Clinical Trial Policy

to CMS:

I am writing in regards to the proposed revisions in CMS policy regarding coverage of routine healthcare expenses in Medicare patients who are participating in clinical trials. This is Proposed Decision Memo for Clinical Trial Policy (CAG-00071R2), at https://www.cms.hhs.gov/mcd/viewdraftdecisionmemo.asp?id=210

These changes will have an adverse effect on the care of Medicare patients. Therefore, I urge you to rescind or delay these proposed regulations.

I am a medical oncologist, caring for adult patients with cancer. We have a strong tradition in our practice of support for clinical research. It is our philosophy that all of our patients should have the opportunity to receive the bestpossible care for their cancers. Standard care isnot curative for most adult cancers. Therefore,each of our patients has the potential to benefitfrom newer therapies, which are offered as part of clinical research trials. The community as a whole also benefits from the knowledge gained from clinical trials. Our experience over the past 30 years, particularly the decline in mortality from breast cancer, colon cancer, and lymphomas, is evidence for the powerful benefit of the American clinical research enterprise. I would note that this is a broad-based enterprise, involving community and University groups,federally-sponsored and commercially sponsored research. The improvements in care from clinical research have been a great economic benefit to the American public, by reducing death and disability.

Unfortunately, less than 10% of adult American patients participate in clinical trials. This contrasts with the European experience. This poor record of participation is in part because of the burden of regulatory review and oversight of studies. This burden, which has increased significantly in the past 10 years, increases the time required to initiate a study, the time required to care for and monitor patients, and ultimately increases the expense of studies. The result is that we cannot open as many good studies. Over the last year, our community clinical oncology program was forced to suspend enrollment for several months because of declining Federal support for clinical research and the increased expense of mounting a study.

The proposed changes in CMS regulations will have the effect of further increasing the burden on clinical research organizations. This will result in a decrease in our ability to offer studies to our patients. Some questions arise:
1. How will clinical research organizations, research groups, and caregivers be compensated for the additional expense and effort needed to meet this new layer of regulation?
2. How rapidly will CMS respond to the request from a research organization for review of their study? In general, CMS has been slow in response to similar requests. In cancer patients, and in studies offered to cancer patients, delay means death. The regulation will effectively kill many studies, delay completion of others, and force our patients to refrain from studies.
3. Where is the compelling evidence that this policy change is necessary? CMS fails to present evidence that the current system of review is leading to inappropriate billing or care patterns in Medicare patients.

In summary, I urge you to rescind or delay these proposed regulations. Perhaps they should be reviewed by the Health and Human Services oversight committees in the Senate and House. This would be appropriate, since these regulations have the potential to limit the options of American citizens to receive the best possible care for a serious disease.

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Introduction

We, at the Eliminating Disparities in Clinical Trials (EDICT) Project, appreciate the opportunity to respond to the revised NCD and applaud CMS efforts to revisit the benefit issues related to clinical trials. The EDICT Project, launched in 2005, is a research study designed to address the problems and find workable solutions to recruiting and retaining populations that are underrepresented in clinical trials such as low income, elderly, racial-ethnic minorities or those who live in rural areas.

We greatly appreciate the fact that the proposed changes have engendered a productive dialogue from various stakeholders in distinct voices. Moreover, we understand the practical concerns that some organizations have noted in response to the proposed changes. Nevertheless, because we believe that the proposed changes enhance the quality of clinical research, facilitate the equal access that Medicare is designed to ensure, and improve returns on investment, we write in strong support of the proposed changes.

Much of the opposition to the proposed changes seems to center around several basic claims. First, there is a sentiment that the proposed changes are not needed since the NIH Revitalization Act requires and FDA guidelines recommend inclusion of underrepresented populations in clinical trials absent compelling nondiscriminatory exclusion criteria. Second, there is a concern that the self-certification process will increase burdens on institutions and research teams that conduct clinical research, potentially decreasing participation by Medicare beneficiaries and reversing the progress made since the last changes in the clinical trials policy in 2000. For several reasons, we do not share these positions.

Federal Initiatives Have Not Prevented Widespread Disparities in Clinical Trials

First, the NIH Revitalization Act applies only to federally funded trials. A 1999 GAO report cited a PhRMA official’s estimate that 80% of all drug trials are funded by industry (1). As such, the reach of the Revitalization Act is inherently limited. Richard Rettig noted in 2000 that “the entire clinical research enterprise is no longer anchored firmly in the public sector” (2) Moreover, the trend over the last twenty-five years has tilted toward greater private and lesser public sponsorship of trials, so it is reasonable to expect further retrenchment on the scope of the Revitalization Act.

Second, the methodology NIH uses to track the rates of underserved populations participating in clinical research measures only enrollment (3). This is important, because unless retention of research subjects is measured, there is simply no way to be sure what percentages of those who enroll are retained. The proportions of members of underserved populations who enroll in clinical trials is not evidence of the proportions of those members retained in clinical trials. A 2001 study, for example, found that subjects who tended to withdraw from the trial tended to be female and members of ethnic minorities, both of which constitute underrepresented populations in clinical trials (4). It is difficult to see how CMS can see a return on its investment in increasing access to clinical trials unless attention is given to insure that members of underserved populations are retained.

Third, IRBs spend an overwhelming amount of their resources on initial review of protocols, with comparatively little attention devoted to continuing review. The applicable regulations require continuing reviews to be performed only once per year (5). The OIG’s comprehensive 1998 report quotes one IRB member as reporting that “he reviews the continuing review summaries during the board meeting to see if a patient has died. If no patient has died, then he generally will not raise questions” (6). Accordingly, even where IRBs scrutinize protocols to be sure they comply with the Revitalization Act, the IRB system is generally not equipped to evaluate protocols as they are conducted to ascertain whether participants who are members of underserved populations are retained.

Fourth, the FDA guidelines are just that – guidelines – and are not compulsory. Even with the requirements of the Revitalization Act, the evidence overwhelmingly demonstrates significant disparities in clinical trials, with the populations that bear the highest disease burdens tending to be dramatically underrepresented in clinical trials. A 2005 AHRQ report indicated that the elderly, those of low socioeconomic status, those living in rural areas, Latino/Hispanic, Asian/Pacific Islander, American Indian/Alaska native men and women, and African-American men are all underrepresented in cancer clinical trials (7). Similarly, a 2006 study in Cancer noted that more than a decade after the passage of the Revitalization Act, “certain populations are still underrepresented in cancer-related clinical trials, including racial and ethnic minorities, older adults, adolescents, rural populations, and individuals of low socioeconomic status (SES)” (8). Even more recently, the Annals of Surgical Oncology has released a study online (published online August 8, 2007) which found that racial/ethnic minorities and elderly persons were less likely to enroll in clinical trials than Caucasians and younger persons (9).

Thus, there is ample reason to believe that populations, such as the elderly (10), that bear disproportionate burdens of disease continue to be dramatically underrepresented in clinical trials. Ameliorating this trend has proved difficult, even with the Revitalization Act and the relevant FDA guidelines.

There is Little Reason to Believe the Proposed Changes Will Prove Impracticable

Two further points are worth mentioning as to the proposed changes regarding self-certification. As to the concerns that the proposed changes are too onerous, Steven Epstein’s extremely recent and exhaustively researched book on the issue of including underserved populations in clinical research documents similar objections being raised to the Revitalization Act (11). Fourteen years later, there are relatively few claims that the Act demonstrably slowed the pace of clinical research or rained down the parade of horribles its most vehement detractors predicted. There is abundant evidence suggesting that certain populations’ underrepresentation in clinical trials remains a serious problem. In contrast, there is little evidence explaining why or how CMS’s modest measures designed to address this problem as to Medicare beneficiaries will prove an impossible burden.

Ameliorating Disparities in Clinical Trials Enhances Research Quality, Social Justice, and Returns on Investment

Finally, ameliorating disparities in clinical trials simultaneously enhances the quality of the research, furthers social justice, and facilitates returns on investment. Regarding research quality, a commitment to evidence-based medicine requires means of assessing what counts as good evidence. In many cases, the best evidence demonstrates that the intervention is generalizable across the entire patient population. In other cases, the best evidence demonstrates the effect of an intervention in a specific population (whether identified by race, ethnicity, gender, disability status, age, etc.).

However, in both cases, the evidence will be stronger if the widespread disparities in clinical trials are ameliorated. This is because a subject population that displays such disparities will not resemble the intended patient population, whether that population is the general public or a specific community. Therefore, reducing these disparities results in better scientific evidence, which can then be translated into better clinical practice, which will provide greater benefit to the public.

As to social justice, ameliorating disparities in clinical trials is consistent with ethical commitments to distribute the fruits of biomedical research justly (12). Many of the underrepresented populations, including Hispanic/Latino women, African-American men, the elderly, children, and disabled persons, were victims of unethical research programs in the twentieth century. These same populations are among those that bear disproportionate burdens of disease. Tracking Plato’s account of justice as giving each person their due, it is reasonable to conclude that justice demands that steps be taken to reduce the continuing disparities in clinical trials. There is no justification for the notion that members of underserved populations are due less benefits of clinical research than others, especially when such populations bear disproportionate burdens of disease and have been victims of unethical research. Ultimately, the proposed changes are an important component in giving each their due, and therefore reflect a deep commitment to social justice.

The reason why ameliorating disparities in clinical trials will promote returns on investment is because results from trials featuring proportionate representation constitute better evidence. As a result, sponsors of interventions can justifiably claim that an intervention that has proved efficacious in a clinical trial that featured proportionate representation is better suited for integration into existing practice guidelines than an intervention arising from a trial that lacked proportionality. In short, ameliorating disparities in clinical trials may provide sponsors an advantage in positioning their products in the stream of commerce.

Conclusion

In conclusion, we again wish to express gratitude to all the stakeholders who have engaged in dialogue on such an important issue. While change is not always easy, it is all-too-often needed, and the proposed changes to the clinical trials policy are responsive to this need. Despite the best intentions of policymakers and stakeholders, the evidence conclusively shows that there remain widespread disparities across the clinical research enterprise. Fears of insurance coverage and reimbursement are a well-known barrier to participation in clinical research (13), and the proposed changes to the clinical trials policy are a crucial step towards ameliorating this barrier in particular. Thus, the proposed changes are needed to ensure that the medically underserved populations that bear disproportionate burdens of disease are treated justly in sharing in the fruits of clinical research.

Sincerely,

Armin D. Weinberg, PhD
Principal Investigator
EDICT (Eliminating Disparities in Clinical Trials) Project
Chronic Disease Prevention and Control Research Center
Baylor College of Medicine
Houston, Texas

(1) See General Accounting Office, NIH Clinical Trials: Various Factors Affect Patient Participation 1, 4 (1999), available at http://www.gao.gov/archive/1999/he99182.pdf (last accessed August 18, 2007); see also Hamilton Moses III, E. Ray Dorsey, David H. Matheson, and Samuel O. Thier, Financial Anatomy of Biomedical Research, 294 JAMA 1333, 1335 (2005).

(2) Richard Rettig, The Industrialization of Clinical Research, 19 HEALTH AFFAIRS 129, 140 (2000).

(3) See Department of Health and Human Services, National Institutes of Health, Monitoring Adherence to the NIH Policy on the Inclusion of Women and Minorities as Subjects in Clinical Research: Comprehensive Report Tracking Human Subjects Research as Reported in Fiscal Year 2005 and Fiscal Year 2006, available at http://orwh.od.nih.gov/inclusion/2007acr-5-2-07.pdf (last accessed August 17, 2007).

(4) See Susan L. Janson, Maria Elena Alioto, and Homer A. Boushey, Attrition and Retention of Ethnically Diverse Subjects in a Multicenter Randomized Controlled Research Trial, 22 CONTROLLED CLINICAL TRIALS 236S, 238S-239S (2001).

(5) 45 C.F.R. § 46.109 (2007).

(6) Department of Health & Human Services, Office of Inspector General, Institutional Review Boards: A Time for Reform 1, 6 (1998), available at http://oig.hhs.gov/oei/reports/oei-01-97-00193.pdf (last accessed August 17, 2007). Since OIG’s report, there is little evidence that significant progress has been made in improving the continuing review process. Indeed, the OIG’s 2000 follow-up report expressly noted that few of its recommended reforms had been enacted, and minimal progress had been made. See Department of Health & Human Services, Office of Inspector General, Protecting Subjects: Status of Recommendations 1, 2 (2000), available at http://oig.hhs.gov/oei/reports/oei-01-97-00197.pdf (last accessed August 17, 2007).

(7) J.G. Ford et al., Knowledge and Access to Information on Recruitment of Underrepresented Populations to Cancer Clinical Trials, 122 AHRQ EVIDENCE REP./TECH. ASSESSMENT 1, 1 (2005).

(8) Shari Bolen et al., Defining “Success” In Recruitment of Underrepresented Populations to Cancer Clinical Trials: Moving Towards a More Consistent Approach, 106 CANCER 1197, 1998 (2006).

(9) See John H. Stewart et al., Participation in Surgical Oncology Clinical Trials: Gender-, Race/Ethnicity-, and Age-based Disparities, ANN. SURG. ONCOLOGY, available at http://www.springerlink.com/content/wr832v6285x154j1/?p=14c72fd1525748dea4925a36cc38c5e8&pi=8 (last accessed August 18, 2007).

(10) See Intercultural Cancer Council Network, Cancer Clinical Trials: Participation by Underrepresented Populations, available at http://www.iccnetwork.org/cancerfacts/cfs11.htm (last accessed August 18, 2007).

(11) Steven Epstein, INCLUSION: THE POLITICS OF DIFFERENCE IN MEDICAL RESEARCH 103-106 (2007).

(12) See, e.g., Dorothy E. Roberts, Legal Constraints On the Use of Race in Biomedical Research: Toward a Social Justice Framework, 34 J. L. MED. & ETHICS 526 (2006); Barbara Noah, The Participation of Underrepresented Minorities in Clinical Research, 29 AM. J. L. & MED. 221 (2003).

(13) See Primo N. Lara, et al., Prospective Evaluation of Cancer Clinical Trial Accrual Patterns: Identifying Potential Barriers to Enrollment, 19 J. CLIN. ONCOLOGY 1728, 1732 (2001); Robert Finn, Surveys Identify Barriers to Participation in Clinical Trials, 92 J. NAT. CANCER INST. 1556, 1557 (2000).

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The Alliance of Dedicated Cancer Centers: Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
City of Hope National Medical Center
Dana-Farber Cancer Institute
Fox Chase Cancer Center
H. Lee Moffitt Cancer Center and Research Institute
M.D. Anderson Cancer Center
Memorial Sloan-Kettering Cancer Center
Roswell Park Cancer Institute
Seattle Cancer Care Alliance
Sylvester Comprehensive Cancer Center

August 18, 2007

By Electronic Delivery

Steve Phurrough, MD, MPA
Director
Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memorandum for the Second Reconsideration of the Clinical Trial Policy, Renamed the Clinical Research Policy (CAG-00071R2)

Dear Dr. Phurrough:

On behalf of the Alliance of Dedicated Cancer Centers (the Cancer Centers), an alliance of ten nationally recognized institutions focusing exclusively on the care of cancer patients, I am writing to comment on the Centers for Medicare & Medicaid Services’ Proposed Decision Memorandum for the Second Reconsideration of the Clinical Trial Policy, Renamed the Clinical Research Policy (“the Proposed Decision”), as published on CMS’s website on July 19, 2007. The Cancer Centers, individually listed above, appreciate the opportunity to submit these comments.

I. Introduction
As institutions that have been responsible for many transformational advances in cancer prevention and treatment, and as we have indicated to you on previous occasions, the Cancer Centers welcome a revisiting of the clinical trial policy that would result in expanded access for Medicare beneficiaries to these potentially life-saving therapies. The Cancer Centers strongly support the policy objective of the original clinical trial national coverage decision (NCD) to expand the availability of clinical trials for Medicare beneficiaries. By providing Medicare coverage for the routine patient care costs associated with qualifying clinical trials, the original NCD has helped many Medicare beneficiaries obtain access to the innovative cancer therapies available at our institutions.However, as CMS is aware, there has been significant confusion and ambiguity about application of the current NCD. Specifically, in many cases, providers have been unclear as to whether it is appropriate to bill for particular services furnished to patients who are enrolled in trials. We have discussed many of these issues with CMS officials in person and telephonically on several occasions, and have submitted a number of comment letters raising these concerns: in response to the tracking sheet posted by CMS on July 10, 2006 that first announced the agency’s reconsideration of the NCD; in connection with our presentation on this topic to the Medicare Evidence Development Coverage Advisory Committee (MedCAC) on December 13, 2006; and most recently in our May 10, 2007 response to CMS’s initial reconsideration of the policy. As described below, although CMS has addressed some of our concerns, there are a number of remaining ambiguities for which we still request clarification. In addition, we have a number of questions and concerns about the self-certification process proposed in this policy and the corresponding elimination of “deemed” status for certain clinical trials.

Our specific comments and concerns about the Proposed Decision are summarized below. Our comments track the subject matter headings in the Proposed Decision.

II. Discussion
A. Scope of Clinical Research Policy
1. Definition of Research
In the Proposed Decision, CMS proposes to define clinical research as follows: “Clinical research, for purposes of this NCD, means any systematic investigation involving human participants which is designed to contribute to generalizable knowledge and which involves a clinical intervention, care delivery strategy, or diagnostic technique designed to potentially improve predefined health outcomes.” The Cancer Centers are concerned that this latter phrase could be construed to exclude from coverage Phase I and certain Phase II trials which are not specifically designed to improve health outcomes. While we understand, based on a number of our interactions with CMS on this topic, that Phase I and II trials are intended to be covered under this policy, we believe the proposed language could lead to a different and unintended interpretation. Therefore, we request that the agency clarify the coverage of Phase I and Phase II trials in the final revised policy. In addition, we ask that CMS clarify the listed examples of the types of clinical studies that would be supported under the policy. In particular, we request clarification as to what is meant by “primary and secondary prevention strategies.” We urge CMS to clarify in the final policy that this language refers to prevention trials. As we have communicated to CMS in the past, we believe the agency should expand coverage for trials focusing on patients who are currently healthy, but are at high risk for developing disease, particularly cancer (e.g., patients at high risk for breast, prostate, and colon cancer due to family history and/or the presence of genetic markers). These types of trials clearly have an important therapeutic purpose, and the research conducted by the Centers in this area suggests that these treatments have enormous potential for reducing the incidence of cancer and enhancing outcomes when cancer occurs. Many cancer prevention trials are also conducted by cancer cooperative groups, which typically do not receive funding from the National Cancer Institute that is sufficient to cover these studies’ costs and thus would greatly benefit from expanded Medicare coverage. We note that the Proposed Decision removes the prohibition on enrolling healthy volunteers in an approved trial, which may signal CMS’s intent to cover prevention trials under the new policy. However, the proposed language is unclear and would likely be subject to varying interpretations by Medicare contractors. Thus, the Cancer Centers request that CMS explain the kind of trials it intends to cover as “primary and secondary prevention strategies” and specifically address whether it intends to cover prevention trials, as we have defined them above. We believe covering these trials would be a major step forward in expanding access for Medicare beneficiaries to these important therapies.
B. Standards for Clinical Research
1. Therapeutic Intent
The Proposed Decision attempts to clarify this issue by proposing a revised standard that “the clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Studies of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life-threatening … and the patient has no other viable treatment options.” We have a number of questions about this latest reformulation of this standard. First, in its initial reconsideration of the policy, CMS stated that “[r]esearch studies, including some Phase I trials, whose protocols commit to measuring therapeutic outcomes as one of the objectives, may meet this standard only if the disease being studied is chronic, life threatening, or debilitating.” CMS’s explicit reference to Phase I trials that measure therapeutic outcomes as only one of the objectives of a covered trial helped clarify that these types of trials were covered under the policy. We urge the agency to reinstate this clear formulation of this standard as it applies to Phase I trials in the final policy.In this regard, we remain concerned about the potentially conflicting language on this issue included in the Proposed Decision. Specifically, the first standard in the Proposed Decision states that “[t]he principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes.” This language could be construed as contravening the standard stating that measuring therapeutic outcomes need only be one of a trial’s objectives. As noted above, the proposed definition of clinical research is also confusing in this respect. Thus, we request that CMS conform these general standards to the more specific standard on therapeutic intent. Next, we are concerned that the Proposed Decision does not provide specific criteria by which to ascertain whether a particular trial satisfies the therapeutic intent standard. In previous discussions with CMS and a Medicare contractor, we were told that a trial should be found to have the requisite therapeutic intent where the trial protocol specifies how therapeutic intent is measured and demonstrates that outcomes will be assessed based on the systematic collection of data and evaluation of the patient. We agree with CMS that this is an appropriate benchmark and request that the agency include these criteria in the final policy.We also request that CMS promptly issue clarifying instructions to its contractors on this standard, including the evidence needed to establish whether a trial has demonstrated sufficient therapeutic intent. Some Medicare contractors have construed the therapeutic intent requirement differently from that articulated in the Proposed Decision. For example, in a May 2006 letter to the legal counsel of one of the Centers, Empire Medicare Services stated that many Phase I trials would not be covered under the NCD because their intent is to “determine safety and toxicity, rather [than] to assess the effect on patient outcome[s].” Thus, this contractor appears to believe that a trial is not covered unless therapeutic intent is the primary purpose of the trial. We also believe that contractors have not adopted a common approach on how to measure therapeutic outcomes. In light of this confusion, we urge CMS to issue instructions to its contractors prior to implementing the final NCD.Finally, we recommend that CMS modify the language in the Proposed Decision that a patient have “no other viable treatment options.” This language is problematic because patients may have a number of treatment options that could be characterized as viable, but a particular clinical trial may be the best option for a patient. Thus, we urge the agency to modify this language to reflect this clinical reality.
2. Trial Registration
CMS is proposing to include as a standard that “[t]he clinical research study is registered on the ClinicalTrials.gov website by the study sponsor/principal investigator prior to the enrollment of the first study subject.” We strongly agree with CMS that research studies generally should be registered. We appreciate CMS’s interest in ensuring that beneficiaries have access to pertinent information about the clinical research that the Medicare program is supporting, and applaud the agency for selecting a website for this purpose with which our institutions are very familiar. However, the Cancer Centers have some operational concerns regarding this proposed requirement.Specifically, complying with this requirement may be quite burdensome and resource-intensive, particularly for institutions such as the Centers that conduct large numbers of trials. Currently, Centers may choose various criteria to identify which protocols are submitted to the ClinicalTrials.gov website. These may include randomized Phase II or III design, non-randomized with multiple treatment arms and protocols with institutional IND numbers. A significant number of trials are not currently registered. For example, of those trials that began enrollment over the past year and a half at one of our institutions, Memorial Sloan-Kettering Cancer Center, only 29 percent have been registered. Thus, requiring all trials to be registered, even on only a prospective basis, will require an investment of substantial additional resources.Therefore, we are concerned that it may be difficult in many cases to ensure registration of a trial prior to enrollment of the first study subject. We recommend that CMS provide a 60-day grace period from the opening of the trial i.e., from when patients are first permitted to enroll to complete the registration process during which time no financial or other penalties would be imposed on the registrant.

3. Release of Study Results
CMS is proposing to include in the final revised NCD a requirement that the research study protocol “specif[y] the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or [the] study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the Internal Committee of Medical Journal Editors. However, a full report of the outcomes must be made public no later than three (3) years after the end of data collection.” The Cancer Centers request clarification as to the precise publication obligations that CMS is proposing to impose on institutions that conduct trials. In the original reconsideration of the policy, CMS included a proposed requirement that a protocol must “specify and fulfill” publication of all outcome results. In a recent public forum, CMS officials noted that the word “fulfill” was removed from the standard in this second reconsideration and emphasized that the only requirement is that a protocol discuss a plan for publication. However, the currently proposed language indicates otherwise because it states that the results of a trial and a full report of the outcomes “must be made public.” We trust that, consistent with its recent public statements on this topic, CMS intends to only require that a protocol include a discussion about publicly releasing results and that there is no specific requirement for publishing the results by a specific date. In other words, we understand this standard to mean that the trial protocol must discuss: 1) that an effort will be made to publish results upon completion of the trial, whenever that may occur; and 2) the proposed method for such publication. This is an important clarification because no institution can guarantee publication in any format, nor by a certain date. For example, a journal may not be interested in publishing negative results from a study. Further, we are aware of only a limited number of public databases that are currently available to publish trial results. Thus, in situations where a trial result cannot be published in a peer-reviewed journal, it would be difficult to comply with this publication requirement using existing outlets. Significantly, requiring publication is simply not necessary. Sufficient incentives already exist to encourage institutions such as the Cancer Centers to publish trial results i.e., that it is central to our mission as research institutions to seek publication of our research findings.We also request that CMS set forth exactly what language the agency would like to have included in a protocol to satisfy this requirement. This type of language typically is not included in protocols. Because modifications to protocols are a significant undertaking, we would like a clear understanding of what CMS would like to have included before beginning this process.If, notwithstanding the above, CMS decides to impose a publication requirement, we seek clarification as to how publication will be tracked by the agency and/or its contractors, particularly where a study may remain open and dormant for a number of years. If publication does not occur or is delayed for many years, would this affect Medicare reimbursement for such trials? Because protocols are often the intellectual property of the trial’s sponsor, we do not always have the legal right to publish the trial results, or we may not have access to all of the data needed for publication. Therefore, it would be unreasonable to tie our Medicare payments to publication of results.Finally, we request clarification that, if a trial involves a cooperative group or other collaborative effort, only one institution would be required to publish the results, as designated by the cooperative group.
4. Health Disparities
CMS proposes to include a new standard that “[t]he research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria affect enrollment of these populations, and a plan for the retention and reporting of said populations in the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary.” In the original reconsideration of the clinical trial policy, CMS included a somewhat different health disparities standard suggesting that the agency was tying clinical trial qualification to patient demographics or other characteristics. However, this newly proposed standard clearly states that the agency is only requiring a discussion in the protocol about how certain populations may be affected by the treatment or technology being studied in the trial. We appreciate this clarification and revised language.We are very supportive of promoting enrollment in clinical trials from underrepresented subpopulations, but patient eligibility for a trial should be based solely on clinical considerations. Significantly, other federal government agencies, including the Office of Human Research Protection and the FDA, already require investigators to be cognizant of health disparities. For example, HHS regulations pertaining to human subject protections require that studies select subjects on an equitable basis and recognize the special circumstances of vulnerable populations. Clinical trial programs that do not meet these requirements are subject to termination or suspension. Further, as part of the comprehensive review that allows the Centers to maintain our status as NCI-designated cancer centers, we are required to discuss how our research programs address health disparities. Specifically, race, ethnicity and sex is tracked for all study participants on intervention and non-intervention studies and reported to NCI at the time of grant submission and every year of the granting period. Finally, the application for NIH-funded extramural research includes specific requirements to ensure the inclusion of subpopulation groups in our research. Thus, there is no need for the revised policy to impose any requirements regarding health disparities beyond the requirement that these issues be addressed in the protocol.
5. Medicare Populations
A newly proposed standard is that “[t]he research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.” In the original reconsideration of the policy, the Cancer Centers were concerned with a similar standard that could have been construed as imposing a requirement that trials enroll a certain number or percentage of Medicare beneficiaries. The revised language clarifies that this is not the case. Rather, CMS is only requiring a discussion in the protocol about how a trial may be generalizable to the Medicare population. As described above with respect to health disparities, we are strongly opposed to tying clinical trial qualification to patients’ enrollment status, demographics, or other characteristics. We are very supportive of promoting enrollment in clinical trials from all sectors of society, but patient eligibility for a trial should be based on clinical and other indications that are not normally related to the type of insurance an individual carries or other socioeconomic factors. Access to a trial should be available to all eligible patients. We applaud CMS for recognizing this important policy in the Proposed Decision.
C. Covered Items and Services
1. Usual Patient Care/Routine Clinical Services/Investigational Clinical Services
The Cancer Centers generally support the proposed definitions of usual patient care, routine clinical services, and investigational clinical services in the Proposed Decision. Under the original policy, routine services were defined as “[i]tems or services that are typically provided absent a clinical trial (e.g., conventional care).” As we have discussed with CMS, it has been difficult for many stakeholders to ascertain whether a particular therapy qualified as “conventional care.” In the Proposed Decision, usual patient care includes “routine clinical services and investigational clinical services in clinical research when the investigational clinical services would be covered outside of the clinical research ….” This proposed language is a significant improvement over the existing definition. Under the proposed policy, routine clinical services are defined to include those “items and services that are covered for Medicare beneficiaries outside of a clinical research study.” Thus, it is clear that any item or service that is covered outside of the trial would be considered a routine clinical service, even if it is not characterized as “conventional care.” In addition, the Cancer Centers appreciate the agency’s recognition that usual patient care includes investigational clinical services when those services would be covered outside of the trial. Thus, a drug that is being provided to a patient for an on-label use would be covered, even if it is administered in the course of a clinical trial – i.e., a drug does not lose its covered status simply because it is being provided in a trial.The Proposed Decision also clarifies the coverage policy for eligibility tests. As we have previously communicated to CMS, issues have arisen under the current NCD with regard to certain tests that both determine eligibility and prevent complications. CMS has previously indicated to us that a test performed in order to determine whether a patient can safely receive an investigational agent should be classified as a covered test necessary to prevent complications, rather than a non-billable eligibility test, even if the patient would be excluded from the trial based on the results of the test. Thus, Hepatitis C testing would be covered in a trial of an investigational drug that is known to have liver toxicity, which would also preclude Hepatitis C patients from participating in the trial for safety reasons. Under the Proposed Decision, CMS states that the policy does not cover administrative services, which are defined as “clinical services provided to solely satisfy data collection and analysis needs that are not used in the direct clinical management of the patient.” Therefore, we construe this language as confirming CMS’s verbal representation that such a dual-purpose test would be covered. If this is not the case, please clarify this question in the final revised NCD.

D. Approval Process
1. Deemed Trials
In this second reconsideration of the policy, CMS is proposing a major departure from the original policy by abandoning the “deeming” process that has operated successfully in the past and imposing self-certification for all trials in order to qualify for coverage. Specifically, CMS would cover usual patient care for Medicare beneficiaries where the sponsor/principal investigator has certified to CMS that the standards set forth in this policy have been met. To self-certify, the sponsor/principal investigator must send a letter to CMS describing the scope and nature of the clinical research, discussing each of the standards in the policy, and certifying that these standards have been met. CMS will then review this letter for completeness only. Following CMS’s approval, the agency will then publish the title and ClinicalTrials.gov registry number of approved trials on its website and in the Federal Register. For a number of reasons, the Cancer Centers believe that this proposed change is problematic.First, we find it difficult to understand why CMS is now requiring self-certification for institutions such as ours that were previously “deemed” to be conducting qualifying trials. CMS’s original policy that certain entities, including the Cancer Centers, by virtue of who they were, were automatically qualified was a sound, effective, and justifiable policy. Our institutions are some of the premier research facilities in the world. It is hard to imagine a group of institutions that exercise more rigorous oversight over their clinical trials than the Cancer Centers. Typically, the Cancer Centers receive a core grant from NCI and the core grant guidelines provide for federal oversight of the grantee’s processes for protocol review. Specifically, the core grant guidelines have extensive requirements for a robust protocol review and monitoring system (PRMS) that our Centers must implement. Among other things, the PRMS must provide a mechanism for scientific review of each study prior to review by the IRB and then assure ongoing internal oversight of all the scientific and research aspects of the trial. Thus, the self-certification process described in the Proposed Decision is entirely duplicative of existing processes. We are also concerned about the impact of the CMS proposal on the coverage decisions of commercial payers, which may be inclined to implement this Medicare precedent in a manner that would unduly restrict coverage to clinical trials for their enrollees. We urge CMS to exempt the Cancer Centers from self-certification and reinstate a process of automatic qualification for, at minimum, trials that are subject to existing oversight processes such as those required for recipients of NCI core grants. In addition, the Cancer Centers are concerned about the potential implications for patient safety and quality of care of the self-certification process described in the Proposed Decision. CMS had originally proposed to eliminate self-certification altogether from the policy, noting that this process was inadequate because it believed that qualified trials needed oversight beyond that provided by the trial investigators, particularly where some studies may not go through a peer review process at all. Now, in a bizarre about-face, the agency is relying solely on self-certification for approval of all trials. Under self-certification, virtually any entity can submit the required letter to CMS and, so long as the form is filled out completely, the trial apparently will be certified as qualifying for Medicare coverage. While the agency holds out the prospect that CMS’s Medical Officer would be authorized to reject a trial as unqualified, the process as described appears to be one where, in practice, virtually all trials would be approved provided that someone has “checked off the boxes” on the form. Indeed, CMS appears to be proposing to replace the previous policy of “deeming” only trials conducted in a high quality research center as qualified for coverage with a policy where virtually all trials are “deemed” to be qualified, regardless of where and by whom they are conducted. Further, CMS is not proposing any kind of audit process that would ensure compliance with any quality standards. While CMS appears to be indicating that self-certification may be a temporary process until another qualification process can be established in a formal rulemaking, we are concerned that, given CMS’s track record for regulating in this area, it may be months, if not years, before such a system is implemented. In the meantime, Medicare beneficiaries may be vulnerable to enrolling in trials of inferior quality. For all of these reasons, we strongly urge CMS not to proceed with its self-certification proposal.

Finally, we are concerned about the timing of the proposed approval process. CMS has indicated that it would only take “a few days” to review a self-certification letter before the agency publishes the certification on its website. However, given the large number of trials that would be seeking certification, we question whether CMS will have the resources it needs to review and approve the self-certification letters in a timely way. We are concerned that there would be unnecessary delays in approval that could impede Medicare beneficiaries from enrolling in trials. Therefore, we request that, if CMS finalizes its self-certification proposal, the agency take the necessary steps to ensure it has the appropriate resources to process the self-certification letters expeditiously and in a manner that will not delay coverage decisions.In sum, we urge CMS not to fix what isn’t broken by abandoning a process which has proven to be an effective and efficient method for qualification of trials.

