evidence or reasonable reinterpretation of existing evidence calls into question past conclusions about the impact on patient health outcome." In one recent instance, CMS reopened a national Medicare coverage determination, found the evidence wanting, and decided to cover the service only within the context of a CED clinical trial. In our opinion, beneficiary access to a technology covered under an existing policy should not be denied while additional information is being gathered through aCED study. CMS should not revoke existing Medicare coverage for beneficiaries unless it can base this on evidence documenting that the medical intervention is ineffective. Existing coverage should remain intact while new studies are conducted that could be used to inform a new national Medicare coverage determination.



• The CED Guidance Document Should Provide More Information On The Role AHRQ Will Play. The draft guidance document (at Section VI) makes general reference to the role that the Agency for Healthcare Research and Quality (AHRQ) can play in CED matters. The draft states that "AHRQ's role will continue to develop as both agencies gain more experience with CED, and that the two agencies may address the implementation challenges together." We ask that CMS provide more detail on the specific ways that AHRQ can assist with CED, so that stakeholders can make use of AHRQ expmiise.



• The CED Guidance Should ClarifY CED Evidentiary Matters. As mentioned earlier in this letter, CMS sought the advice of the MedCAC on the use of CED to generate evidence to infmm coverage detetminations and the evidentiary criteria that could be used to invoke CED. The draft guidance document makes reference to the MedCAC deliberations that took place, but does not provide information on how CMS will proceed in light of the MedCAC discussion. We ask that CMS address this matter in the CED guidance document that is finalized. Stakeholders will look to this guidance document to anticipate when CED will be used in coverage decision-making and to consider the sh1dy designs that may be appropriate to answer outstanding questions concerning the impact of a medical intervention on patient outcomes.

In our opinion, CED studies should be cooperative ventures in which CMS fully engages relevant stakeholders and is sensitive to the challenges associated with evidence generation. To the degree to which CMS chooses to approach CED in a regulatory vein, with overly prescriptive requirements on the type of evidence that should be generated and limited dialogue with stakeholders impacted by the technologies and procedures under review, we believe that an oppmiunity to fill in the evidentiary gaps required for coverage of promising new technologies will have been missed. For this reason, we ask that the draft revised CED guidance be modified to include relevant stakeholders most familiar with the medical intervention- clinicians, patients and caregivers, and technology manufacturers. The collaboration and involvement of these stakehoiders in the design, conduct, and funding of CED studies is essential to the success of the program.

We do not believe this function can be met by an existing federal advisory committee, like MedCAC. While MedCAC can assist CMS by providing general oversight and advice for the CED program as a whole, the expetiise needed to guide specific CED studies should be focused on the particular medical technology or procedure being studied. We believe that separate stakeholder groups should be formed for each CED effort that is undetiaken- drawing on the expertise of those most familiar with the technology in question. The participation of these stakeholders will ensure that the right study questions are asked, that patient-centered outcomes are given their proper consideration, that the challenges associated with study design and funding are approached in a practical and economic way, and that the process has legitimacy.

We also recommend that the guidance make clear that CED evidentiary requirements will be flexible, tailored to the unique circumstances bearing on the technology under consideration. We do not believe that CMS should make use of pre-set evidentiary thresholds or formulas in managing the CED program, or that it specify the study design for CED studies. Rather, CMS should respond to the specific study approaches suggested by stakeholders without pre-judging the merits of these study designs. CMS should not rule out a particular research approach in advance of reviewing the details of a clinical study plan that is suggested.

In the draft guidance document, CMS identifies the potential for a gap in Medicare coverage that might occur following the end of a CED study and a coverage determination based on the results of the CED study. The discussion in the document appears to state that this "coverage gap" might be addressed during the planning of CED studies- but it provides no assurances that this matter will be addressed. In our opinion, the CED guidance document should assure stakeholders that CMS will address this matter prior to the initiation of aCED study. Lack of cetiainty in this area will dampen industry willingness to undetiake CED data collection efforts.

In summary, St. Jude Medical appreciates the effotis CMS has made to update its guidance to stakeholders on the CED program. We consider CED to be an impmiant tool to generate infonnation to address the questions that arise during the national coverage process that prevent the coverage of promising new technologies. The focus of CED should be on generating evidence on important matters that prevent a positive coverage determination from being made; CED should not be used as a means to generate additional information that is not essential for this purpose.

We hope that the comments submitted on this guidance document will lead to fmiher substantive revisions, including added clarity on how CMS intends to proceed with the CED program. In particular, we look forward to CMS incorporating a more explicit role for relevant stakeholders in the CED process, additional specificity on the situations where CED will be used, and a realistic and collaborative approach to evidence generation.

We believe that managing aCED program involves considerable judgment in determining which matters are best suited forCED. It also requires substantial administrative skill and resources given the complexity of the medical interventions under investigation, as well as a sensitivity to the views of stakeholders. In our view, CED should be used only in situations where beneficiaries have the most to gain in terms of access to promising technologies, where the value of infom1ation collected will exceed the cost of evidence generation, and where Medicare participation in a CED study can be of most value.

Thank you for considering these comments on the draft CED guidance document. If you have any questions, please contact me directly at mdomyahn@sjm.com or at (651) 756-6003.

January 28, 2013

Marilyn Tavenner
Acting Administrator
Centers for Medicare and Medicaid Services
Department of Health and Human Services
Room 445-G
Hubert H. Humphrey Building
200 Independence Avenue, S.W.
Washington, D.C. 20201

Dear Administrator Tavenner:

The Association of Community Cancer Centers (ACCC) appreciates this opportunity to comment on the Centers for Medicare and Medicaid Services’ (CMS) Draft Guidance for the Public, Industry, and CMS Staff on Coverage with Evidence Development (Draft Guidance on CED).[1]  ACCC represents more than 17,000 cancer care professionals from approximately 900 hospitals and more than 1,200 private practices nationwide.  These include Cancer Program Members, Individual Members, and members from 25 state oncology societies.  It is estimated that 60 percent of cancer patients nationwide are treated by a member of ACCC.

Similar to CMS, ACCC is committed to improving health outcomes for Medicare beneficiaries, and we share CMS’s interest in developing better evidence for use by patients, physicians, and policy makers.  Cancer is an extremely complex disease with many variations among stages, organs, and complications.  As such, our members depend on a substantial body of valid clinical data to provide the best quality care to their patients, and many of them are involved in the clinical trial research that produces these data.  We believe that continued clinical research is essential to further improve patient care and must be a priority for all stakeholders involved in cancer care, including CMS.  We strongly believe that the development of evidence should not come at the expense of patient access to the entire continuum of quality cancer care, however, including beneficiary access to the most appropriate cancer therapies, both through participation in clinical trials and outside clinical trials.  With that in mind, we offer the following comments on the Draft Guidance on CED.

1. CMS Should Adopt the Principles for the Application of CED Included in the 2006 Guidance.

In 2006, CMS developed a guidance document that established eight principles with respect to the application of CED:

1. National coverage determinations (NCDs) requiring CED will occur within the NCD processes, which is transparent and open to public comment.
2. CED will not be used when other forms of coverage are justified by the available evidence.
3. CED will in general expand access to technologies and treatments for Medicare beneficiaries. 
4. CMS expects to use CED infrequently.
5. CED will lead to the production of evidence complementary to existing medical evidence.
6. CED will not duplicate or replace the Food and Drug Administration’s (FDA) authority in assuring the safety, efficacy, and security of drugs, biological products, and devices.
7. CED will not assume the National Institute of Health’s (NIH) role in fostering, managing, or prioritizing clinical trials.
8. Any application of CED will be consistent with federal laws, regulations, and patent protections.[2]

ACCC strongly supports these principles in light of their potential to “expand access to technologies and treatments for Medicare beneficiaries.”[3]  We also believe that these principles will help ensure that CED fosters the development of important clinical evidence in an efficient manner that does not duplicate or compromise the activities of other federal agencies.  We were disappointed that CMS did not include these principles in the Draft Guidance on CED.  Although CMS indicated that it believes some of these principles are not moot, it did not identify which principles it believes are moot or why it did not include the other, non-moot principles in the Draft Guidance on CED.  Without this information, it is difficult for stakeholders such as ACCC to comment meaningfully on CMS’s draft.  ACCC believes all of these principles continue to be applicable and strongly urges CMS to adopt them in the final CED guidance document.

2. CMS Should Apply CED in a Limited Manner, Recognizing the Value of the Local Coverage Process and Other Means of Generating Evidence Available to CMS.

ACCC believes that CED can play an important role in generating clinical evidence and speeding patient access to innovative cancer care technologies.  CMS should ensure that CED does not interfere with the local coverage process, however.  Because local contractors are able to make evidence-based determinations regarding whether a treatment is reasonable and necessary for a specific patient,[4] Medicare’s local coverage process provides a critical means for beneficiaries to gain access to innovative therapies based on clinical evidence and in conformity with evolving standards of care.  Indeed, in its 2005 draft CED guidance, CMS noted that “it is not the intent of this approach to reduce the importance or frequency of local coverage determinations as a pathway by which new technologies are made available in the Medicare program.  We also do not anticipate circumstances under which CED would represent a net reduction in coverage available under existing local coverage policies.”[5]  CMS confirmed this intent in the 2006 final guidance, when it declared that CED “will not be used when other forms of coverage are justified by the available evidence” and “will in general expand access to technologies and treatments for Medicare beneficiaries.”  We urge CMS to confirm in the new final guidance document that CED will not supplant the local coverage process.

We also want to take this opportunity to note that CMS is not limited to using its coverage authority to further develop evidence regarding treatment options for Medicare beneficiaries.  For example, the agency already has launched an Integrated Data Repository to serve as a comprehensive research resource,[6] as well as implemented several initiatives to collect data regarding the quality of care received by Medicare beneficiaries in a variety of settings.[7]  CMS also supports Medicare beneficiaries’ participation in clinical research through the Clinical Trial Policy.[8]  These initiatives facilitate evidence development on a wide array of items and services without tying data collection to coverage of a particular item or service.  CMS should continue to work with stakeholders to identify methods of encouraging additional research that do not restrict beneficiaries’ access to treatment options.  This is particularly critical for patients battling cancer, many of whom are dependent on innovation for continued treatment options in the fight against their disease.

Relatedly, CMS should remove barriers to coverage in existing NCDs that are not based on analysis of specific technologies.  Several long-standing NCDs establish that any items and services not listed are not covered by Medicare for a particular indication.  In order for Medicare beneficiaries to have access to new technologies for these indications, the existing NCD must be reconsidered.  Failure to do so could delay access to appropriate technologies and impose significant administrative burdens on CMS.  We continue to recommend that CMS review all NCDs that deny coverage for unspecified items and services, remove those provisions from the policies, and allow contractors discretion to cover new technologies in a timely manner.

3. CED Should Not Be Used for FDA-Approved or Medically Accepted Uses of Drug and Biological Therapies.

By statute, Medicare contractors must recognize as “medically accepted” all FDA-approved uses of drugs used in an anti-cancer chemotherapeutic regimen as well as off-label uses of such drugs when supported by citations in certain compendia or by clinical evidence in peer-reviewed literature.[9]  New drugs used by the Medicare population are required to undergo a rigorous premarket approval process with the FDA.  During this process, the FDA reviews data to determine the population for which the therapy is approved, which then is identified clearly in the prescribing information, together with the underlying data.  ACCC urges CMS not to undermine this process by requiring additional post-approval studies regarding the approved indications of these therapies.  Instead, CMS should adhere to its principle that “CED will not duplicate or replace the FDA’s authority in assuring the safety, efficacy, and security of drugs, biological products, and devices”[10] and refrain from using the CED process for FDA-approved uses of such products for the Medicare population (i.e., individuals age 65 and older and the disabled).  In addition, unapproved uses of these drugs that are supported by the compendia or clinical evidence in peer-reviewed literature should not be subject to CED because Congress established clear evidentiary requirements for coverage of these therapies.  CMS correctly recognized this requirement in its NCD with CED for anticancer chemotherapy for colorectal cancer, when the agency expressly stated that “[c]ontractors will continue to make coverage determinations for medically accepted uses of off-label indications based on guidance provided by the Secretary.”[11]  We strongly urge CMS to follow this approach in the future and to explicitly indicate in the final guidance document that it will do so.

4. CMS Should Apply CED Only in the Context of the NCD Process.

In the CED Draft Guidance, CMS does not explicitly state whether it will apply CED beyond the NCD process, although in its public solicitation, it indicated its intent to do so.[12]  If CMS does in fact apply CED in other contexts, this would be a change in policy from the 2006 CED guidance, which, under which Principle 1 states that “NCDs requiring CED will occur within the NCD process, which is transparent and open to the public.”[13]  ACCC strongly supports this principle and believes that CED must be guided by public input to ensure that it is not employed unnecessarily.  No one entity is aware of all of the relevant literature and other evidence that may support or refute the utility of a particular medical technology.  Requesting public comments through a clear and predictable mechanism allows the agency to consider all of the known risks and benefits of the technology before deciding whether to proceed with CED.  The NCD process is ideal for this purpose as it provides stakeholders with access to CMS’s draft decision as well as an opportunity to submit comments as part of a well-established, transparent, public process.  To the extent that CED is implemented through the local coverage process, any such application of CED should adhere to the same principles as NCDs that use CED, including openness, transparency, and minimal burdens on beneficiaries, providers, and other stakeholders.  CMS should make clear in the final guidance document the mechanism or mechanisms by which it intends to apply CED so that stakeholders have adequate notice about the agency’s intentions.

5. CMS Should Not Require Medicare Beneficiaries To Enroll in Clinical Trials to Access the Most Appropriate Treatment.

Even when CED does apply, Medicare beneficiaries should not be required to enroll in clinical trials in order to have access to the treatment options that are most appropriate for their conditions.  As stated above, ACCC believes that clinical research is essential to improving patient care.  Clinical research yields benefits for all patients, either through direct participation in trials or through implementation of improved treatment regimens based on trial results.  We further believe that Medicare beneficiaries should be encouraged to participate in clinical trials appropriate for their condition and care needs.  We note that many patients, however, particularly the elderly, are not eligible to participate in clinical trials due to exclusion criteria.  Indeed, a large majority of Medicare beneficiaries are ineligible to participate in clinical trials due to comorbidities.  This problem would be compounded to the extent that the study criteria under a CED policy are too restrictive.  In addition, beneficiaries may choose not to participate if a trial would require them to experience significant inconvenience, such as traveling long distances for care or having to change physicians.  Beneficiaries inrural areas, for example, might not want to receive care far away from their friends and family.  Also, patients often are reluctant to leave the physicians and nurses they know and trust to participate in clinical trials.  Excluding coverage for these patients would be bad policy.  Instead, as in CMS’s NCD with CED for anticancer chemotherapy for colorectal cancer, NCDs with evidence development should “make[] no change in coverage for any off-label uses of these drugs provided outside of the clinical trials identified” in the decision memorandum.[14] 

6. CMS Should Ensure Beneficiaries Receive Continued Coverage for Their Treatment After the CED Study Ends.

ACCC appreciates that CMS has recognized the need to address patient access to items and services subject to CED in the period between when the CED study ends and a final coverage determination.  As noted above, we strongly believe that Medicare beneficiaries should have access to the treatment options that are most appropriate for their conditions whether or not they are enrolled in a clinical trial.  For patients that do participate in CED studies, however, addressing the potential coverage gap is crucial.  For patients battling cancer, continued coverage for treatment literally can make the difference between life and death. 

In the Draft Guidance on CED, CMS indicates how it “may” address this issue.  ACCC urges CMS to provide more concrete guidance to provide assurance to patients and their caregivers that they will continue to have access to treatments available to them as study participants and transparency regarding what is necessary to secure that access.  ACCC also asks CMS to consider whether potential approaches less burdensome than the ongoing use of observational studies following the end of a randomized controlled trial are available to provide coverage once CMS has the data it needs to make final coverage determination.  This will help ensure that resources are available for the type of clinical trial research that produces the most useful data for stakeholders in the cancer community. 

7. CMS Must Take Steps to Minimize the Financial Burden of CED.

Finally, as CMS knows, there are significant costs associated with conducting a CED stud, including costs associated with collecting data and maintaining registries.  Thus far, the costs of collecting and analyzing data have been borne almost entirely by Medicare providers and innovators, and not by CMS.  ACCC was encouraged to see that CMS believes there is a role for the Agency for Healthcare Research and Quality (AHRQ) in establishing public/private partnerships to financially support CED studies.  ACCC urges CMS to provide additional detail about such partnerships and sources of additional public funding.  ACCC also continues to urge CMS to work with patients and stakeholders to ensure that CED is truly necessary and implemented in the most efficient and cost-effective manner possible.  Finally, we ask CMS to evaluate its payment policies to ensure that providers are compensated adequately for these non-routine costs of participating in clinical research required by CED. 

ACCC greatly appreciates this opportunity to comment on CMS’s Draft Guidance on CED.  We are grateful to CMS for its continuing efforts to expand coverage of innovative treatments for beneficiaries fighting cancer.  Our members constantly search for tools to appropriately diagnose, treat, and manage cancer, and ACCC looks forward to continuing to work with CMS to establish coverage decisions that allow beneficiaries to access important technologies.  We would be pleased to answer any questions regarding these comments.  Please contact Matthew Farber at 301-984-9496, ext. 221 if ACCC can be of any assistance as CMS continues to evaluate its CED process.

  Sincerely,

[1] Draft Guidance for the Public, Industry, and CMS Staff Coverage with Evidence Development in the Context of Coverage Decisions, Nov. 29, 2012, http://www.cms.gov/medicare-coverage-database/details/medicare-coverage-document-details.aspx?MCDId=23 (hereinafter “Draft Guidance on CED”).

[2] Mational Coverage Determinations with Data Collection as a Condition of Coverage:  Coverage with Evidence Development (July 12, 2006) (hereinafter “2006 Guidance Document”).

[3] Id.

[4] CMS’s long-standing instructions to carriers allow coverage when the use is “determined by the carrier to be medically accepted generally as safe and effective for the particular use.”  Medicare Benefit Policy Manual (CMS Pub. 100-02), ch. 15, § 50.4.5.

[5] Draft Guidance for the Public, Industry, and CMS Staff:  Factors CMS Considers in Making a Determination of Coverage with Evidence Development, April 7, 2005.

[6] CMS, Integrated Data Repository, https://www.cms.gov/IDR/.

[7] See, e.g., CMS, Physician Quality Reporting System, https://www.cms.gov/PQRS/.

[8] NCD Manual, § 310.1.

[9] Social Security Act § 1861(t)(2).

[10] 2006 Guidance Document.

[11] Medicare National Coverage Decision Manual (CMS Pub. 100-3), § 110.17.

[12] CED Public Solicitation, Nov. 7, 2011, http://www.cms.gov/medicare-coverage-database/details/medicare-coverage-document-details.aspx?MCDId=8&McdName=CED+Public+Solicitation&mcdtypename=Guidance+
Documents&MCDIndexType=1&bc=AgAEAAAAAAAA&.

[13] 2006 Guidance Document.

[14] Medicare National Coverage Decision Manual (CMS Pub. 100-3), § 110.17.

January 28, 2013

Louis B. Jacques, MD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd
Baltimore, MD 21244

Dear Dr. Jacques:

The World Molecular Imaging Society (WMIS) and National Oncologic PET Registry (NOPR) Working Group are pleased to submit these joint comments on the Centers for Medicare & Medicaid Services (CMS) draft guidance on Coverage with Evidence Development (CED).[1]

WMIS is an international scientific and educational organization dedicated to the understanding of biology and medicine through multimodal in vivo imaging and the utilization of quantitative molecular imaging in patient care. The foremost and authoritative society in molecular imaging, WMIS was formed in 2011, as a result of the merger of two of the premier molecular imaging societies—the Academy of Molecular Imaging (AMI) and the Society for Molecular-Genetic Imaging.

The NOPR is sponsored by WMIS and managed by the American College of Radiology (ACR). The NOPR is one of the first CED projects undertaken by CMS and has been in operation since 2006. The NOPR Working Group’s original belief that data collection is an important tool for both CMS and Medicare beneficiaries has been reinforced by our seven years of experience in implementing, improving, and operating a large-scale CED study.

Statutory Authority for CED Informs Many Aspects of CED

CMS defines the statutory authority for CED by citing two different prongs of Social Security Act, Section 1862(a)(1), which enumerate non-covered services. Subsection (a)(1)(A) denies payment for services not reasonable and necessary in the diagnosis and treatment of disease, and subsection (a)(1)(E) denies payment for services not reasonable and necessary to further the purposes of the Agency for Healthcare Research and Quality (AHRQ). CMS states that it will only invoke CED when a service is not reasonable and necessary under subsection (a)(1)(A), such as when evidence is insufficient for “confident” conclusions. In order to make this determination, CMS must review the existing body of evidence for the service and find it faulty. CMS presumably will define how it has found the evidence to be insufficient, which will usually fall into one of four categories articulated in Section V.A of the Draft Guidance:

1. The evidence is not relevant enough to health outcomes;
2. The evidence is not generalizable enough to the Medicare population;
3. The evidence base has evolved and no longer gives confidence in the benefits of the service; or
4. The evidence is not generalizable enough to typical settings of Medicare beneficiaries.

We believe an effective CED policy should be structured around an evidence review that identifies a promising medical technology for Medicare beneficiaries, but concludes that there is an evidence gap. The CMS review should provide a clear description of the specific data CMS would like to see generated (subject to public comment). This approach will lead in a rational way to a CED-based study that provides sufficient data to address the evidence gap.

The nature of the individual technology may point to a registry as the ideal study, or may reveal an evidence gap that can only be resolved by a randomized controlled trial. Identifying the extent and precision of the evidence needed will also assist the stakeholder sponsors and CMS in developing the study design, projecting the necessary study size and the likely study duration, and establishing the appropriate period of follow-up required. Alternatively, depending upon the type of evidence that CMS seeks to generate, CMS could simply delineate an explicit set of study design elements: design, size, duration, follow-up, and primary end-point. In past instances of CED, CMS has often negotiated the details of the CED with the developer sponsor long after the release of the final decision memorandum.

Ending Data Collection Requirements

The NOPR is one of the first CED programs that successfully moved from data collection to a positive National Coverage Decision. Additionally, CMS has a pending National Coverage Analysis (NCA) to end the data collection requirements for the remaining FDG-PET oncologic indications.[2] To this end, NOPR is concerned that the process for ending data collection for a CED study is still not clearly articulated in the Draft Guidance. In the case of the CED for FDG-PET, it will have taken two NCAs and over three years to end the data collection requirements. Unlike NOPR, which was designed to be self-funded, many CED programs may lack sufficient resources to continue generating data for such an extended length of time. Moreover, there is a policy implementation question of whether a CED study should continue operating after it completes the collection of the data it was designed to collect.

The Draft Guidance’s “overarching principle” is that CED should end in one of three circumstances: 1) When no CED studies are approved within the requisite timeframe; 2) When approved CED studies are not completed within the requisite timeframe; or 3) When CED studies “are completed.” As we noted in our prior comments, our extensive experience in operating the NOPR registries under CED has convinced us of the importance of having in place a clear and defined process for terminating CED prior to the initiation of CED data collection. While the specifics will likely vary from question to question, articulating such a process in advance will expedite the transition without the need for a lengthy (and often nearly year-long) NCA process.

We thus encourage CMS to clearly delineate in the Final Guidance between procedures for ending CED because CED has failed (which would be the case under the first two conditions) and procedures for ending CED because CED has been successfully completed (which would be the case under the third condition). We believe that CMS has already begun to take valuable steps with regard to minimizing the possibility of “failed CED” by establishing timespan rules and requirements in recent NCDs incorporating CED. For example, qualifying CED trials may be required to launch within a stated period, and be completed within a stated period. We believe sponsors will be incented to finish trials within this period, because after this period CMS financial support via payment of the service covered under CED will end.

However, the third condition—in which CED data was successfully collected, analyzed and publically reported (thus completing the CED requirements) is where we believe that CMS needs to provide additional guidance and a clearer time frame and process pathway. We strongly encourage CMS to include in the Final Guidance a transition pathway from a successful CED program to expanded coverage without the typical 9-to-12 month NCA process. As the Draft Guidance acknowledges, at present the coverage status of a service under CED cannot be revised without a second NCA. This approach is lengthy, time consuming, and requires the dedication of significant resources for both the CED sponsors and CMS staff. Indeed, in practice, the formal NCA requirements can allow an unsuccessful CED project to continue operating longer than is warranted. Neither Medicare beneficiaries nor the taxpayer are well served by the current approach.

We thus encourage CMS to provide additional detail in the Final Guidance about how CMS will determine when a successful CED study is deemed “completed,” and to articulate the procedures by which administrators of approved CED studies can seek such a determination from CMS if and when necessary.

Preventing Coverage Gaps Following CED

CMS acknowledges a major beneficiary access issue is that “[u]nder CED, there is a potential period of noncoverage between the end of the study and the agency’s review of the scientific results.” We agree that the potential disruption of coverage that may follow the period of coverage via CED could have adverse consequences for Medicare beneficiaries. We urge CMS to include provisions in the Final Guidance that would mitigate this possibility.

This issue could arise in one of several ways. For instance, in some cases, such as registries, sponsors may enter real-time data as to accrual and metrics into the project database, enabling more rapid analysis of the resulting data. In other cases, interim abstract data or data from other unrelated trials (perhaps international ones) may appear and provide strong evidence that the service is medically valuable. In such instances, hard-wiring the end of coverage into an NCD involving CED and requiring nine months or more to allow coverage through a NCA would potentially harm Medicare beneficiaries.

CMS states in the Draft Guidance that:

"We may address the issue of ongoing coverage by working with investigators to develop integrated research strategies during the planning of CED studies. For example CED studies may be designed to accommodate the complementary roles of randomized controlled trials (RCTs) and practical observational studies to close outstanding evidence gaps and allow coverage after an RCT ends where appropriate. An interim analysis, based on pre-agreed public criteria, would serve to open or close enrollment in the follow up study."

We support the concept advanced in the Draft Guidance that, where this gap in coverage follows an RCT-based CED study, a gap in coverage could be bridged by combining such RCTs with “practical observational studies.” Where the CED study is of the registry type, CMS could work with sponsors to define a rational cut-point for data analysis and publication, but the registry would not need to end at that deadline. Both approaches would allow CMS “to close outstanding evidence gaps and [also] allow coverage after an RCT ends where appropriate.”

Evidentiary Criteria for CED

The Draft Guidance states that CED will be triggered by the discovery of evidence gaps that would otherwise bar full coverage for a service. High-quality CED study design will go a long way toward establishing when a particular service under review will be considered reasonable and necessary, both by defining at the outset how (and by how much) the existing evidence falls short, and by establishing CED trial designs, scope, and endpoints that will bridge the current evidence gap and provide the required evidence for coverage.

From our own experience in implementing CED with the NOPR, we believe it is essential that the Final Guidance provide additional detail on how CMS will—for each proposed CED study—individualize and suggest the primary endpoint of interest to CMS. For diagnostic and prognostic technologies in particular, we believe there is a need to identify acceptable intermediate endpoints of improved patient outcomes. For example, in November 2012 the Medical Imaging & Technology Alliance (MITA) convened a Positron Emission Tomography (PET) Endpoints Workshop that brought together stakeholders to discuss a framework for the coverage of emerging PET radiopharmaceuticals and procedures. The Workshop reached consensus that diagnostic endpoints should most commonly be assessed on the basis of evidence for impact on patient management via changes in treatment planning.