E. Local Coverage Determinations
CMS is proposing to state in the final NCD that items and services provided in a trial remain subject to local contractor policies, including local coverage decisions (LCDs) and claim adjudications. We are concerned that this provision might operate as a “back door” to undermine the patient protections and expanded coverage provided for in the NCD. More restrictive geographical variations should not exist in the administration and coverage of trials under a national policy. Thus, in its final NCD, CMS should provide that LCDs can be more expansive than the NCD in covering items and services provided in trials, but cannot be more restrictive in their coverage. The NCD should operate as the national floor for Medicare coverage of clinical trials.

F. Transition
The Proposed Decision states that the revised policy would not apply to a study that has begun enrollment prior to the effective date of the Decision, which is defined as 60 days after the comment period closes. Thus, the policy would not be applied retroactively to ongoing trials. However, we are concerned about the effective date of the policy with respect to trial protocols that are undergoing IRB approval but have not yet begun enrollment. For example, on the date the final policy becomes effective, our institutions are likely to have a number of fully developed protocols that have been submitted for IRB approval but have not yet commenced enrolling patients. As such, once patient enrollment begins, we would have to amend already finalized trial protocols. To amend such protocols would be extremely burdensome, complex, and potentially violative of our contracts with trial sponsors. Therefore, we request that CMS provide a six-month grace period beginning on the effective date for trials to comply with the new policy.

III. Conclusion
The Alliance appreciates the opportunity to comment on the Proposed Decision. Thank you for the collaborative approach that CMS has taken thus far in its reconsideration of the Medicare clinical trial coverage policy. We hope that CMS will consider the concerns and recommendations described above in revising the NCD. If you have any questions or require additional information, please contact the Alliance’s consultant on these matters, Dr. James Dougherty of the Arcus Group, LLC, at 212.785.2236.

Sincerely,
/s
James S. Quirk
Executive Director
Alliance of Dedicated Cancer Centers

1 Proposed Decision Memorandum for Second Reconsideration of the Clinical Trial Policy, Renamed the Clinical Research Policy (CAG-00071R2) (July 19, 2007), at 8 (emphasis added).
2 Id. at 9.
3 Proposed Decision Memorandum for Medicare National Clinical Trial Policy (CAG-00071R) (April 10, 2007), at 34.
4 Supra, n. 1 at 8 (emphasis added).
5 Specifically, in a May 28, 2004 letter to one of the members of the Alliance, Fox Chase Cancer Center, CMS stated that: (1) the clinical trial protocol should specify how therapeutic intent is measured; (2) the trial’s outcomes must be assessed based on the systematic collection of data and evaluation of the patient; and (3) therapeutic intent may be verified (e.g., by a Medicare payor) by the identification of specific outcomes (primary, secondary or otherwise) being used to measure the therapeutic effects of the interventions.
6 Letter from Empire Medicare Services to Ropes & Gray, LLP (May 5, 2006).
7 Supra, n. 1 at 9.
8 Supra, n. 1 at 9.
9 Supra, n. 3 at 34.
10 See, e.g., Eli Lilly and Company Clinical Trial Registry website, available at http://www.lillytrials.com/.
11 Supra, n. 1 at 9.
12 See 45 C.F.R. § 46.101 et seq. (“In order to approve research covered by these regulations the IRB shall determine that all of the following requirements are satisfied … (3) Selection of subjects is equitable. In making this assessment, the IRB should take into account the purposes of the research and … should be particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons.” Id. at § 46.111(a).); see also 21 C.F.R. § 56.101 et seq.
13 See, e.g., R01 and R21 grants, Public Health Services Grant Application, PHS 398, Section E.
14 Supra, n. 1 at 9.
15 Id. at 8.
16 Id. (emphasis added).
17 Id. at 10.18 Supra, n. 3 at 22.19 Id.

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August 17, 2007

RE: Medicare’s Proposed Clinical Research Policy

Dear Dr. Phurrough:

Thank you for the opportunity to comment on the July 19th proposed Clinical Research Policy (CRP). We appreciate the efforts of the Center for Medicare and Medicaid (CMS) to clarify coverage of services for Medicare beneficiaries enrolled in clinical research. We also appreciate CMS’ clarification of its intent as articulated at the August 7, 2007 Open Forum. We look forward to the addition of those clarifications in the final CRP.

We offer the following comments from our perspective as a nationally known public research institution that also operates an academic medical center, UW Medicine, encompassing two public hospitals, community clinics, physician practice plans and membership in a specialty cancer hospital. Faculty of the University of Washington conduct research throughout UW Medicine and are committed to bringing scientific advancements to the bedside for the benefit of Medicare beneficiaries and others. We urge Medicare to minimize the administrative burden on researchers and clinicians in complying with the CRP and to strike a balance between ensuring the integrity of the Medicare program while at the same time not discouraging innovation and scientific advancement through overly restrictive requirements or denying life-saving treatment to Medicare beneficiaries. We offer the following comments:

Issue: “Items and services furnished to Medicare beneficiaries in clinical research studies that do not meet the requirements of the policy are not covered.”

Comment: We are concerned that limiting coverage of items and services to Medicare beneficiaries enrolled in clinical research to only research meeting the requirements of the policy may discourage innovation and originality in research – the same innovation and originality that are often a necessary condition for federal funding.

Recommendation: We recommend that CMS maintain coverage for items and services that are reasonable and necessary even if a beneficiary enrolls in a study that is not certified. This is consistent with the overarching structure of Medicare’s statutory authority and ensures that Medicare beneficiaries have access to the latest advances. Alternatively, CMS should broaden the required standards such that all bona fide clinical research studies may qualify.

Issue: Standards for clinical research to support Medicare coverage of items and services Bullet 1: “The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes.”

Comment: We are concerned that there is an inherent potential for conflict in interpreting bullets one and nine in that “principal purpose” is often interpreted as “primary purpose” which might be seen as inconsistent with a study that is testing both safety and efficacy. Can a study that tests both safety and efficacy have as the “principal purpose . . . to test . . . health outcomes?” Several researchers expressed concern about Medicare coverage for pharmacogenomics research. This research is defined as “the study of inherited variations in genes that control the body’s response to drugs and the ways these variations can be used to predict whether a patient will have a good or bad response to a drug or no response at all.” We are concerned that the first bullet as drafted might be interpreted to preclude coverage for this type of research which is critical to the development of innovative drugs or new uses of existing drugs.

Recommendation: To avoid any potential confusion we recommend CMS redraft the sentence as follows: “One of the purposes of the research study is to test whether a particular intervention potentially improves health outcomes or provides information on participants’ responses to the intervention.“

Issue: Standards for clinical research to support Medicare coverage of items and services – Bullet 3: “The research study does not unjustifiably duplicate existing studies.”

Concern: Like many commentators who spoke at the August 7th CMS Open Forum, we are concerned about the ambiguity inherent in this standard. In addition, the issue of reliability of existing studies is very important, including the role that peer review plays in disseminating scientifically valid, reliable research results for dissemination to the public.

Recommendation: We recommend adopting the recommendations of the Association of Academic Health Centers (AAHC) to focus on “published studies” or “published peer-reviewed studies” as the population of studies against which “unreasonable duplication” will be evaluated.

Issue: Standards for clinical research to support Medicare coverage of items and services – Bullet 6: “The research study is in compliance with all applicable federal regulations concerning the protection of human subjects found at 45 CFR Part 46. If a study is FDA-regulated, it also must be in compliance with 21 CFR Parts 50 and 56.”

Comment: In the Open Forum, CMS clarified that the certification of the sponsor or principal investigator (PI) means that the standards for clinical research to support Medicare coverage of items and services have been met. Once certified, the billing entity will add codes modifiers and the ClinicalTrials.gov registry number to their claim forms to indicate that the usual patient care provided occurred in a study listed on CMS’ webpage. If the certification is later found to be incorrect, CMS stated that it would not impact the billing entities’ reimbursement. Based on the foregoing, the certification of compliance with all federal regulations concerning the protection of human subjects and the FDA regulations is not well-founded because it is only applicable to one point in time, rather than to the conduct of the entire study.

We agree wholeheartedly with the importance of compliance with federal regulation to protect human subjects and FDA regulatory requirements. We also recognize that the roles and obligations of the sponsor and PI in the conduct of clinical research may be different. This difference creates an inherent ambiguity in the requirement to certify compliance in that what is actually certified may depend on who certifies and at what point in time. Certifying compliance prior to the actual enrollment of subjects adds minimal value to protecting the safety of subjects above and beyond existing requirements. Federal law already requires compliance and federal agencies have substantial enforcement tools available to address non-compliance.

Recommendation: Eliminate bullet 6 as a required standard. Alternatively, adopt AAHC’s recommendation on this point that CMS should accept representation by the sponsor/PI that an institutional review board has reviewed and approved the study.

Issue: Standards for clinical research to support Medicare coverage of items and services – Bullet 8: “The research study has a written protocol that clearly addresses, or incorporates by reference, the Medicare standards.”

Comment: It is difficult to imagine how a protocol might be written to encompass all the Medicare standards and we are struggling to understand the intent of this provision. In light of the fact that the purpose of a written research protocol is to address the scientific inquiry process, specific subject procedures and safety of the research, and in light of the other proposed standards, we do not believe this provision is necessary.

Recommendation: Eliminate this provision.

Comments: This requirement generated a great deal of discussion and concern among our researchers. Many were concerned that the "life-threatening" standard is too high a bar and will hinder the study of therapies for certain diseases common among the Medicare population, for example arthritis and kidney disease, and the availability of critical treatment to beneficiaries. There was also concern over how to interpret "viable treatment options". In addition, there were concerns about precluding clinical research that seeks to prevent progression of disease before it becomes debilitating/life-threatening (e.g., joint disease). Our researchers also found the reference to "medical technologies" ambiguous as it is not a term they commonly use. Lastly, there was concern that the standard might be interpreted to preclude studies in which it is not known whether the treatment will work but the animal studies suggest the possibility of decreasing morbidity and mortality. We believe it is important to cover the population of patients who have very little proven treatment options and that these beneficiaries should have access to research studies that might make improve the patient''s condition. This is important not just for the patient, but also for the advancement of cutting edge treatment.

Recommendation: We recommend adoption of a modified version of AAHC''s proposed language as follows: "The clinical research study is not designed to exclusively test toxicity or disease pathophysiology. Research studies, including some Phase I trials, with protocols that commit to measuring therapeutic outcomes as one of the objectives or have therapeutic goals fit within the criteria."

Issue: Standards for clinical research to support Medicare coverage of items and services – Bullet 10: “The clinical research study is registered on the ClinicalTrials.gov website by the study sponsor/principal investigator prior to enrollment of the first study subject.

Comment: From the discussion at the August 7th CMS Open Forum, it is clear that one of the primary purposes this provision serves is to address application of the new CRP in addition to the public policy goals CMS seeks to achieve through registration generally. In our opinion, it would be better to address application of the new CRP in a different section of the CRP so that CMS may better address the complexity of continuing studies under the existing NCD, application of the new CRP, and, in light of the national confusion about the scope of general Medicare coverage, how to handle studies that meet neither the NCD nor CRP. We address this perplexing issue below.

Recommendation: We recommend that this provision be limited as follows: “The clinical research study is registered on the ClinicalTrials.gov website.”

Issue: Standards for clinical research to support Medicare coverage of items and services – Bullet 11: “The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. However, a full report of the outcomes must be made public no later than 3 years after the end of data collection.”

Comments: The University recognizes and supports the importance of making the results of research available as timely as possible. Publication of research is a fundamental purpose and mission of an academic medical center and University policy prohibits significant restrictions in the rights of the University and its faculty to publish. While some might argue that the standard merely requires the protocol to include certain representations with regards to “public release”, not to actually publicly release or publish, we believe the provision is administratively unworkable and will fail to achieve the intended goal of providing meaningful information to Medicare beneficiaries, regulatory agencies, researchers and the public at large as drafted. A requirement for “public release” ignores the importance of the peer-review process in publishing and disseminating scientifically valid, reliable research results for dissemination to the public. It also ignores the reality that Principal Investigators often have little or no control over publication of data in industry-sponsored research. We share AAHC’s concern over who bears the responsibility and liability for publication in these situations. Multi-centered trials also present unique issues in that data collection may end at different points in time for different institutions and yet no one may publish until all the sites have finished data collection.

Recommendation: We recommend removal of this proposed standard because it is administratively unworkable.

Issue: Standards for clinical research to support Medicare coverage of items and services – Bullet 13: “The research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussion may be necessary for populations eligible for Medicare due to age, disability, or Medicaid eligibility. “

Comments: This section overlaps considerably with Bullet 12. In addition, the requirement for separate discussion for populations eligible for Medicare due to age, disability or Medicaid eligibility is problematic. While it is common for discussion of inclusion/exclusion criteria to focus on demographics, such as age, it is much less common to have inclusion and exclusion criteria based on disability or economic criteria. Requiring discussion of disability or economic criteria as part of the inclusion or exclusion criteria could be contrary to the Principles of Justice contained in the Belmont Report and could open an institution to liability.

Recommendation: We recommend that bullets 12 and 13 be combined as follows: “The research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria affect enrollment of these populations and a plan for retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why the criteria are necessary. The protocol must also explicitly discuss whether the results are expected to be generalizable to Medicare’s age population.”

Issue: Local Coverage Determinations (LCD).

Comment: It is very difficult for multi-centered trials to determine, align, and plan for local coverage decisions that may vary. Such variability may require a separate budget, protocol, and consent for each area depending upon local decisions for coverage. This is operationally very difficult and increases the cost of conducting the research and leads to similarly situated Medicare beneficiaries receiving different coverage for the exact same services. At the same time we are mindful that many providers program specific edits into their billing system to respond to local coverage determinations that would have to be modified if coverage under CRP controlled coverage nationally.

Issue: 5. Approval Process.

Comments: As we understand CMS’ comments at the August 7th Open Forum, CMS intends that sponsors or investigators certify to CMS that the standards in the CRP have been met. We appreciated discussion of your perspective on the liability of the billing entity if a sponsor or investigator certified inaccurately, however, we urge CMS to state this explicitly in the CRP and to consult with the Office of Inspector General for HHS to confirm that your own enforcement arm agrees with the interpretation. We would appreciate your clarification that the above policy is true even when the principal investigator is employed by the billing institution. For example, many Universities employ investigators and operate entities that bill for clinical services to Medicare or might be the sponsor of research in the case of investigator-initiated studies.

Issue: Codes, modifiers and ClinicalTrials.gov registry number on claim forms.

Comments: The University respects and supports the goals that CMS seeks to achieve through application of codes and modifiers to claims. As stated in CMS’ April 2007 clarification on use of modifiers to the Association of Academic Health Centers, CMS stated that the intent is to “monitor beneficiary participation in clinical trials and to report on the number of beneficiaries who enroll in studies, the types of studies they participate in, and the amount of Medicare expenditures associated with clinical research studies.” This is an important public policy goal for all involved. However, there simply must be an easier way than currently contemplated to achieve this goal.

Nationwide, institutions have struggled with the code and modifier requirements of the existing NCD on many levels, including a lack of clear and comprehensive guidance on when to apply the codes and modifiers. For example, many have interpreted the guidance to date as meaning that the codes and modifiers are required on all claims of routine/standard of care related to a Medicare clinical trial enrollee as applying to all care the beneficiary is receiving regardless of whether the standard care is associated with the study. Consider the case of a patient involved in a diabetes trial who breaks a leg (unrelated to the study or care at hospital). Some suggest that the care of the broken leg is also subject to the code and modifier requirement. Such an interpretation would seem to be contrary to Medicare’s stated goal of tracking expenditures associated with clinical research studies. Yet, the most recent CMS guidance suggested that using codes and modifiers only when billing for services that meet the definition of “routine costs” under the NCD was incorrect. In light of the definition of “routine costs” encompassing “items and services typically provided absent a clinical trial (e.g., conventional care)” one is left to conclude that CMS does indeed wants all care the patient receives while enrolled in a trial to contain the codes and modifiers. This will inflate the level of expenditures associated with clinical research as the data set will include care that is not associated with clinical research.

Another critical issue is the limitation of many billing systems to be reprogrammed effectively to capture all care associated with the clinical research, especially if the requirements differ between the NCD and the CRP. This includes not just the care the PI or study team may provide but referrals for essential services such as lab, radiology and so forth. Many organizations are in the process of upgrading billing systems to meet the growing detailed requirements of payers of health care. At the same time, many providers are unable to apply codes and modifiers with the level of precision that Medicare appears to envision. We support CMS’ goals, but hope that CMS can find a way to achieve these goals that reflects the state of technology in use by many health care providers nationwide and minimizes the costs to providers for what is essentially a data collection process. The present regulatory requirements require a very manual claim processing system with a high degree of precision on application of claims and modifiers, leading to delay in claim submission, processing, and accounts receivable. In the August 7th CMS Open Forum, it was clear that drafters of the new CRP understood many of the challenges noted above and welcomed suggestions from industry.

Recommendations: We strongly recommend that CMS find a different path to achieve its policy goals and regret that we are unable to affirmatively suggest a particular one. If CMS continues a code and modifier requirement into the CRP as the vehicle to achieve its stated policy goal we recommend that CMS limit application of the codes and modifiers to usual patient care that is directly related to or provided in conjunction with the clinical research. Alternatively, we recommend that CMS issue a detailed frequently asked questions document that focuses on a wide variety of situations to provide guidance on when the codes and modifiers are to be used. It may be useful to consider a web-based frequently asked questions tool to allow for ongoing guidance to health care providers on this very complex area. For example, the format used to respond to HIPAA privacy questions following the 2003 rule implementation was very helpful to answer questions and drive continuity in practices (http://www.hhs.gov/hipaafaq/). We also urge you to consider the limitations of the existing claim forms and billing systems.

Issue: 6 Exceptions.

Comment: We echo the comments of the AAHC on this issue.

Issue: 11. Transition Plan.

Comments: One of the most challenging aspects of the proposed new CRP is how to effectively grandfather, or transition, clinical research from one set of rules to another. While much of the discussion at the August 7th CMS Open Forum focused on which coverage rule would apply, the Clinical Trial NCD or the CRP, the problem is actually much more complex because of the wide confusion among health care providers about the scope of the original NCD.

To the extent that CMS amends it rules to clearly state that the only going forward pathway to Medicare coverage of items of services provided to a beneficiary enrolled in clinical research is the new CRP, there must be a way to effectively transition research to the new CRP. If CMS retains the requirement that the CRP applies only to clinical research registered prior to enrollment of the first subject, it will be impossible to move any pre-existing clinical research to the new CRP.

Likewise, there may be research conducted under the existing NCD that an institution would prefer to transition into coverage under the new CRP to minimize the operational nightmare of differing requirements, especially different modifier requirements. If CMS retains the requirement that the CRP applies only to clinical research registered prior to enrollment of the first subject, it will be impossible to move any pre-existing clinical research to the new CRP.

Recommendation: We urge CMS to create an ability for an institution to continue to apply the existing coverage rules for ongoing clinical research and at the same time to transition those studies, in its discretion, to the new rule by certifying that the study meets the new criteria. In some cases, this may mean revision of the protocol, new approval from the IRB based on the amended protocol and possibly new informed consent. However, the administrative burden associated with the foregoing may actually be less than the administrative burden of trying to operationalize two sets of rules and the lack of guidance on ambiguities in the existing NCD. If institutions have the discretion to do this, they can evaluate on a study by study basis the feasibility of continuing the status quo or amending the protocol. In light of the depth of confusion about Medicare’s policy in this area, providers need maximum flexibility to re-tool their clinical research enterprise to meet Medicare’s new CRP.

Possible language to accomplish the above might include: “11. Transition Plan. This policy is effective X date for any clinical research study whose items and services have not been billed to Medicare by the billing entity. For a multi-center trial, the effective date of the policy may vary by study site. In addition, in the discretion of the principal investigator or sponsor, this policy may apply to any clinical research study for which Medicare has already been billed, provided the principal investigator or sponsor certifies to CMS that the standards of the CRP have been met.”

Issue: Deemed studies.

Comment: While the simplicity of one path to coverage is appealing, we believe that studies funded by federal research agencies should be deemed in recognition of the scientific and peer review processes inherent in the federal funding of research. In times of continuing fiscal challenge for state and federal entities, duplication of processes should be avoided and we believe that federally-funded trials meet the intent of the standards proposed sufficiently to warrant a less-burdensome process. We urge continuation of the concept of deemed studies.

Thank you for the opportunity to comment on this important issue.

Sincerely,

Sue Clausen
Associate Vice President/Chief Compliance Officer
UW MedicineUniversity of Washington

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Submitted Electronically on CMS Website

August 17, 2007

Steve E. Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
U.S. Department of Health & Human Services
7500 Security Boulevard
Baltimore, Maryland 21244-1850

Re: Proposed Decision Memo for Clinical Trial Policy (CAG-00071R2)

Dear Dr. Phurrough:

St. Jude Medical, Inc. appreciates this opportunity to comment on the Centers for Medicare and Medicaid Services'' (CMS) proposed decision memorandum revising the Medicare National Clinical Trial Policy (hereinafter referred to as the “Clinical Research Policy”). St. Jude Medical is dedicated to making life better for cardiac, neurological and chronic pain patients worldwide through excellence in medical device technology and services.

We support CMS’ overarching goal in its reconsideration of this National Coverage Decision (NCD); specifically, to encourage the conduct of research studies that add to the knowledge base about the appropriate use of products and technologies in the Medicare population, thus improving the quality of care that Medicare beneficiaries receive. Reconsideration of the Clinical Trial Policy (CTP) is essential given the contribution of privately sponsored research to inform medical decision-making.

The proposed decision memorandum issued on July 19th is a significant improvement over the proposed decision that was issued in April 2007 (in connection with the first reconsideration of the 2000 Clinical Trial Policy). We appreciate that this second reconsideration addresses many of the concerns raised by St. Jude Medical and other stakeholders during the first reconsideration. Additionally, we appreciate Dr. Phurrough’s efforts to add clarity to the proposed NCD in the August 7, 2007, Open Door Forum. We were especially encouraged by Dr. Phurrough’s statement that the quality standards are factors to be considered rather than requirements to which compliance must be certified.

We are pleased that the Clinical Research Policy (CRP) will not change Medicare coverage according to the regulations on Category A and Category B investigational device exemptions (IDEs) found in 42 C.F.R. 405.201-405.215, 411.15, and 411.406. We believe the current regulations allowing Medicare coverage of FDA-approved IDE clinical trials are an appropriate means to ensure that Medicare beneficiaries have access to medical technologies being studied in IDE clinical trials. In turn, this fosters both innovation and evidence generation.

However, St. Jude Medical continues to have concerns regarding CMS’ legal authority to exclude otherwise covered items and services from Medicare coverage if used in research, unless the study meets the requirements of the NCD. Although we support the goals of high quality research, a national coverage decision that conditions coverage of benefits in clinical trials upon meeting the requirements of the proposed CRP raises potentially unintended but significant legal risks associated with reimbursement of items and services that are otherwise Medicare covered. We continue to believe that a change of this nature requires rulemaking.

Notwithstanding these concerns, we offer the following comments and recommendations:

Compliance/Legal Issues and Self-Certification Process

As mentioned above, the agency has expressed a helpful clarification that the standards are factors to be considered rather than requirements to which compliance must be certified. Imposing a certification requirement before a clinical trial has commenced would put the sponsor or investigator in the unreasonable position of making a universal certification of compliance before the fact. This stands in sharp contrast to the ordinary Medicare Part A or Part B claim, in which the provider or supplier certifies compliance after the fact of any item or service furnished to a Medicare beneficiary, when all of the relevant facts are known. It also is materially different from the multiple certifications made by a grantee that has received a research grant from NIH; in that setting, the grantee (or prospective grantee) only certifies compliance after the fact for a specified time period. Therefore, in order to avoid placing sponsors or investigators in the untenable position of certifying compliance when all of the relevant facts are not known, St. Jude Medical recommends that sponsors or investigators be permitted to self-certify that all of the relevant standards have been addressed in the study design and protocol. Requiring the certification to relate only to the study design and protocol is important because these elements are structured and evaluated before a study is underway.

RECOMMENDED REVISION: Therefore, we recommend that the CRP clarify that the certification relates only to the study design and protocol. During the Open Door Forum, CMS explained that as long as the sponsor/principal investigator self-certifies that the study design, protocol, and other aspects of the study meet the proposed standards, CMS will not subsequently assert that claims were submitted in violation of the CRP. Our understanding, therefore, is that providers that submit claims to the agency will not be liable as long as the sponsor/principal investigator has certified compliance with the quality standards. Finally, we have also understood CMS to say it will not engage in audits of compliance with the proposed CRP. Similarly, our understanding is that claims submitted under the CRP will not form the basis for liability under the False Claims Act (FCA) because the notice is evidence of both the entity''s good faith intent to comply with the standards in the policy, and because the entity is not acting with the requisite knowledge required under the FCA (barring any material withholding or misrepresentation of the facts). Given the significance of this issue, we ask CMS to clarify this in the final CRP Decision Memorandum to avoid creating unintended private litigation.

We acknowledge that CMS may stop reimbursing claims for a study if the agency learns the study is not in compliance with the quality standards or if safety concerns surface. But, such an action would result in CMS stopping payment prospectively, not a retrospective denial of claims.

RECOMMENDED REVISION: To achieve this clarification, we recommend that CMS add, after part 6 (Exceptions), the following new paragraph:

“Administration”

CMS does not intend to routinely conduct audits to assess the degree to which the study design and protocol address the quality standards in part 2 of this policy. Providers submitting claims may rely in good faith on the agency’s published list of qualifying research, and the agency will not deny claims on the basis that the quality standards were not met for any dates of service prior to the publication of the initial determination of the Chief Medical Officer in part 6 of this policy.”

During the Open Door Forum, CMS indicated that it will provide a template for the self-certification letter. According to Dr. Phurrough, the template’s questions should be answered in 250 words or less.

RECOMMENDED REVISION: The CRP should include a template for the self-certification document and clear instructions on how to complete it. Additionally, a sample of a completed self-certification form should be provided.

Clarifications of the Standards for Clinical Research

St. Jude Medical understands and agrees with many of the standards that CMS has proposed. However, we urge CMS to clarify the standards as much as possible, and to provide additional guidance or guidelines where needed to make the standards more understandable, objective and focused.

St. Jude Medical recommends the following to improve the standards.

BULLET 1: The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes.

Given the current phrasing of this standard, there is some concern that it could be construed to allow for only superiority-based, randomized controlled clinical trials. While these designs should be allowed, there should be language within the standard that acknowledges that some studies are designed to demonstrate that a new treatment is equivalent or non-inferior to standard therapy. Study of products that improve the efficiency of diagnosis may also not meet this standard as written and/or interpreted, though the intention should not be to limit or avoid these important research studies.

RECOMMENDED REVISION: The principal purpose of the research study as addressed by the study design and protocol is to test or clarify whether a particular intervention or diagnostic modality potentially improves or maintains the participants’ health outcomes.

BULLET 3: The research study does not unjustifiably duplicate existing studies.

Multiple scenarios exist within good common research practice that demand the duplication of existing studies: FDA’s requirement of at least two pivotal Phase III trials for any drug being considered for approval; the Declaration of Helsinki, an internationally-recognized standard for good clinical research practices, states that “even the best proven prophylactic, diagnostic, and therapeutic methods must continuously be challenged through research for their effectiveness, efficiency, accessibility, and quality” ; and the growing demand in the US for comparative effectiveness Phase IV trials to further examine efficacy and efficiency that was previously reported in Phase III trials, just to name a few. Leaving this statement vague by retaining the word “unjustifiably” leaves the standard unable to be met in some reliable and predictable way while simultaneously creating potential situations where the evaluative standard used is counter to the standard used in most other research areas of the US health and regulatory systems.

RECOMMENDED REVISION: The research study is not so similar to existing studies that it provides no additional value for clinical decision-making.

BULLET 9: The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Studies of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life-threatening as defined in 21 CFR 312.81(a) and the patient has no other viable treatment options.

RECOMMENDED REVISION: This standard is confusing. CMS needs to clarify what studies would or would not meet this standard and why or remove the language from the CRP.

BULLET 10: The clinical research study is registered on the ClinicalTrials.gov website by the study sponsor/principal investigator prior to the enrollment of the first study subject.

We recommend that CMS recognize the needs of individuals and companies to be able to conduct necessary research while still being afforded the ability to protect proprietary information. Protecting proprietary information in medical device studies is critical to sustaining continued device innovation and to maintaining the competitiveness of the device industry.

RECOMMENDED REVISION: The clinical research study’s non-proprietary information is registered on the ClinicalTrials.gov website by the study sponsor/principal investigator prior to enrollment of the first study subject.

BULLET 11: The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. However, a full report of the outcomes must be made public no later than three (3) years after the end of data collection.

Similar to the previous standard, the public sharing of information is vital to the continual growth of knowledge through research. For researchers to best comply with this standard, however, greater clarification is needed that defines what CMS considers “the end of data collection.” Depending on the type of study being completed, this consideration could change the date for compliance by months. Is data collection deemed complete once the final patient interview takes place or once the supporting database closes, which could be weeks or even months after that final interview? This section of the standard should be rewritten in a way that allows for these differences. For example, the end of data collection could be defined within the original study protocol with reference made in the standard in this fashion. This approach ensures public reporting within the currently allotted timeframe while accounting for differences in how data collection terminates in different studies.

Related to the issue of the public release of all outcomes measured is the question of acceptable manners of making that information public. While this standard mandates that each study protocol specify a method of release, it only mentions publication in a peer reviewed journal as potential means of fulfilling that requirement. What are other options for the public release of findings that would fulfill this requirement if inclusion in a journal is either inappropriate or rejected upon submission? In the absence of a publishable article, CMS should consider the need for alternative methods of making the information publicly available to include, but not necessarily limited to, posting of abstract and/or result summary information on a private sponsor’s website.

RECOMMENDED REVISION: The research study protocol specifies the process for public release of primary outcomes, including release of outcomes should outcomes be negative or if the study is terminated early. The process must include a plan for public release of the results within 24 months after all data collection is complete, as defined within the original study protocol. If the plan is to publish results in a peer-reviewed journal, then the process may provide that the initial report may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. However, a plan should be provided to publish a full report of the outcomes no later than three (3) years after the end of data collection, as defined within the original protocol.

Additional Recommendations on Timeframes and Process

We urge CMS to be clear about the exact timeframes and processes that trigger compliance with the CRP and overall Medicare coverage for the usual patient care in a clinical research study. This will provide study sponsors/principal investigators with a better understanding of how to plan their research activities and will clarify exactly when enrollment of Medicare beneficiaries can begin. We recommend specifying that Medicare contractors will not be involved in the review of clinical research beyond simply ensuring that the ClinicalTrials.gov registry number and code modifiers are on the claims forms. To encourage participation by physicians, hospitals and other providers, it is important for CMS to clarify in its instructions to providers and practitioners that participation in clinical research will not result in delays in payment or additional contractor requirements. Finally, we recommend allowing electronic submission of letters in order to enhance the efficiency of the process, reduce overall paperwork for both the agency and researchers.

RECOMMENDED REVISION: On page 18, in section “5. Approval Process”, after “Baltimore, MD 21244”, insert:

“Letters may also be submitted electronically to the following e-mail address: ______________.

Then also add:

“CMS will review each study sponsor/principal investigator letter and within five (5) days of receiving the letter, will provide both an electronic and a written response to notify the study sponsor/principal investigator whether CMS has determined that the letter is complete. CMS will update the website list of certified research studies within two (2) days of sending out this notification to the study sponsor/principal investigator. CMS will post the list of certified research studies in the Federal Register on a quarterly basis. At any point after CMS has notified the study sponsor/principal investigator that the letter is complete, providers and practitioners will be able to obtain coverage for usual patient care provided in these research studies as long as the applicable ClinicalTrials.gov registry number and code modifiers are used on the relevant claims forms. No separate or additional review of the research study will be conducted by Medicare contractors beyond standard claims review functions.”

We recommend that processes be developed that provide study sponsors or principal investigators with an opportunity to respond and provide additional information demonstrating compliance, in the event that CMS’ Chief Medical Officer finds that a study “does not meet the standards as defined in this policy.” We share CMS’ concern that studies protect the health and safety of beneficiaries, and that such studies be conducted with the utmost scientific and ethical integrity. However, we urge CMS to create a dispute resolution process with reasonable timelines for communication between CMS and study sponsors or principal investigators so that questions regarding compliance can be addressed without having a negative impact on researchers and scientists who are trying ultimately to improve patient care.

RECOMMENDED REVISION: Replace the current language in section “6. Exceptions” with the following: “Medicare will pay for covered services in clinical research studies where the study sponsor/principal investigator has certified that the study design and protocol meets the standards as defined in this policy unless the CMS’ Chief Medical Officer finds that the study jeopardizes the health or safety of Medicare beneficiaries.

In addition, Medicare will pay for covered services in clinical research studies where the study sponsor/principal investigator has provided notice that the study design and protocol meets the standards as defined in this policy unless the CMS’ Chief Medical Officer finds that the study does not meet the criteria outlined in this policy. Any such finding must be in writing to the study sponsor or principal investigator and must allow the study sponsor or principal investigator the opportunity to respond in writing.

Coverage of items and services furnished prior to the effective date of any such findings by the CMS’ Chief Medical Officer would be unaffected by the findings.”

Deemed Status for Studies Funded or Approved by Federal Agencies

We recommend that CMS maintain “deemed” status for all clinical studies reviewed and approved, required or funded by Federal agencies. In the proposed decision memorandum, CMS no longer includes deemed status for studies approved or funded by Federal agencies. While the proposed policy levels the playing field between government studies and private studies, we are concerned that requiring additional compliance with the CRP for studies that have already been approved or funded by Federal agencies is unnecessary and duplicative. To mandate compliance with CMS requirements in addition to what is already required by other Federal agencies will only slow down the process of generating evidence in studies that already have the Federal government’s imprimatur of approval.

RECOMMENDED REVISION: On page 18, in section “5. Approval Process”, after “ . . . outlined in that NCD.”, insert: “Clinical research studies that are reviewed and approved by a Federal government agency (including FDA-required post-market studies), or funded by a Federal government agency, will be deemed to have met the standards and approval process in this NCD.”