Broadening Coverage with Research

While Draft Guidance suggests using a combination of RCTs and practical observational studies to bridge potential gaps in ongoing coverage, we note that all CED programs to date have limited coverage to beneficiaries participating in a study. We believe that this limitation is not necessary in all instances, and encourage CMS to add language in the Final Guidance enabling broader access by Medicare beneficiaries to diagnostic technologies even during the period of the CED study. The concept has been referred to in the academic literature as “only with research,” in contrast to “only in research.”

At present, only those Medicare beneficiaries who are actually participating in the CED-sponsored registry or trial are entitled to coverage for their use of the CED technology. Yet in certain instances, such as a novel therapeutic where the endpoint of interest is survival and the condition of study has no current effective therapy, it may be appropriate for conditional and time-limited coverage to be made available to all Medicare beneficiaries while the technology is being evaluated under CED, regardless of whether those specific individuals are themselves participating in the registry or trial. This approach also addresses, in part, legitimate questions that have been raised about the ethics of CED.[3]

For example, an RCT (or a very complex registry) could be ongoing in a relatively small number of subjects, while all other subjects would be entered into a low-level registry that collects certain key patient attributes, accompanied by a plan to utilize claims data to examine outcomes at some later time. We believe such an inclusive policy would actually result in higher-quality CED data being collected in a subset of patients and/or facilities. Indeed, while there are always concerns for referral or spectrum biases, this approach could allow more in-depth data collection and sub-group analyses.

Most importantly, we believe the importance of ensuring high-quality data need not (and should not) have the consequence of denying the potential benefit of the CED technology during the CED process to Medicare beneficiaries who—through no fault of their own—do not have access to the CED registry or trial.

Conclusion

WMIS and the NOPR Working Group appreciate the opportunity to provide these joint comments on the Draft Guidance for CED. We appreciate the assistance and support that CMS has provided to the NOPR over the past seven years, and look forward to working with CMS to provide any additional information or insight that would be valuable in the decision making process about the future of CED.

Sincerely,

From Joanne Lynn, MD, MA, MS, Director, Center for Elder Care and Advanced Illness, Altarum Institute

I appreciate the work that CMS and others have done to develop the processes and legitimacy of providing coverage during evidence development. I recognize that many astute observers have already contributed to this effort, and I will not aim to duplicate or take issue with that record. I am writing mainly to encourage CMS to consider allowing more consideration of the variety of evidence sources that might make a workable plan for evidence development for the Medicare population. As it stands now, the guidance only addresses classic, formal trials of a particular intervention. In order to have the rigor that the Guidance document aspires to attain, many compromises on generalizability and applicability to the full array of Medicare beneficiaries are routine. Ordinarily, the patient has to be mobile to get to a research center; capable of consent (and actually consenting); untouched by myriad competing causes of illness, disability or death; and in one of a limited number of participating centers. There are issues for which this approach is exactly the right approach.

However, there also are a number of alternative ways of gaining sufficient insight to rule on the merits of an intervention for a particular population. The most obvious is that, especially as we get dramatically larger datasets with clinical information across time, we could mimic clinical trials very efficiently in observational databases. The Archimedes work is an example, though there are more examples coming along often. In a database of linked Medicare claims, Part D use, and MDS and OASIS (as in the Chronic Data Warehouse), estimates of outcome effects could be generated at very low cost in the phase of dissemination in which an intervention is being used at different rates by different providers. The database is large enough to support substantial sub-set analyses. It may well be that this sort of approach would clarify the merits of coverage for part of the population or some of the indications for use (both showing merit and justifying coverage, and showing harms or lack of merit and justifying non-coverage). In addition, some issues might remain unclear and require focused investigation, which could be well-targeted and efficient with the grounding of insight from concurrent and historical data.

This is one example of the research that could be allowed under a broader CED guidance document. I believe that we are only a few years away from being able to give advice to patients and families on the basis of concurrent analysis of large databases (whether from a large cohort, a regional repository, or a particular provider’s experience base). A patient will be able to get answers to questions like, “For the group of patients relevantly similar to me that you treated 1 to 2 years ago, how many have died, how many live in nursing homes or have serious ADL impairments, and how many resumed independent living?” We will have to work on the “relevantly similar” and standardizing the documentation of outcomes, but that work is a useful side-effect of the standard-setting in meaningful use of electronic records. The point here is that, if patients can ask for that sort of information, surely CMS can also. In parallel, CMS can ask, “For the beneficiaries with relevantly similar situations, how did those who got the proposed intervention do, compared with those who did not?” Obviously, we would need to work on how to stratify or adjust for differences in the cohorts, and we would need to weigh the risks of observational data in making judgments about the insights gained. This is, however, not different from having to weigh, for randomized clinical trials, the impact of all the restrictions on inception cohorts and the differences in practice settings that can support rigorous research

Thus, I would encourage CMS to finalize this guidance but also to open the possibilities of building on a “learning health care system” and taking advantage of the opportunities now and in the near future to learn quickly and efficiently from naturally occurring variations in implementation of services. This approach might well apply to many more coverage determinations than the rare use of the methods now endorsed.

January 28, 2012

Via Electronic Submission

Marilyn Tavenner, Acting Administrator
Centers for Medicare and Medicaid Services
Department of Health and Human Services
Room 445–G 
Hubert H. Humphrey Building 
200 Independence Avenue, SW 
Washington, DC 20201

Re: Coverage with Evidence Development Draft Guidance

Dear Acting Administrator Tavenner:

On behalf of the Medical Device Manufacturers Association (MDMA), a national trade association representing the innovative sector of the medical device market, I am submitting the following comments in response to the Centers for Medicare & Medicaid Services’ (CMS) Draft Guidance for the Public, Industry, and CMS Staff Coverage with Evidence Development (CED) in the Context of Coverage Decisions (CED Draft Guidance).[1  MDMA represents hundreds of medical device companies, and our mission is to ensure that patients have access to the latest advancements in medical technology, most of which are developed by small, research-driven medical device companies.

Introduction and Summary of Recommendations

MDMA appreciates this opportunity to comment on the CED Draft Guidance.  Medical devices are a critically important part of the health care system, and MDMA’s members devote considerable resources and effort to improving and expanding the clinical evidence to help Medicare beneficiaries and providers make the most appropriate diagnostic and therapeutic decisions.  MDMA therefore supports CMS’s efforts to improve the CED process to reduce barriers to innovation and improve health outcomes for Medicare beneficiaries.  Our primary concern is that such efforts do not inadvertently limit patient access to advanced medical technologies.  MDMA’s comments and recommendations focus on the following issues:

• Principles Governing the Application of CED
• CMS should identify the principles governing the application of CED set forth in its 2006 CED guidance document that it believes are moot and explain the basis for that determination so stakeholders can provide meaningful feedback;
• CMS should adhere to the principles governing the application of CED set forth in its 2006 CED guidance document because they were developed with extensive stakeholder input and continue to be relevant today;
• Applying CED
• CMS should proceed cautiously and in collaboration with manufacturers when considering the use of CED for a particular item or service to ensure that it does not hinder access to appropriate care and the development of clinical evidence through other means, including the local coverage process;
• CMS should clarify that when CED is applied, it will occur within the national coverage determination (NCD) process;
• In instances where manufacturers have worked collaboratively and transparently with the Medicare Administrative Contractors (MACs) in a manner that has not been burdensome and has expanded patient access to innovative treatments, CMS should ensure that these local coverage determinations (LCDs) with evidence collection requirements may continue under the final CED Guidance.
• In applying the standards of scientific integrity, CMS should carefully analyze the value of additional information and require only the minimum amount of data necessary to enable the agency to make an informed “reasonable and necessary” determination;
• Ending CED
• CMS should clarify that it will clearly define the endpoint for data collection at the outset of each application of CED;
• CMS should clarify the process by which it will make a coverage decision after CED ends;
• CMS should find a less burdensome means of covering an item or service after the end of CED study until a coverage determination is made than requiring other, ongoing studies;
• Role of the Agency for Healthcare Research and Quality (AHRQ)
• CMS should more clearly define the role of AHRQ in the CED process and in particular how it will provide funding through public/private partnerships;
• Formal Evidentiary Criteria
• CMS should define evidentiary thresholds in general terms in its final guidance document;
• CMS should involve stakeholders in defining the specific evidentiary threshold necessary to invoke CED for a particular item or service;
• CMS should make explicit that thresholds for invoking CED will be established at levels that ensure that CED continues to be used infrequently and not when other forms of coverage are justified by the available evidence; and
• Existing National Non-Coverage Decisions
• CMS should review its existing national non-coverage decisions and remove any provisions that deny coverage to new technologies that CMS has not specifically reviewed.

Principles Governing the Application of CED

CMS includes in the CED Draft Guidance information related to goals, history, and authority for CED; however, the agency fails to include principles to guide the application of CED, such as those included in the 2006 CED guidance document.[2  CMS indicates that “some” of these principles are now “moot.”  CMS does not identify the specific principles that it believes are moot nor does it discuss its basis for finding them to be so.  MDMA would like CMS to provide more discussion around its decision to not include the principles CED Draft Guidance so that MDMA and other stakeholders can provide specific input to the agency on that decision. 

The principles in the 2006 guidance document were developed with extensive stakeholder input and continue to provide appropriate guideposts for the use of CED today.  To ensure that CED does in fact produce gains in innovation that benefit Medicare patients and does not inadvertently stifle new technology, MDMA urges CMS to adhere to those principles, which include the following:

1. NCDs requiring CED will occur within the NCD processes, which is transparent and open to public comment.
2. CED will not be used when other forms of coverage are justified by the available evidence.
3. CED will in general expand access to technologies and treatments for Medicare beneficiaries.
4. CMS expects to use CED infrequently.
5. CED will lead to the production of evidence complementary to existing medical evidence.
6. CED will not duplicate or replace the Food and Drug Administration’s (FDA’s) authority in assuring the safety, efficacy, and security of drugs, biological products, and devices.
7. CED will not assume the NIH’s role in fostering, managing, or prioritizing clinical trials.
8. Any application of CED will be consistent with federal laws, regulations, and patient protections.

By emphasizing that the use of CED will be limited, intended to expand access, and not overlap with or duplicate the efforts of other regulatory agencies, the principles simultaneously facilitate collection of data that help Medicare, as well as patients and providers, make better informed decisions about current diagnostic and treatment options while also ensuring that the collection of additional data does not impede medical technology innovation.  These principles should be included in the final guidance document.

Applying CED

In the CED Draft Guidance, CMS explains the reasons why Medicare considers applying CED to various items and services.  It does not, however, elaborate on how it will implement CED.  We urge CMS to proceed cautiously and in collaboration with manufacturers when considering the use of CED.  In many cases, CMS may find that CED is not necessary because evidence of clinical benefit sufficient for Medicare coverage purposes will be developed as new technology makes its way through the local coverage process.  Except in cases where there is an existing national non-coverage decision, CMS should give this process time to work before determining whether CED is appropriate.

When CMS does determine CED is appropriate for a particular item or service, MDMA urges the agency to give the public as much information as possible about why CED is being used, what the specific research question is and how the proposed data collection will answer it, when the beginning and ending of evidence collection is anticipated, what the expected cost of the evidence collection is, and what AHRQ’s specific role will be.  It is critical for CMS to explain in detail how the CED’s proposed design will answer a specific meaningful clinical question about the particular item or service involved.  CMS should give interested stakeholders and the public an opportunity to comment on this information before deciding whether and how to proceed with CED.  It is important that this process be open, predictable, and transparent. 

One of the principles in the 2006 CED guidance document is that NCDs “requiring CED will occur within the NCD process, which is transparent and open to public comment.”  MDMA strongly supports the use of CED through a process that is transparent and open to public comment when the agency determines that the application of CED is appropriate and urges CMS to clarify in the final guidance document that CED will occur in this context.  Stakeholder input, particularly from manufacturers, is essential to CMS’s ability to understand the evidence supporting a technology, any gaps in that evidence, and any additional research efforts underway to address those gaps.  The manufacturer’s comments are especially important because the manufacturer has the most knowledge of any stakeholder regarding its technology.  Only by collaborating with a device’s manufacturer can CMS learn about the full body of evidence on a technology and plans for future studies that could shape the decision of whether and how to apply CED.  This input also is critical for ensuring that any data collection requirements established through CED can be implemented successfully.

Although MDMA believes that CED should occur within the NCD process, we are aware of instances in which CED has been applied locally with great success.  Manufacturers have worked collaboratively and transparently with the MACs in a manner that has not been burdensome and has expanded patient access to innovative treatments.  We ask CMS to ensure that these LCDs with evidence collection requirements may continue under the final CED Guidance.

MDMA supports the standards of scientific integrity and relevance to the to the Medicare population that are included in the CED Draft Guidance.  These standards will help ensure that CED is used appropriately and does not inadvertently inhibit medical technology innovation.  CMS should be sure that in applying these standards, it carefully analyzes the value of additional information to the coverage process and require only the minimum amount of data necessary to enable the agency to make an informed “reasonable and necessary” determination.  MDMA recognizes the appeal of gathering as much data as possible on a technology, but CMS should not use the coverage process as a means of imposing extensive, open-ended research projects on a technology when a more focused and limited study would provide the data necessary for a Medicare coverage determination.  Doing so would unduly burden providers and manufacturers and potentially thwart further innovation by creating uncertainty about coverage and reimbursement and diverting resources from more beneficial research and development.

MDMA appreciates that CMS has clarified in the CED Draft Guidance when CED for an item or service will end.  This guidance, however, leaves unaddressed the critical issue of how the agency will define the endpoints for the CED study itself. In cases in which CMS does not specify the length of time for data collection, a burdensome reporting requirement may continue indefinitely.  Such uncertainty is unfair to those that are shouldering the burden and the cost of the data collection and inserts unnecessary unpredictability into the CED process.  CMS should address in the final guidance document that it will be clear about the endpoint for data collection at the outset of CED.

CMS also should provide additional guidance regarding the pathway for coverage after the end of CED.  CMS acknowledges that there may be gap between the end of a CED study and a decision regarding coverage of an item or service based on that study, but provides no guidance about the process the agency intends to use to evaluate the CED study data and make a coverage determination.  CMS should elaborate on this process, including establishing timeframes for decisions and opportunities for public input, in the final guidance document.

CMS does address the issue of patient access to an item or service subject to CED in the time between the end of the CED study and a coverage determination by saying that it “may address the issue of ongoing coverage by working with investigators to develop integrated research strategies during the planning of CED studies,” by, for example, using “practical observational studies to close outstanding evidence gaps and allow coverage after a [randomized controlled trial] ends where appropriate.”[3] MDMA appreciates that CMS has at least addressed the issue of patient access after the end of CED, but is very concerned that CMS’s proposed approach could result in multiple, overlapping, and duplicative studies that unnecessarily impose additional, burdensome requirements on manufacturers, providers, and patients.  MDMA urges CMS to find a less burdensome means to ensure coverage between the end of the CED study that provides the data necessary to make a coverage determination and the issuance of the coverage determination itself that would preserve scare resources for more productive activities.

Role of AHRQ

As noted above, MDMA’s primary concern is that the use of CED does not restrict access to innovative medical technology.  The costs associated with data collection and analysis under CED are not insignificant and are not wholly funded by CMS.  These costs include the non-clinical research costs of clinical trials, as well as registry development and maintenance.  MDMA members devote considerable resources to clinical research on new and innovative medical devices.  The additional costs of CED, borne in part by manufacturers, must not be so burdensome that they force manufacturers to limit the resources available for innovation.  This is a particular concern for small companies who must invest a significant percentage of their resources to get a new technology through the approval or clearance process and typically have few resources left to collect data beyond that required by the Food and Drug Administration (FDA).

In the CED Draft Guidance, CMS indicates that the authority for the application of CED is the provision of the Social Security Act that authorizes Medicare coverage in the context of research conducted and supported by AHRQ.  One of the roles of AHRQ with regard to CED, according to CMS, is its “capacity to establish public/private partnerships to financially support CED studies.”[4] Because the statutory authority for CED is premised on AHRQ’s research activities, it is important for CMS to clarify AHRQ’s role in CED process generally, particularly because AHRQ’s mission is different from CMS’s.  In particular, to address concerns regarding the costs of CED studies and the effect of those costs on medical innovation, MDMA urges CMS to more clearly articulate the types of partnerships that ARHQ may establish and the public funding that will be available for evidence collection and analysis.

Formal Evidentiary Criteria

Before it released the CED Draft Guidance, CMS convened a meeting of the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC).[5]  Among the topics the MEDCAC addressed was the use of formal evidentiary criteria in the application of CED.  CMS describes the conclusions of the MEDCAC in the CED Draft Guidance, but does not provide any of its own guidance on the use of evidentiary criteria for CED.  MDMA believes it is important for CMS to define these thresholds in general terms in a guidance document that will help improve the predictability and transparency of CMS’s coverage decisions.  CMS also should seek comments on any changes to the thresholds defined in the guidance as it gains more experience with CED. 

With regard to each individual application of CED, the evidentiary threshold will vary based on a number of circumstances, including but not limited to whether the item or service is diagnostic or therapeutic in nature, the severity of the disease, the safety profile of the technology, etc.  The specific evidentiary threshold necessary to invoke CED for a particular item or service must be identified through extensive input from stakeholders, such as physicians, researchers, and manufacturers who are deeply familiar with the technology, the existing evidence, and the opportunities and challenges associated with collecting additional data.  Only with appropriate input from the manufacturer and other stakeholders can CMS identify an appropriate evidentiary threshold for invoking CED for any item or service.  CMS should make clear in the final guidance document that it will do so.

In general, MDMA believes that the thresholds for invoking CED should be established at levels that ensure that CED continues to be used infrequently and not when other forms of coverage are justified by the available evidence, consistent with the principles established in CMS’s 2006 guidance document on CED. MDMA is confident that the appropriate use of CED can improve health outcomes for Medicare beneficiaries.  We also recognize, however, that CED involves considerable investment of time and resources by CMS and stakeholders, and therefore only should be applied when necessary.  This should be reflected in the final guidance document to avoid any uncertainty that might have a chilling effect on ongoing medical innovation.

Existing National Non-Coverage Decisions

MDMA has previously asked CMS to review its existing national non-coverage decisions and remove any provisions that deny coverage to new technologies that CMS has not specifically reviewed.  This will help ensure that Medicare’s coverage decisions do not inhibit innovation and access to improvements in care.  Some NCDs specify that only the listed items or services are covered and all other technologies are non-covered, regardless of whether CMS has reviewed those technologies.  These policies discourage innovation by shutting the door to new technologies until CMS completes a coverage analysis on each technology.  They also create an administrative burden for CMS by requiring these technologies to be reviewed through a national coverage analysis, rather than allowing local contractors to decide whether to cover them.  Rather than establishing blanket non-coverage policies for unspecified technologies, CMS should identify the exact items and services that are covered or are not covered, and provide local contractors discretion to determine whether to cover any remaining technologies.   CMS did not address this issue in its CED Draft Guidance, but MDMA continues to believe that it is an area of vital importance to continued medical innovation and urges CMS to respond accordingly.

Conclusion

In conclusion, MDMA supports CMS’s efforts to revise its CED process to reduce barriers to innovation and improve health outcomes for Medicare beneficiaries.  We ask you to take our comments into account when finalizing the CED Guidance and look forward to working with you in the future on this important issue.  Thank you.

Sincerely,

/s/
Thomas C. Novelli
Vice President of Government Affairs
Medical Device Manufacturers Association

[1] CED Draft Guidance (Nov. 29, 2012), at http://www.cms.gov/medicare-coverage-database/details/medicare-coverage-document-details.aspx?MCDId=23. 

[2] Although CMS removed this document from its website when it issued the CED Public Solicitation, the agency confirmed that CED continues to remain in place during review.

[3] CED Draft Guidance at 8.

[4] Id. at 9.

[5] MEDCAC Meeting 5/16/2012 - Evidentiary Characteristics for Coverage with Evidence Development (CED), at http://www.cms.gov/medicare-coverage-database/details/medcac-meeting-details.aspx?MEDCACId=63&bc=
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January 28, 2013

Louis Jacques, MD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Mail Stop S3-02-01
7500 Security Boulevard
Baltimore, MD 21244-1850

Dear Dr. Jacques:

Onyx Pharmaceuticals, Inc. ("Onyx") welcomes this opportunity to submit comments on the Draft Guidance on Coverage with Evidence Development (CED) in the context of coverage decisions, recently issued by the Department of Health and Human Services (HHS) Centers for Medicare and Medicaid Services (CMS).¹

Founded in 1992, Onyx is a mid-sized biopharmaceutical company focused on developing innovative therapeutics used in the treatment of rare cancers. On July 20, 2012, Onyx received accelerated U.S. Food and Drug Administration (FDA) marketing approval of Kyprolis. (carfilzomib) for injection for the treatment of patients with multiple myeloma whose disease is progressing within 60 days of treatment despite prior treatment with at least two other therapies, including bortezomib and an immunomodulatory agent. Multiple myeloma is a lifethreatening blood cancer that starts in the plasma cells of human bone marrow. The National Cancer Institute estimates that nearly 11,000 patients die of multiple myeloma each year, with about 20,000 new cases diagnosed each year.² In partnership with Bayer HealthCare, Onyx also co-markets NexavarR (sorafenib) tablets, an oral cancer therapy approved to treat certain latestage kidney and unresectable liver cancers. Also, in mid-2012, Onyx in partnership with Bayer began co-promoting within the United States a newly approved orally available colorectal cancer treatment, StivargaR (regorafenib). Kyprolis and Nexavar are orphan drug therapies approved for rare-disease populations affecting fewer than 200,000 people in the United States.

On the basis of these recent breakthroughs, Onyx has grown to more than 750 employees in the United States and Europe. As the company grows, Onyx remains deeply committed to innovating and bringing to market next-generation therapies through the development of scientifically rigorous clinical evidence for evidence-based decision-making by CMS, the Food and Drug Administration (FDA), physicians and patients.

In light of our specialized oncology focus, we offer our comments on the draft guidance from the perspective of supporting public policies that enable continued innovation and appropriate patient access to our medicines. We appreciate CMS transparency in the development and improvement of the CED process, and support CED as part of national coverage determination (NCD) decision-making. Onyx also supports the objectives of CED to improve patient access to innovative medicines and technologies and enhance the agency's decision-making capacities. Accordingly, Onyx's comments address the following proposals relating to CED:

• Application of CED to medically accepted indications. Onyx is concerned by the potential for CED to hinder and encumber an otherwise efficient physician-patient decision-making process that relies on FDA-approved indications, regularly updated major drug compendia, authoritative medical literature and accepted standards of medical practice. We believe that to protect patient access to innovative therapies, CMS should not engage in CED decision-making for therapies that are used for "medically accepted indications" as defined by the Social Security Act (SSA) § 1861, or pursuant to longstanding Medicare guidance.³
  
  
• Establishment of standards of scientific integrity. Onyx supports CMS' continued development of clear standards of scientific integrity for CED studies, and recognizes the standards established in the draft guidance as firm railings ensuring the data produced by CED investigations benefits the Medicare population. However, Onyx is concerned that CMS establishes an unfeasible requirement by stipulating that CED studies explicitly discuss how study results are or are not expected to be generalizable to subsections of the Medicare population. Accordingly, Onyx encourages CMS to remove from the list of standards of scientific integrity the requirement to discuss how results of CED studies may be applied to subsections of the Medicare population.
  
  
• Coordination between CMS and FDA. Onyx appreciates the agency's dedication to streamlining the approval-to-coverage process, as it advances the stability and predictability of the ever critical post-approval phase, and importantly ensures that patients have timely access to therapies. Yet, Onyx is concerned that CMS' proposed policy does not clarify whether the agency will apply the CED process to therapies that are subject to FDA post-approval studies. As a company that recently received accelerated approval for our flagship product, Kyprolis, Onyx strongly urges CMS to establish a policy of refraining from applying the CED process to therapies that are engaged in FDA-initiated post-market studies, as such a policy would ensure that the most innovative products are not subject to multiple and potentially duplicative studies.
  
  
• Institution of the 2006 principles governing CED. Onyx supports CMS' periodic evaluation and updating of the CED process as a means to ensure the agency is utilizing effective methodologies that fully comprehend advances in technology and the evolving landscape of the healthcare system. However, as CMS evolves the CED process, Onyx strongly urges the agency to frame its progress with the governing principles that were established in 2006 using significant public input and stakeholder collaboration. These principles are just as important today as when CED was conceived.

1. Application of CED to medically accepted indications

CMS' current policies utilizing agency-authorized compendia and standards of medical practice as sources for use in the determination of medically accepted indications of drugs and biologicals used in an anti-cancer chemotherapeutic regimens ensure timely patient access to innovative and medically appropriate treatments.⁴ As cancer therapeutics progress into the era of personalized medicine, the rapid adaptation of standards of care is increasingly critical for patient access. Accordingly, as CMS updates the CED process, Onyx urges the agency to implement revisions to the process that maintain these historically successful policies and preserve timely patient access to innovative therapies.

Post-approval, anti-cancer therapeutics experience significant changes in labeling and compendia descriptions as clinical evidence is rapidly developed and integrated into standards of medical care. As a result, applying CED in this context is duplicative, potentially cumbersome to evidence development, and in effect interjects, to the detriment of timely patient access, CED into the physician-patient decision-making process. Notably, previous efforts by the agency to apply CED-like policies to cancer therapeutics have yielded minimal benefits to patients. ⁵ As the cancer community progresses into increasingly personalized therapies and regimens, the challenges associated with applying CED to anticancer therapies and regimens are only amplified. As such, Onyx encourages CMS to continue the policy of utilizing FDA approved indications, major drug compendia, authoritative medical literature and accepted standards of medical practice as efficient and evidence-based tools for determining appropriate use of anticancer therapeutics.

2. Establishment of standards of scientific integrity

Onyx supports CMS' development of clear standards of scientific integrity for CED studies and appreciates the importance of establishing standards that ensure the applicability of CED data to the Medicare population. However, Onyx is concerned that CMS establishes a potentially regressive requirement by stipulating that CED study protocols explicitly discuss how study results are or are not expected to be generalizable to subsections of the Medicare population. Principally, Onyx is concerned that the CMS standard does not reflect the clinical reality that efficacy demonstrated in clinical trials for defined populations is not immediately generalizable to other subpopulations such as older patients who are regularly underrepresented in clinical trials because of high rates of comorbidites.⁶ Onyx urges CMS to revise the proposed standard of protocol generalizability to ensure evidence developed by CED studies does not unintentionally bar coverage for certain subpopulations within the Medicare program. [Is there more you can add about Onyx's experience studying rare cancers? It strikes me that you have a compelling example of precisely why this standard is unfeasible that would be helpful to share with the agency.]

Regular underrepresentation of older patients due to comorbidities has been reported in clinical trials for cancer treatments.⁷ Additionally, cancers, heterogenic in their root, exhibit significant pathophysiological variances by stage, site of localization, and the genetic makeup of individuals that develop these diseases. Coupled, these factors challenge and often make it impossible to accurately generalize study results to subsections of the Medicare population. Yet, Onyx believes that these factors should not stand as barriers to coverage for these populaiton subgroups; rather, Onyx supports revising the proposed standard to more accurately reflect the heterogeneity of certain diseases and the progression of medicine towards personalized regimen development.