Transition Plan

Given the significant changes in billing that will need to be implemented by practitioners and providers in light of this policy, St. Jude Medical recommends that CMS set an extended time period for implementation of the final policy. Organizations representing investigators and providers have expressed that it will take a minimum of six months, from the date of release of the final decision memorandum, for institutions and individuals to update policies and procedures, educate billing and coding staff, and potentially change information technology management and billing systems to allow for the capture of data related to the CRP. This period of time will be crucial to avoid problems with claims submission and to ensure a smooth transition.

While we continue to appreciate and encourage CMS to comply with the timeframes for the NCD process that were legislated in the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, we believe that the CRP presents extenuating circumstances that require additional time for implementation. We urge CMS to allow providers and practitioners this time so that they can implement the Clinical Research Policy accurately and appropriately.

RECOMMENDED REVISION: On page 18, in section 11, insert the following after “this decision.”: “The effective date of this decision will be six months after the date that this final decision memorandum is issued.”

Medicare Secondary Payer

St. Jude Medical remains concerned that even with revisions and clarifications to the clinical research policy, the outstanding questions regarding the interaction of this policy with the Medicare Secondary Payer (MSP) rules remain a barrier to Medicare beneficiaries’ participation in clinical research. While we understand that these concerns extend beyond the scope of the NCD, we urge the Office of Financial Management to provide guidance to the public through a transparent process directed at removing MSP as a barrier to access. We appreciate the opportunity to comment on the proposed Clinical Research Policy and would welcome the opportunity to work with CMS on this and other related Medicare coverage issues.

Sincerely,
Susan Walker
Senior Director, Health Policy and Reimbursement

Cc: Leslye K. Fitterman, Ph.D.

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The American Society of Clinical Oncology (ASCO) is the leading medical society for physicians involved in cancer treatment and clinical research. The Association of American Cancer Institutes (AACI) is comprised of 89 of the nation’s leading academic and freestanding cancer research centers that are the nexus of both basic cancer research and clinical investigations. Members of ASCO and AACI conduct the overwhelming majority of cancer clinical trials in the United States. We regard the 2000 Clinical Trial Policy as central to our general shared mission of progress against cancer through clinical research, as well as to our more specific challenge of increasing participation by Medicare beneficiaries in cancer clinical trials. In our view, the proposed changes in the Medicare policy will be devastating not just to Medicare cancer patients but also to the cancer research enterprise generally.

The 2000 Medicare Clinical Trial Policy Has Been a Great Success.

ASCO, AACI, and others in the cancer community uniformly welcomed the 2000 Clinical Trial Policy with its generous scope of coverage and its relative ease of administration, relying on oversight judgments by the National Institutes of Health (NIH) and other federal funding agencies or by the Food and Drug Administration (FDA) for products within its jurisdiction. Medicare officials wisely declined to embark on an independent review of the validity of the thousands of clinical trials underway at any given time, but rather deferred to the expertise of federal funding agencies and FDA as the premier science-based health regulatory agency in the federal government, finding those trials to be “deemed” covered. We are aware of no questions that have been raised regarding the cost of the policy or the quality of patient care.

In fact, there are persuasive data suggesting that the 2000 Clinical Trial Policy exerted a measurable positive impact on participation in clinical trials by Medicare beneficiaries. A study by the Southwest Oncology Group found that Medicare participation rates in cancer clinical trials rose from 25 to 38 percent following adoption of the 2000 Clinical Trial Policy, at least for those with supplemental insurance. The cancer community has pursued a variety of strategies to encourage participation in clinical trials by Medicare beneficiaries, but none has been as successful in a relatively short period of time as the initiation of the 2000 Clinical Trial Policy. Given that record of achievement through the current policy, it is extremely puzzling that the Center for Medicare & Medicaid Services (CMS) would seek to deconstruct that policy in favor of an alternative that is not only completely untested but also was a target for elimination in the April 10, 2007 proposed decision memorandum.

There is No Reason to Deviate from the Current Clinical Trial Policy.

CMS has offered various explanations for its plan to amend the 2000 Clinical Trial Policy, but none of them withstands scrutiny. The 2000 policy was absolutely clear that coverage extended not just to federally funded trials but also to privately sponsored clinical trials of drugs or biologics under the purview of FDA. If there is confusion at this point, it may be because of the proposal made by CMS in the April 10, 2007 national coverage decision to eliminate coverage of one category of FDA trials: the so-called IND-exempt trials. We believe that IND-exempt trials should continue to be covered as they have been since initiation of the policy in 2000.

The only significant category of clinical trials not covered by the 2000 policy would be studies of surgical procedures that are not federally funded or not emanating from a cancer center or cooperative group under NIH auspices. All privately funded drug or biologic trials would be covered as either under an IND or as IND-exempt, and medical devices have their own separate coverage policy for investigational devices. If CMS wishes to employ self-certification for surgical trials that could not otherwise qualify for coverage, that would be a reasonable solution to ensure quality in such studies that might otherwise not be adequately monitored.

Use of Self-Certification for Trials Previously “Deemed” Covered Will Deter Participation by Medicare Beneficiaries.

CMS proposes that coverage should be available only for those sponsors or principal investigators who have self-certified as to 13 different criteria. There are numerous problems with the criteria, including their subjectivity, their tendency to duplicate information already provided elsewhere, and their potential inconsistency with existing requirements. The overarching issue, however, is the reasonable fear of retrospective reviews of compliance with the self-certification. Institutions are already burdened with a multiplicity of paperwork and other regulatory demands, any one of which can turn into a compliance situation; as a result, institutional counsel are understandably risk-averse in undertaking additional commitments of the sort suggested by the 13-point self-certification. Many institutions will no doubt conclude that this exercise, which contributes little if anything to the research effort, is not worth the trouble and the risk. Thus, Medicare beneficiaries will once again be systematically under-represented in cancer clinical trials.

The Clinical Research Enterprise Will Suffer if Coverage Policy is Unclear, Inconsistent, or Not Based on Science.

The Medicare Clinical Trial Policy was unchanged for more than five years, during which period participation in research studies by Medicare beneficiaries climbed significantly. CMS injected a considerable degree of uncertainty into the process by its initiation of a “reconsideration” of the policy in July 2006. Then CMS further stimulated concerns when, in April 2007, it proposed to eliminate from coverage the IND-exempt trials, which likely number in the thousands and thus have a substantial impact on access for Medicare beneficiaries. Now, without responding to the many comments objecting to the move against IND-exempt trials, CMS has proposed eliminating the entire superstructure of the 2000 Clinical Trial Policy and replacing it with a complex, burdensome, and untested self-certification process. In the April 2007 proposed decision memorandum, CMS also rejected out of hand the concept of self-certification as a meaningful oversight measure. As CMS stated at that time:“While we wish to encourage participation in high quality studies by Medicare beneficiaries, we do not believe self-certification is sufficient. We propose deletion of the self-certification in the new policy.”Now, the previously rejected self-certification process has become the only option. It is extremely difficult for institutions, or even individual providers, to make decisions about investment of personnel and other resources in a context where the standards are (and have been in recent history) very changeable, with, at this point, little confidence about the future direction of policy.

Conclusion

The 2000 Clinical Trials Policy has worked well since its inception, as demonstrated by increased rates of participation in cancer clinical trials by Medicare beneficiaries. It should be reaffirmed without significant change.

Sincerely,

American Society of Clinical Oncology
Association of American Cancer Institutes
Abramson Cancer Center of the University of Pennsylvania
Arizona Cancer Center
Barbara Ann Karmanos Cancer Institute
Cancer Research Center of Hawaii
Case Comprehensive Cancer Center and Ireland Cancer Center at University Hospitals of Cleveland
City of Hope National Medical Center and Beckman Research Institute
Cleveland Clinic Taussig Cancer Center
Dana-Farber Cancer InstituteDuke Comprehensive Cancer Center
Fox Chase Cancer CenterFred Hutchinson Cancer Research Center
H. Lee Moffitt Cancer Center & Research Institute at the University of South Florida
Holden Comprehensive Cancer Center at the University of Iowa
Hollings Cancer Center at the Medical University of South Carolina
Huntsman Cancer Institute at the University of Utah
Kansas Masonic Cancer Research Institute
Lombardi Comprehensive Cancer Center at Georgetown University
Louisiana Cancer Research Consortium of New Orleans at the Tulane Cancer Center
Mary Babb Randolph Cancer Center at West Virginia University
Massey Cancer Center at Virginia Commonwealth University
Medical College of Wisconsin Cancer Center
Nevada Cancer Institute
Norris Cotton Cancer Center
Oregon Health and Sciences University Cancer Institute
Roswell Park Cancer Institute
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University
SimmonsCooper Cancer Institute
Stanford University Comprehensive Cancer Center
The Alvin J. Siteman Cancer Center
The Barrett Cancer Center at University of Cincinnati
The Carole & Ray Neag Comprehensive Cancer Center
The Dan L. Duncan Cancer Center at Baylor College of Medicine
The Ohio State University Comprehensive Cancer Center – James Cancer Hospitals & Solove Research Institute
UAB Comprehensive Cancer Center
UNC Lineberger Comprehensive Cancer Center
University of Chicago Cancer Research Center
University of Colorado Cancer Center
University of Miami Sylvester Comprehensive Cancer Center
University of Minnesota Cancer Center
University of New Mexico Cancer Center
University of Pittsburgh Cancer Institute
University of Virginia Cancer Center
University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
UNMC Eppley Cancer Center
USC/Norris Comprehensive Cancer Center
Vanderbilt-Ingram Cancer Center

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Centers for Medicare & Medicaid Services
Via e-mail

Re: Comments on Clinical Trial Policy (CAG-00071R2)

The Blue Cross and Blue Shield Association (BCBSA), an association of 39 independent Blue Cross and Blue Shield Plans that collectively provide health insurance benefits to 99 million Americans, appreciates the opportunity to provide comments on the Proposed Decision Memo for Clinical Trial Policy. BCBSA supports the efforts of CMS to clarify this policy and increase consistency of application.

The Clinical Research Policy must ensure that evidence obtained from covered research will be of the highest quality possible and will answer questions that are important to understanding the effectiveness of technologies for Medicare beneficiaries. Given this imperative, we offer comments on the following aspects of the proposed policy:

August 17, 2007

BY ELECTRONIC DELIVERY

Steve Phurrough, M.D., MPA
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services Department of Health and Human Services
Mail Stop C1-12-28
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memorandum for Second Reconsideration of the Clinical Trial Policy, Renamed the Clinical Research Policy (CAG -00071R2)

Dear Dr. Phurrough:

Boston Scientific Corporation (Boston Scientific) welcomes the opportunity to comment on the Centers for Medicare and Medicaid Service’s (CMS) proposed decision memorandum for its second reconsideration of the Clinical Trial Policy (hereinafter “Clinical Research Policy”).

As the world’s largest company dedicated to the development, manufacturing, and marketing of less-invasive therapies, we are particularly interested in Medicare policies geared toward promoting access to new medical technology that improve patient health outcomes, while ensuring strong clinical research standards are used in evaluating treatments. Boston Scientific supplies medical devices and technologies used in the following medical specialty areas:

August 17, 2007

Leslye K. Fitterman, Ph.D.,
Lead Analyst
Centers for Medicare & Medicaid Services
Mail Stop C1-10-23
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: Comments to the Proposed CMS Clinical Research Policy

Dear Dr. Fitterman:

On behalf of Vanderbilt University, I would like to express our appreciation to the Centers for Medicare & Medicaid Services (CMS) for the opportunity to submit Comments on the Second Reconsideration of the National Coverage Decision for the CMS Clinical Trial Policy (CAG-00071R2). Vanderbilt University is an independent, private research university located in Nashville, Tennessee comprised of a well-recognized academic medical center and a highly-respected university offering degrees from several undergraduate, graduate, and professional schools and colleges. Vanderbilt’s growing research enterprise exceeds $300 million in total research expenditures, and the Vanderbilt-Ingram Cancer Center is designated as a comprehensive cancer center by the National Cancer Institute. The Vanderbilt University Medical Center is a Level 1 Trauma Center comprised of several hospitals and institutes, including the Vanderbilt University Hospital, the Vanderbilt Children’s Hospital, the Vanderbilt Stallworth Rehabilitation Hospital, the Vanderbilt Clinic, and the Vanderbilt Heart Institute.

We appreciate the work and effort that CMS has invested in revising the Clinical Trial Policy and welcome CMS’s further consideration of this important policy for Medicare beneficiaries. In particular, we commend CMS for the clarification of coverage for routine clinical services and investigational clinical services. We are concerned, however, that some of the other features of the new policy could lead to confusion and the possibility that research institutions might submit bills to Medicare for clinical research studies that, unbeknownst to the research institution, do not qualify for coverage. We would appreciate your consideration of the following Comments.

COMMENT 1: Therapeutic Intent

Section 2 of the Clinical Research Policy contains two separate standards relating to therapeutic intent and a clinical research study is required to satisfy both standards.

Standard One: The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes.

Standard Nine: The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Studies of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life-threatening as defined in 21 CFR 312.81(a) and the patient has no other viable treatment options.

In order for a clinical research study to satisfy both of these standards, there may be some unintended confusion. A strict reading of these two provisions together seems to narrow the scope of clinical studies that would meet both standards to only clinical research studies that (a) include therapeutic outcomes as a primary objective AND (b) study life-threatening diseases or conditions.

First, the use of the word “principal” in the Standard One seems to imply that therapeutic outcomes must be a primary endpoint or objective for the study, while Standard Nine implies that therapeutic outcomes only need to be one of the objectives as opposed to primary. Secondly, it is also unclear whether the requirement that the disease being studied is life-threatening applies to just Phase I studies that test toxicity or all clinical research studies.

We believe that the intent of the provisions, taken together, was to include clinical research studies that have therapeutic outcomes as one of the objectives regardless of the seriousness of the disease being studied, unless the study tests toxicity or disease pathophysiology as a primary endpoint. If the study tests toxicity or pathophysiology as a primary endpoint, then it must involve the study of a life-threatening disease or condition.

We would suggest, however, that the requirement that the participant have no other viable treatment options is an unmanageable requirement. The designer of the protocol is typically not the individual enrolling patients into the study, and determination of the treatment options available to any particular patient would only be known to that particular patient’s treating physician. We would suggest that the use of a defined term for “life-threatening” would be sufficient to limit coverage to extremely serious circumstances. We would also suggest that the policy should include “severely debilitating” diseases or conditions which is also a defined term included in 21 CFR 312.81.

We would respectfully propose that the Standards be combined and revised as follows:

The purpose of the clinical research study is to test whether a particular therapeutic or diagnostic intervention potentially improves the participants’ health outcomes, and the research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Research studies, including some Phase I trials, whose protocols include testing toxicity or disease pathophysiology as the primary objective, but which nevertheless also commit to measuring therapeutic outcomes as an additional objective, will meet this Standard regarding health outcomes only if the disease or condition being studied is life-threatening or severely debilitating as defined in 21 CFR 312.81.

COMMENT 2: Standards of Scientific Integrity

Standard Seven: All aspects of the research study are conducted according to the appropriate standards of scientific integrity.

This Standard does not refer to any definitive guidance for appropriate standards of scientific integrity which can vary depending upon the relevant field of study. It also references scientific integrity in the conduct of the study (rather than the design of the study) which occurs after the study commences. This leaves the study certification vulnerable to reversal if a rogue staff member is later found to have engaged in scientific misconduct. We would suggest that existing regulations under Federal law such as 42 CFR Part 93 adequately address violations of scientific integrity that occur during the conduct of a research study. We would suggest that this Standard be revised as follows:

The research study protocol is designed in accordance with generally accepted practices for scientific integrity in the relevant field of study.

COMMENT 3: Public Release of Research Study Outcomes

Standard Eleven: The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early.

We are unsure of the methods envisioned by CMS to fulfill this requirement, in particular for studies with negative outcomes that may have difficulty being published. As the competition for publication intensifies, we feel that this requirement might unnecessarily exclude less noteworthy but nevertheless valuable research studies.

Respectfully, we would like to recommend that the Standard be revised to explicitly state:

This Standard may be satisfied by placing the outcomes or results of a clinical research study on a publicly accessible sponsor or institutional website for a pre-determined period of time.

COMMENT 4: Clinical Trial Registry Requirement

Standard Ten: The clinical research study is registered on the ClinicalTrials.gov website by the study sponsor/principal investigator prior to the enrollment of the first study subject.

While we understand CMS’s desire to ensure its beneficiaries have pertinent information about the research CMS supports, we are concerned that CMS’s requirement that the research study be registered “prior to enrollment of the first study subject” could lead to unintended consequences. For example, in a large multi-center study with over 100 centers (including foreign study centers), an individual study center would have no knowledge of the enrollment activities of the other centers. If any one of these other centers inadvertently enrolled a participant before the study was registered by the sponsor, then all of the Medicare charges made by the remaining centers would have been submitted in violation of the Clinical Trial Policy with no knowledge of the disqualifying early enrollment.

As an alternative, we would respectfully suggest that the Standard should only require that a clinical research study be registered on ClinicalTrials.gov but not before the enrollment of the first study subject. Instead we would propose that any clinical research study that is registered on ClinicalTrials.gov should qualify for this Standard with a caveat that any clinical services for study subjects who are enrolled before the study is registered will not be covered. Then, any study subjects who are enrolled after the research study is registered would still be covered by the Clinical Research Policy, regardless of the enrollment of subjects at other study centers prior to registration of the study.

Thus, we would respectfully propose that the Standard for clinical trial registry be revised as follows:

The research study is registered on the ClinicalTrials.gov website. Coverage, however, will not be available for any clinical services provided to a study subject prior to the registration of the research study.

COMMENT 5: Inclusion Criteria for Relevant Subpopulations

Standard Twelve: The research study protocol must explicitly discuss subpopulations affected by the treatment under investigation….

Institutional Review Boards (IRBs) routinely assess proposed exclusion criteria during their review to ensure that patient subpopulations are appropriately, and not systematically, excluded. Unless data is available clearly showing differences between subpopulations, the subpopulations should be allowed access to a clinical study. A better way of controlling this is to explicitly define relevant subpopulations that the study should not enroll as exclusion criteria. Examples of this would be patients who the intervention was unlikely to be beneficial to or patients who the intervention is more likely to be harmful. These patients are usually better defined according to disease processes as opposed to strict demographics. If patients do not fall into one of the exclusion criteria, the risk/benefit ratio for the intervention being studied is favorable to them and they should be allowed to be enrolled. Since study population is a routine assessment of risk/benefit ratio performed by IRBs, we recommend that this be left to the discretion of the IRB.

In addition, the requirement to have specific inclusion criteria language based on demographics may prohibit participation by a Medicare beneficiary in a clinical study simply because it is not explicit that they can participate. In these instances, Medicare beneficiaries may miss out on a potential intervention. Furthermore, once the study is completed, the results will not be able to be extrapolated to a Medicare subpopulation, because patients were not explicitly included. In order for these results to apply to the Medicare subpopulation, an additional study would have to be done, exposing additional patients to the risks of the study.

Finally, not all Medicare beneficiaries fit one specific demographic. Some non-elderly beneficiaries may be excluded from a clinical trial because the foresight of including explicit language about their condition or situation may not have been included in the protocol inclusion criteria.

Thus, we would respectfully propose that this Standard for inclusion criteria for relevant subpopulations be revised as follows:

The research study protocol should not explicitly exclude relevant subpopulations without an explanation.

COMMENT 6: Generalization to the Medicare Population

Standard Thirteen: The research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention….

This Standard proposes that the study be powered to address outcomes in each subgroup separately. This is a very inefficient method of conducting research. It places additional participants at unnecessary risk. The reason that subpopulations are analyzed separately is because they are thought to be different from the general population with respect to their response to the intervention or the adverse effects of the trial. In these instances, reasonable data exist suggesting that the subpopulation is different. Unless the Medicare population differs from the other included populations, ensuring that the study is powered sufficiently to draw conclusions specifically about the Medicare population will unnecessarily require additional Medicare participants to be placed at risk in the study in order to answer this question. If the outcome in the Medicare patients in the study is congruent with the overall study outcome, the results can be extrapolated to that population. This would require fewer Medicare participants to be enrolled. Also, there are too numerous to count subpopulations enrolled into each clinical trial, and the division of subpopulations is arbitrary.

The Standard also suggests an alternative of analyzing the subgroups together and then testing for an interaction. Unfortunately, the power to test for an interaction in any study is considerably smaller than the overall power of the study. In order to obtain enough power to see anything other than a very large interaction, the number of enrollees must be increased significantly. This proposal will then, place additional participants at risk by increasing the number of participants needed to complete the study.

We respectfully recommend that this Standard for generalization to the Medicare population be deleted.

COMMENT 7: Free Services

We are pleased to see the revisions to Section 3 regarding Coverage. In particular, we are pleased to see the revision clarifying that only items and services provided free to all enrollees cannot be billed to Medicare. This revision is consistent with the Medicare Benefit Policy Manual (Chapter 16, Section 40.2 – Provider, Physician, or Supplier Bills Only Insured Patients) which provides that study sponsors and providers may provide items and services to research participants who do not have sufficient insurance or coverage for clinical research while still allowing the provider to bill Medicare for items or services provided to Medicare beneficiaries pursuant to a qualifying trial. However, we believe a statement is needed at the end of the first paragraph in Section 3 affirming this position. We respectfully request that the following language be added:

However, if usual patient care is provided free of charge to individual study subjects who lack sufficient insurance coverage to enroll in the study, Medicare coverage of that usual patient care will still be available for Medicare beneficiaries pursuant to this policy.

COMMENT 8: Approval Process and Provider Liability

Section 5 requires providers and practitioners to add code modifiers and the ClinicalTrials.gov registry number on claim forms for reimbursement under this policy. During the Open Forum hosted by CMS during the comment period of this Second Reconsideration, Dr. Steve Phurrough stated that it was the intent of CMS that providers and practitioners should not have any liability for claims submitted under this policy so long as the study was listed on the CMS website as a certified study and the provider or practitioner included the code modifiers and the ClinicalTrials.gov registry number for the study, regardless of whether or not the study was properly certified. We would respectfully suggest that language be added to the end of the first paragraph of Section 5 affirmatively stating that providers are not responsible for the proper certification of the research study. We respectfully suggest that the following provision be added to the end of the first paragraph of Section 5:

Providers and practitioners are not responsible for determining whether or not a research study has been properly certified and shall not be liable to Medicare for any amounts paid pursuant to this Policy so long as the research study was listed on the CMS website as a certified study and the provider or practitioner included the appropriate code modifiers and the ClinicalTrial.gov registry number on the claim forms.

COMMENT 9: Transition Period

The Policy proposes to grandfather any studies which have commenced enrollment under the prior Clinical Trial Policy, however, studies that have already been approved by their Institutional Review Board (IRB) but which have not begun enrollment would be covered by the new Clinical Research Policy. Many of the new requirements for this Policy apply to the content of the protocol itself, which is usually prepared in the earliest stages of a research study. Thus, most studies would need to submit amended protocols to their Institutional Review Board and possibly the FDA for review in order to meet the requirements of the new Policy. This would create a significant backlog of work for IRBs around the country in order to re-review all of the studies that were approved but had none begun enrollment.

We respectfully suggest that the effective date of the new Medicare Clinical Research Policy apply only to clinical research studies which have not yet been approved by the applicable Institutional Review Board to allow for ample time to revise the protocols before they are submitted for review.

If you have any questions, please feel free to contact me at (615)343-0077 (phone), (615)343-4479 (fax), or Gordon.bernard@vanderbilt.edu (email).

Thank you for your time and consideration.

Respectfully submitted,
Gordon R. Bernard, M.D.,
Assistant Vice Chancellor for Research

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I am pleased to see CMS taking a positive step in the coverage of patients that are enrolled in peer reviewed clinical trials. I would like to make sure that consideration is given to expand currently approved treatments to new indications. These treatments are currently considered as a standard of care to established indications but may show promise in other similar diseases. When these treatments are being tested in for these new indications the treatments should be considered as "Usual Patient Care" and not as "Investigation Clinical Services". For example, the use of Intraperitioneal Chemotherapy is one standard of care for Ovarian Cancer that holds promise for patients with peritoneal carcinomatosis from GI or other primary tumors. Another example would be the use of Stereotactic Radiation Therapy which has has become the standard of care for medically inoperable lung cancer. This treatment holds great promise in other sites. Its investigation in other thoracic and abdominal malignancies needs to be supported. Similar examples are the use of approved drugs for some cancers but now being tested in new combinations. Our nation''s cooperative groups frequently conduct clinical trials of this sort. CMS needs to support the investigation of these new indications of existing therapies.

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August 17, 2007

Steve E. Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
U.S. Department of Health & Human Services
7500 Security Boulevard
Mail Stop C1-09-06
Baltimore, Maryland 21244-1850

Re: Proposed Decision Memo for Clinical Trial Policy (CAG-00071R2)

Dear Dr. Phurrough:

I am writing on behalf of the Advanced Medical Technology Association (AdvaMed) regarding the Centers for Medicare and Medicaid Services (CMS) proposed decision memorandum revising the national coverage decision on the “Clinical Trial Policy” (hereinafter referred to as the “Clinical Research Policy” or “CRP”). AdvaMed member companies produce the medical devices, diagnostic products and health information systems that are transforming health care through earlier disease detection, less invasive procedures and more effective treatments. Our members produce nearly 90 percent of the health care technology purchased annually in the United States and more than 50 percent purchased annually around the world. AdvaMed members range from the largest to the smallest medical technology innovators and companies.

Our members seek to improve the lives of Medicare beneficiaries, their children and grandchildren through earlier detection of disease, improved diagnostics, and better treatments for seniors and disabled Americans to live healthier and more independent lives. Clinical research further advances the opportunities to improve patient care and AdvaMed would like to work with you to achieve a clinical research policy that encourages beneficiary participation in research, and that is clear and timely. We were pleased that the proposed decision memorandum issued on July 19, 2007 contained significant improvements over the proposed decision that had been issued in April 2007 (in connection with the first reconsideration of the 2000 Clinical Trial Policy).

AdvaMed’s members continue to have concerns regarding the proposed policy. Although AdvaMed supports the goals of high quality research, a national coverage decision that conditions coverage of benefits in clinical trials upon meeting the requirements of the proposed Clinical Research Policy (CRP) raises potentially unintended, but significant legal risks associated with reimbursement of items and services that are otherwise Medicare covered. Our concerns and recommendations fall into six key areas: (I) compliance/legal issues and self-certification process; (II) clarifications for the standards for clinical research; (III) timeframes and process; (IV) deemed status for studies funded or approved by Federal Agencies; (V) transition/implementation plan; and (VI) other significant issue.

I. COMPLIANCE/LEGAL ISSUES AND SELF-CERTIFICATION PROCESS

First, AdvaMed was encouraged by Dr. Phurrough’s comments in the August 7, 2007, Open Door Forum, which explained that the quality standards are factors to be considered rather than requirements to which compliance must be certified. AdvaMed believes the agency can achieve this objective in a manner consistent with the governing procedural statutes that many stakeholders, including AdvaMed have raised.

There are at least three procedural pathways the agency might be considering with regard to this CRP rulemaking, the national coverage determination process, and guidance development. To date, the agency has opted for the national coverage determination process, but many stakeholders have raised concerns that the NCD process was intended for specific items and services, and not for announcing new requirements that apply to all items and services. The agency itself has raised the prospect of using rulemaking for some unspecified portion of the policy, but has never explained its intentions in that regard and has continued employing the NCD process. AdvaMed believes it would be helpful if the agency clarified its plans with regard to rulemaking and the topics that will be addressed through rules.

Given the agency''s objective of listing factors that sponsors and others ought to consider as they design clinical trials, it is apparent that this topic is ideally suited to guidance. While this procedural option would necessitate a change in the wording of the current draft, much of the change would be in form rather than in substance. To implement these clarifying points in the most clear and efficient manner that would be suitable for the guidance development process, among other things AdvaMed recommends that the proposed CRP be revised to convert its legal effect into a presumption that the required quality standards are met, rather than providing for outright coverage of “usual patient services” that are provided in accordance with the policy. While this may be a subtle change, AdvaMed believes it is important to recognize that compliance with the quality standards is but one possible route for coverage of items and services that fall within the definition of usual patient care, and that change with some other modifications would allow CMS to use the guidance development process. In practical terms, the agency does not need to worry about the lack of a binding requirement because providers will insist that a sponsor (and other responsible parties, as applicable) follow the CRP process in order to get the benefit of the presumption that the provider''s claims are reasonable and necessary. So, the agency would achieve its policy objectives and would do so using a guidance development process that may be acceptable to the agency in terms of speed and resources required.

RECOMMENDED REVISION: Accordingly, throughout the CRP, AdvaMed recommends that CMS revise the text to provide that, using the process outlined in the policy, usual patient care will be “presumed to meet the quality standards necessary for an item or service used in the study to be covered.” For example, the two introductory paragraphs to the CRP would read as follows:“Effective for items and services furnished on or after XXX XX, 2007, Medicare affirms that usual patient care in a clinical research study, under the circumstances described more fully below, will be presumed to meet the quality standards necessary for an item or service used in the study to be covered. The subject or purpose of the study must be the evaluation of an item or service that falls within a Medicare benefit category under Part A or Part B (e.g., physicians'' service, durable medical equipment, diagnostic test) and is not statutorily excluded from coverage (e.g., cosmetic surgery, hearing aids). In addition, Medicare covers reasonable and necessary items and services used to prevent, diagnose, and treat complications arising from participation in these research studies.Items and services furnished to Medicare beneficiaries in clinical research studies for which the responsible parties have not complied with the approval process in this policy are not presumed to meet the necessary quality standards for the items or services used in the study to be covered.” Other conforming changes should be made throughout the document.Second, as mentioned above, the agency has expressed a helpful clarification that the standards are factors to be considered rather than requirements to which compliance must be certified. In light of this explanation, AdvaMed believes CMS should clarify that the self-certification process in fact is a notification made when a study is launched. Imposing a true “certification” requirement before a clinical trial has commenced would put the sponsor or investigator in the unreasonable position of making a universal certification of compliance before the fact. This stands in sharp contrast to the ordinary Medicare Part A or Part B claim, in which the provider or supplier certifies compliance after the fact of any item or service furnished to a Medicare beneficiary, when all of the relevant facts are known. It also is materially different from the multiple certifications made by a grantee that has received a research grant from NIH; in that setting, the grantee (or prospective grantee) only certifies compliance after the fact for a specified time period. Therefore, in order to avoid placing sponsors or investigators in the untenable position of certifying compliance when all of the relevant facts are not known, AdvaMed recommends that sponsors or investigators be permitted to notify CMS that all of the relevant standards have been addressed in the study design and protocol. Requiring the notification to relate to the study design and protocol is important because these elements are structured and evaluated before a study is underway.

RECOMMENDED REVISION: Therefore, AdvaMed recommends that the CRP, refer to the “certification” process as a “notification” process, and that the document clarify that the notification relates to the study design and protocol. For example, in the first paragraph under part 5, revise it to state as follows:“Effective XXXX, XX, 2007, CMS will presume that usual patient care for beneficiaries enrolled in clinical research studies meets the necessary quality standards if a responsible party has notified CMS that those quality standards listed in part 2 of this policy were addressed in the study design and protocol prior to commencement of the study.” Third, currently, in an ambiguous fashion, the proposed CRP simply provides that the “study sponsor/principal investigator” must make the notification. However, as CMS is aware, when a study is privately sponsored, sponsors and investigators each have discrete regulatory responsibilities under FDA and other relevant regulations. Additionally, the proposed CRP does not take into account other parties that may assume primary responsibility for regulatory responsibilities associated with a clinical study, such as contract research organizations. AdvaMed believes that CMS will receive the most robust and accurate notifications when the entities that are closest to the study submit the notification to CMS. Further, the parties that conduct or oversee a study are in the best position to decide among themselves who should submit the notification.

RECOMMENDED REVISION: Hence, the parties responsible for notification should be those that are closest to the particular standard being examined. Under part 5, AdvaMed recommends that CMS replace the existing second paragraph with the following:“The parties responsible for filing the notice with CMS may be (1) the study sponsor, (2) the investigator, (3) a contract research organization, (4) another party directly responsible for the design or conduct of the study or (5) any combination of the above. It is the responsibility of these entities to determine which party will file the notification described in this part, and it will be acceptable to allocate that responsibility, provided that each of the quality standards in part 2 are addressed in one or more notices filed with CMS prior to the commencement of the clinical trial.”Additionally, throughout the CRP, replace the phrase “study sponsor/principal investigator” with the phrase “responsible parties.”Fourth, although CMS has not yet published a proposed notification form, our current understanding is that an individual must sign and make the notification, even if the individual is merely making the notification on behalf of an entity, such as a sponsor/manufacturer. While AdvaMed understands that an individual must actually sign and submit the form, AdvaMed asks CMS to clarify that the individual(s) signing the notice is signing on behalf of, and reflects the collective assessment of, the entity with which they are affiliated.

RECOMMENDED REVISION: In part 5, AdvaMed recommends that CMS add the following paragraph:“The individual(s) signing the notice are attesting to the collective assessment of the entity they represent, and need not themselves have specialized knowledge regarding the technical adequacy of the study design and protocol in addressing all of the quality standards.”Finally, during the Open Door Forum, CMS explained that as long as the relevant responsible parties notify the agency that the study design, protocol, and other aspects of the study meet the proposed standards, CMS will not subsequently assert that claims were submitted in violation of the CRP. Our understanding, therefore, is that providers that submit claims to the agency will not be liable as long as the relevant responsible parties have notified CMS of compliance with the quality standards. AdvaMed has also understood CMS to say it will not engage in audits of compliance with the Proposed CRP. Similarly, our understanding is that claims submitted under the CRP will not form the basis for liability under the False Claims Act because the notice is evidence of both the entity''s good faith intent to comply with the standards in the policy, and because the entity is not acting with the requisite knowledge required under the FCA (barring any material withholding or misrepresentation of the facts). Given the significance of this issue, AdvaMed asks CMS to clarify this in the final CRP Decision Memorandum in order to avoid creating unintended private litigation.Notwithstanding the above, AdvaMed acknowledges that CMS may stop reimbursing claims for a study if the agency learns the study is not in compliance with the quality standards. For example, if an IRB halted a study on the basis of unforeseen and substantial risks, CMS might assess and determine that the IRB decision necessarily resulted in the study being out of compliance with CMS’ quality standards. But such an action would potentially result in CMS eliminating the presumption in favor of coverage prospectively, not a retrospective denial of claims.

RECOMMENDED REVISION: To achieve these clarifications, AdvaMed recommends that CMS add, after part 6 (Exceptions), the following new paragraph: “AdministrationCMS does not intend to routinely conduct audits to assess the degree to which the study design and protocol address the quality standards in part 2 of this policy. Providers submitting claims may rely in good faith on the agency’s published list of qualifying research, and the agency will not deny claims on the basis that the quality standards were not met for any dates of service prior to the publication of the initial determination of the Chief Medical Officer in part 6 of this policy.”

II. STANDARDS FOR CLINICAL RESEARCH

AdvaMed understands the objectives behind many of the standards that CMS has proposed. However, we urge CMS to clarify the standards as much as possible, and to provide additional guidance or guidelines where needed to make the standards more understandable, objective, and focused. AdvaMed also believes that the standards should be harmonized with the role of the Institutional Review Board (IRB). AdvaMed recommends the following to improve the standards.

A) CMS PROPOSED: The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes.

Given the current phrasing of this standard, there is some concern that it could be construed to allow for only superiority-based, randomized controlled clinical trials. While these designs should be allowed, there should be language within the standard that acknowledges the fact that some studies are designed to test whether a new intervention provides equivalent outcomes to an existing intervention. Often such studies are at the same time improving the efficiency of care delivery in some way. Study of products that improve the efficiency of diagnosis may also not meet this standard as written and/or interpreted, though the intention should not be to limit or avoid these important research studies.

RECOMMENDED REVISION:

“The principal purpose of the research study as addressed by the study design and protocol is to test or clarify whether a particular intervention potentially improves the participants’ health outcomes or maintains health outcomes.”

B) CMS PROPOSED: The research study does not unjustifiably duplicate existing studies.

Multiple scenarios exist within good common research practice that demand the duplication of existing studies: FDA’s requirement of at least two pivotal Phase III trials for any drug being considered for approval; a recognized standard for clinical research practices states that “even the best proven prophylactic, diagnostic, and therapeutic methods must continuously be challenged through research . . .”; and the growing demand in the US for additional research through Phase IV trials to further examine study findings that were previously reported in Phase III trials, just to name a few. Leaving this statement vague by retaining the word “unjustifiably” leaves the standard unable to be met in some reliable and predictable way while simultaneously creating potential situations where the evaluative standard used is counter to the standard used in most other research areas of the US health and regulatory systems.AdvaMed recommends deleting this standard because the CRP already includes other standards that would ensure that clinical research under this policy would be “good” research both from a scientific and a public health perspective. However, if CMS decides to maintain a standard, AdvaMed recommends the following revision.

ALTERNATIVE RECOMMENDED REVISION:“The research study is not so similar to existing studies that it is expected to provide no additional value for clinical decision-making.”

C) CMS PROPOSED: The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46. If a study is FDA-regulated, it also must be in compliance with 21 CFR Parts 50 and 56.

RECOMMENDED REVISION: “The research study design and protocol is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 C.F.R. Part 46. If a study is FDA-regulated, it also must be in compliance with 21 C.F.R. Parts 50 and 56.”

D) CMS PROPOSED: The research study has a written protocol that clearly addresses, or incorporates by reference, the Medicare standards.AdvaMed recommends that CMS delete this standard in its entirety because as part of the process of obtaining approval under the CRP, study sponsors or principal investigators will already need to address “the Medicare standards” that are contained in the CRP. To require this standard is simply duplicative.If, however, CMS decides to maintain this standard, AdvaMed recommends that CMS clarify that the “Medicare standards” to which it refers are simply the standards set forth in this NCD. Specifically, AdvaMed would recommend the following language:

ALTERNATIVE RECOMMENDED REVISION:“The research study has a written protocol that clearly addresses, or incorporates by reference, the Medicare standards enumerated in this national coverage determination.”

E) CMS PROPOSED: The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Studies of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life-threatening as defined in 21 CFR 312.81(a) and the patient has no other viable treatment options.This standard is confusing as it relates to therapeutic intent. AdvaMed recommends that CMS adopt the language recommended by the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC).

RECOMMENDED REVISION: “The study must not be designed primarily to test toxicity or disease pathophysiology. Phase I trials that have therapeutic intent as one of the objectives may meet the standard only if the disease is chronic, life threatening, or debilitating.”

F) CMS PROPOSED: The clinical research study is registered on the ClinicalTrials.gov website by the study sponsor/principal investigator prior to the enrollment of the first study subject. Currently, AdvaMed members register many of their clinical research studies on the www.ClinicalTrials.gov website. While the exchange of information is important, AdvaMed is concerned that this requirement could have a detrimental impact on small medical device and diagnostic companies.

AdvaMed recommends that CMS recognize the needs of individuals and companies to be able to conduct necessary research while still being afforded the ability to protect proprietary information. Protecting proprietary information in medical device studies is critical to sustaining continued device innovation and to maintaining the competitiveness of the device industry. When applicable, AdvaMed recommends that any registration for device trials delay disclosure of research information until 30 days after FDA clearance or approval. For research studies conducted after FDA clearance or approval, AdvaMed recommends that clinical research information not be publicly released until 24 months after the end of data collection, as defined in the original study protocol.

RECOMMENDED REVISION: “The clinical research study is registered on the www.ClinicalTrials.gov website by the study’s responsible parties prior to the enrollment of the first study subject. No clinical research information for applicable device research will be publicly posted until 30 days after FDA clearance or approval. Clinical research information for device-related studies conducted after FDA clearance or approval, will not be publicly released until 24 months after the end of data collection, as defined in the original protocol."

G. CMS PROPOSED: The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. However, a full report of the outcomes must be made public no later than three (3) years after the end of data collection. Similar to the previous standard, the public sharing of information is vital to the continual growth of knowledge through research. In order for researchers to best comply with this standard, however, greater clarification is needed that defines what CMS considers “the end of data collection.” Depending on the type of study being completed, this consideration could change the date for compliance by months. Is data collection deemed complete once the final patient interview takes place or once the supporting database closes, which could be weeks or even months after that final interview? This section of the standard should be rewritten in a way that allows for these differences. For example, the end of data collection could be defined within the original study protocol with reference made in the standard in this fashion. This approach ensures public reporting within the currently allotted timeframe while accounting for differences in how data collection terminates in different studies.Related to the issue of the public release of all outcomes measured is the question of acceptable manners of making that information public. While this standard mandates that each study protocol specify a method of release, it only mentions publication in a peer reviewed journal as potential means of fulfilling that requirement. What are other options for the public release of findings that would fulfill this requirement if inclusion in a journal is either inappropriate or rejected upon submission? In the absence of a publishable article, CMS should consider the need for alternative methods of making the information publicly available to include, but not necessarily limited to, posting of abstract and/or result summary information on a private sponsor’s website.

RECOMMENDED REVISION:

“The research study protocol specifies the method and timing of plan for public release of pre-specified all primary outcomes to be measured including release of outcomes if outcomes are negative or early study is terminationed early. The plan must include instructions for a public release of the results must be made public within 24 months of the end of data collection after all data collection is complete, as defined within the original study protocol. If a report is planned to be published in a peer-reviewed journal, then the plan may provide that the initial release report may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. However, The plan should also include publishing a full report of the outcomes must be made to the public no later than 36 months after the end of data collection.”

H. CMS PROPOSED: The research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria affect enrollment of these populations, and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary.

AdvaMed recommends that this standard be clarified further by explicitly linking it to the current definition of underrepresented groups used by the National Institutes of Health in their grants application process. This minor change will not only offer standardization among federally-funded research, but it will also give researchers a clear standard that they can meet. This could easily be done by modifying the first line of this standard to read as follows.

RECOMMENDED REVISION: “The research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies as defined by the NIH….”

III. ADDITIONAL RECOMMENDATIONS ON TIMEFRAMES AND PROCESS

AdvaMed has three recommendations related to timeframes and process.

First, AdvaMed urges CMS to be clear about the exact timeframes and processes that trigger compliance with the CRP and overall Medicare coverage for the usual patient care in a clinical research study. This will provide a study’s responsible parties with a better idea of how to plan their research activities and will clarify exactly when enrollment of Medicare beneficiaries can begin. AdvaMed recommends specifying that Medicare contractors will not be involved in the review of clinical research beyond simply ensuring that the ClinicalTrials.gov registry number and code modifiers are on the claims forms. To encourage participation by physicians, hospitals, and other providers, it is important for CMS to clarify in its instructions to providers and practitioners that participation in clinical research will not result in delays in payment or additional contractor requirements. Finally, AdvaMed recommends allowing electronic submission of letters in order to enhance the efficiency of the process, reduce overall paperwork for both the agency and researchers.

RECOMMENDED REVISION: In part “5. Approval Process”, after “Baltimore, MD 21244”, insert:

“Letters may also be submitted electronically to the following e-mail address: ______________.

Then also add:

“CMS will review each responsible party’s letter and within five (5) days of receiving the letter will provide both an electronic and a written response to notify the responsible parties whether CMS has determined that the letter is complete. CMS will update the website list of certified research studies within two (2) days of sending out this notification to the responsible parties. CMS will post the list of certified research studies in the Federal Register on a quarterly basis. At any point after CMS has notified the responsible parties that the letter is complete, providers and practitioners will be able to obtain coverage for usual patient care provided in these research studies as long as the applicable ClinicalTrials.gov registry number and code modifiers are used on the relevant claims forms. No separate or additional review of the research study will be conducted by Medicare contractors beyond standard claims review functions.”

Second, AdvaMed recommends that CMS adopt Option A (below), not requiring parties to update their submissions as research studies progress. Once a letter has been submitted to CMS (and is considered complete by CMS), that submission applies for purposes of maintaining coverage for usual patient care throughout the study. The notification or submission would be evaluated at the time of the submission and based only on the facts as they existed at that time.

If CMS does not adopt Option A, then AdvaMed recommends that CMS adopt Option B (below) to address changes over time in study protocols that may cause a study to be materially inconsistent with the initial notification or submission. In this case, CMS should create reasonable processes that permit study sponsors or principal investigators to amend or modify the notification or submission after the initial notification or submission has been made. Such protocol amendments may be unanticipated but necessary to conduct a research study effectively. Reasonable timeframes and processes to address these changes will foster continued compliance by study sponsors or principal investigators over time. Ultimately, CMS and Medicare beneficiaries will benefit from updated and accurate information on clinical research studies.

RECOMMENDED REVISION:

Option A: After the above language addition, insert,

“This policy does not require responsible parties to update their notifications with regard to compliance with the standards as the study progresses.”

Option B: After the above language addition, insert,

“Re-submission of a notice by a responsible party is necessary only in instances where protocol amendments may cause a study to be materially inconsistent with the initial submission. Any re-submission of a notice would need to be submitted to CMS within thirty (30) days of the protocol amendment. The regular timeframes for CMS notification and postings would apply thereafter.”

Third, AdvaMed recommends that processes be developed that provide study sponsors or principal investigators with an opportunity to respond and provide additional information demonstrating compliance, in the event that CMS’s Chief Medical Officer finds that a study “does not meet the standards as defined in this policy.” AdvaMed shares CMS’s concern that studies protect the health and safety of beneficiaries, and that such studies be conducted with the utmost scientific and ethical integrity. However, AdvaMed urges CMS to create a dispute resolution process with reasonable timelines for communication between CMS and study sponsors or principal investigators so that amendments and supplements may be clarified and addressed without having a negative impact on researchers and scientists who are trying ultimately to improve patient care.

RECOMMENDED REVISION: Replace the current language in part “6. Exceptions” with the following:

“Medicare will pay for covered services in clinical research studies where the responsible party has provided notice that the study meets the standards as defined in this policy unless the CMS’ Chief Medical Officer concurs with an approving IRB that the study jeopardizes the health or safety of Medicare beneficiaries.

In addition, Medicare will pay for covered services in clinical research studies where the responsible party has provided notice that the study meets the standards as defined in this policy unless the CMS’ Chief Medical Officer finds that the study does not meet the criteria outlined in this policy. Any such finding must be in writing to the study sponsor or principal investigator and must allow the study sponsor or principal investigator the opportunity to respond in writing and take corrective action to resolve the dispute.

Coverage of items and services furnished prior to the effective date of any such findings by the CMS’ Chief Medical Officer would be unaffected by the findings.”

IV. DEEMED STATUS FOR STUDIES FUNDED OR APPROVED BY FEDERAL AGENCIES

AdvaMed recommends that CMS maintain “deemed” status for all clinical studies reviewed and approved, required or funded by Federal agencies. In the proposed decision memorandum, CMS no longer includes deemed status for studies approved or funded by Federal agencies. While the proposed policy levels the playing field between government studies and private studies, AdvaMed is concerned that requiring additional compliance with the CRP for studies that have already been approved or funded by Federal agencies is unnecessary and duplicative. To mandate compliance with CMS requirements in addition to what is already required by other Federal agencies will only slow down the process of generating evidence in studies that already have the Federal government’s imprimatur of approval.

RECOMMENDED REVISION: In part 5, after “. . . outlined in that NCD.” insert the following:

“Clinical research studies that are reviewed and approved by a Federal government agency (including FDA-required post-market studies), or funded by a Federal government agency, will be deemed to have met the standards and approval process in this NCD.”

V. TRANSITION/IMPLEMENTATION PLAN

Given the significant changes in billing that will need to be implemented by practitioners and providers in light of this policy, AdvaMed recommends that CMS set an extended time period for implementation of the final policy. Providers have expressed that it will take a minimum of six months from the date of release of the final decision memorandum for institutions and individuals to update policies and procedures, educate billing and coding staff, and potentially change information technology management and billing systems to allow for the capture of data related to the CRP. This period of time will be crucial to avoid problems with claims submission and to ensure a smooth transition.

AdvaMed continues to appreciate and encourage CMS to comply with the timeframes for the NCD process for individual devices and other medical technologies as legislated in the Medicare Prescription Drug, Improvement, and Modernization Act of 2003. However, we believe that the CRP presents extenuating circumstances that require additional time for implementation. We urge CMS to allow providers and practitioners additional time to implement the Clinical Research Policy accurately and appropriately.

RECOMMENDED REVISION: In part 11, insert the following after “this decision.”: “The effective date of this decision will be six months after the date that this final decision memorandum is issued.”

VI. OTHER SIGNIFICANT ISSUE

In addition to the above-stated issues and recommended revisions, AdvaMed is concerned that the definition of “clinical research” in the proposed CRP is extremely broad and the “exclusions from required standards” are too narrow. In particular, CMS proposes to exclude certain “data collection processes,” including studies where data is collected “in such a manner as not to influence current patient management or health outcomes.” We understand that CMS is interpreting this to mean that any study requiring an informed consent would affect human behavior and therefore such studies would not qualify for exclusion. Due to requirements to comply with HIPAA, however, informed consent is required for almost any study that involves patient data. We recommend that CMS consider clarifying and expanding its exclusion language to address this issue.

* * *

Thank you again for the opportunity to comment on the proposed Clinical Research Policy. Given the complex nature of this topic, AdvaMed would like to meet with you and your staff to discuss our concerns and recommendations. Should you or your staff have any questions, please contact Teresa Lee (via e-mail at tlee@advamed.org, or via phone at 202/434-7219) or me. AdvaMed looks forward to continuing to work with you and your staff on the Clinical Research Policy.

Sincerely,

/s/

Ann-Marie Lynch
Executive Vice President

Cc: Leslye K. Fitterman, Ph.D.

APPENDIX I

June 7, 2007

Mr. Christopher L. White
Executive Vice President, General Counsel, and Assistant Secretary
AdvaMed—The Advanced Medical Technology Association
701 Pennsylvania Ave., NW, Suite 800
Washington, DC 20004-2654

Re: Legal Analysis of Required Reimbursement for Costs Associated with Clinical Research under the Existing and Proposed Medicare Clinical Trial Policies

Dear Mr. White:
The Advanced Medical Technology Association (“AdvaMed”) asked us to offer an opinion on the legality of a recently reported construction both of the existing Medicare Clinical Trials Policy and a proposed Medicare Clinical Research Policy, as published by the Centers for Medicare & Medicaid Services (“CMS”) and its predecessor agency. We have analyzed the relevant issues presented by the reported construction and concluded that it is substantively inconsistent with the law, and is advanced through a legally defective process. This letter sets forth our legal analysis and conclusions. For ease of reference, this letter refers to the existing Clinical Trial Policy as the “Existing Policy”, and the proposed revisions to the Existing Policy as the “Proposed Policy.”

EXECUTIVE SUMMARY

As described in detail below, CMS seeks to reconstrue the Existing Policy and construe the Proposed Policy to exclude otherwise covered items and services from Medicare coverage if used in research, unless the study meets the special requirements of the policy. For research conducted privately, and therefore not qualified for deemed status, such a construction would exclude those items and services from Medicare coverage completely. We conclude, for reasons set out below, that CMS lacks legal authority to remove Medicare coverage for items and services covered under separate authority, merely because their use is part of research. In short, the agency’s stated construction is inconsistent with the Social Security Act (“the Act”). Further, the process CMS used to announce this new construction, as well as to publish the underlying policies, violated the Administrative Procedures Act (“APA”) because the policies and the construction were not developed in compliance with notice and comment rulemaking. Importantly, though, even if CMS had followed a proper process, it would not cure the underlying invalidity of the construction under the Act.

TABLE OF CONTENTS
BACKGROUND 3
FACTS 3
I. Provisions of the Existing Policy 3
II. Provisions of the Proposed Policy 3
III. CMS Construction 3
IV. Implications 3
LEGAL ANALYSIS 3
I. Overview of Conclusions 3
II. CMS’ proposed construction is substantively inconsistent with the agency’s authority under the Act. 3
A. CMS’ authority for the Existing and Proposed Policies comes from sections 1862(a)(1)(E) and 1142 and does not remove the previous coverage afforded the items and services at issue. 3
B. In the context of clinical research, the relevant authorities only add – not remove – coverage for items and services that are not otherwise covered under section 1862(a)(1)(A). 3
C. Only statutorily-defined studies can be subjected to the requirements of the Existing and Proposed Policies. 3
III. CMS’ construction is arbitrary and capricious under the APA. 3
A. Medicare coverage should apply uniformly to similar items and services that are used indistinguishably, whether or not they are part of clinical research. 3
B. Making a coverage distinction for items and services based on their use in clinical research is an unlawful, arbitrary or capricious agency action. 3
C. CMS’ construction would impermissibly subject the same products, used in the same clinical settings, to vastly different requirements. 3
D. There is no rational connection between the facts and the agency’s proposed action. 3
IV. In addition to the substantive violation of the Act, CMS was required to use notice-and-comment rulemaking to promulgate the Proposed Policy, but failed to do so, and instead employed the less rigorous NCD process. 3
A. The statutory NCD process is only available for decisions with respect to particular items or services, rather than with respect to the entire Medicare program. 3
B. CMS has stated it also has authority to engage in “scope of benefit” NCDs. 3
C. Instead of using the NCD process, the Existing and Proposed Policies’ breadth of application requires APA rulemaking. 3
D. The Existing and Proposed Policies are substantive rules that require APA rulemaking. 3
V. The notices relating to the Existing and Proposed Policies did not give the public a reasonable opportunity to comment, thus violating the law. 3
A. Whichever process CMS was supposed to follow, the law requires CMS to provide notice that is adequate to allow meaningful comment. 3
B. The Existing Policy did not notify parties that it excluded already-covered items and services from the scope of the policy. 3
C. The Proposed Policy did not notify parties of CMS’ current construction. 3
CONCLUSION 3

BACKGROUND
The Existing and Proposed Policies generally seek to clarify Medicare’s coverage of health care items or services used in a clinical study. Recent reports suggest a CMS construction not plainly evident from the face of the documents, under which items or services used in a study would be covered by the Medicare program only if a study satisfies the Existing Policy (or, once effective, the Proposed Policy) – even though these same items and services, used outside a study, face no such coverage limitation. Such a construction would have important implications for Medicare beneficiaries’ access to these items or services. It would also raise questions about administration of Medicare claims over the nearly seven years the Existing Policy has been in effect. Recitation of the key facts and our analysis and conclusions, follow.

FACTS
I. Provisions of the Existing PolicyThe Existing Policy was issued in September 2000 as an NCD pursuant to section 1862(a)(1)(E) of the Act, in order to enhance the participation of Medicare beneficiaries in clinical studies by expanding coverage for the costs of items and services associated with clinical research. In light of this overarching goal, the Existing Policy provides that Medicare covers the “routine costs” of certain qualifying clinical trials. “Routine costs” include “all items and services that are otherwise generally available to Medicare beneficiaries (i.e., there exists a benefit category, it is not statutorily excluded, and there is not a national noncoverage decision)” as well as “items or services that are typically provided absent a clinical trial (e.g., conventional care).” The Existing Policy excludes the “investigational item or service, itself” from the scope of routine costs. Importantly, though, the Existing Policy explicitly states that it “does not withdraw Medicare coverage for items and services that may be covered according to local medical review policies ….” Further, our review of numerous Medicare instructions, transmittals, and other agency communications did not evidence any notice by Medicare that the Existing Policy disturbed coverage of already-covered items or services. Indeed, some CMS communications describe the policy’s intended effect to expand – not restrict or remove – existing coverage in the context of clinical studies.
II. Provisions of the Proposed Policy
On July 10, 2006, CMS opened a national coverage reconsideration of the Existing Policy and invited public comments. The relevant National Coverage Analysis (“NCA”) Tracking Sheet identified several issues that CMS said were objects of the reconsideration, including the following:“Clarify the definitions of routine clinical care costs and investigational costs in clinical research studies including clinical trials . . .

“Determine if coverage of routine clinical care costs is warranted for studies beyond those covered by the current policy.”

The tracking sheet did not identify any issues concerning coverage within a trial of items already covered outside a trial. In December 2006, the Medicare Evidence Development & Coverage Advisory Committee met to discuss the potential revisions to the Existing Policy, including CMS’ proposals for these revisions. Although this meeting would have been an opportune time to discuss the construction that CMS is now advancing, no such discussion seems to have occurred. On April 10, 2007, CMS issued the Proposed Policy. The Proposed Policy asserted that the Existing Policy “exclude[s] the costs of the investigational item or service from the definition of routine costs, even if covered outside the study.” Further, the Proposed Policy proposed to define the term “investigational clinical services” to include investigational items in a clinical trial that are currently available to beneficiaries and thus eligible for coverage outside the trial. The Proposed Policy noted that “CMS did not request public comment on a specific definition of investigational clinical services. Even so, commenters generally were in favor of adding coverage for the investigational item if it is covered outside the trial.” In discussing these proposed changes, the Proposed Policy stated that these already-covered items and services were not necessarily experimental or investigational:In some instances, the investigational item or service in a clinical trial is an item or service that is currently available to the Medicare beneficiary and thus eligible for coverage outside the trial . . . . [T]he item or service that is being investigated as an objective within a study is not necessarily experimental or investigational. If it has been determined to be reasonable and necessary under 1862(a)(1)(A), then it has been determined to not be experimental or investigational. Thus, we believe it appropriate to cover these items and services within a covered research study even if they are the item under investigation.

In terms of compliance with its requirements, the Proposed Policy provides that certain studies are “deemed” to comply with the policy’s standards for “scientifically and technically sound” studies. These “deemed” studies include those that are required or somehow sanctioned by certain federal agencies. However, the Proposed Policy does not provide a process for determining how studies that are not “deemed” to comply with the requirements for “scientifically and technically sound” studies can, in fact, comply with those requirements. For research conducted privately – and therefore not qualified for “deemed” status – it is unclear how such studies would demonstrate that they comply with the requirements for “scientifically and technically sound” studies. Finally, as with the Existing Policy, the Proposed Policy stated that it did “not withdraw Medicare coverage for items and services that may be covered according to local coverage determinations (LCD).” CMS provided the public 30 days to comment on the Proposed Policy.
III. CMS Construction
Before submitting its comments, AdvaMed discussed certain clinical trial issues with CMS officials. Through these and subsequent discussions, as well as published news reports, it has become apparent that CMS plans to construe the Proposed Policy in the following manner: Costs of services provided under conditions that comprise “clinical research” (within the meaning of the Proposed Policy) cannot be Medicare-reimbursed unless the Proposed Policy is satisfied, even if those costs are otherwise reimbursable under separate Medicare authority. That is, the Proposed Policy is Medicare’s exclusive means for determining reimbursement for any activities that comprise “clinical research.” As such, a provider that seeks Medicare reimbursement for services delivered under conditions that comprise “clinical research” effectively commits itself to satisfying the Proposed Policy.

Thus, under the CMS construction, an item or service that is already covered by Medicare, but that is used in “clinical research,” could only be Medicare-reimbursed in a research context if the requirements of the Proposed Policy were satisfied. AdvaMed contested this construction in its comments on the Proposed Policy.
IV. Implications
The CMS construction would likely have far-reaching adverse implications for Medicare beneficiaries, as well as hospitals, physicians, other health care providers, and manufacturers that make technologies used by Medicare beneficiaries. In particular, beneficiaries participating in a privately sponsored post-market study on a Medicare-covered item or service would effectively see coverage of the items and services furnished in that study withdrawn. To be clear, by providing that an investigational service can be covered, the Proposed Policy would provide ostensibly more favorable treatment of an investigational item or service within a study – that is, if the study can satisfy the Proposed Policy. However, many studies of which Medicare beneficiaries are a part simply could not meet the Proposed Policy’s requirements due to the absence of any approval process for these studies. Therefore, because of the broad array of items and services for which beneficiaries would be denied coverage, in reality this “expanded coverage” would likely confer a small benefit to Medicare beneficiaries. Indeed, avoiding such forfeiture could well cause would-be sponsors to abstain from initiating studies altogether – the very antithesis of the Existing and Proposed Policies intentions to encourage research and to encourage beneficiaries to participate in such research. Further, sponsors that did decide to go forward with their research might decide to exclude Medicare beneficiaries from their study population, which would mean discrimination against beneficiaries in terms of participation in research. Again, this result is diametrically opposed to the intended effect of the Existing and Proposed Policies to enhance beneficiaries’ participation in research and to improve the clinical evidence base for CMS’ coverage of items and services. Moreover, given the lack of notice we describe below and the reliance on private meetings and public speeches to publicize the agency’s intent, the agency is creating an environment of intolerable legal risk for sponsors and providers that engage in clinical research. This letter analyzes CMS’ proposed construction in light of applicable law. As we explain below, we conclude that the CMS construction is unlawful.

LEGAL ANALYSIS
I. Overview of Conclusions
CMS’ proposed construction is unlawful because:

- It violates the Act.
- It is arbitrary and capricious under the APA.
- The coverage determination process cannot substitute for the required notice-and-comment rulemaking as a valid means for promulgating the Existing Policy, the Proposed Policy, and CMS’ construction of both policies.
- CMS did not provide the public adequate notice of its construction. Each of these reasons is explained in detail below.

II. CMS’ proposed construction is substantively inconsistent with the agency’s authority under the Act. CMS cites as authority for the Existing and Proposed Policies two provisions of the Act – section 1862(a)(1)(E) and section 1142. These provisions must be read with the Act’s section 1862(a)(1)(A), which provides authority to cover certain “reasonable and necessary” items and services. Reading the three provisions in full context makes clear that sections 1862(a)(1)(E) and 1142 are only available to CMS to cover items and services that are not otherwise covered under section 1862(a)(1)(A). Thus, for an item or service covered under section 1862(a)(1)(A), it is not possible for CMS to reach the question of whether the item or service should be covered under sections 1862(a)(1)(E) or 1142. The CMS construction would ignore this statutory framework, effectively permitting the agency to disregard section 1862(a)(1)(A). Such a construction is particularly disingenuous in that the agency has long treated section 1862(a)(1)(A) as the principal basis – and, impliedly, even the exclusive basis – for Medicare coverage. Indeed, we are unaware of any CMS resort to sections 1862(a)(1)(E) and 1142 until the year 2000, when the Existing Policy was issued. Moreover, sections 1862(a)(1)(E) and 1142 authorize discrete types of research – types of research far narrower than what CMS seeks to affect through its Proposed Policy. Studies that a private sponsor might initiate, for example, would not fall within the scope of sections 1862(a)(1)(E) and 1142 of the Act and thus could not be addressed by CMS through the Proposed Policy.
A. CMS’ authority for the Existing and Proposed Policies comes from sections 1862(a)(1)(E) and 1142 and does not remove the previous coverage afforded the items and services at issue.CMS bases its statutory authority for the Existing and Proposed Policies on section 1862(a)(1)(E) of the Act, which provides that “no payment may be made … for any expenses incurred for items or services … in the case of research conducted pursuant to section 1142, which is not reasonable and necessary to carry out the purposes of that section ….” In turn, section 1142 of the Act sets forth certain responsibilities of the Agency for Healthcare Research and Quality (“AHRQ”). Thus, the statutory authority for the Existing and Proposed Policies is derived from the combination of section 1862(a)(1)(E) and section 1142.
B. In the context of clinical research, the relevant authorities only add – not remove – coverage for items and services that are not otherwise covered under section 1862(a)(1)(A). Sections 1862(a)(1)(E) and 1142 operate only to give CMS the authority to cover items and services that are not otherwise covered under section 1862(a)(1)(A). They do not provide authority to withdraw coverage provided under section 1862(a)(1)(A) or under any other provision of law. Coverage for the vast majority of items and services under the Medicare program is authorized consistent with section 1862 (a)(1)(A), which provides that:Notwithstanding any other provision of this title, no payment may be made under part A or part B for any expenses incurred for items or services— which, except for items and services described in a succeeding subparagraph, are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. Thus, the law provides that no payment may be made for expenses for items or services if the items and services are not reasonable and necessary. The “except” clause necessarily refers to situations in which an item or service, even though it is not reasonable and necessary, can nonetheless be covered. The Act makes clear that the conditions for determining these situations are established in succeeding subparagraphs. Thus, the “succeeding subparagraphs” serve to identify additional ways in which an item or service can be covered when it is not covered under subparagraph (A). By definition, the “succeeding subparagraphs” cannot apply to an item or service that is covered under subparagraph (A) and thus cannot affect the coverage status of such an item or service. Importantly, as described above, CMS’ authority for the Existing and Proposed Polices rides on one of these “succeeding subparagraphs” – subparagraph (E). Because the policies are based on this discrete authority, they cannot reach – and thus cannot change the coverage status of – items and services that qualify for coverage because they are reasonable and necessary under subparagraph (A).The Act’s plain meaning is supported by the agency’s own characterization of the Existing and Proposed Policies. For example, CMS’ explanation in the NCA Tracking Sheet for the Proposed Policy describes the Act’s provisions very well:The Clinical Trial Policy was developed under the authority of section 1862(a)(1)(E) of the Act. This paragraph prohibits payment for items and services that are not reasonable and necessary to carry out the research purposes of section 1142. In other words, it broadens the limitations on the scope of permissible Medicare payments (in section 1862(a)(1)(A) of the Act) to include making payments for what is reasonable and necessary for the Secretary, acting through AHRQ, to carry out research under section 1142. It permits payment for clinical care that is being studied under section 1142 for its effectiveness and appropriateness.

The agency’s interpretations of section 1862(a)(1)(E) in other, related contexts, also support the interpretation that subparagraph (a)(1)(E) operates only when (a)(1)(A) does not apply: - CMS has said that, “[i]f the evidence is not adequate for coverage under section 1862(a)(1)(A), an item or service may be considered for coverage under the CMS Coverage with Evidence Development (CED) policy in which ‘reasonable and necessary’ is established under 1862(a)(1)(E) of the Act.”

- The agency has also said that that form of CED known as Coverage with Study Participation, which – like the Existing and Proposed Policies – is directly based on sections 1862(a)(1)(E) and 1142, “will allow coverage of certain items or services for which the evidence is not adequate to support coverage under section 1862(a)(1)(A) and where additional data gathered in the context of clinical care would further clarify the impact of these items and services on the health of Medicare beneficiaries. In the past, this level of evidence would have prompted non-coverage decisions.” Finally, even though the Act’s meaning is clear, ancillary materials to aid interpretation compel the same conclusion. For example, the history underlying the Existing and Proposed Policies supports the conclusion that CMS should only exercise those policies to provide additional coverage for items and services that are not otherwise covered. In particular, the genesis for the Existing and Proposed Policies is an Executive Memorandum issued by President Clinton, which directed CMS to cover and pay for routine and other costs associated with clinical studies. This Executive Memorandum clearly evidences an intent to provide Medicare coverage where it did not exist – not to remove coverage where it did exist. For example, in setting forth the rationale for Medicare payment of clinical studies expenses, the Executive Memorandum provides:One factor contributing to seniors’ low participation rate in clinical trials is the Medicare program’s failure to guarantee Medicare payment for the care associated with participation. This uncertainty regarding reimbursement often deters patients from participating in these trials, and deters physicians and other clinicians from recruiting patients, contributing to low participation rates and slowing the development of new medical treatments and diagnostic tests that could benefit the entire Medicare population.