3. Coordination between CMS and FDA

Onyx credits CMS' for its proposed use of CED as a vehicle for streamlining the approval-to-coverage process, as greater coordination between FDA and CMS advances postapproval predictability and ensures that patients have timely access to therapies. However, Onyx is deeply concerned that the agency's proposed policy does not clarify whether CED will be applied to therapies that are subject to FDA post-approval studies. Applying CED to therapies undergoing FDA post-approval studies is unnecessary and risks duplicating evidence development efforts, burdening healthcare providers and potentially delaying the development of evidence in progression towards broader access that would benefit patients.

Onyx's clinical development of Kyprolis, our first independently developed and marketed product, offers a fitting example of how the application of CED would be duplicative and potentially burdensome to healthcare providers. Kyprolis received accelerated approval from FDA on July 20, 2012 for the treatment of multiple myeloma patients who have been treated with at least two prior therapies and who have also progressed on or within 60 days of completing their last therapy. Kyprolis was granted accelerated approval in part based on the understanding that Onyx would complete the three phase 3 trials that were initiated prior to approval. The trials currently underway at Onyx are intended to demonstrate the efficacy of Kyprolis in treating relapsed and refractory multiple myeloma and confirm the endpoints on which FDA's approval was based. Were CMS to apply CED to Kyprolis, it is likely that the data sought by the agency would parallel the intended outcomes of the clinical trials, an unnecessary burden to healthcare providers and the use of agency resources.

Given the increasingly complex nature of clinical development, Onyx's experience is not altogether unique; rather, Onyx views the development and post-approval studies associated with Kyprolis as a likely norm for biopharmaceutical development in the era of genetic pathway targeting. Consequently, Onyx encourages CMS to establish as part of its finalized revisions to the CED process, a policy of refraining from applying CED to products subject to FDA postapproval studies.

4. Institution of the 2006 principles governing CED

Onyx supports the regular updating of the CED process as a means to ensure the agency is utilizing effective and advanced methodologies that reflect the progress of technology and biopharmaceutical development. However, as CMS evolves the CED process, Onyx strongly urges the agency to frame its progress with the eight governing principles that were established in 2006 with significant public input and stakeholder collaboration. Notwithstanding CMS' proposed revisions, Onyx believes the following principles should continue to govern the CED process:

• NCDs requiring CED will occur within the NCD processes, which is transparent and open to public comment.
• CED will not be used when other forms of coverage are justified by the available evidence.
• CED will in general expand access to technologies and treatments for Medicare beneficiaries.
• CMS expects to use CED infrequently.
• CED will lead to the production of evidence complementary to existing medical evidence.
• CED will not duplicate or replace the FDA's authority in assuring the safety, efficacy, and security of drugs, biological products, and devices.
• CED will not assume the NIH's role in fostering, managing, or prioritizing clinical trials.
• Any application of CED will be consistent with federal laws, regulations, and patient protections.

Applied properly, CED can provide earlier patient access to promising and innovative therapies while also generating important evidence that will inform healthcare choices. As a company that is committed to developing and bringing to market innovative therapies that extend and improve the lives of people with cancer, Onyx is support the premises underlying CED and appreciates CMS' efforts to keep the process current and useful. Thank you for your consideration of our comments, and we look forward to continuing to work with CMS and others to promote the health and well-being of individuals with significant healthcare needs.

Sincerely,

(i) the drug has been approved by the Food and Drug Administration; and

(ii)(I) such use is supported by one or more citations which are included (or approved for inclusion) in one or more of the following compendia: the American Hospital Formulary Service- Drug Information, the American Medical Association Drug Evaluations, the United States Pharmacopoeia-Drug Information, and other authoritative compendia as identified by the Secretary, unless the Secretary has determined that the use is not medically appropriate or the use is identified as not indicated in one or more such compendia, or

(II) the carrier involved determines, based upon guidance provided by the Secretary to carriers for determining accepted uses of drugs, that such use is medically accepted based on supportive clinical evidence in peer reviewed medical literature appearing in publications which have been identified for purposes of this subclause by the Secretary.

January 28, 2013

Louis Jacques, MD
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mail Stop S3-02-01
7500 Security Boulevard
Baltimore, MD 21244

Dear Dr. Jacques:

The CyberKnife Coalition (CKC) is pleased to submit the following comments in response to the Centers for Medicare and Medicaid Services’ CMS public solicitation regarding coverage with evidence development (CED). Formed in May 2003 and incorporated in April 2005, the CKC is a non-profit association of academic and community based CyberKnife user institutions, dedicated to protecting patients’ access to this life-saving technology. Since 2003, the CKC has supported efforts to collect and develop data demonstrating the therapeutic, quality of life, and economic benefits of CyberKnife treatments and has worked collaboratively with payers to ensure appropriate patient access. Over 100,000 patients worldwide have been treated with CyberKnife since it received approval in 1996 in Japan and in 1999 from the United States Food and Drug Administration (FDA).

In April, 2010 CMS held a Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) meeting on Radiation Therapy for Localized Prostate Cancer. As part of this process, the Agency for Healthcare Research and Quality (ARHQ) reviewed the clinical evidence for radiation therapies including, stereotactic body radiation therapy (SBRT), external beam radiation therapy (EBRT): 3-dimensional conformal radiation therapy (3-D CRT), intensity modulated radiation therapy (IMRT), proton therapy (PT), and low- and high-dose rate brachytherapy (BT). In its technology assessment¹ for the MEDCAC AHRQ noted:

Prior to this assessment2, AHRQ has also published a report² in 2008 on prostate cancer treatments that included surgery. In the Executive Summary of this report AHRQ concluded:

After two comprehensive assessments by AHRQ on prostate cancer treatments, which found no clear winner in terms of disease free survival and side effects, it was not surprising that, at the conclusion of the 2010 MEDCAC, Dr. Marcel Salive³, CMS Director, Division of Medical and Surgical Services, Coverage and Analysis Group, stated:

While the lack of comparative data led Dr. Salive to this conclusion, it did not mean that CMS was not interested in the production of it. On the contrary, there was a great deal of discussion on how the radiation oncology community should be doing more in this area. Given the challenges of conducting RCTs, registry was a solution many felt would help fill in the gaps. Members of the CyberKnife Coalition shared their experience of developing a registry as a means to obtain payment for prostate SBRT at the local level, which at that time was focused on meeting the requirements of the Medicare contractor in Florida, First Coast Service Options, set forth in October of 2009. The Florida prostate SBRT registry was subsequently launched in July of 2010 after consulting with CMS to ensure the data being collected included all of the elements CMS felt were important for the Medicare population.

The development of this registry, now called the Multi-Institutional Registry for Prostate Cancer Radiosurgery (RPCR), was especially interesting as much of the discussion at the 2010 MEDCAC - and since then – including the MEDCAC on CED in May 2012, has included registry as one possible solution to addressing the evidence gap. The RPCR has become an important tool that can also provide patients and clinicians with other information mentioned by AHRQ as important for decision making, such as cost and convenience. Because CMS concluded it would not be implementing a NCD for radiation therapy for the treatment of localized prostate cancer, this registry in particular, has been extremely useful to Medicare as it has provided a mechanism for data collection through local coverage determinations (LCD).

Today the RPCR has evolved from a local state registry of 10 centers in Florida to the largest SBRT prostate registry in world. As of January 2013, 1301 men have been enrolled in 37 community and academic institutions in 15 states. The registry, listed on www.clinicaltrials.gov (NCT01226004) has now been adopted in local Medicare coverage policies in 26 states and the District of Columbia (see attachment for summary). We present our experience as an example of how registry can be used as a means to collect additional data for Medicare beneficiaries in conjunction with Local Coverage Policies. Summarized below, are our lessons learned and recommendations to CMS on utilizing registry, either at the local or national level:

• Development of registries, such as the RPCR, should be a collaborative approach, involving both care providers and local Medicare contractors
• Registries can be a cost-effective way to provide Medicare beneficiaries access to innovative therapies while gathering additional data to demonstrate that the treatment is as good as or better than other currently covered options
• Registries can be developed without placing an undue burden on stakeholders - RPCR has not been burdensome for providers or for Medicare contractors
• Successful implementation of registries can be done as long as there is transparency and collaboration between multi-stakeholder groups (e.g., Medicare , users of the technology, manufacturers, etc.) that:
  • Set realistic and standard expectations for evidence development across all therapy options
  • Avoid an ever moving goal post
  • Include mutually agreed on, defined, timeframes and sign posts for success (or failure) that can:
    • Detect serious adverse events
    • Determine equivalence/reasonableness
    • Show statistical significance
  • Once agreed upon criteria are met, local contractor would remove registry requirement for continued coverage

With respect to the draft guidance we believe that our experience can be helpful for CMS as it finalizes its CED guidance. Because the guidance document is ambiguous on local contractor use of CED, we respectfully request that CMS include language in the final guidance document that does not hinder the efforts of local contractors to gather data – either as a condition of coverage and/or an appropriateness determination. We suggest the following language:

The CyberKnife Coalition appreciates the opportunity to provide comments on CED. If you have any questions on these comments, please feel free to contact us.

Regards,

Footnotes:

Novitas - MAC Jurisdictions H (TX, CO, OK, NM, AR, LA, MS) - LCD L32670 - Stereotactic Body Radiation Therapy: The clinical experience with SBRT for carcinoma of the prostate is of short term duration relative to the natural history of prostate cancer. Published peer reviewed studies of the success and complication rates are still small and of short or medium term duration. Prominent specialty societies and academicians suggest SBRT is still investigational for the treatment of early stage prostate cancer, while others who currently use the equipment feel SBRT has some selected advantages. Treatment of prostate cancer is covered only when the patient is enrolled in a clinical study listed on ClinicalTrials.Gov.

Novitas - MAC Jurisdictions H (PA, MD, DC, NJ, DE) - LCD L30277 - Stereotactic Body Radiation Therapy (SBRT): The clinical experience with SBRT for carcinoma of the prostate is of short term duration relative to the natural history of prostate cancer. Published peer reviewed studies of the success and complication rates are still small and of short or medium term duration. Coverage and payment of SBRT for prostate cancer will require:

1. Physician documentation of patient selection criteria (stage and other factors);
2. Documentation and verification that the patient was informed of the range of therapy choices, including risks and benefits, AND
3. Documentation of the specific reasons why SBRT was the treatment of choice for the specific patient.

Noridian - MAC Jurisdiction F (WA, ID, SD, ND, WY, UT, OR, AZ, MT, AK, Legacy MN) - LCD 32234 - Stereotactic Radiosurgery (SRS) and Stereotactic Body Radiation Therapy (SBRT): Low or intermediate risk prostate cancer may be covered when the patient is enrolled in an IRB-approved clinical trial and which clinical trial meets the “standards of scientific integrity and relevance to the Medicare population” described in IOM 100-03, National Coverage Determinations Manual, Chap 1, Part 1, section 20.32, B3a-k (with l-m desirable). Similarly, enrollment in a clinical registry compliant with the principles established in AHRQ’s “Registries for Evaluating Patient Outcomes: A User’s Guide”, such as the Registry for Prostate Cancer Radiosurgery (RPCR), may qualify the treatment for coverage.

First Coast Service Options - MAC Jurisdiction 9 (Florida) - Summary of Public Comments on LCD L30366: Other factors considered favorable for payment of the treatment delivery include enrollment of the patient in an appropriate clinical registry (that includes tracking of late toxicities) for planned assessment and publication).

Palmetto GBA - MAC Jurisdiction 1 (CA, NV, HI) - LCD L28301 - Stereotactic Body Radiation Therapy: The clinical experience with SBRT for carcinoma of the prostate is of short term duration relative to the natural history of prostate cancer. Published peer reviewed studies of the success and complication rates are still small and of short or medium term duration. Prominent specialty societies and academicians suggest SBRT is still investigational, while others who currently use the equipment feel SBRT has some selected advantages. We will cover SBRT for prostate cancer only when:

1. Other forms of first line therapy are not available or feasible since other forms have known long term success and complication rates; and
2. All of the criteria listed above are documented in the medical record; or
3. The patient is enrolled in an approved clinical study listed in ClinicalTrials.Gov.

January 28, 2013

Louis Jacques, MD
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mail Stop S3-02-01

7500 Security Boulevard Baltimore, MD 21244

Dear Dr. Jacques:

Stryker appreciates the opportunity to comment on the Centers for Medicare & Medicaid Services’ (CMS) draft guidance on Coverage with Evidence Development in the Context of Coverage Decisions (Draft CED Guidance).

Stryker is one of the world’s leading medical technology companies and is dedicated to helping healthcare professionals perform their jobs more efficiently while enhancing patient care. Stryker is committed to bringing the best possible solutions to patients, providers, and Medicare. This philosophy has placed Stryker at the forefront of medicine’s most promising breakthroughs in joint replacements, trauma, spine, orthobiologics, surgical navigation systems, and related procedures.

Stryker strives to ensure that effective, high-quality medical technologies and services are available to Medicare beneficiaries. To make this beneficiary access a reality, Medicare policies must promote meaningful coverage of reasonable and necessary care. We applaud CMS’s attempt, through the coverage with evidence development (CED) process, to provide a mechanism to allow Medicare coverage for “promising new technologies that do not currently meet the standard for full coverage.” We believe that CED must be used judiciously, however, to ensure that it does not actually serve as barrier to coverage of proven technologies, or impose burdens on the health care community beyond what is needed to assure that technologies are reasonable and necessary for Medicare beneficiaries.

In the Draft CED Guidance, CMS states that it intends to discontinue use of the term “coverage with appropriateness development” (e.g., patient registries) as a form of CED because it “does not fundamentally encompass the concept of research.” As CMS is aware, registries are an important source of ongoing data on patient care, and they are increasingly used to address key questions about various medical interventions. The medical community has invested substantial resources in establishing and maintaining registries to continue enhancing patient care. We urge CMS to make clear that national registries will still have a place in Medicare coverage policy.