In sum, sections 1862(a)(1)(E) and 1142 simply authorize CMS to cover items and services that the agency otherwise would not have had authority to cover. If an item or service is covered under subparagraph (a)(1)(A), sections 1862(a)(1)(E) and 1142 do not apply – and certainly do not provide CMS authority to remove existing coverage.
C. Only statutorily-defined studies can be subjected to the requirements of the Existing and Proposed Policies. CMS’ authority under the Existing and Proposed Policies only extends to research within the scope of section 1862(a)(1)(E) and section 1142. In particular, section 1862(a)(1)(E) encompasses research that is "conducted pursuant to section 1142 . . .” In turn, section 1142 sets forth certain AHRQ responsibilities, which include an obligation to “conduct and support research with respect to the outcomes, effectiveness, and appropriateness of health care services and procedures in order to identify the manner in which diseases, disorders, and other health conditions can most effectively and appropriately be prevented, diagnosed, treated, and managed clinically . . . .”Section 1142’s scope therefore includes only research that the Secretary conducts or supports and that otherwise satisfies the provision’s requirements. Moreover, to the extent that the Secretary “supports” research under section 1142, this must be done within the confines of other statutory provisions, such as section 1862(a)(1)(A), as discussed above. The structure of the Proposed Policy also suggests that its scope is restricted to studies conducted or supported by AHRQ or a related federal agency. In particular, under the Proposed Policy, certain studies are “deemed” to comply with the Proposed Policy because they are required or somehow sanctioned by certain federal agencies. Indeed, the policy notes that these “deemed” studies will “assure that the research is conducted with AHRQ support pursuant to section 1142 of the Act.” The Proposed Policy does not even provide a process for determining how studies that are not “deemed” to be covered under the policy can comply with the policy. In particular, while the policy says that Medicare contractors will determine whether Medicare-specific standards are met, it does not address how studies that are not “deemed” may demonstrate that they meet the policy’s requirements for “scientifically and technically sound” studies. Now, after the fact, CMS proposes to sweep such privately-sponsored studies into the Proposed Policy’s requirements, yet does not offer guidance on how such studies can even meet the policy’s requirements. This is inconsistent with CMS’ authority under the Act.
III. CMS’ construction is arbitrary and capricious under the APA. As explained above, the agency’s construction of the Existing and Proposed Policies violates the coverage provisions of the Act. That reason alone makes the construction impermissible under current law. Additionally, CMS’ construction violates the requirements of the APA.
A. Medicare coverage should apply uniformly to similar items and services that are used indistinguishably, whether or not they are part of clinical research.The Act sets forth service categories that comprise covered benefits under Parts A and B of the Medicare program. Medicare reimburses providers for claims involving individual items and services that fall within these prescribed benefit categories, unless, under section 1862(a)(1)(A), a type of item or service is not “reasonable and necessary” for the diagnosis and treatment of illness or injury or to improve the functioning of a malformed body member. If an item or service is “reasonable and necessary,” it is considered “covered.”The Act gives the Secretary the authority to publish coverage determinations for items and services. Under this authority, CMS nationally – or Medicare contractors locally – may develop a coverage policy that describes the circumstances in which a type of item or service is “reasonable and necessary.” In many instances, however, there is no applicable policy, and local contractors determine coverage case-by-case, based upon whether an item or service is reasonable and necessary in a given patient-care circumstance. Therefore, a type of item or service may be Medicare-covered by virtue of an explicit national policy, an explicit local policy, or local case-by-case determinations. In all such instances, the item or service is “reasonable and necessary” within the meaning of the Act and therefore covered. Coverage requirements are applied uniformly to the individual items and services that comprise the pertinent item or service type. Through its apparent construction of the Existing and Proposed Policies, CMS seeks authority to carve out certain items and services – and to subject those items and services to requirements that go beyond the “reasonable and necessary” authority of section 1862(a)(1)(A). However, CMS has no basis – legal or factual – for doing so. CMS is effectively withdrawing Medicare coverage for those items and services, even though those items and services retain the qualities that made them – and continue to make them – “reasonable and necessary.” To apply Medicare policies in a way that produces such disparate treatment of essentially identical items and services violates the arbitrary and capricious standards under the APA.
B. Making a coverage distinction for items and services based on their use in clinical research is an unlawful, arbitrary or capricious agency action.The APA prohibits the construction of the Existing and Proposed Policies as CMS has suggested because the construction would result in arbitrary and capricious actions. Agencies act in an arbitrary and capricious manner when they adopt an unreasonable construction of a governing statute, or when they cannot demonstrate a “rational connection between the facts found and the choice made.” Courts have also explained that an agency action is considered arbitrary and capricious if the agency relies on an explanation for its decision that runs counter to the available evidence, or if the agency action is so implausible that it could not be ascribed to a difference in view or the product of agency expertise. An example is illustrative here. In a case involving the U.S. Food and Drug Administration (“FDA”), a court rejected an FDA decision where the agency treated some manufacturers’ products as new drugs, while treating a competitor’s similar product as a device. In rejecting this differential treatment, the court explained that an agency cannot “permit two sets of similar products to run down two separate tracks, one more treacherous than the other, for no apparent reason.” Such disparate treatment of “functionally indistinguishable products is the essence of the meaning of arbitrary and capricious.”
C. CMS’ construction would impermissibly subject the same products, used in the same clinical settings, to vastly different requirements.CMS’ proposed actions under the Existing and Proposed Policies would treat products that are fundamentally the same in a dissimilar manner, to the disadvantage of one set of products and the beneficiaries who seek access to them. The law does not allow this result. We illustrate our reasoning through a hypothetical, below.
i. Hypothetical: Care Satisfies Proposed Policy
Fred Smith is a Medicare beneficiary who needs an artificial hip. For the type of hip that Fred needs, there are three brands currently on the market, all three FDA-approved, and, by virtue of section 1862(a)(1)(A) of the Act, covered by Medicare. Medicare has also issued a national coverage determination that describes certain conditions for coverage. These conditions address: the type of orthopedic surgeon who must perform the procedure; the type of hospital in which the procedure must be performed; and the type of required clinical condition – specifically, certain impaired mobility and pain. Fred – who meets these clinical criteria – has the hip implanted in Hospital A, which satisfies the requirements of the NCD. Dr. Brown performs the procedure, and Dr. Brown also meets the NCD criteria. Because the coverage criteria are met and the artificial hip is medically necessary for Fred, Medicare covers the hip for Fred.
ii. Hypothetical: Care Does Not Satisfy Proposed Policy
The next week, Cindy Jones, who also meets the clinical criteria for limited mobility and pain, and who also is a Medicare beneficiary, comes to Hospital A, where Dr. Brown performs the same procedure, implanting the same type of FDA-approved hip. Within the past week, Hospital A, which happens to be part of an academic medical center, has initiated a study on the three marketed brands of the hip. The study consists of a head-to-head comparison of the effectiveness of the three hips. Dr. Brown explains the study to Cindy and asks if she would consent to be a subject in the study. Cindy agrees because the study does not affect her clinical care – she is receiving the same FDA-approved hip, for the same use, implanted by the same physician, in the same hospital. Because the study does not qualify for “deemed” status under the Proposed Policy, Hospital A does not seek to qualify the study under the Proposed Policy. Under CMS’ construction of the Proposed Policy, Medicare would not cover the hip and associated services for Cindy because the agency would view the statutory source of coverage for Fred’s situation – section 1862(a)(1)(A) of the Act – as not applying. Instead, CMS would view the statutory provisions underlying the Proposed Policy – Act sections 1862(a)(1)(E) and 1142 – as representing the exclusive statutory bases for covering Cindy’s care.
iii. Discussion
This result is arbitrary and capricious. CMS’ construction would allow a given item or service to be covered for a particular usage in a particular setting by a particular clinician, while the exact same item or service would not be covered for that same usage in that same setting by that same clinician, simply because in the second case the usage encompasses activities that CMS consider “clinical research.” Thus, in one setting, the item is reasonable and necessary under section 1862(a)(1)(A), but in the exact same setting, the item is considered experimental, therefore failing to satisfy the requirements of this same section. Such disparate treatment of the same items, in the same setting, used by the same clinicians is – as stated by the courts – “the essence of the meaning of arbitrary and capricious.”
D. There is no rational connection between the facts and the agency’s proposed action.CMS’ proposed action is also arbitrary and capricious because CMS’ decision runs counter to the evidence before the agency. Indeed, we can discern no basis in the administrative record that could in any way support CMS’ proposed action. The products at issue here are covered by virtue of the “reasonable and necessary” provisions of section 1862(a)(1)(A) of the Act. By definition, this means that the products at issue are not “experimental” or “investigational” products. The items at issue are also cleared or approved for marketing by FDA and are therefore not experimental or investigational. Indeed, when used in the context of a clinical study, they are subject to heightened oversight and scrutiny, including study monitoring, informed consent, Institutional Review Board review, and other applicable requirements associated with Good Clinical Practice. Moreover, for that (growing) number of items and services for which CMS or its contractors have issued a national or local coverage determination, positive coverage decisions that allow Medicare beneficiaries access to medical technologies rest on substantial medical literature and significant amounts of clinical data.CMS’ construction would disregard all these facts and considerations, simply because a sponsor took the initiative to collect additional information and data. The construction would also disregard the beneficiary’s satisfaction of existing coverage criteria, and the fact that the item or service is medically necessary for the beneficiary. Such action on the part of CMS bears no rational relationship to the facts and is arbitrary and capricious under the APA.For the reasons above, CMS’ construction would draw unwarranted and unsupported distinctions in its coverage decisions, thereby producing results that are arbitrary and capricious.
IV. In addition to the substantive violation of the Act, CMS was required to use notice-and-comment rulemaking to promulgate the Proposed Policy, but failed to do so, and instead employed the less rigorous NCD process.Beyond the above two independent bases of illegality discussed above, the Proposed Policy – and CMS’ construction of it – exceeds the bounds of an appropriate NCD and therefore was required to have been promulgated under traditional notice-and-comment rulemaking. However, even if promulgated pursuant to an appropriate process, CMS’ construction of the policies remains illegal for the reasons discussed above. Any remedy by the agency must address all bases of illegality.
A. The statutory NCD process is only available for decisions with respect to particular items or services, rather than with respect to the entire Medicare program.The Act defines a national coverage determination as “a determination by the Secretary with respect to whether or not a particular item or service is covered nationally” under the Medicare program. As described by CMS, NCDs “outline the conditions for which a service is considered to be covered (or not covered) under § 1862(a)(1) of the Act or other applicable provisions of the Act.” , In other statements, CMS has explained that NCDs address coverage for “a specific medical item or service.” In developing an NCD, the Act requires CMS to consider “applicable information … with respect to the subject matter of the determination”, which includes “clinical experience and medical, technical, and scientific evidence.” The Act also sets forth a process for developing an NCD, which includes truncated notice and comment. Thus, the notice and comment allowed under the Act for an NCD is not as rigorous as the notice and comment required for informal rulemaking under the APA.
B. CMS has stated it also has authority to engage in “scope of benefit” NCDs.We note that the agency has stated that it has the authority to develop “scope of benefits” determinations and that these determinations are a form of NCD that fall within the Act’s NCD definition. The agency has described these “scope of benefits” NCDs as follows: Typically, scope of benefits NCDs would further specify whether services would be covered under specific statutory categories that exist under Part A and Part B of the Medicare Act. (Section 1812, 1832, and 1861(s)). Thus, a scope of benefits NCD could be used to establish a policy on whether a particular device is considered durable medical equipment. Similarly, the Medicare Act prohibits payment for certain specific services. We may choose to establish an NCD describing those types of procedures (for example, whether care constitutes a routine physical examination, or cosmetic surgery). As explained below, the Existing and Proposed Policies far exceed the bounds of an NCD, including even a “scope of benefits” NCD.
C. Instead of using the NCD process, the Existing and Proposed Policies’ breadth of application requires APA rulemaking.The Existing Policy, the Proposed Policy, and CMS’ construction of both far exceed the bounds of the Act’s definition of an NCD, even assuming “scope of benefits” determinations legitimately fall within that definition. The Existing and Proposed Policies quite obviously purport to apply to broad swaths of items and services that are subjects of clinical research – and thus twist beyond recognition the Act’s requirements that an NCD pertain to a “particular” or “specific” item or service. Even the purported “scope of benefit” theory does not provide CMS the ability to use a single NCD to cut through all other existing benefit categories. One need only peruse CMS’ publicly available listing of NCDs to see that the Existing and Proposed Policies stand out as asserting an extraordinary breadth of application. Moreover, the agency purports to apply the Existing and Proposed Policies to items and services across all Part A and B benefit categories. So broad an application, affecting all of fee-for-service Medicare, requires rule-making under the APA – not the abbreviated process that the law allows for NCDs that, by definition, are relatively narrowly targeted.
D. The Existing and Proposed Policies are substantive rules that require APA rulemaking.The Existing and Proposed Policies, including CMS’ recent construction, constitute a “substantive rule” within the meaning of the APA because it affects the rights and interests of Medicare beneficiaries, as well as Medicare-participating hospitals, physicians, and other providers. More specifically, the Existing and Proposed Policies constitute “the whole or part of an agency statement of general or particular applicability and future effect designed to implement, interpret, or prescribe law or policy ….” The Existing and Proposed Policies implement and interpret law generally for beneficiaries, Medicare contractors, and providers. They will also exert a future effect on the Medicare program. Substantive rules require notice and comment rulemaking under the APA. Importantly, the type of broad and expansive rule that the policies set forth is not suited for the truncated notice-and-comment process that the Act allows for NCDs. That process was promulgated to address more discrete, scientific issues, rather than far-reaching rules that fundamentally alter the scope of all of the benefit categories set forth under the Medicare program. Such a broad rule should be subject to the heightened scrutiny mandated by the APA in order to protect Medicare beneficiaries and to ensure that CMS receives all comments and other inputs needed to inform the rule.
V. The notices relating to the Existing and Proposed Policies did not give the public a reasonable opportunity to comment, thus violating the law. As with the other basis of illegality discussed in this letter, CMS’s failure to provide the public a reasonable opportunity to comment – discussed below – is an independent reason for the unlawfulness of CMS’ construction of the Existing and Proposed Policies. Even if promulgated pursuant to an appropriate process, CMS’ construction of the policies remains illegal for all of the separate reasons discussed in this letter.
A. Whichever process CMS was supposed to follow, the law requires CMS to provide notice that is adequate to allow meaningful comment. The APA requires agencies to publish general notices of proposed rulemaking that, among other things, include “either the terms or substance of the proposed rule or a description of the subjects and issues involved.” This notice must be sufficient to fairly apprise interested parties of all significant subjects and issues such that interested parties have the opportunity to participate in the rulemaking process. The purpose of notice and the subsequent comment period is to allow interested members of the public to communicate information, concerns, and criticisms to the agency during the rulemaking process. If the notice of proposed rulemaking fails to provide an accurate picture of the reasoning that has led the agency to the proposed rule, interested parties will not be able to comment meaningfully upon the agency''s proposals. As a result, the agency may operate with a one-sided or mistaken picture of the issues at stake in a rulemaking. Importantly, the mere fact that comments are submitted on an issue does not necessarily mean that the agency provided adequate notice. That a few stakeholders perceive and comment on the unstated consequences of an agency’s proposal does not satisfy the agency’s responsibility to give notice with sufficient clarity to permit all interested parties to perceive such consequences and comment on them. CMS did not give adequate notice of its proposed action and construction. Indeed, in some passages, the language of the Existing and Proposed Policies suggest a result exactly the opposite of what CMS apparently intends – i.e., a result in which already-covered items and services are and would continue to be covered under CMS’ policies.
B. The Existing Policy did not notify parties that it excluded already-covered items and services from the scope of the policy. As mentioned above, the Proposed Policy asserts that the Existing Policy “exclude[s] the costs of the investigational item or service from the definition of routine costs, even if covered outside the study.” At best, though, the language of the Existing Policy is unclear, and the policy can easily be read to say that items and services studied within a clinical study retain coverage under section 1862(a)(1)(A) of the Act – a conclusion exactly opposite the one CMS now asserts, for the first time, nearly seven years after the policy’s promulgation. Specifically, the Existing Policy states that it provides coverage for “routine costs,” which are defined to include “all items and services that are otherwise generally available to Medicare beneficiaries (i.e., there exists a benefit category, it is not statutorily excluded, and there is not a national noncoverage decision).” The Existing Policy further states that these routine costs include “items or services that are typically provided absent a clinical trial (e.g., conventional care).” Under the most direct reading of this language, the referenced items and services include those that are reasonable and necessary under section 1862(a)(1)(A) – and thus that would logically form an element of the “routine costs” for which the Existing Policy pays. The Existing Policy excludes coverage for “the investigational item or service, itself,” but this would not in any event encompass items that are reasonable and necessary under section 1862(a)(1)(A) because such items and services – as CMS itself has said in the Proposed Policy – are not “investigational.” Moreover, the Existing Policy also notes that it “does not withdraw Medicare coverage for items and services that may be covered according to local medical review policies ….” (The current Proposed Policy also contains similar language, as discussed below.) If an already-covered item or service is automatically “disqualified” from coverage if provided as part of a study, as CMS asserts, how can such a result be reconciled with the Existing Policy’s explicit language saying that local coverage cannot be withdrawn? If one grants CMS the benefit of every conceivable doubt, the most one can say in the agency’s favor is that the issue is so complex as to defy understanding – and thus to require an explication that errs on the side of informing the public and inviting its comments. Finally, it is with no small amount of sympathy that we observe that in the Proposed Policy CMS itself confesses that “it is not completely clear as to the reasoning that was used in the current policy for not covering items and services that would be covered outside the trial.” Understandable though the agency’s confusion may be, it underscores the fact that there is no basis for CMS to render a retrospective construction so wholly at odds with the Existing Policy’s wording.
C. The Proposed Policy did not notify parties of CMS’ current construction.The Proposed Policy also does not provide adequate notice of CMS’ intention to require privately sponsored studies to comply with the requirements of the Existing and Proposed Policies in order to maintain coverage for already-covered items and services. The document is simply silent on this issue. The agency’s published notices provide no basis for establishing the construction that CMS now asserts – or even communicating the existence of such a construction. We note that AdvaMed and perhaps a very limited number of other commenters (many of them AdvaMed members) raised this issue in their comments. However, we understand that AdvaMed raised this issue only after it became aware of CMS’ construction through oral discussions. Other members of the public – including Medicare beneficiaries whose medical care is at stake – were (and remain) undoubtedly oblivious to CMS’ intention. Moreover, as noted above, the fact that a few parties comment on an issue does not relieve an agency of its obligation under the APA to provide notice of sufficient clarity to alert others. As courts have held, an agency is obligated to provide notice to all interested parties. It is irrelevant that a few commenters are able to discern a possible interpretation or policy consequence.

CONCLUSION
In conclusion, based on facts currently available, we believe that CMS’ construction of the Existing and Proposed Policies violates the law on several independent legal grounds. In particular, the construction violates the coverage provisions of the Act and is arbitrary and capricious under the APA. In addition to these substantive arguments, which stand alone, the Existing and Proposed Policies were also required to have been effectuated through the NCD process rather than through notice-and-comment rulemaking. CMS has also failed to satisfy requirements for public notice with respect to its construction.

Please let me know if you have any questions.

Very truly yours,
Bradley Merrill Thompson, Shareholder
EPSTEIN,
BECKER & GREEN, P.C.

cc: Stuart Gerson
Wendy Goldstein
Douglas Hastings
Ted R. Mannen
David Matyas
Lynn Shapiro Snyder
Carrie Valiant

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August 17, 2007

Steve E. Phurrough, M.D., M.P.A.
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Mail Stop C1-09-06
Baltimore, MD 21244

Dear Dr. Phurrough:

UPMC Cancer Centers and the University of Pittsburgh Cancer Institute (UPCI) appreciate the opportunity to provide comments addressing the proposed Clinical Trial Policy (CAG-00071R2), renamed the Clinical Research Policy. UPMC Cancer Centers and UPCI support Medicare’s actions to reduce barriers and improve access for Medicare beneficiaries to research.

Proposed Policy (CAG-00071R2)

UPMC CC and UPCI fully support the deeming process as an integral component of any clinical trial NCD. Echoing the comments of organizations including ASCO and AACI, we do not support the creation of a clinical research policy that does not include a deeming process consistent with the current NCD. While we are in favor of modifications to the current policy, the deeming process has provided Medicare beneficiaries access to clinical trials for nearly seven years in an effective and efficient manner. During that time the scope and quality of the clinical trials was appropriately evaluated by organizations well suited to the role. Removing the tested process of deeming and replacing it with a completely new process of self-certification would significantly undermine the advances made through the 2000 NCD.

In order to determine whether a clinical research trial will be covered by Medicare, we would like to propose that CMS use a combination of deemed trials and self-certification. Our suggestion is in keeping with the original NCD and represents the most appropriate means of certifying the requirements necessary for Medicare reimbursement. The following paragraphs will outline our recommendations on the thirteen standards (to be used for self-certification), the approval process, and implementation of the new policy.

Standards

A priority during the reconsideration process was to clarify the language and structure of the NCD, which presumably would result in widely understood criteria for coverage and well defined payment policies. The definitions included in the July 2007 proposed final rule do act to clarify many of the uncertainties from the original document. Unfortunately, the drastic departure to self-certification from the deemed qualified ruling for Medicare coverage provides a situation wrought with uncertainty.

We applaud CMS’ efforts to allow investigators the ability to certify their own trial as appropriate for coverage. Our concern is that the proposed self-certification process does not provide enough certainty that the trial will be covered and free from future penalty. If self- certification is implemented, we would recommend that CMS clearly state the actions that may be taken if a sponsor is found to be in violation of the self-certification process. At a minimum, the description should state what would constitute a punishable violation, who would be held responsible, and the corrective actions that may be taken.

Further, it is vital that clear and manageable standards are developed for self-certification to be a successful option. This sentiment is reflected in the original NCD:

From the 2000 NCD: Qualification Process for Clinical Trials …to develop qualifying criteria that will indicate a strong probability that a trial exhibits the desirable characteristics listed above. These criteria will be easily verifiable, and where possible, dichotomous. Trials that meet these qualifying criteria will receive Medicare coverage of their associated routine costs.

The thirteen standards proposed in the current decision are not easily verifiable or dichotomous once the burden of proof is considered. Further, the proposed system of approval operates without verification, other than a notice of completion, providing less certainty of coverage than the current Clinical Trial NCD.

With regards to specific standards (numbers correspond to bullet points in the proposal):

• Standard #1- #7: UPMC Cancer Centers and UPCI agree that the first seven standards are basic components of good clinical research. Additional guidance on what is required to satisfy these standards would be appreciated.
• Standard #8: We recommend removing this standard. It is not appropriate to require trials to specifically reference the Medicare specific standards in the protocol. We do support that all trials have a written protocol that is available for reference.
• Standard #9: The ninth standard should be removed. President Clinton’s original executive memorandum did not include any restrictions on the type of trial to be covered.
• Standard #10: UPMC Cancer Centers and UPCI support CMS’s effort to increase awareness of clinical trials and fully endorse registration of all trials (including deemed trials) on ClinicalTrials.gov. This could be insured by the requirement to place the web registration number on the claims instead of including the action as a standard.
• Standard #11: We recommend removing any time oriented reporting requirement from this proposal. The timing of release for results in a public forum is a difficult measure to administer and the trial proponent may fall short on this requirement through no fault of their own. If tracking of trials registered on ClinicalTrials.gov indicates a major issue with reporting the standard could be added at a later time with the weight of evidence as support.
• Standard #12: This standard should be removed as unnecessary. UPMC Cancer Centers and UPCI are active proponents for the inclusion of vulnerable or sub-populations in clinical trials and we do not believe that the clinical research policy is the appropriate forum to address the issues surrounding these groups.
• Standard #13: The final requirement on generalizability to the Medicare population should be removed from this policy. The standard has an understandable utility for the CMS administration; however, the requirement is unnecessary and could develop a cumbersome precedent if other insurers follow suit. Clinical research is conducted for the benefit of the entire population. It is impractical to attempt to tailor results to specific sub-groups unless the sub-groups are one of the focuses of the research.

UPMC Cancer Centers and UPCI would like to state that any requirement that trials be “powered” to draw specific statistical conclusions for sub- populations or the Medicare population should be avoided due to the additional burden on clinical trial design and completion. We would also recommend that standards are not created which address actions that are to occur after the initiation of the trial. The original Executive Memorandum issued by the President on June 7, 2000 asked that HCFA, now CMS, track clinical trials, collaborate with researchers on pertinent issues, and use the results to guide future NCDs. As originally spoken these items were not mandates to decide what research warranted coverage but guidance as to how the medical community and CMS could work together in advancing care for the elderly.

Approval Process

During the reconsideration process, CMS has vacillated between deemed status and self- certification, both intended components of the original Clinical Trial NCD. It is our recommendation that CMS return to the outline of the original NCD and implement both certification processes fully. The new policy should use the updated language, definitions, and structure developed though the recent reconsiderations. The result of this action would be a clear policy which includes both a deemed status for trials with federal approval and a self-certification process for non-federally supported research endeavors. Deemed qualifying research would be subject to the governance of the approving body which generated the deemed status not the CMS standards. This action would recognize that inclusion in a federally regulated activity requires compliance with the standards of good research while offering non-federal proponents the appropriate forum to gain Medicare participation. The deemed status could hold the caveat that the trial must be registered on ClinicalTrails.gov. for tracking purposes.

Specifically, trials would be deemed qualified for Medicare coverage if they meet one or more of the following criteria:

• Studies of health outcomes reviewed and funded by a program component of DHHS, the Veterans Administration, or the Department of Defense.
• Studies reviewed and approved by health care research centers or cooperative health care research groups, funded by one of the above Federal Agencies, provided that the Federal Agency reviews and approves the applicant research centers’ or cooperative research groups’ subcontract and sub-grant funding requirements, selection procedures and oversight methods, and determines that those processes provide the same level of protocol review as provide by the supporting Federal Agency.
• Studies conducted under an Investigational New Drug (IND) when the FDA has reviewed the study protocol and the IND is not currently on hold.
• The study is required and approved by FDA as a post-approval study.
• The study is required as an outcome of the NCD process using CED.

The deeming process provides a clear and efficient process for allowing Medicare beneficiaries to participate in appropriately regulated clinical research. We also recommend that IND exempt studies be a part of the deemed coverage on the basis that the study remains under the purview of the FDA even though full IND status is not required. When deeming is used in conjunction with the self-certification process the result is the most comprehensive research coverage proposed to date. We believe this a sound compromise between the all inclusive coverage described in President Clinton’s Executive Memorandum which authorized reimbursement for the routine costs of all clinical trials and the current NCD.

We would also support a move to institute the actions described in the President’s original directions for coverage of all routine clinical trial cost without a mention of the necessity to certify the trial. (See original Executive Memorandum found online at http://www.gpoaccess.gov/wcomp/index.html)

Implementation

The proposed policy includes several new requirements including additions to the protocol, new registration requirements, and new billing requirements. Large and small organizations will be required to update forms, processes, and systems which cross departments and may involve outside vendors. Further, CMS has proposed and removed new combinations of requirements at each evolution of this policy making it impossible to begin preparations for a transition. Due to these facts, it is our recommendation that the implementation of the policy take effect in the following manner:
1. A time period of six months is granted from policy finalization to implementation
2. All existing studies are grandfathered under the previous NCD guidelines
3. Proposals submitted for IRB review at the time of implementation are subject to the NCD in effect at the time of IRB submission
4. Changes to existing studies do not effect which NCD covers the study unless the sponsor or a representative wishes to update to the current NCD.
5. A requirement that Local Coverage Decision do not supersede the NCD

Medicare Advantage

In addition to our comments on the proposed NCD, we would like to again take this opportunity to note our continued focus on clinical research coverage for Medicare Advantage beneficiaries. We appreciate CMS recognition of the coverage issues surrounding Medicare Advantage beneficiaries in the discussion on the proposed NCD and the referral of the issue to the CMS organization responsible for administration of the Medicare Advantage Program. We request that, as the CMS organization responsible for the creation of the Clinical Research NCD, you would continue to actively engage CMS as a whole to resolve the coverage issues currently affecting Medicare Advantage. Specifically, there is a need for Medicare Advantage programs to directly cover the clinical research related care described in the NCD. The current system of switching the beneficiary to fee-for-service coverage for clinical trial related activities creates a cost barrier to participation and is confusing to patients and providers. The switch to fee-for-service places the beneficiary in an inconsistent state of medical coverage where they are paying for managed care benefits, receiving standard Medicare benefits, and not-eligible for Medi-Gap coverage to cover co-insurance.

The original Clinical Trial NCD made note of the requirement for the Medicare Advantage program (know as M+C in 2000) to cover items in NCDs. Further, the Balanced Budget Act provided a means for Medicare Advantage’s to transition into coverage of any NCD policy CMS might pass.

From the 2000 NCD: “Medicare Regulations require Medicare + Choice (M+C) organizations to follow HCFA’s national coverage decisions.”

Federal Register v.63, n.123, p. 35079 422.109(a) “If HCFA determines and announces that an NCD meets the criteria for “significant cost” described in paragraph (c) of the section, an M+C organization is not required to assume risk for the costs of that service until the contract year for which the annual M+C capitation rate is determined on a basis that includes the cost of the NCD service.” (Note: underline added for emphasis.)

Unfortunately neither provision was fully recognized, and a substitute payment structure involving a change in coverage was implemented. Please take this opportunity to incorporate all of the necessary changes in policy, financing and administration to make the proposed Clinical Research NCD a success at initiation by providing equitable access to clinical research for all beneficiaries of products carrying the Medicare name.

Final Thoughts

UPMC Cancer Centers joined with others during the last comment period in supporting the reconsideration of the current Clinical Trials NCD. We would like to thank CMS for clarifying existing components of the NCD as well as extending the coverage to a more diverse array of clinical research though the possibility of self- certification. Most importantly, however, we will provide a warning that a clinical research policy without deemed status will not work as proposed in this policy. We also remain adamant that CMS continue to work towards a resolution that allows Medicare Advantage beneficiaries access to clinical trials without an increase in financial responsibility or a change in coverage.

Sincerely,

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August 19, 2007

Steve Phurrough, M.D.
Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Department of Health and Human Services
Mailstop: C1-09-06
7500 Security Blvd.
Baltimore, MD 21244

RE: Proposed Decision Memo for Clinical Trials Policy (CAG-00071R2)

Dear Dr. Phurrough:

On behalf of the 2,300 members of the Society for Vascular Surgery (SVS), we offer the following comments on the Centers for Medicare & Medicaid Services’ (“CMS”) Proposed Decision Memorandum for second reconsideration of the National Clinical Trial Policy (hereinafter renamed the, “Clinical Research Policy”).

SVS appreciates CMS’ willingness to undertake a second reconsideration based on the concerns and issues that arose during the initial comment period. SVS members have been actively involved in many of the vascular surgical and endovascular device trials that fall under these regulations. Many of these trials are either company-sponsored, post-market clinical studies or IDE Category B investigations. Thus, while we support CMS’ goal in revising the Clinical Research Policy to expand access to new technologies and treatments for Medicare beneficiaries, we are also concerned about interpretation of the Proposed Revised Policy.

Category B Investigational Device Exemption (IDE) Trials:

SVS thanks CMS for explicitly calling out Category B IDE trials, with their own section in the new proposed policy. We believe that this specific section with the statement that this new policy does nothing to change CMS’ current and future processes established by the Carriers/Fiscal Intermediaries for granting coverage to Category B IDE trials will ensure that there is no confusion or disruption in coverage for devices in these trials.

Definition of “Usual Patient Care:”

We appreciate CMS clarifying “Usual Patient Care” as including both routine clinical services and the clinical intervention/service under investigation (assuming that service is ordinarily covered outside of a clinical trial), with identification of both as covered by Medicare under the clinical research benefit. However, we are concerned that the burden of adapting protocols to meet the standards for self-certification may result in discontinuation of some high-quality post-market studies.

With many of these studies being undertaken to provide technical assessments on device features, comparisons of analogous devices, procedure time, anesthesia requirements, quality of life, etc., the self-certification standards may be a barrier, particularly the specific time deadline for publication of results. Also, we are concerned that Medicare lacks the resources to undertake timely completeness reviews of all the company-sponsored, post-market trials currently in the planning process.

Self-Certification Process for Clinical Research:

SVS commends CMS for providing a well-defined process for all clinical research seeking coverage of the “Usual Patient Care” under this Medicare clinical research benefit. However, we would suggest the following:

August 17, 2007

Steve Phurrough, M.D., M.P.A.
Director of Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memorandum for Second Reconsideration of the Clinical Trial Policy, Renamed the Clinical Research Policy (CAG -00071R2)

Dear Dr. Phurrough:

On behalf of Cyberonics, Inc., thank you for this opportunity to comment on CMS’ July 19, 2007, Proposed Decision Memo for Second Reconsideration of the Clinical Trial Policy, renamed the Clinical Research Policy (CAG-00071R2). Please consider this comment and suggestion in connection with issuing a final decision.

We applaud CMS’ proposal to add FDA post-approval studies to the list of approved studies, however it is unclear if these studies will be appropriate under the proposed decision memo if the item or service is already the subject of a national non-coverage decision (NCD). We request that the final decision memo clarify this by confirming that FDA post-approval studies and registries are “approved studies” under the final Clinical Research Policy regardless of the existence of a non-coverage NCD.

Thank you again for the opportunity to comment on the proposed memo. We look forward to working with CMS for further guidance on these issues. Feel free to contact me for additional information.

Respectfully,

George Parker
General Manager

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Genentech, Inc.
Government Affairs
1399 New York Ave, NW, Suite 300
Washington, DC 20005
Phone: (202) 296-7272
Fax: (202) 296-7290

August 17, 2007

By Electronic Submission

Steve Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Mailstop: C1-12-28
7500 Security Blvd.
Baltimore, MD 21244

Re: Proposed Decision Memorandum for Second Reconsideration of the Clinical Trial Policy(CAG-00071R2)

Dear Dr. Phurrough:
Genentech, Inc. (“Genentech”) appreciates the opportunity to submit the following comments on the Proposed Decision Memorandum for Second Reconsideration of the Clinical Trial Policy(“CTP”), renamed the Clinical Research Policy(“CRP”) proposed by the Centers for Medicare & Medicaid Services (“CMS”).

Genentech is a leading biotechnology company focused on discovering, developing, manufacturing,and commercializing biotherapeutics that address serious unmet medical needs. Genentech has discovered and introduced over a dozen significant therapies for serious and life-threatening diseases affecting the lives of Medicare patients,including cancer, heart disease, pulmonary disease, rheumatoid arthritis, and age-related macular degeneration. Medicare coverage of clinical trials is critical to Genentech’s exploration of new therapies that may address unmet medical needs.

Genentech is pleased CMS is continuing its efforts to revise its existing CTP to address the considerable confusion that exists in the clinical research community and among beneficiaries about the scope of Medicare coverage for clinical trial sunder the current policy. Genentech provided comments on the April 10, 2007 Proposed Decision Memorandum and acknowledges that the current proposal addresses some of its concerns with the previous version.

We continue, however, to be concerned about the current proposal. In particular, we are concerned that CMS is, for the first time, taking the position that reasonable and necessary patient care will not be covered and reimbursed by Medicare if it is provided in a clinical trial that does not meet certain standards proposed byCMS. Such denial of usual patient care conflicts with the central purpose of the CRP to encourage participation in clinical trials by Medicare beneficiaries. In addition, Genentech is concerned that CMS lacks the legal authority to implement this change through the national coverage determination process. Genentech also believes that CMS should retain the current “deeming” process in the existing CTP for all, or at least some, clinical trials and that the self-certification process, if implemented, must be much more clearly defined. We believe the standards for clinical research proposed by CMS must be clarified so that they are objective and can be accurately self-certified by a sponsor at the time of certification in the event the self-certification process is adopted. Finally, we are concerned that the transition plan proposed by CMS is inadequate and will unnecessarily delay the initiation of clinical trials that are currently being, or will shortly be, reviewed by the U.S Food and Drug Administration (“FDA”) and institutional review boards (“IRBs”).

Genentech therefore proposes that CMS make the following modifications to the proposed CRP:

August 17, 2007

VIA E-MAIL AND U.S. MAIL

Leslye K. Fitterman, Ph.D.
Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Department of Health and Human Services
Mailstop: C1-09-06
7500 Security Blvd.
Baltimore, MD 21244

Re: Second Reconsideration of Clinical Trial Policy (CAG-00071R2)

Dear Dr. Fitterman:

The Pharmaceutical Research and Manufacturers of America (PhRMA) appreciates this opportunity to comment on the proposed decision memorandum of the Centers for Medicare and Medicaid Services (CMS) on Medicare’s Clinical Trial Policy. CMS released the memorandum July 19 as part of the agency’s second reconsideration of the current National Coverage Decision (NCD) on this policy. We also appreciate CMS holding an Open Door Forum on August 7 to provide further opportunity to receive information from the agency and provide stakeholder input.

PhRMA is a voluntary, nonprofit association representing the country''s leading research-based pharmaceutical and biotechnology companies. Our members are devoted to discovering new medicines that allow patients to lead longer, healthier, and more productive lives. PhRMA member companies invested nearly 80 percent of the overall biopharmaceutical company research and development expenditures of $55.2 billion in 2006. Through this investment, PhRMA’s member companies play a leading role in discovery of new therapies and advancement of scientific and clinical knowledge.

PhRMA appreciates the improvements that CMS has made in the July 19 proposed decision memorandum compared to the proposed decision memorandum it released April 10 in the prior reconsideration. For example, we support CMS’ inclusion of a provision making clear that ongoing research will remain covered under the agency’s existing clinical trial policy and clarification that items and services otherwise covered outside of a clinical trial will remain covered under the Clinical Research Policy even when they are the subject of the research study.

PhRMA also believes that, if properly designed and implemented, a self-certification process offers an effective, efficient mechanism for researchers to receive Medicare coverage for costs of clinical research. However, we believe substantial changes must be made in the policy to ensure that researchers have the confidence they need that costs of usual patient care can be covered by Medicare. Without this assurance, the policy will not achieve its goal of encouraging Medicare beneficiary participation in clinical trials and supporting continued medical advances for Medicare beneficiaries.

Goal of the Clinical Research Policy

Medicare’s current clinical trial policy was initiated with a strong patient-centered focus, premised on the belief that reimbursement of routine trial costs “can lead to breakthroughs in diagnostics, treatments, and cures for many of the most devastating diseases afflicting millions of Americans . . .” Over the nearly seven years that Medicare’s current clinical trial policy has been in place, it has proved an important tool in encouraging beneficiary enrollment in clinical research on promising interventions. While PhRMA supports the efforts of CMS to modernize and clarify its existing policy, we urge the agency not to lose sight of the overarching goal of supporting beneficiary access to clinical research and continued medical innovation.

The July 19 policy describes narrower, more restrictive goals that would be less conducive to supporting Medicare beneficiary participation in clinical trials. In particular, CMS says one goal of the proposed new policy is the encouragement of studies that “will generate evidence that can be used for determining Medicare coverage . . .” CMS also describes the policy as extending “Medicare coverage only to clinical research that is likely to result in evidence that we would accept to demonstrate that the specific interventions are reasonable and necessary.”

In order to encourage Medicare beneficiary access to clinical trials of promising medical technologies and therapies, we recommend that, in Section III of the memorandum, CMS adopt language consistent with the original intent of the 2000 policy, to state that the agency is extending “Medicare coverage to clinical research that is likely to result in evidence that advances medical knowledge or medical technology that improves the health and well-being of Medicare patients.”

Specific Comments

1. Legal Authority Issues
As currently drafted, the proposed Clinical Research Policy would apparently deny Medicare coverage for otherwise-covered items or services, if they were furnished to Medicare beneficiaries who enrolled in a research study that fell within the policy’s scope but was not self-certified. We urge CMS to renounce that approach, which would exceed CMS’ legal authority, and instead to make clear that the policy does not withdraw coverage for any items or services that Medicare covers outside of the research context. Under the Medicare statute, the program’s beneficiaries are entitled to coverage for healthcare items and services that fall within a Medicare benefit category, are not statutorily excluded from coverage, and are reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.

We recognize that CMS also has authority (under SSA § 1862(a)(1)(E)) to cover additional items and services that are reasonable and necessary to carry out certain research. However, this provision permits CMS to promote research-related goals by expanding coverage to certain services that are not reasonable and necessary to diagnose or treat illness or injury; it does not permit CMS to promote research-related goals by withdrawing coverage for services that do meet the reasonable and necessary standard. Consequently, CMS may not deny coverage of a reasonable and necessary service, otherwise covered by Part A or B, merely because the beneficiary receives that service as part of a clinical research study that does not meet the Clinical Research Policy’s standards. There is no authority to deny coverage on these grounds, and doing so would both arbitrarily penalize Medicare beneficiaries who had enrolled in a clinical research study and discourage most beneficiaries from enrolling in research. Accordingly, CMS should reverse course on this issue, recognizing the legal and practical problems inherent in a policy that sought to promote research by asking Medicare beneficiaries enrolled in research to forfeit coverage for care that normally would be Medicare-covered.

We also note that the NCD process is confined to decisions about whether “a particular item or service is covered nationally” and thus is not properly used for developing broad policies governing coverage of the full spectrum of items and services that may be needed by clinical research participants. We recommend that CMS consider whether other mechanisms, such a guidance or rulemaking, are more appropriate for establishing new policy in this important, broadly defined area. However, regardless of the approach taken, CMS should ensure that the policy does not deny a Medicare beneficiary coverage of otherwise-covered, reasonable and necessary services merely because the beneficiary has enrolled in certain research. CMS should abandon this approach and advance its research goals by using the tools available to it to expand coverage. By doing so, CMS can more effectively promote the goals of covering costs of usual patient care in clinical trials within the legal framework established by the Medicare statute.

2. Retain “Deemed” Status as a Decisional Pathway

Under current policy, Medicare recognizes that certain trials supported by or subject to regulation by designated federal agencies are “automatically qualified” for coverage because they are “deemed” as “highly likely to have . . . desirable characteristics of clinical trials.”

In addition to this decisional pathway for “deemed” trials, current policy envisions a separate and distinct approval process for coverage of other clinical trials. This second pathway calls for development of qualifying criteria to help determine whether a non-deemed trial exhibits desirable characteristics and therefore should be covered. In this second pathway, coverage is available “after the trial’s lead principal investigator certifies that the trial meets the criteria.”

Though the current policy clearly contemplates an approval process based on qualifying criteria and self-certification, Medicare, over the last seven years, has been unable to implement it. Given the inherent difficulties in establishing this type of process, PhRMA recommends that CMS not attempt to implement such a process on the rapid timetable the agency proposes. This certainly should not be tried as CMS simultaneously proposes to terminate the “deemed” process, which has been implemented successfully.

No Basis in Record for Terminating “Deemed” Status

In the first reconsideration of the Medicare clinical trials policy (CAG-00071R), CMS noted that its proposed decision memo took into account recommendations developed by the Medicare Evidence Development and Coverage Advisory Committee and a Federal Panel convened by the Agency for Healthcare Research and Quality, as well as 2006 comments submitted by stakeholders. Based on this record, the CMS proposed decision memo retained “deemed” status as a pathway for approving coverage for a clinical research study. After considering additional stakeholder comments, CMS issued a final decision memo. Nothing in this final decision memo altered the availability of “deemed” status as a basis for coverage approval.

In the current reconsideration, the CMS proposed decision memo states:“During the last reconsideration of this policy, it became apparent that significant confusion existed about the deeming process and whether non-Federally funded trials were exempt from this process.”

Even assuming the confusion that CMS references, PhRMA is unaware of anything in the public record that could justify terminating the deeming process itself. As such, there is no justification for discarding “deemed” status as a basis for Medicare coverage of clinical research.

The deeming process remains an effective, efficient mechanism for qualifying federally funded or regulated research for Medicare coverage. CMS should retain “deemed” status in its current form. If the agency believes rulemaking is required to accomplish this, then such a rulemaking should proceed as quickly as possible and that “deemed” status, as currently structured, not be altered prior to the effective date of any new regulation.

3. Establish Clear, Objective and Practical Standards for Self-Certification

As noted above, Medicare, over a period of nearly seven years, has been unable to establish qualifying criteria or to implement a self-certification process. This reflects the substantial difficulty of establishing clear, workable Medicare standards in the area of clinical research.

The challenges inherent in developing sound standards were illustrated at the August 7 Open Door Forum held by CMS, at which stakeholders and agency staff noted the difficulties of establishing clear definitions for standards such as research that does not “unjustifiably duplicate existing studies.” Without clear definitions, certifying compliance to such standards requires a judgment call that is very difficult to make and could easily be second-guessed (thus posing potential liability risks). Similarly, some of the standards in the draft policy are problematic because they would call for certifications regarding future events or other matters that may be outside the control of the certifying party.

As a result of these problems in the current language of the certification, the legal risks associated with executing the self-certification could deter prinicipal investigators and sponsors from doing so. No matter how carefully and responsibly they acted, certifying parties could be vulnerable to charges of violating the civil False Claims Act (31 U.S.C. 3729 et seq.) by submitting to CMS a certification with the sort of ambiguities and other defects contained in the current standards. The penalties for violating this statute are significant, and the costs and disruption involved in defending against a False Claims Act suit (which can be filed by private citizens as well as the government) are themselves large. Study sponsors and investigators who are acting in good faith should not be put in a position where they be may be exposed to such risks in a policy intended to encourage beneficiary enrollment in clinical trials. .

In the absence of revised standards that eliminate ambiguous language and language about matters outside the certifying party’s control, PhRMA is concerned that potential study sponsors and/or principal investigators could be unable to execute the certification – a result that would reduce enrollment in studies by Medicare beneficiaries, thereby defeating the very objective that the 2000 policy was designed to achieve.

The 13 standards proposed by CMS for clinical research must be modified so that they establish clear, objective standards as the basis for a workable self-certification process. First, PhRMA recommends that CMS provide a clear definition of the term “sponsor” in the CRP policy. Unlike the existing clinical trial policy, in which self-certification would have applied to principal investigators, the July 19 draft policy refers to “the study sponsor/principal investigator” certifying to CMS that the standards in the policy “have been met.” CMS should clarify this definition in its final policy.

In addition, CMS should ensure that the clinical research standards it establishes relate to the actual role of study sponsors. For example, the proposed policy would require study sponsors to be “capable of executing [the research] successfully.” However, study sponsors in many instances do not carry out research themselves but instead rely on clinical institutions and investigators to conduct the research. As a result, this standard as proposed could mean that many sponsors of IND trials could not certify compliance.

We appreciate the clarification made by CMS officials at the Aug. 7 Open Door Forum on the desired level of detail for certification submissions. We recommend that the agency develop a template or model certification letter to provide further, needed clarity on the level of detail and type of content required.

CMS also should make changes to several specific standards it proposes. PhRMA provides the CMS-proposed language and recommended revisions to each of the standards below.

1) Proposed standards #1 and #9 should be modified and combined to clarify the types of studies that qualify, particularly for Phase I clinical trials, for which current language could be confusing.

Current proposed standard #1: The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes.

Current proposed standard #9: The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Studies of all medical technologies measuring therapeutic outcomes as one of the objectives, may meet this standard only if the disease being studied is life threatening as defined in 21 C.F.R. § 312.81(a) and the patient has no other viable treatment options.

Suggested revision: For a research study that is not a Phase I study, the principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes or to compare the outcomes of interventions evaluated in the study. For a Phase I study, the study must be designed to not only test toxicity or disease pathophysiology in healthy individuals; but also to measure at least one therapeutic outcome as a primary or secondary end-point in a disease or condition defined as life-threatening in 21 C.F.R. § 312.81(a).

2) Because the purpose of research is to address gaps in scientific or medical knowledge, the second proposed standard should be revised to make clear that it is the rationale or study hypothesis that must be well-grounded in current medical information and knowledge.

Current proposed standard #2:The research study is well-supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use.

Suggested revision: The rationale for the end-point or hypothesis being tested in the research study is well-supported by available scientific and medical information, or the study is intended to clarify or establish the health outcomes of interventions already in common clinical use.

3) Ensuring that research “does not unjustifiably duplicate existing studies,” as required in proposed standard three, is a sound goal. However, as noted above, it is very difficult to craft a standard to meet this goal that is clear and objective and based on factors that are under the control of the certifying entity.

Current proposed standard #3
The research study does not unjustifiably duplicate existing studies.

Suggested revision: The research study has been designed with a goal of not duplicating identified existing studies, except to the extent justified by scientific or regulatory considerations.

4) Current proposed standard #4
The research study design is appropriate to answer the research question being asked in the study.

Suggested revisions: The research study design has been evaluated by the sponsor and/or principal investigator to assess whether it is appropriate to answer the research question being asked in the study and is considered appropriate for this purpose.

5) As described above, CMS’ research standards should clarify the roles of study sponsors and those executing the research as they relate to the need for expertise to conduct the research.

Current proposed standard #5
The research study is sponsored by an organization or individual capable of executing the proposed study successfully.

Suggested revisions:The research study is sponsored by an organization or individual capable of executing the proposed study successfully (or is sponsored by an organization that has engaged clinical institutions and investigators considered capable of executing the proposed study successfully).

6) Standards #6 and #7 should be revised so that they address factors under the control of the certifying entity at the time of certification. PhRMA agrees that it is essential that all research is performed to the highest standards of scientific integrity. However, sponsors of trials may not be in a position to ensure that study investigators will always carry out all of the standards that are in trial protocols.

Current proposed standard #6:The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46. If a study is FDA-regulated, it also must be in compliance with 21 CFR Parts 50 and 56.

Suggested revisions:The research study has been designed to comply with all applicable Federal regulations concerning the protection of human subjects found at 45 C.F.R. Part 46, and (if an FDA-regulated study) to comply with 21 C.F.R. Parts 50 and 56.

Current proposed standard #7:All aspects of the research study are conducted according to the appropriate standards of scientific integrity.

Suggested revisions:All aspects of the research study have been designed so that the study may be carried out in accordance with the appropriate standards of scientific integrity.

7) Proposed standard #8 would require research studies to have protocols that clearly address or incorporate by reference the Medicare standards. This criterion is redundant with the rest of the proposed policy and should be deleted.

8) As noted in our May 10 comments on CMS’ first reconsideration of the Clinical Trial Policy, PhRMA supports appropriate public disclosure of clinical trial results. We appreciate the modifications proposed by CMS in its second reconsideration in response to public comments. However, further changes should be made to ensure that this requirement is clear and practicable. For example, revisions are needed so that, for research used to support an FDA premarket application, timelines for public release of data are in step with FDA action on the premarket submission. Similarly, the standard should be modified to recognize that matters involving publication and release of data are not usually addressed in the study protocol.

Current proposed standard #11
The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. However, a full report of the outcomes must be made public no later than three (3) years after the end of data collection.

Suggested revisions: The research study protocol specifies the plans of the study’s sponsor or principal investigator regarding the method and timing of public release of all pre-specified outcomes to be measured, including release of outcomes if outcomes are negative or the study is terminated early. Such plans must anticipate that the results will be made public within the latest of the following timeframes: (1) 24 months of the end of data collection; (2) three years after the end of data collection, if a report is planned to be published in a peer-reviewed journal, provided that an initial release of such as an abstract that meets the requirements of the International Committee of Medical Journal Editors is planned within two years after the end of data collection; or (3) if the study concerns a new product subject to FDA approval (or an FDA-approved product for which a new FDA-approved indication is sought), promptly after FDA’s approval of the product or new indication. It is recognized that the ability of a study sponsor to make public the results of a study depends on cooperation by study investigators.

9) The research standards also should be modified to clarify CMS’ expectations in regards to how study protocols addresses subpopulations affected by the treatment under investigation.

Current proposed standard #12: The research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria affect enrollment of these populations, and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary.

Suggested revisions: The research study protocol or related materials explicitly discuss any clinically relevant subpopulations affected by the treatment under investigation (particularly groups traditionally underrepresented in clinical studies), how the inclusion and exclusion criteria may affect enrollment of these subpopulations, and any plans that exist for retaining such subpopulations in the trial and/or for reporting outcomes specific to such subpopulations. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented subpopulations considered clinically relevant, the protocol or related materials must discuss why these criteria are necessary.

4. Improve the Self-Certification Process

In addition to revising the proposed standards for clinical research, CMS should define open, transparent procedures for study sponsors and principal investigators to certify their compliance with the standards. Specifically, the final NCD should provide for the following:

1) Process for obtaining additional guidance: CMS should describe an open, transparent process under which guidance will be provided to study sponsors/principal investigators on how they should interpret the clinical research standards.

2) Responses to submissions: CMS should include a clear process for responding to certifying entities to notify them that their certification is either considered complete or not considered complete, so that the process is more predictable.

3) CMS determinations that a study does not meet the clinical research standards or that a study jeopardizes health and safety: The clinical research policy should clearly describe the criteria that the CMS chief medical officer will use to make these determinations. It also should provide a mechanism for study sponsors and principal investigators to provide input into these determinations and to request reconsideration/appeal. Finally, any CMS chief medical officer decision that a study does not meet the clinical research standards or jeopardizes health and safety should only apply prospectively and should not call into question the propriety of Medicare coverage of usual patient care previously covered for study participants.

4) Amendments to certifications: CMS also should implement a mechanism to allow study sponsor and principal investigators to amend certifications during the research, as study protocols and the state of medical knowledge can change in ways that could affect the certification.

5) Transition period: PhRMA appreciates CMS’ provision for a clear transition period from the current Clinical Trial Policy to the new Clinical Research Policy. This transition period should be extended until additional rulemaking and guidance related to the policy are in effect. This will ensure that sponsors and researchers have a clear understanding of the new standards when they go into effect and minimize the potential for confusion, which could have the effect of discouraging Medicare beneficiary enrollment in clinical trials.

To ensure a clear, workable final policy with an orderly transition, CMS should, if it continues to use the NCD process as the mechanism for establishing the policy, take the time to carefully consider the public comments submitted in response to the proposed decision memorandum on this complex issue, including input it will receive at the upcoming CMS Town Hall meeting on September 20. In order to do this, CMS may need to wait more than 60 days after the close of the comment period. The 60-day deadline for final decisions on NCDs derives from section 1862(l)(3) of the Act, which sets forth various time periods for action on “requests” for NCDs. The term “request” does not reasonably apply to a self-initiated proceeding, such as the current reconsideration of the clinical research policy. Moreover, under section 1862(l)(3)(A), the legally permitted time period of six or nine months for the proposed decision begins “on the date a request for a national coverage determination is made. . . .” In the case of an internally initiated proceeding, there would be no such date, thus further demonstrating that “request” in the statute refers only to external requests. In light of the broad and significant impact of the proposed CRP policy, CMS should warrant a longer, fuller consideration of the issues, and CMS’ should exercise its discretion to provide a longer, fuller consideration of the issue.

5. Make Technical Improvements in Revised Policy

PhRMA recommends the following additional revisions in CMS’ proposed clinical research policy:

a. Local Coverage Determinations CMS should revise Section 7 of the proposed policy to ensure that it maintains local Medicare contractors’ discretion to cover items and services outside of the confines of the clinical research policy. It is very important for CMS to maintain this avenue for Medicare beneficiaries to gain access to medically appropriate items and services. PhRMA urges CMS to include language on local coverage determinations that the agency proposed in the previous reconsideration of the clinical trials policy. This provision stated: “This policy does not withdraw Medicare coverage for items and services that may be covered according to local coverage determinations (LCD). For information about LCDs, refer to http://www.cms.hhs.gov/Medicare/Coverage/DeterminationProcess/04_LCDs.asp#TopOfPage, a searchable database of Medicare contractors’ local policies.”

b. Definition of “Usual Patient Care”

Based on our understanding of the agency’s intended policy, we recommend that the section 1 definition of “usual patient care” be amended to read as follows:

“Usual patient care includes the following:

August 17, 2007

Steve Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Department of Health and Human Services
Mail Stop C1-12-28
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memorandum for Second Reconsideration of the Clinical Trial Policy, Renamed the Clinical Research Policy (CAG-00071R2)

Dear Dr. Phurrough:

The Heart Rhythm Society (HRS) appreciates this opportunity to comment on the Centers For Medicare & Medicaid Service’s (CMS) proposed policy titled Proposed Decision Memorandum for Second Reconsideration of the Clinical Trial Policy, Renamed the Clinical Research Policy (CAG-00071R2) (Hereafter, referred to as The Proposed Policy).

HRS is the international leader in science, education, and advocacy for cardiac arrhythmia professionals and patients. Representing more than 4,500 specialists in cardiac pacing and electrophysiology, HRS is committed to being the primary information resource on heart rhythm disorders. Our members are dedicated to discovering and providing new and effective therapies that allow Medicare patients to lead longer, healthier, and more productive lives. HRS’ members perform electrophysiology studies and curative catheter ablations to diagnose, treat, and prevent cardiac arrhythmias. Electrophysiologists also implant pacemakers and implantable cardioverter defibrillators (ICDs) in patients who have indications for these life-saving devices. After device implantation, physicians continue to monitor these patients and their implanted devices. As part of CMS’ Coverage with Evidence Development (CED) policy, HRS continues to spearhead the ICD RegistryTM effort to obtain high quality, real-world data for Medicare patients receiving ICDs.

We support the objective to ensure that all sponsors and investigators conduct valid research that is designed to maximize health outcomes and minimize risk for Medicare beneficiaries. Specifically, we support the thoughtful standards for clinical research that were enumerated in the proposed decision memo for Clinical Trial Policy of July 19, 2007. We have no objections to the intent of these criteria, but we are concerned about legitimate differences of interpretation of the stated requirements in The Proposed Policy. Accordingly, we offer the following comments for your consideration.

HRS urges CMS to:

August 17, 2007

Steve Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, Maryland 21244-1850

ELECTRONICALLY SUBMITTED

Re: Clinical Research Policy CAG-00071R2

Dear Dr. Phurrough:

Medtronic, Inc. is one of the world’s leading medical technology companies specializing in implantable and interventional therapies that alleviate pain, restore health, and extend life. We are committed to the continual research and development necessary to produce high quality products and to support innovative therapies that improve health outcomes.

Medtronic supports the goal of ensuring Medicare beneficiaries have timely access to high quality clinical research thereby improving the available evidence for better physician and patient decision-making. We recognize the value of evidence-based approaches and the need to invest in robust clinical and economic evidence to ensure appropriate dissemination of life-saving and life-enhancing therapies to patients. We also agree that such research should be designed and conducted with scientific and ethical integrity, offering protections for the safety of human subjects.

We therefore appreciate the thought that CMS has given to the establishment of scientific and technical standards for clinical research and the opportunity to provide comments on the Centers for Medicare and Medicaid Services (CMS) proposed National Coverage Determination (NCD) for the Medicare Clinical Research Policy (CRP). At the outset, we are pleased CMS has proposed an appropriate transition policy to ensure that ongoing clinical studies can proceed without interruption. We believe this transition policy preserves beneficiary access and sustains critical evidence generation of ongoing clinical research. In addition, Medtronic is pleased CMS has also proposed to maintain contractor discretion in determining coverage for Investigational Device Exemptions (IDEs) and Humanitarian Use Devices (HUDs) with a Humanitarian Device Exemption (HDE). We appreciate CMS’ efforts to provide clarity in these and other areas of the policy.

While we wholeheartedly support the goals of the NCD for CRP, we are very concerned that CMS lacks the legal authority to use the NCD process to make coverage of usual patient care in clinical studies of already covered items and services contingent upon sponsor-certified compliance with the policy requirements. We note that Medtronic and other stakeholders urged CMS not to proceed with the NCD process, but look to other means. While we once again urge CMS to consider an alternative approach, we recognize that the proposed decision memorandum evidences CMS’ position to use the NCD process to implement its clinical research policy. We have a number of concerns regarding this proposal. Our concerns, along with very specific recommendations to address them are focused in the following areas:

I am pleased to submit comments on the Proposed Decision Memorandum for Second Reconsideration of the Clinical Trail Policy, renamed the Clinical Research Policy (CAG-00071R2). My comments are provided on behalf of the University of Pittsburgh Medical Center (UPMC).

On June 7, 2000 the President issued an executive order directing Health and Human Services to explicitly authorize Medicare payment of routine patient care costs and costs due to medical complications associated with participation in clinical trials. The intent was to encourage greater use of clinical trials by older Americans. While the proposed Clinical Research Policy National Coverage Determination (CRP NCD) generally supports reaching this goal, modifications should be made to further support this goal.

To be effective, the CRP NCD should provide clear, reasonable guidelines that can be implemented with minimal additional cost to the health care system. The policy must address the responsibilities and liabilities of the researchers (sponsors and investigators) and the providers of service. The policy must not serve to slow the progress of clinical research by adding administrative hurdles and placing providers of care at increased risk when they provide services to participants in clinical research.

The following is a discussion of specific sections of the proposal and suggestions for changes.

Standards
We agree with CMS’ statement that “appropriate study design is critical to ensure that not only are participants in research studies exposed to the least risk possible, but also to ensure that the results from the study will be useful in improving healthcare delivery” . We think that the process outlined in the proposal can be simplified and still meet this standard.

Section C of the Memorandum sets forth thirteen standards of clinical research that must be met for a study to qualify for Medicare payment. The proposal does not include the previous option of “deeming” a study based on it being funded by various agencies and organizations. We propose that these deeming criteria be retained and that the thirteen standards for certification only be applied to studies that do not meet the deeming criteria. Additionally, some of the thirteen standards should be clarified, modified or eliminated. Below is a redlined version of this section of the proposal with comments and suggestions.

“Medicare will cover items and services furnished through clinical research only when the following standards are met:

1. The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes

2. The research study is well-supported by available scientific and medical information or it is intended to clarify or establish health outcomes of interventions already in common clinical use.

Please clarify by providing criteria or further guidance how this standard may be met.

3. The research study does not unjustifiably duplicate existing published studies.

Again, please clarify how what is needed to meet this standard.

4. The research study design is appropriate to answer the research question being asked in the study.

5. The research study is sponsored by an organization or individual capable of executing the proposed study successfully.

6. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46. If a study is FDA regulated, it also must be in compliance with 21 CFR Parts 50 and 56.

This is a good standard however studies that have been reviewed and approved by an Institutional Review Board (IRB) should meet this standard. A statement that the research has such IRB approval should be sufficient.

7. All aspects of the research study are conducted according to the appropriate standards of scientific integrity.

8. The research study has a written protocol that clearly addresses or incorporates by reference the Medicare standards.

This standard will require additional effort with little value added. An IRB approved study will have many of these elements already.

9. The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. This may include Phase I studies that have therapeutic intent as one of its objectives. Studies of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is chronic, life-threatening or severely debilitating as defined in 21 CFR 312.81(a) and the patient has no other viable treatment options.

10. The clinical research study is registered on the ClinicalTrials.gov website by the study sponsor/principal investigator prior to the enrollment of the first study subject.

This may pose some logistical problems that should be addressed. It is possible for a study to be registered multiple times? If this results in multiple numbers for the same study, will all be accepted on Medicare claims? How much time does it take to register – are numbers provided quickly?

11. The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. However a full report of the outcomes must be made public no later than three (3) years after the end of data collection.

It is difficult to predict when and where the results of a study will be published. This standard places the investigator in the position of making a promise that s/he may not be able to keep. Additionally, what happens if the study is not published? It is not appropriate to penalize the provider by retrospectively taking back payment for services rendered during the study if publication doesn’t occur as planned. This standard will be difficult to administer.

12. The research protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria affect enrollment of these populations and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary

This standard should be deleted or significantly modified. This issue is often addressed in the IRB review process. At most, CMS could ask for a representation from the sponsor or principal investigator that the study is not discriminatory toward potential participants in its design.

13. The research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility. ”

This is potentially burdensome and duplicative. Study protocols generally address the rationale for the study and what types of individuals may benefit from the study results.

The following language (from the April 2007 proposal with a clarification) should be added to the policy so that the deeming process continues:

“The following processes will assure that the general standards of scientifically and technically sound clinical research study are met and assure that the research is conducted with AHRQ support pursuant to section 1142 of the Act. Therefore, clinical research studies will be “deemed” to have met the standards in the policy.

The American Medical Association (AMA) appreciates the opportunity to comment on the Proposed Decision Memorandum for Second Reconsideration of the Clinical Trial Policy, Renamed the Clinical Research Policy (the Policy) (CAG – 00071R2). In general, the AMA welcomes clarification of the Policy that governs National Coverage Determinations for Medicare beneficiaries participating in clinical trials, but has a number of concerns with the proposed changes and the process utilized to revise substantive aspects of the Policy. Below we have outlined our comments.

Deeming and Federally Funded Clinical Trials.
The agency has deemed federally funded trials as Medicare-covered since establishing its initial clinical trials policy, published in 2000. In this proposed decision memorandum, the agency is now proposing to do away with deeming and set-up a single self-certification process for federally and privately funded research. The proposed Policy represents a marked departure from existing policy. Although the agency has indicated that a single process applicable to both federally and privately funded clinical trials would simplify the process, instead it would create additional regulatory burdens on federally funded clinical trial sponsors, the agency, and beneficiaries. Sponsors of federally funded clinical trials are already subject to rigorous clinical research standards and oversight. The self-certification process outlined in the proposed memorandum is duplicative of existing requirements for federally funded clinical trials. In addition, requiring federally funded clinical trials to meet redundant requirements will delay the initiation of clinical trials and add to the resources required by the agency to meet its review and reporting obligations. Furthermore, there is ambiguity in the current proposed decision memorandum as to who is responsible for submitting the requisite certification in the context of multi-state and investigator clinical trials. This problem is alleviated where federally funded clinical trials are deemed to meet the standards.

Clinical Trial Studies of Medical Technologies and “Life-Threatening” Standard.
We are very concerned with the modification of the clinical research study standard that provides that studies of medical technologies meet the standard “only if the disease or condition being studied is life-threatening as defined in 21 C.F.R. section 312.81(a) and the patient has no other viable treatment options.” The prior language offered by the agency stated that conditions or diseases that are “chronic, life threatening, or debilitating” would meet the standard. We urge CMS to adopt the latter language because the most recent iteration would significantly reduce the access that Medicare beneficiaries have to clinical trials. In addition, the language contained in the memorandum is not consistent with the language contained in the cited regulation.

“Unjustifiably Duplicates Existing Studies” Standard.
We are concerned that the proposed standard that clinical trials “not unjustifiably duplicate existing studies” may undermine efforts to confirm the validity of scientific findings, and also net the unsuspecting who, despite good faith efforts, are unaware of “duplicate” studies. First, it can be difficult to judge when research “unjustifiably” duplicates existing studies. Second, studies with similar designs may produce significantly different and valuable results. We recommend clarification of this standard to account for the benefits that may be gained from similar studies and contain a proviso for those who engage in good faith efforts to ensure no unintended duplication occurs.

“Scientific Integrity” Standard.
The agency has proposed a standard that “[a]ll aspects of the research study are conducted according to the appropriate standards of scientific integrity.” However, the memorandum does not specify what the scientific integrity standards are and how they would be met or evaluated. Also, this standard conflates Medicare payment policy with scientific standards. We recommend removing this standard altogether; or, at a minimum, the standard should be clarified and more guidance provided to ensure compliance.

“Public Release of Outcomes” Standard.
The proposed determination memorandum includes a standard governing the public release of study outcomes including publication within a specific time frame. While public dissemination is important, there are no assurances that reports submitted by sponsors for peer-reviewed publication will, in fact, be accepted. Furthermore, in the absence of peer review, posting of the outcomes or results in summary fashion may not be sufficiently informative for patients and/or clinicians, and opens the possibility that such a document may be misleading. We recommend that this standard be deleted, as it has nothing to do with the scientific rigor of the trial or its conduct, or the rationale for covering clinical services.

Local Coverage Determinations.
The Policy would continue to allow local coverage determinations to impact the coverage of services in clinical trials. The National Coverage Determination should, at a minimum, serve as a “floor.” Local coverage determinations add another layer that needlessly creates confusion and may adversely impact the integrity of a clinical trial to the extent beneficiaries who would otherwise be equally situated may have outcomes impacted as a result of variance in local coverage determination(s) in multi-state clinical trials. The proposed decision memorandum should be clarified to address this issue.

Beneficiary Participation in Non-Approved Clinical Trial & Coverage.
Currently, CMS policy provides that when a beneficiary enrolls in a clinical trial that has not been approved, no services are covered even if they would be covered had they not been enrolled in the clinical trial. This is unduly punitive to beneficiaries and is not consistent with the statutory language that Medicare covers services that are reasonable and necessary “for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.” We urge CMS to revise this policy in the final decision memorandum.

Medicare Secondary Payor and Medicare Advantage.
The agency has yet to address coverage and payment issues in the context of clinical trials in two other separate areas: Medicare Secondary Payor policy and Medicare Advantage plans. There is significant confusion as to how the agency’s Medicare clinical trial policy impacts payment and coverage in these two areas. There is a need to harmonize these policies, clarify gray areas, and resolve outright conflicts. We urge the agency to adopt an integrated policy discussion. As the number of beneficiaries in MA plans has grown, it has become increasingly important that the agency augment existing policy in this area in particular.

Posting Self-Certification.
If the agency adopts the self-certification process in final decision memorandum, the AMA urges the agency to post this information on the web within 15 days of receipt of a complete letter. Sponsors will not be willing to enroll Medicare beneficiaries until they are assured that the study will be covered. Any agency delays in making this information public will be detrimental to beneficiaries. The agency should also publish a quarterly compilation in the Federal Register of new certification information that has appeared on its web site.