As CMS is aware, one strong concern raised with CMS’s current CED policy is the ambiguity with regard to the authority of Medicare Administrative Contractors (MACs) to impose local CED requirements. In fact, CMS notes that one of the main themes raised in response to its public comment solicitation on CED policy last year was whether local contractors should have the discretion to apply CED in local coverage. It does not appear, however, that CMS has addressed these concerns in its Draft CED Guidance or otherwise provided any limitations on local CED policies. It is also unclear whether CMS’s suspension of “coverage with appropriateness development” for purposes of the national coverage policy would eliminate or otherwise limit the future use of registries by MACs as part of local coverage determinations (LCDs).

Stryker believes that the LCD process in general is an important tool for providing flexibility to Medicare contractors so they can respond to changes in local practice patterns and the diffusion of advanced medical technologies in the absence of national coverage policies. Coverage with evidence development, however, is a concept that does not readily lend itself to application at the local level. We are concerned that if restrictions are not imposed on the local use of CED, MACs will have virtually unlimited authority to impose significant, uncompensated costs on manufacturers, even though (1) the data collected would be less robust than on a national scale, and (2) the MACs may not have the expertise or other resources needed to effectively design appropriate studies and analyze the evidence.

Both clinical trials and patient registries are complex, lengthy, and costly undertakings that benefit greatly from economies of scale. Evidence collected through either clinical trials or patient registries is enhanced when a greater number of participants operate under standardized protocols, rather than when data is collected under an assortment of different local standards. It is doubtful whether local registries or clinical trial obligations will result in meaningful data that justifies the cost and delay in widespread patient access to the medical technology. Local MAC registry requirements also would be a burden for physicians, particularly specialists who operate in multiple states served by more than one MAC.

Stryker therefore urges CMS to ensure that the final CED guidance specifically prevents local CED policies from restricting Medicare beneficiary’s timely access to medical technology determined to be safe and appropriate by their physician. While there might be a framework under which a local carrier could take the lead on a nationally-available registry or trial, CMS’s national CED policy should avoid promoting a patchwork of local registries or overlapping CED research protocols that effectively block traditional Medicare coverage of medical technologies. Furthermore, to the extent that local CED policies are permitted, we request that CMS specify whether MACs are authorized to impose patient registry requirements at the local level in light of the proposed discontinuance of national “coverage with appropriateness development” determinations.

Thank you for your consideration of our comments. If you have any questions, please do not hesitate to contact me.

Sincerely,

January 28, 2013

Marilyn Tavenner, Acting Administrator
Centers for Medicare and Medicaid Services
Department of Health and Human Services Baltimore, MD 21244-8016

Re: Coverage with Evidence Development in the context of coverage decisions

Dear Administrator Tavenner:

Bayer Healthcare LLC (“Bayer”) appreciates the opportunity provided by the Centers for Medicare and Medicare Services (“CMS” or “Agency”) to submit comments on the draft guidance regarding Coverage with Evidence Development (“CED”) in the context of coverage decisions (“draft guidance”).

With more than 6,000 healthcare employees across the United States, Bayer aims to discover and manufacture products that will improve human health worldwide by diagnosing, preventing and treating diseases. We focus our efforts where we can have the most beneficial impact on the lives of those who depend on our nearly 150 years of experience researching and developing new pharmaceuticals and medical devices.

On the basis of this long experience, Bayer wishes to comment on several proposals contained within the draft guidance, which are summarized below:

• The Draft Guidance Changes Long-Standing CMS Policy in a Substantive Manner and, Therefore, Can Only Be Undertaken Through a Legislative Rule: Bayer requests that the Agency not make substantive changes to existing policy, as it attempts to do here, except in a correctly noticed legislative rule.



• Provide Greater Detail Regarding the CED Process: Bayer supports CED as a driver of innovation. However, the current draft guidance is ambiguous and does not provide sufficient detail for active stakeholder participation. Bayer urges CMS to supply greater detail regarding when and how CED will be utilized.



• Re-Incorporate the Eight CED Governing Principles Found in 2006 Guidance: The draft guidance does not contain the eight guiding principles found in the 2006 guidance. These principles provide essential beneficiary protections and should be re-incorporated into the draft guidance. Bayer also requests that the Agency clarify that CED may only occur through the NCD process.



• Exclude from CED Evaluations FDA-Approved Indications, Orphan Drugs, and Drugs in Part D Protected Classes: FDA-approved indications, orphan drugs, and drugs in Part D protected classes have already undergone extensive review. Applying CED to these drugs and uses has the potential to unnecessarily endanger beneficiary health by limiting access to critically important treatments. Therefore, applying CED in these circumstances would only incur unnecessary expense and limit necessary and established treatment options. For these reasons, the Agency should prohibit the application of CED to these drugs and uses.



• Base CED Coverage Decisions on the Statutory Criteria: The Social Security Act requires coverage for items that are reasonably necessary for the treatment or diagnosis of a disease. The Agency’s use of an “outcomes” improvement standard in the draft guidance is not the appropriate standard. Specifically, the draft guidance should clarify that outcomes improvement is not the standard to evaluate diagnostic agents.



• Provide Clear Criteria Describing When CED Will Be Utilized: While the draft guidance does list four quite general factors when CED may be applied, Bayer requests that the Agency provide stakeholders with additional detail regarding when CED will be required.



• Provide Access to CED Services and Items Outside of Clinical Trials: Bayer urges the Agency to provide alternatives to clinical trial participation to allow greater beneficiary access to CED services and items.



• Clarify CED Clinical Trial Requirements: Bayer requests that the Agency clarify how CED trials will be approved, what end-points are required for CED trials, and when and how the CED process will conclude.



• Clarify the Role of the Agency for Healthcare Research and Quality (AHRQ): The draft guidance contemplates the involvement of AHRQ in the CED process. Bayer requests that the Agency provide additional information regarding the role of AHRQ in this process.



• Continue to Allow Medicare Administrative Contractors (“MACs”) to Determine Coverage for Routine Clinical Trial Costs: Bayer strongly supports the Agency’s plan to continue to allow MACs to determine which routine clinical trial costs to cover.

1. The Draft Guidance Changes Long-Standing CMS Policy in a Substantive Manner and, Therefore, Can Only Be Undertaken Through a Legislative Rule

The draft guidance makes substantial changes to long-standing CMS policy on CED. As an APA matter, we believe that imposing these new requirements necessitates a more transparent, complete, and formal regulatory process than draft guidance posted to the agency's website without official notice in the Federal Register. Agency guidelines that create new rights and duties are subject to the APA’s requirement of notice-and-comment rulemaking. Further, the Agency must provide sufficient information in its notice to permit interested parties to meaningfully comment and participate in the rulemaking.¹

The draft guidance does not provide sufficient detail to allow meaningful comment regarding when CED will be utilized, the standard by which CED evidence will be judged, or how such evidence must be gathered. Bayer believes all stakeholders involved in the CED process would benefit from a more formal review of the CED process and urges the Agency to issue CED regulations using notice and comment rule-making procedures.

2. Provide Greater Detail Regarding the CED Process

Bayer supports CED as a driver of innovation and as a means of ensuring that Medicare beneficiaries have access to treatments and diagnostic agents that they otherwise may not receive. However, Bayer is concerned about the Agency’s stated intent to use CED more frequently for new products and to re-evaluate existing technologies, which are already in use and on which beneficiaries are dependent.

Bayer believes that CMS should continue its policy of generally allowing local Medicare contractors to make initial coverage decisions. CED should only be considered when new or existing technologies show promising potential, but have not garnered enough evidence to support local coverage. Use of CED in such limited circumstances will truly drive innovation and improve Medicare beneficiaries’ access to treatment and diagnostic agents.

If CMS does intend to use CED more frequently, it must provide clear, detailed guidance that will allow stakeholders to participate in the CED process. CED will only be effective if stakeholders understand when and why CED will be implemented. The current draft guidance does not provide answers to these critical questions. Indeed, without this certainty, investment in innovation will inevitably be stifled and the stated purpose of the proposed rule will be undermined.

Further, like other stakeholders, including patient and provider advocacy groups, Bayer is concerned that the current draft guidance may provide CMS with a means to eliminate coverage for medically necessary services and items based on cost considerations. Bayer requests that, prior to finalizing the draft guidance, CMS clarify that CED will only be used to encourage innovation and improve beneficiary health outcomes by developing additional support for the use of treatments and diagnostics in the Medicare population.

In addition, Bayer urges CMS to clarify that CED will not be triggered or used as a method to make coverage decisions based on comparative effectiveness claims. Section 1182 of the Social Security Act explicitly states that the Secretary may not deny coverage or services solely on the basis of comparative effectiveness research.² Bayer urges the Agency to clarify that CED will not be used for this purpose. We are concerned that when CMS states that it is considering “cost” it is, as a practical matter, undertaking comparative effectiveness analyses in a fashion inconsistent with the statute.

3. Re-Incorporate the Eight CED Governing Principles Found in 2006 Guidance

The draft guidance does not include the eight CED governing principles found in the 2006 guidance. These principles state that: 1) NCDs requiring CED will occur within an NCD process, which is transparent and open to public comment; 2) CED will not be used when other forms of coverage are justified by the available evidence; 3) CED will in general expand access to technologies and treatments for Medicare beneficiaries; 4) CMS will use CED infrequently; 5) CED will lead to the production of evidence complementary to existing medical evidence; 6) CED will not duplicate or replace the FDA’s authority in assuring the safety, efficacy, and security of drugs, biological products, and devices; 7) CED will not assume the NIH’s role in fostering, managing, or prioritizing clinical trials; and 8) any application of CED will be consistent with federal laws, regulations, and patient protections.

Like other stakeholders, including most notably patient and provider groups, Bayer is extremely concerned about the abandonment of these critical safeguards. With these principles absent, the lack of clear guidance regarding the use of CED in the current draft guidance is all the more troubling. Bayer urges CMS to explicitly re-incorporate each of these missing principles that are critical to protecting beneficiary access to essential treatments.

Specifically, Bayer urges CMS to clarify that CED can only occur within the NCD process. In addition to disregarding the principle that CED must occur within the NCD process, the draft guidance deletes sections III and IV from the 2006 guidance that linked CED to the NCD process. However, in several instances, the draft guidance references CED as part of an NCD. For example, on pg. 7, the draft guidance states that “to the extent that the NCD does not identify specific clinical trials…”. Therefore, the draft guidance appears to use the NCD process interchangeably with CED.

The NCD process is an established, transparent process that ensures stakeholder participation. The CED process will only be successful with active participation from providers, patients, researchers, advocacy groups, manufacturers, and all other interested stakeholders, and the NCD process is the most effective approach to enable robust and critical participation from these stakeholders.

4. Exclude from CED Evaluations FDA-Approved Indications, Orphan Drugs, and Drugs in Part D Protected Classes

The draft guidance does not specify which treatments, agents, or specific uses will be eligible for CED. Bayer requests that the draft guidance specifically exclude the following categories from the CED process: 1) CED should not be used to limit coverage for FDA-approved indications of drugs and devices; 2) CED should not be used to limit coverage for “medically accepted indications” for treatments that have been appropriately established through the compendia process, given the statutory basis for compendia supported coverage;³ and 3) CED should not be applied to orphan drugs and drugs in Part D protected classes.

Specifically, CMS should look to both the United States Pharmacopeia and the American Hospital Formulary Service for evidence of medically accepted indications. Further, CMS should also look to the peer-reviewed medical literature to determine if sufficient evidence exists for coverage.⁴ If these sources support the use of the treatment or diagnostic agent, CED should not be utilized.

In addition, Medicare beneficiaries suffering from orphan diseases or requiring drugs found in protected classes have limited options for effective treatment. Therefore, it is critical that the Agency not utilize CED for these essential therapies. CED in these contexts would have a devastating impact on the most vulnerable Medicare populations.

Excluding these categories from potential CED decisions will ensure that the CED process does not negatively impact access to validated, essential treatments. A failure to exclude these categories would also be fundamentally inconsistent with CMS’s stated goal of encouraging innovation. If these basic areas of coverage support are eroded through the draft guidance, innovation and the investment necessary to sustain it will inevitably suffer.

5. Base CED Coverage Decisions on the Statutory Criteria

The draft guidance repeatedly references “outcomes” improvement as the standard for Medicare coverage.⁵ Bayer is concerned about the use of this standard for CED decisions, which is not consistent with the statute. The focus on outcomes improvement is not the correct standard to use when determining what treatments and diagnostic agents will receive coverage.

The Social Security Act provides for coverage of enumerated types of services and items so long as those services and items are reasonably necessary for the diagnosis or treatment of a disease or to improve the functioning of a malformed member.6 There is no authority to limit coverage to the least costly item or the one that may, according to one study or another, have the most promise for affecting outcomes. Such an approach would fail to appreciate the unique circumstances of a particular Medicare patient, would not provide flexibility to account for differences in patient populations, would dictate a single approach to treatment and diagnosis, would make impossible the use of combination treatment approaches that in oncology and other areas are a driver for innovative and personalized treatment, and would be utterly inconsistent with the desire to encourage innovation in health care.

Medicare beneficiaries are statutorily entitled to access to important diagnostic agents. Although diagnostic agents often lead to beneficial outcomes, by allowing disease to be accurately managed, they are covered, as a matter of statute, even if there is no effect on the ultimate outcome of a disease process, where they produce a diagnosis. This is why the statute refers to coverage for “diagnosis or treatment.”

Similarly, many treatments, such as pain management, are not designed to improve outcomes, but to address symptoms. The management of the symptom is beneficial regardless of any outcome improvement.⁷ The Medicare statute nowhere refers to an “outcomes” test for coverage; it does not exist. Accordingly, Bayer asks that the agency strike its “outcome” references in the draft guidance, as they are inconsistent with the statute.

6. Provide Clear Criteria Describing When CED Will Be Utilized

Bayer is concerned that the draft guidance does not provide sufficiently clear criteria regarding when CED will be utilized. The draft guidance lists four general situations in which CED will be considered. These include instances: 1) when the relevance to the Medicare population is uncertain; 2) when available evidence is not representative of the Medicare population; 3) when evolution and reevaluation of evidence on older products occurs; and 4) when evidence was not developed in a setting that represents the typical Medicare community care setting. It will not increase innovation for the Medicare program to be vague as to the circumstances under which coverage will not be provided; by injecting uncertainty into the development process, it will diminish innovation.