Rulemaking.
The significant substantive changes to Medicare coverage of services that are reasonable and necessary “for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member” in the context of clinical trials, warrants utilization of a process whereby the agency is able to solicit a broad level of public comment and feedback. We urge the agency to utilize the notice of proposed rulemaking process, and allow for an additional comment period before issuing a final rule. The current process allows a mere 30-days for comment and almost immediate implementation. This is not adequate to consider the issues and has limited the stakeholders who are aware of proposed changes. More importantly, use of the National Coverage Determination mechanism may create unnecessary hardships and/or confusion because it would become immediately enforceable and an adequate transition period would be lacking.

The AMA appreciates your consideration of our comments.

Sincerely,

Michael D. Maves, MD, MBA

Less

CAG-00071R2
I very much appreciate the opportunity to comment on the proposed clinical research policy. As a member of the provider community working with research coverage issues, I want to be sure that I am providing correct claim information to CMS for Medicare beneficiaries in clinical research studies.

USUAL and ROUTINEDoes CMS consider "usual and routine" within a clinical trial to mean an individual physician''s usual and routine testing practices outside of a trial? How do national guideline (ie, NCCN, ACC, etc) recommendations apply? What about "Standard of Care"? Examples:
* A routine ECG is included as part of screening tests for an Oncology drug study and no cardiotoxic drug is involved. My assumption is that the NCD for ECGs would govern in this case and that it is not a covered benefit because it is a screening test.
* Frequency of CT scans in the multiple years of follow-up for a lung cancer patient presents another question. The protocol requires chest/abdomen /pelvis CTs every 3 months for 2 years, then annually. The NCCN guidelines may recommend chest/abdomen CTs every 6 months for 2 years and after that only when there are signs or symptoms exhibited by the patient. What does CMS consider usual and routine in this case? How do I decide what is covered and billable?
*A physician routinely sees post-treatment cancer patients for surveillance every 3 weeks. NCCN guidelines indicate visits every 3 months. The physician views the 3-week interval as his standard of practice. What does Medicare consider routine to be in this case? Are all the visits billable?

Currently when evaluating a research protocol for Medicare coverage, the first place I go is to the CMS website for NCDs and LCDs. Then I look for guidelines written by groups and societies. Absent guidance from these sources, I review the practices of the physician PI. Is that the hierarchy that I should continue to use or has the individual physician''s routine practice become the most important consideration, the standard to follow?

IDE# TRIALS
Several times the phrase "includes all clinical research" appears in the memorandum. I heard Dr. Phurrough say at the Open Door Forum that IDE# trials will not be covered under this CRP. Using the word "all" gives the impression that IDE# device trials are included. My understanding has been that they are excluded from the 2000 CTP unless there is federal funding. Yet I have many discussions with device sponsors who quote the policy because thay believe it applies to their IDE devices. Are the IDE# trials covered under both the Category B regs and the existing CTP or the new CRP? To be covered under this new CRP would they not have to have their protocols certified by CMS?

PROVIDERS
Dr. Phurrough mentioned several times that providers will only have to be concerned that the correct NCT number and modifiers are on the claim. Does this mean that providers will be held “harmless” when they bill a CMS certified protocol-required surveillance CT every 3 months on an asymptomatic patient? Or are we to be following other rules and guidelines as well?

TRIALS
* Will the Oncology Co-OP Studies go through the certifying process once or will each group (ie CALGB, ECOG) be required to submit it?
* How will IND-exempt studies become certified? Will there be some other mechanism?
* Will drug and device Post-Market Approval trials be required to be certified?

Will any of the above trials qualify for Medicare coverage if they are not certified by CMS? Will they have to be identified as clinical trials if they don''t have CMS certification or are not listed on the clinicaltrials.gov website? I would like to see CMS add self-certification without replacing the current "deemed" status categories.Your guidance is very much awaited. Sincerly,Laurel Henschel RN

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August 17, 2007

Steve Phurrough, MD, MPA
Director
Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Mail Stop C1-09-06
Baltimore, MD 21244

RE: Proposed Decision Memorandum for Second Reconsideration of the Clinical Trial Policy, Renamed the Clinical Research Policy (CAG-00071R2)

Dear Dr. Phurrough:

On behalf of the American Cancer Society we appreciate the opportunity to submit comments regarding the Centers for Medicare & Medicaid Services’ (CMS’) Proposed Decision Memorandum for the Second Reconsideration of the Clinical Trial Policy (CAG-00071R2).

This year, approximately 1.4 million Americans will be newly diagnosed with cancer. Of these more than 60 percent will be over the age of 65. For many of these cancer patients, new treatments available through high-quality, peer reviewed clinical trials offer their best hope for survival and improved quality of life. The Society believes that clinical trials should be an option for all cancer patients. Advocating for increased access to quality clinical trials for all cancer patients has long been one of the Society’s top priorities.

While we welcome CMS’ proposed changes as an opportunity to update the clinical trial policy and improve its implementation, we believe it is essential to ensure that any proposed clarifications or other changes will result in continued access to high quality, scientifically based clinical trials that provide transparency and address disparities in clinical trial participation. We hope that any revisions made to this policy will not jeopardize the Medicare patient enrollment progress made since issuance of the final National Coverage Decision (NCD) in September 2000.

Covered Items and Services

The Society is pleased that this Proposed Decision Memorandum incorporates the changes made by the July 9, 2007 NCD that amended the 2000 NCD. We are very appreciative that CMS considered the comments received to expand coverage to items and services under investigation if they were also covered outside of the study. Thus, investigational items and routine clinical services will be covered under a new definition of “usual patient care.”

We are also pleased that CMS will permit Coverage with Evidence Development (CED) when appropriate. This will allow coverage of items and services in clinical trials for which there is insufficient evidence to support a “reasonable and necessary” determination if there is significant medical benefit and the research will likely result in evidence to show that these would be “reasonable and necessary.” We think this expansion in coverage will improve patients’ access to life-saving items and services as needed, without unnecessary delays.

Deemed Trials and Self-Certification Policy

As written, the September 2000 NCD provided specific criteria for qualifying trials to receive payment for the routine costs of participating beneficiaries, as well as a “self-certification” process to determine which clinical trials would be eligible for payment. Some clinical trials funded or approved by federal agencies like the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC) were “deemed” to be qualified and not required to go through this process. The self-certification process was proposed for the purpose of providing coverage for other clinical trials that were not government-sponsored, but it was never developed or implemented by CMS. The current proposal would eliminate the “deemed” status for any clinical trial and require that all clinical trials be subject to a self-certification process. The Society believes the current policy allowing federally funded trials to be automatically deemed eligible for Medicare payment has served cancer patients and researchers well, and we do not believe that substantial changes to the policy are necessary or advisable.

We believe that subjecting currently “deemed” trials to a certification process would be unnecessary, duplicative, and burdensome. Federally funded clinical trials, such as cooperative clinical trial groups and designated cancer centers, are vetted at various levels and already subject to a rigorous certification process. It would be unnecessary to subject these “deemed” clinical trials to another certification process that in many respects resembles the processes already required by many other federal agencies. This additional requirement would only serve to increase the bureaucratic requirements and hence the costs for these trials. We do not want CMS to impose a process that would increase the burden on existing research resources and discourage researchers from seeking certification, and could threaten patient participation in future clinical trials.

Standards for Clinical Research

While the Society does not believe the self-certification policy should be applied to already “deemed” trials, we note the need for the following clarifications or changes to the proposed standards:

August 17, 2007

We appreciate the opportunity to comment on the National Coverage Analysis for Clinical Research Policy (CAG-00071R2) issued July 19, 2007 regarding changes to the National Coverage Decision (NCD) for Clinical Trial Policy established by a June 7, 2000 Executive Memorandum. Mayo Clinic has reviewed the National Coverage Analysis (NCA) and respectfully submits the following comments.

Timing of NCA issuance

We are concerned that CMS is proposing a significant change to this NCD at the same time they will be starting a proposed rulemaking process for the same issue. We encourage CMS to close this NCA without change and continue with the current policy until the rulemaking process is completed.

Medicare beneficiary access to research trials

We are very concerned that the proposed NCD will limit Medicare beneficiary access to research trials and will be detrimental to CMS’ intent to enhance and broaden beneficiary access to research trials. By limiting payment for usual care to only trials “certified” by Medicare, it is very likely that many Medicare beneficiaries will not have coverage for services currently covered under existing Medicare guidelines. While we appreciate CMS’ desire to monitor research services, we believe it is inappropriate to create policy that would deny Medicare payment for services that are medically necessary and reasonable and would be covered without the existence of a research trial. This will become a disincentive for seeking Medicare and Medicaid patients to enroll in research trials.

Effective date of NCD requirements

We are concerned that making the policy effective on October 17, 2007 will not provide sufficient time for the research and provider community to be prepared to submit claims in the manner CMS is requesting. We appreciate the direction from Congress to provide coverage for services as quickly as possible under the Medicare Modernization Act of 2003, by making the decision memo date the effective date for a NCD. Unfortunately, the information and billing systems that hospitals and physicians utilize will most likely not be able to incorporate the required data elements for claims submission without more time to incorporate the requirements into their systems. In addition, the research community will have difficulty providing the certification forms to CMS before the October 17 deadline, since the forms will not be published until October 17. The provider community will not be able to report accurate claims information on the same date the NCD becomes effective when additional data elements are required to be reported. We recommend CMS not implement this NCD and wait for a proposed rulemaking process to be completed.

Determination of duplicate studies

We are concerned that the NCA does not provide more specific detail as to what constitutes a duplicate study that would not be receiving certification. There is a potential that more than one independent research study may occur for the same service or drug. The studies may appear to be duplicative but in actuality the research intent or outcomes may vary. We are concerned that without accurately defined outlines, studies may be considered to be duplicated when they are actually independent of each other and may have different research outcomes. This would limit Medicare beneficiary access to research studies.

Timing of NCD application for multiple location studies

We are concerned with the timing of when the NCD will be applicable. A national study may have enrolled patients at one location and the NCD would not apply. A study at another location may be beginning the enrollment process after the NCD effective date. This could appear to the new location to be a study that would be subject to the NCD while in actuality the study was already enrolling patients and not subject to the new NCD. We request that CMS clarify that the new study location will not be required to follow the new NCD.

Certification requirements

In order to obtain Medicare coverage under the new policy, the sponsor or principal investigator must certify that each of 13 separate criteria has been satisfied. We are concerned that Principal Investigators and manufacturers will have difficulty certifying all 13 criteria. Several of the criteria will be problematic as the Principal Investigator cannot control the timeliness of their completion. For example, this would include the requirement for the results of a study to be published within 24 months of the trial completion. Principal Investigators do not always have direct control over whether their results will be published, even if they are submitted for publication.

Late enrollment of Medicare/Medicaid subjects

A research protocol may not identify Medicare or Medicaid beneficiaries as potential subjects at a study onset. If a Medicare patient would benefit from the study but enrollment has already started, the proposed policy would not provide Medicare coverage for the patient because the certification was not approved prior to enrollment the first subject. This would result in non-covered services or potentially, no beneficiary access to the research study. We do not believe CMS’ intent is to deny access to Medicare and Medicaid patients because the trial did not receive certification before patient enrollment began. We request that CMS allow Medicare certification and coverage for a clinical trial that is presented with Medicare patients after the enrollment process has begun.

Changes to study protocol

Although CMS stated, at the August 7, 2007 Open Door Forum, that no claims will be retroactively denied if a certified study is subsequently determined to not be compliant with the NCD, we are concerned that this is not addressed in the NCD. CMS has a directive under this NCD that no Medicare coverage is available for usual care related to a trial that is not certified. However, there is no written direction in this NCD stating that claims will not be denied retroactively if a certified study is determined to be noncompliant. In addition, we would appreciate CMS communicating the initiative to other federal and state agencies that review claims to ensure that they also will not attempt to recoup payments, if this event should occur.

Access by Medicare disabled and Medicaid beneficiaries

The information provided by Dr. Phurrough during the August 7, 2007 Open Door Forum was very helpful in our understanding of the proposed NCA. We would appreciate further clarification on some of the comments. When Dr. Phurrough described who would be subject to the NCA, only the “over 65” Medicare patients were identified. No mention of the Medicare disabled or Medicaid populations was referenced in the forum. Will the NCA only apply to Medicare aged and not Medicare disabled beneficiaries?

Reporting of NCT number

During the August 7, 2007 Open Door Forum, it was suggested the National Clinical Trials (NCT) number should be reported on claims in a similar manner that the IDE number for a device is reported. We believe that generally, provider systems would not have the capability to “store” the NCT number in the same manner as a specific device’s IDE number. The NCT will have to be stored in a separate manner than an IDE and will require reporting only when a service is provided as “usual care” related to a certified trial.

Thank you for the opportunity to comment. We sincerely appreciate your consideration of these comments. Please contact either Don Hertel at (507) 284-8605 or me at (507) 284-4627 if you have any questions.

Very truly yours,
Ronald Grousky
Director, Medicare Strategy
Mayo Clinic

cc: D. Hertel
G. Warner
J. Mills, J.D.
K. Otte, J.D.
K. Tarvestad
M. Monosmith
M. Benson
V. Kight
S. Olson
K. Wenk

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The Accelerated Community Oncology Research Network, Inc. (ACORN) is a network of over 30 community oncology sites that conduct clinical research trials collaboratively with the aim of achieving a higher quality, more effective, and efficient research process. Our goal is to advance the science of oncology care in order to bring needed improvements in treatment options to our patients. On behalf of ACORN and our member sites, I am submitting these comments regarding the changes proposed by the Centers for Medicare & Medicaid Services (CMS) to the Medicare clinical trial policy, which has been renamed as the Clinical Research Policy — Proposed Decision Memorandum for Second Reconsideration of the Clinical Trial Policy, Renamed the Clinical Research Policy (CAG -00071R2).

We are extremely concerned that specific policy changes proposed by CMS outlined in CAG-00071R2 (herein referred to as the “Proposed Changes”) will substantially hinder clinical research by introducing needless bureaucracy and economic hurdles. These Proposed Changes reverse the policy that CMS in response to President’s Clinton’s June 7, 2000, Executive Memorandum, a policy that for six years has provided payment coverage for qualified clinical trials. Of significant note, the Proposed Changes will only add to the bureaucracy and cost that is seriously impeding the translation of research into effective cancer treatment.

We additionally note that if the Proposed Changes are implemented they will seriously disadvantage senior cancer patients covered by Medicare by restricting their access to potentially life-saving clinical trials. This is because the time and monetary costs inherent in the Proposed Changes will in practicality virtually eliminate Medicare patients from consideration to participate in clinical trials.

As a result, we request that CMS not implement the proposed changes, but instead continue to implement the current policy, which has served so well in ensuring the participation of seniors covered by Medicare in high quality clinical trials.

We base this request, and our conclusions, on the fact that the Proposed Changes will replace the time-tested current policy with an untested self-certification process involving 13 study criteria. This will require review of each of the 13 criteria and justification that each is being met by the study. Because much of this is based upon the subjective judgment of the research investigator, and because there are no clear, quantifiable metrics provided by CMS, it introduces new elements of uncertainty and concern that in a post hoc audit CMS will have a subjectively different opinion. The result will be research investigators forced to take the conservative route of not including Medicare patients in clinical trials, instead of risk the unknown possibility that Medicare claims filed according to best judgment will be disallowed by CMS. It is ironic to note that in the precise and quantifiable field of clinical research CMS is introducing such subjectivity as a precursor to implementing a clinical trial.

Examination of the 13 criteria clearly reveals that they are highly subjective in nature. For example, what is the objective criteria that the “The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes?” To our knowledge, that is never the intent of a phase I safety trial, for instance. Additionally, what is the objective criteria that satisfy that “the research study is well-supported by available scientific and medical information?” Who decides what constitutes “well-supported”? Furthermore, the criterion that “the research study protocol must explicitly discuss subpopulations affected by the treatment under investigation” is already covered by the Institutional Review Board (IRB) process.

In addition to the subjectivity, and therefore impracticality, of the self-certification process, we are very concerned that the CMS approval process for a new clinical trial introduces a level of bureaucracy that will significantly slow any clinical trial involving seniors covered by Medicare. We call the attention of CMS to the report to President Bush (2004-2005 President’s Cancer Panel) identifying serious problems translating research into viable, effective cancer drugs:

The clinical trials system in the United States must be simplified and made more cohesive, efficient, and effective without compromising the safety of study participants. It was suggested that for any clinical trials system to be successful, it must: (1) have a mandate and a philosophy that embraces clinical trial enrollment as a central precept, (2) offer provider incentives and recognition associated with doing the extra work involved in trial participation, (3) have stable resources, (4) have a structure that provides a broad base of opportunity for participation by community providers and patients, and perhaps, (5) employ navigators to help patients through the system.

2004-2005 President’s Cancer Panel

Unfortunately, the Proposed Changes are diametrically opposed to making the clinical trials system more “cohesive, efficient, and effective.” To the contrary, the Proposed Changes add no value to patient safety but instead only add unneeded bureaucracy and cost, and will decidedly slow the clinical trial process. Certainly, the uncertainty introduced by the Proposed Changes actually provides a substantial disincentive to the research investigator.

As a result, we strongly urge CMS not to implement the Proposed Changes, but instead further strengthen the existing time-tested policy.

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August 17, 2007

Steve Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Blvd.
Mail Stop C10-9-06
Baltimore, Maryland 21244-1850

RE: Proposed Decision Memo for Clinical Trial Policy (CAG-00071R2)

Dear Dr. Phurrough:

The undersigned cancer organizations, representing cancer patients, researchers, and caregivers, are writing to express their strong objections to the proposed decision memo for clinical trial policy (CAG-00071R2) issued on July 19, 2007. The proposal represents a significant reversal of the standards for Medicare coverage of clinical trials that have been in effect since 2000, and it poses a threat to the ability of Medicare beneficiaries to receive care in clinical trials. We urge the Centers for Medicare & Medicaid Services (CMS) to rescind this proposal. If any changes in the 2000 policy are necessary, they relate only to narrow questions of minor refinements to a responsible policy that has enhanced health care quality for many Medicare beneficiaries.

The Benefits of the 2000 Clinical Trial Coverage Decision

The cancer community engaged in a decade-long effort to secure Medicare coverage of the routine patient care costs for those enrolled in clinical trials, culminating in President Clinton’s issuance in 2000 of an Executive Memorandum requiring Medicare coverage of clinical trials. This coverage policy was essential for ensuring that cancer patients have access to quality care in a clinical trial (perhaps their best or only treatment option); furthering our knowledge about the best cancer therapies for senior citizens; and accelerating accrual to and the completion of clinical trials answering important treatment questions for cancer patients of all ages.

Before the 2000 Executive Memorandum, it was estimated that as few as 1 to 3 percent of Medicare beneficiaries participated in clinical trials. This low participation rate meant that Medicare patients were often not receiving the cutting-edge therapy they needed. In addition, because as many as 60 percent of cancer diagnoses occur in the elderly, the low rate of trial participation among this population affected overall trial accrual and the pace of clinical research.

In less than a decade, the Medicare clinical trial coverage policy has had a significant impact on seniors’ participation in clinical research. Researchers at the Southwest Oncology Group (SWOG), one of the several cancer clinical trials cooperative groups funded by the National Cancer Institute (NCI), reported in 2006 that the 2000 coverage policy had resulted in an increase in Medicare beneficiaries’ participation in cancer clinical trials. Prior to the 2000 coverage standard, the proportion of senior citizens in SWOG trials was only 25 percent, even though they accounted for 63 percent of the U.S. cancer population. In the period from 2001 to 2003, after the trials policy was implemented, seniors accounted for 38 percent of SWOG trial participants. The SWOG researchers considered other factors that might have influenced trial participation by seniors and concluded that the Medicare reimbursement policy was the major change in policy that positively influenced trial participation. Footnote 1

The Potential Impact of the Self-Certification Policy

In our years of advocacy for a responsible Medicare clinical trials policy, the cancer community argued that the standards for trial coverage needed to be simple and straightforward. We believed that trials that had been approved by federal agencies possessed the indicia of quality for Medicare coverage. These included trials reviewed and approved by the National Institutes of Health (NIH) (NCI, its cancer centers, and its cooperative groups) through peer review or other review processes, by the Veterans Administration (VA) or other federal agencies, or by the Food and Drug Administration (FDA) in granting an investigational new drug (IND) application (or determining that a trial is IND-exempt). We were gratified that CMS, in implementing the 2000 Executive Memorandum, determined that trials approved by federal agencies would be deemed covered by the Medicare program.

We recommended that, for those trials that did not fall squarely in the category of “deemed” trials, the process for certifying that they were quality trials needed to be simple, well-defined, and reasonable. CMS never defined that certification process in connection with the 2000 policy.

The cancer community objects to the introduction of a complex, resource-intensive, and potentially lengthy process for self-certification that will be imposed on clinical trials investigators. The self-certification process, which in the CMS proposal will replace entirely the deemed category of trials, requires that investigators answer 13 questions about their clinical trials in order to be eligible for Medicare reimbursement. Although the process is described as “self-certification,” CMS would evaluate the documents submitted by investigators before declaring them eligible for Medicare payment. As delineated in the coverage proposal, the self-certification would be a time-consuming exercise for investigators and one of dubious value to the integrity of the research.

Clinical researchers reported prior to the issuance of this proposal that the regulatory and paperwork requirements for initiating a trial were mounting at the same time that reimbursement for the research aspects of a trial was shrinking. In this research and fiscal environment, we fear that investigators may choose not to seek certification for Medicare reimbursement, thereby effectively denying senior citizens the opportunity to enroll in clinical trials.

The possible negative impact of the proposed clinical trial policy on senior citizens is clear. However, the policy may also affect the overall quality of cancer care if it impedes investigation of the most effective cancer therapies.

Cancer patients have demonstrated a keen interest in enrolling in clinical trials, not only to guarantee their access to quality care but also to advance the development of new and improved cancer treatments. The proposed clinical trial policy would thwart the altruism of Medicare beneficiaries as well as deny them access to the full range of treatment options. At a time when the population is aging and the proportion of cancer patients enrolled in Medicare is projected to increase, a policy that discourages research among the elderly with cancer is ill-advised.

We strongly urge CMS to withdraw this proposal, its second re-evaluation in slightly more than a year of the 2000 policy that has worked well for cancer patients and others and that we believe requires no revision.

Sincerely,

Cancer Leadership Council

American Society of Clinical Oncology
American Society for Therapeutic Radiology & Oncology
Association of American Cancer Institutes
Bladder Cancer Advocacy Network
C3: Colorectal Cancer Coalition
Cancer Care
Cancer Research and Prevention Foundation
The Children''s Cause for Cancer Advocacy
Coalition of Cancer Cooperative Groups
International Myeloma Foundation
Kidney Cancer Association
Lance Armstrong Foundation
The Leukemia & Lymphoma Society
The Lung Cancer Alliance
Lymphoma Research Foundation
Multiple Myeloma Research Foundation
National Coalition for Cancer Survivorship
National Lung Cancer Partnership
North American Brain Tumor Coalition
Ovarian Cancer National Alliance
Pancreatic Cancer Action Network
Susan G. Komen for the Cure
Us TOO International Prostate Cancer Education and Support Network
The Wellness Community
Y-ME National Breast Cancer Organization

Footnote 1: Unger JM, Coltman CA, Crowley JJ, et al., Impact of the year 2000 Medicare policy change on older patient enrollment to cancer clinical trials. J Clin Oncol 24:141-144, 2006.

Contact:
Ellen Stovall
National Coalition for Cancer Survivorship
1010 Wayne Avenue - Suite 770
Silver Spring, MD 20910
Phone: 301/950-9127
Fax: 301/565-9670
E-mail: estovall@canceradvocacy.org

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Re: Proposed Decision Memorandum for Second Reconsideration of the Clinical Trial Policy, Renamed the Clinical Research Policy (CAG-00071R2)

Dear Dr. Phurrough:

These comments are submitted on behalf of the Johnson & Johnson Family of Companies in response to the proposed decision memorandum that would revise the Medicare Clinical Research Policy. The proposed decision memorandum would revise the national coverage determination (NCD) under which Medicare currently covers the routine costs that patients incur in participating in clinical trials.

We appreciate the fact that CMS has substantially modified its original proposal after considering comments from the public. Nevertheless, we continue to have significant concerns with the proposed revisions. Our comments are set forth in detail below. The principal conclusions can be briefly summarized as follows:

August 17, 2007

Steve Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Blvd.
Mail Stop C10-9-06
Baltimore, Maryland 21244-1850

RE: Proposed Decision Memo for Clinical Trial Policy (CAG-00071R2)

Dear Dr. Phurrough:

The North American Brain Tumor Coalition (NABTC), a network of brain tumor organizations dedicated to improving the treatments for brain tumors, appreciates the opportunity to comment on the proposed decision memo for clinical trial policy (CAG-00071R2). For brain tumor patients, clinical trials may present the best treatment option and are also the only means for advancing brain tumor treatments. Medicare coverage policy must protect access to care in quality clinical trials and facilitate, rather than hinder, clinical research. Not only will brain tumor patients benefit from better treatments; the Medicare program also benefits from clinical research data regarding treatments provided to Medicare beneficiaries.

We are concerned that the self-certification process that the Centers for Medicare & Medicaid Services (CMS) has proposed will hamper access to care and slow the speed of research. The process requires investigators to respond to 13 separate questions regarding their clinical trials in order for those trials to be eligible for Medicare reimbursement. Some of the information required in the self-certification is already provided during peer review or government regulatory review, and other questions are overly broad and will be difficult to answer.

CMS has not made a convincing case that the self-certification process is necessary. We have observed that “deeming” those trials that are federally funded or that are subject to Food and Drug Administration (FDA) jurisdiction to be covered by Medicare, as has been the practice since the 2000 coverage memorandum, has been effective and efficient. CMS suggests that there are privately funded trials that are not included in the deemed category. We recommend that for those trials, which might include surgery trials of importance to brain tumor patients, there be a streamlined certification process that could be completed more easily than the proposed self-certification system. To accomplish this result, it is not necessary to eliminate the deemed category of trials.

Our gravest concern is that investigators and their institutions may be dissuaded from completing the certification process, thereby denying Medicare beneficiaries access to care in trials. Among individuals age 65 to 74, the most common primary brain tumor is glioblastoma. Individuals with a diagnosis of glioblastoma have limited treatment options, and eliminating the possibility of care in a clinical trial for these patients is not a result acceptable to the brain tumor community.

We fear that another impact of the clinical trial coverage proposal will be to chill the investigation of new brain tumor treatments. As the result of funding restraints, brain tumor clinical trials have been eliminated as an area of investment by certain cancer cooperative clinical trial groups. Any further actions that would discourage brain tumor trials will hamper a field that is already moving at a pace that is much too slow for those with a brain tumor diagnosis.

Over the last year, CMS has considered a number of different policies for clinical trial coverage. We recommend that CMS reject its various proposals, including the most recent one, and return to the standards of the coverage memorandum released in 2000 to implement the Executive Memorandum requiring clinical trial coverage. This will send an important message to clinical researchers that Medicare beneficiaries may participate in clinical trials and that the Medicare program values a vibrant clinical research system.

Sincerely,

Paul McKay, Co-Chair, North American Brain Tumor Coalition

Contact Information:
15 Magnum Court, #14
Smithfield, RI 02917
Phone: 617/594-2343
E-mail: pmckay2002@hotmail.com

Jeanne Young, Co-Chair, North American Brain Tumor Coalition

Contact Information:
20312 Watkins Meadow Drive
Germantown, MD 20876
P: 301/515-2900
F: 301/540-8367
E-mail: jpyoung88@aol.com

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Summary

Novartis appreciates the opportunity to submit comments on CMS Clinical Research Policy. We hope that the CMS finds these comments useful in producing a final set of clear regulations that provides Medicare beneficiaries with increased access to clinical research trials that further the development of innovative pharmaceutical products. In review, Novartis:

I would like to thank the Agency for the opportunity to comment on the Proposed Decision Memorandum for the Clinical Research Policy (CAG-00071R2). My comments will address three distinct subjects:

SynCardia Systems, Inc. (“SynCardia”) appreciates the opportunity to comment on the Centers for Medicare and Medicaid Services (“CMS”) proposed national coverage determination regarding Medicare’s clinical research policy (“Proposed NCD”). As the developer of biomechanical cardiac replacement and assist devices that are approved by the Food and Drug Administration (“FDA”) and devices for which we are seeking FDA approval, we have a strong interest in ensuring that Medicare’s clinical trial policy promotes access to clinical trials and the full range of services provided within the context of a clinical trial. Given that the clinical trials involving our devices have small numbers of patients, sometimes five or fewer at a site, we strongly recommend that the final policy take into account how the policy will impact trials with small numbers of patients.

BACKGROUND

SynCardia manufactures the CardioWest™ temporary Total Artificial Heart (“TAH-t”). This medical device is the modern version of the Jarvik 7 artificial heart first implanted in 1982. The TAH-t is the only FDA approved temporary total artificial heart. It is used as a bridge to heart transplant for transplant-eligible patients dying from end stage biventricular failure.To save the lives of these morbidly ill patients, the diseased heart is removed and the TAH t is implanted. All implants are done in carefully selected institutions that must be on the Medicare approved list for adult heart transplant centers and destination therapy for ventricular assist devices. The TAH-t pumps more blood, up to 9.5 liters per minute, than any ventricular assist device. This higher level of perfusion helps patients regain their strength, making them better heart transplant candidates. Currently, the TAH-t utilizes an external driver to function, and the size of the driver dictates that the patient remain in the hospital while awaiting a transplant. SynCardia is working with the FDA toward approval of a new driver that is much smaller and would allow patients to be discharged from the hospital while awaiting a transplant. We hope to obtain approval from the FDA for Category B investigational device exemption (“IDE”) status this year.

DISCUSSION

Medicare’s Clinical Research Policy Should Promote Participation in Clinical Trials By Avoiding Overly Burdensome Requirements for Clinical Trials

SynCardia is very concerned about the extensive requirements that are proposed as part of the standards for clinical research. As discussed below, we believe that some of these requirements may prove to be quite burdensome and could impede beneficiary access to clinical trials, which we understand would be contrary to one of the CMS policy objectives. Accordingly, we request that CMS finalize standards that are not overly burdensome on trial sponsors and trial sites, and that the agency be especially cognizant of the burdens that the standards will place on sites that have a small number of patients in their study (e.g., fewer than 10 patients).

One of the proposed standards is that the study design is appropriate to answer the research question being asked in the study. SynCardia supports this standard, but is concerned about how it would be implemented. It is not clear who would judge whether this standard is met, and whether those making such decisions would be sufficiently versed in the varied areas of clinical research. The research that we conduct on mechanical circulatory devices involves a very precise expertise that not many share.

Another standard requires that the study protocol explicitly discuss subpopulations affected by the treatment under investigation, how inclusion and exclusion affect enrollment of such populations, and a plan for retention of such populations. SynCardia believes that CMS should refine this standard to make clear that it applies to studies involving large sets of patients. While appropriate diversity in clinical trial enrollment is extremely important to the integrity of the findings, small trials with limited enrollment have explicit criteria customized to the specific outcome under evaluation. Imposing subpopulation requirements would hinder, rather than facilitate, the conduct of these small trials.

CONCLUSION

SynCardia appreciates the opportunity to comment on the important issues raised by the Proposed NCD. As detailed above, we urge CMS to ensure that its final clinical research policy facilitates Medicare beneficiary participation in clinical trials, particularly in trials with smaller patient populations.

If you have questions concerning this letter, please do not hesitate to contact me at (520) 547-7467. Thank you for your consideration.

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I am submitting the following comments on behalf of the Association of American Medical Colleges:

The Association of American Medical colleges represents all 125 accredited U.S. and 17 accredited Canadian medical schools; nearly 400 major teaching hospitals and health systems, including 68 Department of Veterans Affairs medical centers; and 94 academic and scientific societies. Through these institutions and organizations, the AAMC represents 109,000 faculty members, 67,000 medical students, and 104,000 resident physicians.

The Association appreciates the time and effort that CMS has to devoted to developing a policy covering Medicare payments for beneficiaries enrolled in clinical trials, including the August 7 Open Door Forum (ODF). However, we believe that the policy needs further major revisions, as discussed below, so that the system that finally is implemented will not impede the enrollment of Medicare beneficiaries in clinical trials, will not put hospitals and physicians at risk on the one hand for not getting paid for services that are needed by the patient, or on the other hand being subjected to False Claims Act suits, and will be easy to administer.

Rather than rushing to meet the October 17 deadline mandated by the national coverage decision (NCD) process, the AAMC urges CMS to use a rulemaking process to adequately consider the many issues that have been raised over the months since revisions to the 2000 NCD were first considered in late 2006. The NCD process was developed as a way for Medicare to add new items and services to national coverage. As such, it makes sense that there are extremely short comment periods and that the decision is effective on the date of coverage. Clinical trials cover a broad and complex system of items and services that would benefit from the longer comment period that rulemaking allows, and a reasonable amount of time to transition to new requirements once a final rule is published. The comments received on this second reconsideration would be extremely useful in forming the basis for a proposed rule.

During the Open Door Forum Dr. Phurrough indicated that CMS will be engaging in rulemaking related to clinical trials, though there was no hint as to the issues that might be addressed. This leads one to wonder whether the requirements developed through the NCD process will be replaced by a rulemaking, or whether the rulemaking will address other, though related, topics. As stated above, the AAMC suggests that the proposed NCD not be finalized and that CMS issue a proposed rule instead. However, if CMS persists with the NCD process, then we request that any future rulemaking neither conflict with nor replace requirements in a final NCD, as it would be extremely burdensome to providers to implement a new system in October of 2007 only to learn that it will be changed shortly thereafter.

As CMS considers its responses to the comments on this second reconsideration, we urge the agency to remember that when Medicare coverage for clinical trials was proposed, a simple, easily administered system was envisioned by the Institute of Medicine. We hope that the system finally adopted by CMS¡Xwhether it be through the NCD process or a formal rulemaking avoids the complexities that have been introduced thus far and provides the clarity that all affected entities and individuals seek.

The AAMC has many concerns with the CMS proposal, as discussed below.