Bayer requests additional information regarding these circumstances. The CED MEDCAC meeting held in May specifically identified the need for clear factors establishing when CED would be utilized for different product types. In the absence of greater specificity, the criteria listed in the draft guidance could apply to practically every new and existing technology available and leaves many important questions unanswered. For example, will the same factors and criteria be used for both drugs and devices? How will CMS determine when a reevaluation of past evidence is appropriate? The MEDCAC meeting clearly identified the need for clear answers to these questions in any draft guidance.

7. Provide Access to CED Technologies Outside of Clinical Trials

Per the 2006 guidance, beneficiaries could receive coverage for CED technologies either through a Coverage with Appropriateness Determination (“CAD”) or through Coverage with Study Participation (“CSP”). The draft guidance no longer includes the CAD approach and limits coverage to beneficiaries participating in a clinical trial. Bayer is extremely concerned about this significant restriction in access.

Limiting coverage for CED to clinical trial participation is clearly inconsistent with the stated goal of encouraging innovation. Bayer, along with many patient and provider stakeholders, is concerned that the true intent of the change in policy may be to restrict coverage to innovative items and services. Only by providing adequate access options will CED be able to accomplish its goals of both collecting sufficient information for CMS coverage and driving innovation.

Therefore, Bayer urges CMS to develop flexible, alternative procedures to allow Medicare beneficiaries to access CED items or services while evidence is gathered during clinical trials. This is especially important for beneficiaries who are ineligible for available CED clinical trials. Medicare should not establish a “two tiered” system of access.

In this regard, we note that, at present, the draft guidance only contemplates potential observational studies as a method to provide coverage at the conclusion of all prospective clinical trials. Such observational trials should be designed in tandem with prospective studies to provide access for those beneficiaries ineligible for prospective clinical trials.

In addition, CMS should also develop alternative measures to allow beneficiaries to access CED technologies while evidence is being developed. Specifically, the draft guidance should require all CED decisions to establish coverage for beneficiaries if their care will be provided in a fashion consistent with trial requirements, even if they are not in a clinical trial. Beneficiaries should not be discriminated against based on whether they can gain access to a trial.

Without such alternative measures, beneficiaries will be denied access for significant periods of time given the length of most clinical trials and the subsequent time required for Agency review of clinical trial results. Alternative evidence collection (such as a registry) would ensure that beneficiaries have access to needed technologies, while also allowing CMS to gather additional evidence to support coverage.

8. Clarify CED Clinical Trial Requirements

The draft guidance lists 13 factors that CED trials should meet. However, the draft guidance does not require the Agency to state what evidence a trial sponsor must provide to the Agency at the conclusion of the CED process. Bayer requests that the draft guidance clearly require any CED decision to include specific questions from the Agency to assist in the design of a meaningful CED clinical trial. Only by clearly describing what evidence is missing will trial sponsors be able to design clinical trials capable of meeting the Agency’s identified evidence gap.

The draft guidance also defines the following three situations in which CED coverage may conclude. Clearly defining the end of CED is an important issue, as stakeholders are concerned that CEDs will linger unnecessarily, limiting coverage in circumstances where such limitations cannot be justified. CED trials will conclude if any of the following three criteria are satisfied: 1) No CED trials are approved; 2) no CED trials are completed in the timeframe required in the CED opinion; or 3) CED trials are completed.

The first criteria implies that all clinical trials must be approved. However, the draft guidance does not clarify who must approve these trials, how long a sponsor has to seek approval, or what factors the trial must meet to gain such approval. Bayer requests that CMS clarify who will be responsible for approving such trials and how the process will work.

Bayer urges the Agency to also provide additional information regarding the conclusion of CED trials. All CED decisions should include clearly defined end-points for each CED trial. This clarification will allow sponsors to develop effective trials and also will provide clear timelines to ensure that the CED process does not continue indefinitely.

Further, the draft guidance allows for a potential period of non-coverage while CMS reviews the results of completed CED trials. Bayer is extremely concerned about this total restriction on CED technologies during the time period during which the Agency reviews the results of CED trials. Since coverage for CED technologies is limited to participation in a clinical trial, once all trials have been completed, CMS’ contractors should be permitted to provide coverage pending action by the Agency. At the very least, CMS should be required to act within 90 days of the conclusion of the data collection, the timeline that applies for various NCD actions.

9. Clarify the Role of the Agency for Healthcare Research and Quality (AHRQ)

The draft guidance discusses the potential role for AHRQ in the development of CED. However, the draft guidance contains little detail regarding the role AHRQ will play in the development of CED trials. The draft guidance does generally describe three potential areas of AHRQ involvement: 1) assisting with the design of clinical trials; 2) form partnerships to fund CED clinical trials; and 3) provide confidentiality protections for CED data. Bayer requests that the Agency provide additional information regarding AHRQ’s role in the CED process. It is critical that all stakeholders understand the role of AHRQ to ensure the successful operation of the CED process.

10. Continue to Allow MACs to Determine Coverage for Routine Clinical Trial Costs

Bayer supports, with great enthusiasm, CMS’ proposal to continue to allow MACs to determine what routine items and services are covered outside of the CED clinical trial.

Bayer appreciates the opportunity to comment on the draft guidance and looks forward to working with CMS in the future to improve access to quality, affordable healthcare coverage.

Sincerely,

January 28, 2013

Louis Jacques, MD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop S3-02-01
7500 Security Blvd.
Baltimore, MD 21244

Dear Dr. Jacques:

The Biotechnology Industry Organization (BIO) is pleased to submit the following response to the Centers for Medicare and Medicaid Services’ (CMS) Draft Guidance for the Public, Industry, and CMS Staff on Coverage with Evidence Development (CED) in the Context of Coverage Decisions (Draft Guidance).¹ BIO represents more than 1,100 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products.

As the representative of an industry that is devoted to improving health care through the discovery of new therapies, BIO shares CMS’s desire to use evidence to accelerate Medicare beneficiaries’ access to innovative items and services. Our members invest billions of dollars each year in clinical research to develop and disseminate evidence to help guide the effective use of their therapies. This investment continues long after the Food and Drug Administration’s (FDA’s) stringent approval requirements for each of our therapies are met. We also support Medicare policies, such as the Clinical Trial Policy (CTP),² which encourage beneficiaries to participate in clinical research.

As CMS recognized when it first developed principles for applying CED, the need to provide for a predictable coverage and reimbursement environment is still critical today. The additional costs incurred as a result of a poorly designed and vague CED policy or inappropriate application of CED may culminate in a chilling effect on innovation, harming patient care both now and in the future. In addition, if manufacturers are unclear about the rationale for CMS’s application of CED, investment in new medical technologies may be deterred and patient access to new and improved therapies may be delayed. Our comments are provided with these concerns in mind, to ensure that the CED policy achieves its goals without creating unpredictability or hampering future medical innovation.

CMS first provided guidance regarding the use of CED in 2006.³ That guidance included principles that were developed after careful consideration of stakeholder comments. The eight principles governing the application of CED as articulated in the 2006 guidance document are: ⁴

1. National Coverage Determinations (NCDs) requiring CED will occur within the NCD processes, which is transparent and open to public comment.
2. CED will not be used when other forms of coverage are justified by the available evidence.
3. CED will in general expand access to technologies and treatments for Medicare beneficiaries.
4. CMS expects to use CED infrequently.
5. CED will lead to the production of evidence complementary to existing medical evidence.
6. CED will not duplicate or replace the FDA’s authority in assuring the safety, efficacy, and security of drugs, biological products, and devices.
7. CED will not assume the NIH’s role in fostering, managing, or prioritizing clinical trials.
8. Any application of CED will be consistent with federal laws, regulations, and patient protections.

BIO strongly supports these principles because they protect beneficiary access to appropriate care; encourage development of useful clinical evidence; ensure that any applications of CED use the limited resources of CMS, providers, and manufacturers efficiently without unnecessary duplication of efforts; and were developed with the support of a broad set of stakeholders. CMS decided to remove these principles from the Draft Guidance, and the Agency does not propose alternate principles to guide the application of CED in the future. BIO continues to believe that all of these principles are relevant to the application of CED and that without them CED would impose significant burdens on beneficiaries, healthcare providers, and manufacturers. Therefore, BIO urges CMS to incorporate all of them into the final CED guidance document that the Agency issues. Once CMS recommits to these principles, it should focus on mechanisms to strengthen adherence to them, especially to those that focus on the evidentiary threshold for applying CED, the intended infrequent use of CED, and the requirement to produce evidence through CED that is complementary to existing medical evidence.

In the Draft Guidance, CMS indicates that it excluded the principles from the 2006 guidance document because “some of the ‘principles’ are now moot.”⁵ It does not, however, identify which of the principles it considers to be moot or why. If CMS continues to believe that some of these principles are moot, BIO asks that CMS identify those specific principles and the basis for its determination that those principles are obsolete or unnecessary. This will allow stakeholders to provide specific input to CMS on whether and why those principles continue to be relevant or not.

In the Draft Guidance, CMS indicates that CED is appropriate where there are “reasonable grounds, based on the available evidence, to question whether improved health outcomes reported in narrower settings” would be realized by Medicare beneficiaries as well as where “new research or evolving scientific thought raises important questions about the clinical usefulness, and thus the medical necessity, of older established technologies.”⁶ Although BIO agrees that CED can and should be applied to provide more immediate patient access to promising technologies, we urge CMS to proceed cautiously in applying CED to “older established technologies.” CMS surely recognizes the need for predictability in coverage and reimbursement. BIO is concerned that the application of CED to older established technologies would create a less predictable coverage and reimbursement environment, which can discourage continued innovation. Moreover, applying CED to older established technologies is unnecessary since there is an evidence base on which to draw by virtue of these therapies having been utilized over a period of time already.

In addition, BIO urges CMS to state specifically that, with regard to drugs and biologics, CED will be limited to off-label uses of FDA-approved products. Drugs and biologics are subject to a rigorous FDA review process, and their approved prescribing information clearly describes the population for which each therapy is approved and includes the data supporting each indication. CMS should not second-guess the FDA’s decisions by requiring additional post-approval studies of a drug or biological for its approved indications. By that same measure, CED should not be applied to Premarket Approval (PMA)-approved diagnostic products. Moreover, the Social Security Act’s (SSA) definition of “drugs or biologicals” requires that each drug or biological be included or approved for inclusion in the United States Pharmacopoeia or other listed compendia or be “approved by the pharmacy and drug therapeutics committee (or equivalent committee) of the medical staff of the hospital furnishing such drugs and biologicals for use in such hospital.”⁷ These requirements, combined with FDA approval, provide additional assurance that the therapy has been thoroughly reviewed by independent experts prior to coverage.

In addition to FDA approval and compendia support, the Medicare statute and long-standing Medicare policy approve the use of these products for medically accepted indications. In the case of drugs and biologics used in anti-cancer chemotherapeutic regimens, “medically accepted indications” include the FDA-approved uses as well as uses that are listed in certain compendia or are supported by peer-reviewed literature.⁸ Medicare also has long granted its contractors authority to determine that unlabeled uses of other drugs are “medically accepted” based on “the major drug compendia, authoritative medical literature and/or accepted standards of medical practice.”⁹ By using authoritative compendia and medical literature to define “medically accepted indications,” the statute and Medicare’s guidance protect beneficiaries’ timely access to drugs and biologicals while also ensuring that Medicare’s coverage policies are truly evidence-based. CMS also has previously recognized physicians’ authority to prescribe drugs off-label, stating that “medical decisions are best made by the physician treating the patient. FDA rules do not prohibit physicians from ordering off-label uses of a drug. Current accepted medical practice may include the use of drugs for indications that are not covered by the FDA label but are supported by clinical evidence in peer-reviewed medical literature.”¹⁰

Many types of conditions for which physicians use products off-label are rare diseases where compendia or literature supporting their use is difficult to build, even though the products provide clinical benefit to the patient.¹¹ The difficulty in securing an adequate number of patients for a trial and/or conducting effectiveness studies poses a major hurdle given the rarity of certain diseases. CMS should not use the CED policy to create access barriers for these patients, but instead should rely on the judgment of the clinician using an FDA-approved product within the standards of medical practice.

In general, BIO believes CMS should initiate CED only as an alternative to otherwise limiting coverage. Specific circumstances under which we believe CED may be appropriate include:

1. When the alternative is national non-coverage based on limited evidence;
2. When there is considerable non-coverage at the local level, creating a de facto national non-coverage policy;
3. When the final NCD will be more restrictive than current use, as signaled by the draft NCD; or
4. Prior to removing coverage for an item or service that was previously covered by Medicare.

BIO largely supports the standards of scientific integrity and relevance to the Medicare population that CMS included in the Draft Guidance, which generally mirror the standards included in the 2006 guidance document. CMS has, however, added new standards that are of concern to BIO because they may not always be feasible to achieve and therefore could limit the applicability of CED where it otherwise would be justified and provide expedited patient access to innovative therapies.

In particular, BIO is concerned that the requirement that a CED study protocol must “explicitly discuss subpopulations affected by the item or service under investigation”¹² may limit the feasibility of conducting CED studies. For example, including a subpopulation of Medicare beneficiaries may be difficult because many are ineligible to participate in clinical trials due to age, comorbidities, or complications. This difficulty is compounded for therapies treating patients with rare diseases due to their unique vulnerabilities, an already narrow population, heterogeneity, and other issues characteristic of those patient groups. Similarly, the standard requirement of head-to-head studies would be infeasible for these therapies. Study criteria under a CED policy that are defined too narrowly, and therefore unnecessarily restrict the study’s population, risk denying access to care for such beneficiaries. Therefore, BIO recommends that CMS apply these standards flexibly as circumstances require.

The draft guidance suggests specific standards for the method and timing of public release of CED studies, including a requirement that results be made public within 24 months of the end of data collection. BIO does not believe that an inability to make study results publically available within 24 months of the end of data collections should be used to inhibit the application of CED if it is otherwise warranted. Our members adhere to accepted standards for the methods and timing reporting of results from studies of drugs and biologics. These standards provide consistency and predictability for manufacturers in their pre-and post-market clinical studies, and therefore should serve as the standard for CED studies. BIO believes that mandating a separate 24-month standard for the method and timing of public release for CED studies is unnecessary and would require manufacturers to comply with multiple, and potentially conflicting, sets of rules potentially without enhancing scientific integrity.

BIO appreciates that CMS has provided guidance on when CED will end. It is important that CED have a definitive resolution in order to avoid unnecessary burdens on beneficiaries, healthcare providers, and manufacturers. BIO believes that more guidance is needed, however, on what specifically will happen after the CED study ends. The Draft Guidance does not clearly articulate the process under which CED studies will be evaluated for “graduation” to a new or revised coverage determination, if any. For example, the Draft Guidance is silent with regard to who will review the CED studies, what opportunities will be available for manufacturer input, and whether the decisions will be available for public comment. BIO urges CMS to include a more complete discussion in the final guidance document of the process it will follow for making a coverage determination after CED ends and believes strongly that this process should include an opportunity for public comment.

As part of its discussion of ending CED, CMS acknowledges the potential for a period of noncoverage between the end of a CED study and the Agency’s review of the study results, and indicates that it “may address the issue of ongoing coverage by working with investigators to develop integrated research strategies during the planning of CED studies.”¹³ Although BIO appreciates that CMS has acknowledged the potential for a coverage gap during the period between the end of the CED study and a new or revised coverage determination and has recognized that it should take steps to ensure continued patient access during this period, BIO is concerned about CMS’s proposed approach. Specifically, CMS says that it may design CED studies “to accommodate the complementary roles of randomized controlled trials (RCTs) and practical observational studies to close outstanding evidence gaps and allow coverage after an RCT ends where appropriate.”¹⁴ BIO is troubled by the potential for CED to involve multiple, overlapping studies that may not produce necessary data and that may result in a situation where the study requirements for a technology seem to be never-ending. This is of particular concern in situations involving therapies that treat rare or ultra-rare diseases for which no other treatment options are available. In these situations especially, any gap in coverage could be life-threatening to beneficiaries. BIO asks CMS to consider whether there are less burdensome means of enabling continued coverage until CMS issues a new or revised coverage determination following the end of a CED study. Continuous coverage is critical for our patients, particularly those battling cancer or fighting a chronic disease, and must be a top priority for the agency. In the final guidance, CMS should explicitly provide for continuous coverage between the end of CED and the issuing of a new or revised coverage determination.

We urge CMS to ensure patient access to necessary therapies during the review period by including the scientific “review period” and time needed to make a coverage determination as part of the total CED study period under which uninterrupted coverage of the therapy would be available.

In the Draft Guidance, CMS addresses coordination with the FDA by mentioning the memorandum of understanding (MOU) between CMS and the FDA, as well as the Federal Register notices on parallel review. FDA and CMS each have separate and distinct mandates that CMS must adhere to in its application of the CED guidance. Although BIO supports the two agencies working together to ensure patients have access to needed therapies, it is critical that the unique missions of these two agencies remain distinct and not be comingled or compromised in the course of the application of CED. Congress deliberately bestowed FDA and CMS with distinct authorities and standards for approval and coverage decisions respectively, consistent with the different missions and constituencies of the agencies. FDA has the appropriate combination of expertise and resources to review and approve study design and results of clinical trials needed to demonstrate that drugs and biologics are safe and effective. CMS should not attempt to use its limited resources to duplicate this mandate.

CMS also notes that “FDA has at times required ongoing research and data submission as a condition of approval,” and “[w]hile the alignment of CED with an FDA post-approval study requirement presents an opportunity for greater research efficiency, we believe that this is simply an example of a CED application rather than a new CED paradigm.”¹⁵ BIO appreciates this clarification, but we also believe that patients and manufacturers should not be put into a “double jeopardy” situation in which CED is applied to those products that are already subject to Risk Evaluation and Mitigation Strategies (REMS) or other post-market studies required by the FDA. CED should not be used to limit access to care using therapies subject to a REMS if the FDA approval allows patients to receive the therapy without participating in a study. If therapies already subjected to REMS or other FDA post-market studies are also subject to CED, manufacturers—especially the often smaller manufacturers of orphan drugs—may face significant resource burdens associated with conducting multiple studies, which could potentially impose delays in conducting the FDA post-market research. Similarly, there is the potential that a CED study may directly conflict with the requirements of the FDA post-market study. In all of these instances, imposing CED on products or services already subject to FDA post-market requirements could inappropriately interfere with the division between the roles of the FDA and CMS, and could directly threaten patient access to innovative and novel therapies. Therefore, BIO urges CMS to prohibit the application of CED to products already subject to an FDA post-market study.

CMS indicates that its authority to use CED is based on the provision of the SSA that permits coverage of items and services in the context of research conducted and supported by AHRQ.¹⁶ Section 1142 of the SSA describes the authority of AHRQ to conduct and support research on outcomes, effectiveness, and appropriateness of services and procedures, among other things.¹⁷ Although CMS discusses how ARHQ’s “authority and resources complement CED,” it does not describe AHRQ’s role in identifying, conducting, or supporting CED studies, but rather says that that “AHRQ’s role will continue to develop as both agencies gain more experience with CED.”¹⁸ BIO believes that AHRQ’s role should be limited to activities that support, as appropriate, the goal of expanding patient access to novel therapies through CED. Thus, CMS must clarify this role given that the statutory authority for CED is premised on AHRQ’s research activities.

In particular, BIO believes that it is crucial for CMS to clearly explain how it plans to fund CED studies and the role AHRQ will play in such funding. CMS fails in the Draft Guidance to address the costs of CED and who bears them. The drug development and FDA review and approval processes require significant investment by manufacturers. Imposing additional clinical research requirements on manufacturers may limit the ability to support continued innovation, especially for therapies for the Medicare population. Provider and patient costs also must be taken into consideration. CMS does indicate that AHRQ has the ability to establish public/private partnerships to financially support CED studies. Thus, concerns regarding the costs of CED studies and the effect of those costs on patient access remain. To address these issues, BIO urges CMS to more clearly articulate the types of partnerships that AHRQ may establish and the public funding that will be available to minimize the financial burdens of CED whenever possible.

CMS also indicates in the Draft Guidance that AHRQ “has the ability to invoke certain confidentially protections regarding certain uses of data.”19 Although BIO agrees with CMS regarding the need for confidentiality of sensitive data, we urge CMS to use the final guidance document to identify how data ownership and patient confidentiality will be protected, and how other usage issues inherent in CED will be addressed. This is particularly important to ensure that manufacturers who sponsor research under CED have timely and complete access to the data the research produces.

In developing its Draft Guidance, CMS convened the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) to evaluate, among other things, how to define the evidentiary criteria for the application of CED.²⁰ CMS discusses the MEDCAC’s findings in the Draft Guidance, but provides no guidance regarding the evidentiary criteria it intends to use. BIO recommends that CMS provide additional information regarding the types of evidentiary standards it intends to use; however, BIO believes that it would be inappropriate for CMS to apply a single evidentiary threshold to invoke CED for all types of items and services because the coverage determination process involves complex judgments and values, and interventions are highly variable. For example, the level of evidence that CMS may require for drugs, biologics, devices, diagnostics, or medical procedures will vary based on the characteristics of these interventions. Even within the drugs and biologics categories, orphan therapies may require unique evidentiary standards because of the small size of these patient populations and the resulting data limitations. Similarly, novel therapies that fulfill unmet needs in disease areas such as cancer should be judged by a higher threshold before invoking CED. As discussed in detail above, BIO continues to believe that CED is inappropriate for FDA-approved drugs and biologics used on-label and for medically accepted off-label uses. Additionally, BIO believes that the appropriate focus of CED studies for diagnostic products (e.g., molecular diagnostic tests should be on whether the diagnostic test meaningfully alters clinical decision-making, rather than measuring impacts on clinical outcome.

In the Draft Guidance, CMS states that “adherence to the following standards of scientific integrity and relevance to the Medicare population should be demonstrated in all CED studies… [including that] the principal purpose of the study is to test whether the item or service meaningfully improves health outcomes of patients who are represented by the enrolled subjects.”²¹ BIO cautions CMS in application of evidentiary standards for all medical products uniformly, without attention to the unique characteristics for appropriate clinical utilization.

BIO recognizes that payers, including CMS, have expressed concerns that some diagnostic tests in the market are superfluous, and may be ordered by a provider despite the fact that the result will not meaningfully alter how the provider will treat the patient. However, the above language included in the Draft Guidance—a focus on impacting clinical outcomes—is a metric more appropriately applied to a therapeutic intervention. In that case, there is a one-to-one, direct relationship between administration of the therapeutic intervention and the clinical outcome; that is, there is nothing downstream of the therapeutic intervention that cannot be controlled for in the study.

In contrast, diagnostic tests provide information for physicians to use to guide the course of treatment. In a clear case, such as for a companion diagnostic test that specifies a particular drug/biologic in its labeling based on the results, this evidentiary burden of meaningful impact on clinical decision-making is met per se. However, many clinically useful diagnostic tests are 1) used in the context of other clinical information; and 2) may produce different courses of action for patients with the same result, either due to other contextual clinical information or based on the individual experience of the physician. There exists variability downstream from administration of the diagnostic test that cannot practically be controlled for in the real world use of these products. Accordingly, the most appropriate metric for clinical utility should be whether the results of the test meaningfully alter clinical decision-making.

BIO encourages CMS to explore evidentiary standards for diagnostic tests that are more appropriate and valid to measure the clinical utility of these products. To this end, CMS should consider whether diagnostic tests exist that would fall into a per se category of meeting this evidentiary burden. For example, as mentioned above, companion diagnostic tests include labeling that direct the use of a particular drug/biologic based on the result of the test. Such diagnostic tests have a meaningful alteration of clinical decision-making, and thus meet this evidentiary burden, per se. As mentioned in other sections of this comment, BIO believes that CED is not appropriate for products that have been through a rigorous clinical review by the FDA, such as those approved under a new drug application (NDA), biologics licensing application (BLA) or a PMA. A more appropriate focus for the evidentiary standard for coverage of diagnostic tests will ensure that Medicare beneficiaries have access to tests that are used in a clinically meaningful manner by providers.

Stakeholders previously recommended that a MEDCAC meeting be convened prior to each proposed application of CED. CMS rejected this recommendation in the Draft Guidance.²² BIO maintains, however, any application of CED requires input from stakeholders with relevant expertise, including manufacturers and those with public and private sector expertise in designing and conducting clinical trials. In order to determine the appropriate evidentiary threshold for each application of CED and to determine whether a particular item or service meets that threshold, CMS should work collaboratively with stakeholders representing the full range of expertise and values—manufacturers, providers, and relevant academia—in evaluating the existing evidence, assessing the need to collect additional evidence, and constructing studies that can be used for CED. Because this process would be sensitive to the unique issues raised by each particular intervention, it is critical that CMS work closely and transparently with all stakeholders involved.

The Draft Guidance does not clearly articulate the mechanism CMS intends to use to apply CED. BIO continues to believe that CED should occur within the auspices of an NCD and therefore, only be implemented at the national level. Any application of CED must be developed in a clear and predictable manner, with opportunity for public comment, to ensure that CMS reaches an appropriate decision. This can be accomplished by using the NCD process, which has well-established procedures to garner input from stakeholders and has protections in place to ensure that inappropriate coverage determinations do not occur. In addition, by implementing CED at the national level, CMS can overcome a number of potential challenges related to small study sample sizes, limited agency resources, and duplicative clinical trials.

In the Draft Guidance, CMS says that it expects that “all CED approved studies will be analyzed and published in peer-reviewed clinical journals,” and that CMS “intends to maintain information on ongoing CED research studies on its website along with links to the ClinicalTrials.gov” website.²³ CMS’s Draft Guidance fails to ensure transparency regarding the decision to initiate CED, end a CED study, and evaluate CED for purposes of making a new or revised coverage determination. It also fails to make specific provisions for ensuring meaningful manufacturer engagement in the creation, governance, and implementation of CED.

It is critical that CMS establish a well-defined, transparent, and inclusive CED policy that encourages innovation and that is initiated only after clearly communicating the reasons for applying CED and identifying the research questions justifying the application of CED. These communications should occur early in the coverage review process and be understood by all interested stakeholders. BIO urges CMS to engage manufacturers in determining how to define and implement technology-specific CED studies and in governing the approved CED registry or clinical trial. Without this engagement, CED may impose significant and unnecessary burdens on manufacturers and providers and may not productively complement and enhance existing medical evidence. The timeline for sufficient evidence development also should be part of the ongoing dialogue between CMS, stakeholders, and appropriate expert advisors, such as clinical epidemiologists and scientists. CED should describe CMS’s proposed process for communication with manufacturers and other relevant stakeholders prior to the opening of a national coverage analysis and the potential application of CED, and its proposed process for involving them in an open and transparent dialogue as the issue is considered and the research questions are generated. In addition, CMS should describe in more detail the process it will use to apply the CED study results to a coverage decision. BIO recommends that decisions relating to applying and ending CED should be subject to public notice and comment. Finally, CMS should be transparent in how it defines metrics—such as ‘last patient last visit’—that govern progression through the CED process, especially those used to determine its conclusion.

BIO appreciates the opportunity to comment on the Draft Guidance. We look forward to continuing to work with CMS to address this and other important issues in the future. Please feel free to contact me at 202-962-9220 if you have any questions or need any additional information. Thank you for your attention to this very important matter.

Sincerely,