I. Deeming and Self-Certification

1. CMS Should Retain the Category of Deemed Studies

The AAMC strongly supports allowing certain studies to be 'deemed.' Studies that are federally funded or otherwise undergo rigorous review by federal agencies already are subject to adequate oversight and thus should be accorded special status. Further, allowing some studies to be deemed¡Xand a substantial portion of studies at teaching institutions are supported by federal funding rather than by industry funding¡Xwill mean that hospitals and providers have absolute assurance that these studies qualify for Medicare coverage and will provide beneficiaries with prompt access to them. Finally, allowing some trials to be deemed will reduce the administrative burden by not requiring the extensive paperwork that will be needed to meet the self-certification requirements.

The AAMC recommends that CMS adopt the deeming language from the April 10 proposed decision memorandum, with a slight revision in the third bullet, as follows:

Studies that meet the following criteria are deemed to meet the standards set forth above and do not need to go through the certification process:

August 16, 2007

Centers for Medicare and Medicare

Re: Changes in CMS coverage for clinical trials

To Whom It May Concern:

I want to register with you my deep concern about your proposed decision to alter Medicare coverage for participation in clinical trials. After the last few decades spending significant money to develop new agents for the treatment of cancer, a disease that primarily affects the age groups that are covered by Medicare, this proposal would then limit the access of Americans to the opportunities for new and better therapy.

The proposed policy would merely add bureaucracy to a system that works relatively well.

I believe that many of our patients are already concerned about the difficulties of entering into clinical studies. If Medicare makes this even more difficult, this will certainly create frustration.

If American citizens were aware of this change, I believe that they would be as outraged as I am.

I strongly recommend that you reconsider this proposed policy.

We will take the steps necessary to notify our patients about this upcoming proposed change so that they too can make their feelings known to their elected members of Congress.

Sincerely,

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Thank you for the opportunity to comment on the Clinical Trial Policy.

In review of the policy, there is a clear overlap with other government agencies that also have a supervisory and regulatory role. The duplication of oversite is excessive, not necessary and inhibitory to trial function. The "qualifications for trial endorsemement are vague and potentially arbitrary. The net result will be an inhibitory influence to trial availability such that patients/beneficiaries will suffer from a lack of innovative treatment options.

If CMS does not wish to pay for clinical trials it would be preferable to simply just exclude payment than to create an unworkable charade of governmental regulatory "oversight." A little honesty would help restore public trust.

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The American Society of Hematology (ASH) represents over 11,000 hematologists in the United States who are committed to the treatment of blood and blood-related diseases. ASH members include hematologists and hematologist/oncologists who regularly render services to Medicare beneficiaries. The Society appreciates this opportunity to provide comments to the Center for Medicare and Medicaid Services (CMS) on the proposed revisions to the Medicare National Clinical Research Policy (CRP).

Clinical trials are pivotal in the research and treatment efforts of our members who combat cancers such as leukemia, lymphoma, and myeloma, as well as a multitude of other life-threatening, non-malignant hematologic conditions. The issue of paramount importance is ensuring that Medicare beneficiaries are not, in any way, discouraged from participating in clinical trials.

The Society would like to commend CMS for reexamining this issue and recognizing the much of the feedback it received in response to the initial reconsideration of the CRP earlier this year and appreciates the opportunity to provide additional comments. Though ASH supports many of the proposed revisions to the policy, the Society believes that a number of the proposals require additional changes or clarification; these concerns are noted below.

Part C – Standards for Clinical Research to Support Medicare Coverage of Items and Services

August 16, 2007

Steve Phurrough, MD, MPA
Director, Coverage & Analysis Group
Office of Clinical Standards & Quality
Centers for Medicare & Medicaid Services
ATTN: Clinical Study Certification
Mailstop: C1-09-26
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memo for Clinical Trials Policy (CAG-00071R2)

Dear Dr. Phurrough:

On behalf of the American College of Gastroenterology (ACG), we want to commend CMS for reconsidering the Clinical Trial Policy, renamed the Clinical Research Policy (CAG-00071R2), which you reissued on July 19, 2007. The revised policy clarifies several issues of concern, but it also creates new potential challenges.

The American College of Gastroenterology is a physician organization representing gastroenterologists and other gastrointestinal specialists. Founded in 1932, the College currently numbers more than 9,500 physicians among its membership of over 10,000 health care providers of gastroenterology specialty care. Although the vast majority of these physicians are gastroenterologists, the College’s membership also includes surgeons, pathologists, hepatologists, and other specialists in various aspects of the overall treatment of digestive diseases and conditions. The College has chosen to focus its activities on clinical gastroenterology – the issues confronting the gastrointestinal specialist in treatment of patients. The primary activities of the College have been, and continue to be, educational efforts directed at promoting and optimizing quality care.

The College is dedicated to the provision of high-quality care and evidence-based medicine and believes that clinical research is pivotal to this evidence base and the development of clinical practice guidelines. Our journals further the dissemination of such research and many of our members participate in trials as clinical investigators. We support the efforts to expand Medicare beneficiaries’ participation in clinical trials, and appreciate the agency’s willingness to hold an Open Door Forum and seek comments on the proposal in order to benefit from the input of affected stakeholders like the ACG.

CMS has rejected IRB approval as being sufficient for coverage of usual patient care in clinical studies. Investigators however, are charged by the federal agencies that regulate research with the task of informing potential subjects of expenses that are and are not covered by the research study. IRBs diligently and methodically review this information and make certain that it is incorporated into the Informed Consent Document that subjects sign in order to acknowledge their potential liability for costs related to participation in the study. Mandating that each investigator submit their protocols for prior review by CMS will slow the process dramatically, since each investigator involved in a multi-center study would have to individually submit the study for review and could not proceed with the study until approval was granted. This process would be more efficiently done by the study sponsors that design and carry out the protocol. We are disappointed in this decision to reject the sufficiency of IRB approval, but would urge the agency if it insists on creating new requirements to take a “least burdensome” approach.

Usual Patient Care
The College believes strongly that items and services that would be covered by Medicare outside of clinical trials should be covered by the program inside such trials, and applauds the agency’s attempt to clarify what constitutes “routine costs,” by adopting a clear definition of “usual patient care,” and services that fall under this category. This clarification should help to remove financial impediments to Medicare beneficiaries’ participation in clinical trials.

Self-Certification
Nonetheless, the College is troubled by some aspects of CMS’ proposed new self- certification process. We believe that this process is overly burdensome and may create new legal liabilities and risks for physician investigators, thereby creating a disincentive for including Medicare beneficiaries in clinical trials that might offer them access to care levels which in some cases may have life-extending possibilities.

For example, during the Open Door Forum on August 7, agency representatives stated that CMS would develop a checklist for the self-certification process. The College urges the agency to do so in order to minimize the burden of this process on physician investigators. Timeframes and processes for compliance should also be reasonable and should allow principal investigators or sponsors to amend self-certifications if unanticipated changes to the study are required. Information and guidance on the kinds of standards that would be used if CMS or HHS were to audit the submissions would also be helpful. Without such information and assurances that the processes will be fair and not impose unjust administrative burdens, practicing GIs will be disincentivized to participate in studies given the potential legal liabilities. Accordingly, patient care and outcomes are potentially at risk.

CMS should also clarify that a physician investigator can rely on a study sponsor’s self-certification. If a physician investigator can show good faith reliance, there should be no penalty or attempt to collect fees paid if the sponsor’s certification later turns out to be incomplete or inaccurate.

The College believes that investigators should only be required to self-certify to consideration of each of the standards in the proposed decision memorandum, rather than achievement of such standards. Several of the standards, as written, are too ambiguous to understand how they would apply in a particular instance. Instead, CMS should clarify that the self-certification process is based solely on the study purpose and design, which is the only information available at the time of certification.

Protocol Criteria
Furthermore, the ACG is also concerned about a number of the specific standards listed given that several are duplicative of criteria review by IRBs and others are very subjective. For example, the criterion “the research study does not unjustifiably duplicate existing studies” raises several questions. Does this criterion refer only to published studies? Can an investigator rely on Medline and Clinicaltrials.gov searchs to meet this criterion? What does “unjustifiable” mean? It often takes several studies to establish evidence-based guidelines, for example.

Additionally, the criterion “the research study has a written protocol that clearly addresses, or incorporates by reference, the Medicare standards,” is unclear at best. As currently drafted, this standard seems to require the protocol to address the Medicare standards which have already been met through other criteria.

We are also troubled by the criterion: “The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including regardless of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection…..” It is unclear to the ACG how a principal investigator could certify in advance that a study would be released in a certain time frame.

Investigational Device Exemptions
Separately, we are pleased that nothing in this proposed decision affects existing coverage of Investigational Devices Exemptions (IDE), as devices are often essential to the provision of less-invasive, high-quality GI care, particularly in the area of endoscopy. Participation in IDE trials allows physician investigators to gain necessary clinical, hands-on experience with new devices, experiences which can increase their clinical quality.

Deemed Status
CMS proposes to no longer give deemed status for studies approved or paid for by Federal Agencies. This provision is unnecessarily burdensome and will require study sponsors and clinical investigators to certify compliance for studies already reviewed and approved by another Federal Agency.

Timing
The proposed policy states that “CMS will notify beneficiaries, providers, and practioners of those research studies that have certified compliance with this policy by posting the research study title and ClinicalTrials.gov registry number on our website and in the Federal Register.” ACG understands that the agency will only review the certification for completeness but suggests that CMS provide information as to how long this process will normally take and urges the agency to conduct expeditious reviews so as not to delay reimbursement for important clinical studies or create risks that potential trial enrollees will be lost if there is undue delay while investigators wait for approval. Given the vagueness of some of the proposed criteria, it may be hard for the self-certification for studies initially covered under this new policy to be “complete.”

The College wishes to echo the comments of others that the use of enrollment as a cut-off for whether this policy or previous policies apply to a given research study might be problematic. The data of the first enrollment is usually not a significant event in the clinical trial, administrative billing and administrative processes. Instead, studies often track IRB approvals but not enrollment dates.

Coding
Lastly, the proposed policy would require providers to add code modifiers and the ClinicalTrials.gov registry number to claim forms. We urge CMS to work with Medicare fiscal intermediaries and carriers to ensure that they are well versed in this new policy in order to prevent the payment delays that can come with new modifiers and fields.

Thank you for this opportunity to comment on this important policy. We look forward to working with the agency to ensure that Medicare beneficiaries can continue to participate in important GI clinical research. Please do not hesitate to contact and use the ACG as a resource if we can clarify any of these issues- all of which have direct implications on our members providing quality of care service to our patients.

Respectfully submitted,

David A. Johnson, M.D., FACG
President, American College of Gastroenterology

Edward L. Cattau, Jr., M.D., FACG
Chair, National Affairs Committee
American College of Gastroenterology

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The development of a Medicare policy to assure better representation of recognized minorities in the cancer clinical trial process should be encouraged.

To adequately assess the efficacy and safety of a particular therapy the study popualtion should accurately represent the cancer prone popuation in this country. This populaton includes the elderly as well as ethnic minorities and rural residents.

This policy would offer an opportunity to define and eliminate barriers to clinical trial participation as well as encourage participants to remain in the study.

In this way the good cancer care that is enjoyed by participants in clinical trials can be more equitably experienced by the entire cancer patient population in this country. Enabling more cancer patient participation in clinical trials would ultimately be a better utilization of healthcare funds because quality care would be more frequently provided and new knowledge of the disease process and its treatment would be created.

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I would prefer to see greater clarification of what is considered to be a malformed body member. This can be subjective and open for dispute.

Notwithstanding any other provision of this title, no payment may be made under part A or part B for any expenses incurred for items or services—which, except for items and services described in a succeeding subparagraph, are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member…

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Diabetes is a disease which disproportionately affects racial and ethnic minorities. According to the Agency for Healthcare Research and Quality (AHRQ), diabetes prevalence rates for most minority groups are two to six times greater than that for non-Hispanic Whites. In addition, CDC estimates that 18.5 percent of Americans 65 – 74 years of age have diabetes. On behalf of all minority Medicare beneficiaries with diabetes, the American Diabetes Association (ADA) submits for your consideration the following comments regarding the second reconsideration of the Clinical Trial Policy, renamed the Clinical Research Policy (CAG-00071R2).

The Association is encouraged that CMS recognizes the importance of including minority Medicare beneficiaries in clinical research studies and is therefore addressing minority under-representation in these studies. To date, adequate data supporting therapeutic options for minorities remains substandard. Unfortunately, minority under-representation occurs in various types of clinical studies, including research on diseases and interventions predominantly affecting minorities.

Minority inclusion language in the Proposed Decision Memo demonstrates that CMS recognizes the importance of minority participation in clinical research. However, ADA respectfully urges CMS to strengthen this language to take into account the increased burden of certain disease states on minority populations. Research study protocols should discuss demographics of the disease under investigation. Subsequently, if a disease such as diabetes disproportionately affects racial and ethnic minorities, measures should be taken to ensure minority inclusion in study activities to produce more meaningful data.

ADA appreciates the opportunity to comment on the Clinical Research Policy. If you have any questions or require additional information, please contact Jennifer Hersh, Director of Policy, at (703) 299-2069 or jhersh@diabetes.org.

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Thank you for allowing us the opportunity for comment on this important proposal. We are pleased with the overall recommendations but do have some comments. One area of concern is definition of "enrollment" as it relates to the transition period. We would appreciate clarification for the term Enrollment Date:

The use of the term “enrollment date” creates confusion because it can have several different definitions such as: date the consent form was signed date the patient was registered to the study at which point screening procedures can begin date the patient was randomized to a treatment arm date the first study treatment was delivered

In addition, in using “enrollment date” as the guideline for instituting the new CMS Clinical Research Policy it is possible to have a study with some patients enrolled prior to the October 17th date and some enrolled after that date, complicating the budgeting issues for such a study.

We would recommend the use of the study registration date for the date the study will have to comply with the new regulations. All studies registered on or after the October 17th date would have to comply with the new regulations. This information should be readily available to sponsor, study site, IRB and CMS personnel. It allows for a very clear-cut application of the new regulations and would not necessitate study personnel making adjustments in the middle of a study.

Additionally, we are enclosing some comments provided by a researcher:

In general, the definitions seem appropriate. My main concern is with several of the proposed “standards” of a clinical research study for the revised Clinical Research Policy (p. 4 and 6-7 of the 7/23/2007 memorandum), which I have numbered consecutively:

(9) The exclusion of phase 1 trials in healthy volunteers, which usually are designed primarily to determine toxicity and maximum tolerated dose, is understandable. However, as written the standard seems also to exclude a phase 1 clinical trial in patients wherein the primary goal is to evaluate safety and tolerability, but also measures of clinical efficacy. Only trials in patients with life threatening conditions for which no other viable treatment is available are potentially included. Since patients who enter phase 1 trials may receive clinical benefit and the results contribute to the body of generalizable information, in my opinion routine clinical services that would otherwise be used for monitoring such patients should be covered.

(11) The results of early phase clinical trials do not always merit publication. However, I would agree that disclosure of results is a reasonable standard. Currently, ClinicalTrials.gov does not have a place to report results, at least not that I have been able to discern. If this is the case, I recommend that a mechanism to report the results of completed or terminated trials be added to ClinicalTrials.gov, and that this be acceptable for meeting this standard when publication is not deemed appropriate.

(12) If inclusion/exclusion criteria do not specifically limit or exclude subpopulations, is it still necessary to discuss subpopulations less likely to be available for participation? In some areas of the country, minorities are underrepresented in the general population and therefore are much less likely to be enrolled. Also, in many trials, age < 18 is an exclusion criterion. The reasons usually are obvious. Does this standard require specific discussion of why young individuals are excluded? The same is true for women who are pregnant. In these situations, separate discussion in the protocol seems unnecessary.

(13) This seems unnecessary and perhaps even conceptually flawed. If the age distribution of the patients in the trial includes patients eligible for Medicaid or Medicare and the trial is well designed, the results should be generalizable to patients with the same clinical characteristics as those who enrolled in the trial. The generalizability of clinical trials always is limited by the design of the trial and the specific characteristics of patients in the trial. I recommend that protocols include an explicit discussion only if the results are unlikely to be generalizable to a larger population of patients, including Medicare and Medicaid patients, similar to those included in the trial.

Thank you for your consideration and efforts in revising the Clinial Trial Policy.

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a copy of these comments preserving endnote formatting and references and contact information is also submitted to CAGinquiries

TO: Steve Phurrough, MD, MPA
Director, Coverage and Analysis Group

Leslye K. Fitterman, PhD
Lead Analyst

Office of Clinical Standards and Quality
Centers for Medicare and Medicaid Services (CMS)
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, Maryland 21244-1850

RE: Proposed Decision Memo for Clinical Trial Policy/Clinical Research Policy (CRP) (CAG- 00071R2)

Dear Dr. Phurrough and Dr. Fitterman:

I Introduction and Context of Comments

Thank you for renewing the opportunity to comment on the CMS Clinical Trial Policy/Clinical Research Policy (CRP). I am a member of the San Francisco Department of Public Health (SFPDH), Research Section, Community Advisory Group and a community advocate member of related organizations representing participants in human subjects research. San Francisco is home to one of a number of coordinated multicenter clinical trial sites operating in public (NIH and CDC sponsored) and private networks for studies to prevent and treat HIV/AIDS infection.

The importance of a robust research effort to improve health outcomes for those infected by HIV, almost certainly fatal or severely debilitating if left untreated, and its intersection with CMS Medicare policies cannot be overstated. Those affected by HIV/AIDS include persons who may qualify under each of the means Medicare (or dual Medicare/Medicaid) eligibility can be established: 1) the growing number of HIV infected persons over 65 for which new issues of aging and infection are understudied, 2) persons <65 years old with HIV/AIDS defining disabilities, and 3) persons for whom investigators now know that HIV related kidney failure leading to increased ESRD is becoming an area of greater concern.

CMS recognizes that there are ~100,000 Medicare beneficiaries with advanced AIDS defining illness; 19% of all people with HIV/AIDS were covered by Medicare alone or as dual eligibles. Older HIV patients are disproportionately reliant on Medicare as are minorities and lower income beneficiaries. In FY 2006, Medicare accounted for 26% of federal HIV/AIDS care spending, second only to Medicaid in scope of federal support.

The NIH and CDC sponsored HIV/AIDS research efforts alone are substantial and a high federal priority. However, previous funding increases in research budgets do not continue at their earlier rates. Recently, NIH engaged in a major reorganization of its HIV/AIDS clinical trial networks. It renewed efforts to make sure those studies maintain good enrollment rates and that it can sustain its ability to care for large numbers of diverse trial participants in complex often lengthy studies. The CRP could be implemented to work well with that effort if it is properly rolled out.

The importance of Medicare and the CRP is not limited to persons already infected with HIV. Medicare (or dual) eligible individuals at risk of infection may be important candidates for studies to prevent HIV acquisition and to avert consequences of co-morbidities or co-infections. Research studies focused on HIV prevention also must recruit HIV infected individuals on occasion to evaluate programs to minimize HIV transmission. Therefore, the number of persons affected by the CRP or its implementation and by infectious illness issues is larger than those already estimated in the HIV/AIDS budget, as is the need to encourage participation in trials that may not be immediately related to the underlying basis establishing a person’s eligibility for Medicare. Another of the previous comments CMS received quite rightly stated on a prior version of the CRP that great support is necessary for, and rational public health policy demands, “coverage of research studies that enroll patients who have not yet been diagnosed with a disease, but are at high risk of acquiring it…”. Prevention offers a chance to get a good bang for scarce public bucks.

It is with this contextual background that these comments are offered. These comments strongly agree with the almost universal support others have expressed for the general intent of the CMS effort to adapt its CRP for the public health agenda. That agenda recognizes both the obligation and the great opportunity to work with other federal agencies, academic research centers and the private sector to improve public health, maximize “bench to bedside” outcomes, facilitate greater participation in research by underrepresented populations affected by diseases disproportionately, and sanction good clinical practice oversight to protect human subjects participating in research..

Research that leads to a marketable therapy does not guarantee it will be used well. Important studies by AHRQ, the Institute of Medicine, WHO and others help us understand that facilitating universal, protected and patient centered inclusion in research is necessary to build public trust in the process and yield great benefits in acceptance and use of proven interventions once they can be marketed. The chance for CMS to act as a significant partner in that enterprise is welcome.

This contextual background serves as the grounding principles for specific comments that follow. To accomplish the desired goals, the CRP can and should be improved. Please consider these remarks in your revision of the proposed CRP.

II Specific Comments on the CRP Text.

The overall CRP approach for setting standards of research is worthwhile and describes measures of well run studies with a clinical translation research focus. However, CMS has received comments expressing caution about an overly prescriptive process that may deny coverage based on technicalities. To avoid that result CMS could consider ways to add flexibility in its certification reviews. CMS should err in favor of coverage if the principal standards are explained for a study and substantially documented, especially when IRBs, FDA or NIH have already provided significant oversight. The suggestion to CMS by the National Organization For Rare Disorders on July 26, 2007 to include a “decertification” process would act as a later check on inclusion of studies that cannot continue to meet standards or that fall short of performance oriented measures.

A. Standards

Clarifications and improvements to the standards could be made as follows:

1. Phase I Studies/Toxicity Testing Standard

The latest CRP proposal text differs from its predecessors in significant, undesirable ways. It now describes one study standard to be:

The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Studies of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life-threatening as defined in 21 CFR 312.81(a) and the patient has no other viable treatment options.

Previous CRP proposals did not limit studies covered by this standard only to those that are “life threatening” as defined; the earlier proposals included therapeutic measures to study chronic or debilitating outcomes. There appears to be no basis to retrench on the allowable scope to study serious conditions that can easily progress to life threatening situations without good treatment in an infectious disease along a continuum of harm. CMS ought not to limit them only to those that are life threatening. [The relationship between the two sentences and the meaning or scope of the second sentence in this standard are unclear. ] Please restore the broader scope.

Many commentors have raised questions about how Phase I studies would be viewed under this standard. CMS had expressed its reluctance to include studies for which therapeutic outcomes were not primary features and which were “merely” toxicity studies, a euphemism a few commentors sometimes applied casually ( and mistakenly) to some Phase I studies. Those previous discussions appear to have created an artificial and misplaced construct on the continuing role of toxicity or safety testing in all phases of research up to and even after approved marketing.

Toxicity and safety studies are regarded as principal objectives in all study phases. Their importance grows in later stages because larger study populations offer better chances to detect adverse events that the statistics of a smaller study could not reveal. CMS should not base its CRP on the “relative” importance or prominence of toxicity testing; it is always relatively prominent.

At the same time, many Phase I studies – especially now in HIV/AIDS research – serve as significant opportunities to spot major therapeutic or health outcome signals based on biomarkers, immune system function, correlates of protection and other basic measures. To proceed efficiently, many such Phase I studies may be split or sequenced into A and B stages based on careful biostatistic analyses to determine whether the intervention or therapy can meet health benchmarks or progress to further investigation. Sophistication in proposing benefit hypotheses make Phase I study research crucial in the accumulation of outcome improvement data leading to approval. FDA recognizes the role of Phase I studies to gain early evidence of effectiveness. On the other hand, some so-called Phase I or “first-in-man” trials for novel therapeutics may be limited to basic PK data objectives or signals that only help to form worthwhile Phase I therapeutic outcome objectives. Only this latter category of study would appear to be much outside the scope of a workable CRP. Other Phase I studies should be included in the scope.

Consistent with the remarks earlier in this letter, I request also that CMS revise its reference to studies in healthy individuals. Prevention studies are a legitimate area of inquiry within the CRP as is research that may recruit Medicare beneficiaries to join studies that are not immediately related to the explicit basis of their Medicare eligibility. The proposed CRP language may also cause inadvertent confusion in the treatment of healthy controls or those given placebo in a double blind study.

For all these reasons, this CRP standard could be revised instead to read:

The clinical research study is not designed to exclusively test toxicity, pharmacokinetic or distribution data or disease pathophysiology alone without any therapeutic, biomarker, correlate, preventive or other health improvement study objective. To clarify the preceding sentence further, research studies, such as some Phase I trials, whose protocols commit to measuring these health improvement outcomes as one of the objectives, meet this standard, for example, if the disease being studied is chronic, life threatening, or debilitating.

2. Registration, Public Release of Outcomes and Results Reporting

The CRP inclusion of commonly accepted standards to document the registration and results reporting of studies is much appreciated. These criteria help to extract public value from government expenditures that may support private sector rewards. The public deserves a minimum return on its “investment” and needs good access to accurate information to do so.

Please consider other ways to meet that objective. All results publication in peer reviewed journals for research that had received any government or taxpayer funding should be required to be posted in PUBMED Central and/or in journals that provide open/public access. The move to public access for government funded research publication is expected to be a federal legislative requirement soon and a followon to current NIH policies.

For results reporting, CMS may be aware that the WHO and other authoritative organizations favor harmonized norms to describe the kinds of results that registries may document and the consensus of which registries to use especially for multicenter international trials that involve U.S. sites. These reports supplement and add to other ways in which the public may learn about the studies it funds or supports.

For these reasons, the CRP standard could be revised to read:

The clinical research study is registered by the study sponsor/principal investigator prior to the enrollment of the first study subject on the ClinicalTrials.gov website and other registries accepted by authorities with jurisdiction over the trial, such as those used by the World Health Organization. The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. Registries adopted by competent authorities may also be one method that investigators can use for additional results reporting. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. Full text articles published in peer review journals must be deposited in PUBMED Central and/or published by means to make public/open access freely available promptly. A full report of the outcomes must be made public no later than three (3) years after the end of data collection.

3. Principal Purpose of Research.

As these comments and those of others already mention, the CRP should be clarified to recognize prevention. In the case of HIV prevention research, significant public health benefits and protection from seriously life threatening infections are expected from important ways to reduce HIV incidence rates, a major federal priority of the CDC, NIH and others. Including Medicare beneficiaries for all studies for which they may meet protocol design inclusion criteria, regardless of the reasons for their Medicare status, will serve the objective to maximize participation by underrepresented populations and advance the recruitment goals of priority research. For these reasons, the CRP standard could be revised to read instead as:

The principal purpose of the research study is to test whether a particular intervention potentially or significantly improves public health outcomes.

4. Inclusion of Subpopulations.

Many previous comments to the CMS cautioned against an overly proscriptive standard for recruitment of subpopulations when that analysis may be irrelevant to a scientifically justified study hypothesis, study outcomes are unaffected by subpopulation differences or result in undesirable obstacles to efficient, prompt recruitment for the study as a whole. These cautions are worth appreciating.

A skewed incentive for recruitment could cause investigators, unconsciously or not, to alter inclusion or screening criteria in ways that provide biased or undue inducements to participate. On the other hand, CMS is right to request that investigators explain efforts in good faith to expand study populations and meet CMS goals of inclusion in the study process. In the case of studies to evaluate genetic, gender or sex differences these explanations may be particularly valuable to report on the study objectives.

The goal of this standard should be to eliminate, in earnest, the real disparities in research CMS identified and to remove barriers to participation without disturbing the scientific credibility of the protocol design or ethical ground rules for the study. For these reasons, the CRP standard could be revised to read:

The research study protocol must discuss those subpopulations which the objectives are designed to explain will be affected by the treatment under investigation. The protocol should also explain in a practical, reasonable manner how recruitment efforts may remove barriers to participation among traditionally underrepresented groups in clinical studies and a plan for the retention and reporting of these populations in the trial. Barriers include obstacles caused by lack of public trust in the research process, accessibility, economic factors, or difficulties in providing meaningful public outreach or education to Medicare beneficiaries that potentially or otherwise meet protocol inclusion criteria. If the medically relevant inclusion and exclusion criteria are expected to cause a pronounced negative effect on the recruitment or retention of underrepresented populations, the protocol should offer some explanation why these criteria are necessary.

5. Clarification Request for Prospective Studies.

Regarding the CRP discussion for “prospective studies,” please clarify that CMS appreciates the value of much epidemiological investigation necessary to improve public health outcomes and that some costs in these studies may also be necessary and reasonable reimbursements.

B. Coverage – CRP Revisions Necessary for Research Related Injuries.

The CRP discussions and proposals to date create much confusion and result in undesirable outcomes on coverage for study participant medical treatment when an adverse event is probably caused by a study intervention. This confusion arises from the complex way the CRP defines “investigational clinical services,” “routine clinical services,” “usual care” and the underlying coverage determination. Although CMS recognizes that “treatment of research related adverse events” should be covered by Medicare, the coverage decision may exclude items for beneficiaries otherwise provided free elsewhere.

Commentors remain in the dark whether the exclusions are affected by ways in which other guarantors or insurance could accommodate treatment for these injuries. The MDMA, the Biotechnology Industry Organization, Genentech, Johnson and Johnson and others have explained in their previous comments how this confusion and the difficulties of identifying first or secondary payors adds to the complexities of treatment by means of private insurance or cost absorption by sponsors, investigators and nongovernment payors. Other commentors take note of how payors look to Medicare when establishing their own payment criteria and the CMS model of responsibility. What CMS does, matters.

Please apply serious efforts and creativity to resolve the issues these earlier commentors raise. In doing so, the approach CMS should take as a government agency is to craft cooperative solutions that inure to the genuine benefit of patients supported by Medicare and all other study participants. Volunteers who experience adverse events caused by research, least able to withstand or control the consequences of an unintended injury and most vulnerable to further harms or damages should not be placed at a disadvantage or in the middle of the private concerns of study sponsors or third party payors. CMS itself should not adopt a CRP or other policy that creates disincentives for private sector participation in jointly administered efforts to protect entire study populations from adverse event consequences. Study participants would not be well served if the effect of the CRP is to restrict the willingness of public or private investigatrs/sponsors to obtain insurance or guarantee treatment purely to avoid overwhelming costs that CMS could help to reduce.

The IOM, the Nuffield Council on Bioethics, the CIOMS/WHO and others agree that ethically designed trials should compensate or treat physical injuries caused by research on a no-fault basis, without regard to negligence. CIOMS refers to this aspect of good clinical practice as uncontroversial now. Left untreated or at the participant’s expense, these events have substantial potential to erode confidence in the research process and drive volunteers away from participation.

It is naïve to say on the other hand that study subjects, especially those in underserved populations in the U.S., consent to research risks and are aware of the problems with payment for research related injury when they volunteer; they could refuse to participate, the argument goes. This way of thinking asks these study subjects to make a Hobson’s Choice. It is inequitable and a mistake of the influences and pressures on study participants to ask them to incur these burdens. The population level risks to public health from not participating in a trial should not be offered to the person as the choice he/ she must make compared with the individual risk incurred from joining the study. Seen in this way, study subjects are not, simplistically, altruistic recruits who consent to put themselves in harms’ way; they are uninjured partners in population level research and deserve proper care.

Without commitments to proper treatment, the CMS may itself create a barrier to inclusion of underrepresented populations when the CRP was designed to remove those barriers. The CRP emphasis on verification of study standards to good clinical practice norms demands that the policy act to place patient health, safety and welfare first and to maximize it.

A useful review of the difficulties in different clinical trial settings – along with citations to the authorities that have made the case to provide coverage for research related injury, such as the Institute of Medicine - was published last year in the New England Journal of Medicine. Dr. Steinbrook was right to conclude:

Although the ethical arguments for compensating injured research subjects are compelling, the practical details are complicated — particularly the determination of the extent and duration of coverage and the assignment of the responsibility for paying compensation. However, the actuarial expense of covering direct medical costs may be relatively low, because serious injuries are unusual. In the United States, national leadership — from the clinical trials industry, academic medical centers, and the federal government — will be needed to catalyze major change. (emphasis added).

Dr. Steinbrook’s remarks explain some of the motivations deterring private insurors or sponsors from contributing to treatment efforts. He was also right to announce the need for national leadership to effect change. Lead, CMS.

Neither CMS nor the private sector should develop arguments of how each has little responsibility for treatment or that the liability is too great; both could devote their resources to provide that treatment on a no-fault basis as a measure of good clinical practice. Lack of actuarial data for real risk skews participation. If the CMS were also to look first to private payors before assisting Medicare patients, those private liability risk estimates will only get worse and create disincentives to join into cooperative arrangements for the protection of all research subjects combined, including those not covered by Medicare. The CRP should be implemented in ways that mitigate risks to all payors partially able to treat adverse event injuries, not scare those resources away.

Please adopt a CRP that does not provide disincentives to joint participation in the treatment of adverse event physical injuries for all study participants. CMS need not insist on first and secondary payment rules that act to the detriment of patients. In no event should such treatment be delayed or withheld because the patient or his/her caregiver has not received immediate authorization for reimbursement or is uncertain where it will come from.

For these reasons, please consider revising the definitions for “investigational clinical services,” “routine clinical services,” “usual care” and the underlying coverage determination. At a minimum the description for usual care coverage should be revised to read:

Except in the case of items or services for the prevention, diagnosis or treatment of research related adverse events, Medicare does not cover usual patient care when it is provided free to the Medicare beneficiary or when the study sponsor agreement with an investigator site or the informed consent documents provided to the patient specify that the clinical service will be provided free to all enrollees (§1862(a)(2); 42 CFR 411.4). In the case of adverse events, Medicare will work cooperatively with other potential payors or guarantors to secure the best and most prompt treatment options for beneficiary study participants experiencing physical injuries as a result of participating in research. Treatment of physical injuries for research related adverse events should not be delayed or withheld because the patient or his/her caregiver has not received timely authorization for reimbursement or is uncertain where it will come from.

Alternatively, CMS could determine that when sponsors/sites line up insurance or service resources for treatment for research related adverse events and inform participants they will use them, that is not a “legal obligation to pay for the service” of treatment within the narrow regulatory description of CMS exclusions under 42 C.F.R. §411.4. For purposes of this specific coverage determination, the treatment could be considered a jointly useful means for CMS and the sponsor both to follow a shared yet committed standard of care without reference to other nonregulatory obligations.

III Conclusion.

The chance to offer comments on this CMS effort is much appreciated. The Medicare eligible population affected by or at risk for HIV/AIDS has particular concerns the CRP may address, and the circumstances of life threatening transmissible illness deserve proper attention in this policy.

Please let me know if I can answer any questions.

Sincerely,

Robert Reinhard
Member, Community Advisory Group, SFDPH Research Section

References
https://www.cms.hhs.gov/mcd/viewdraftdecisionmemo.asp?id=210
http://www.kff.org/hivaids/upload/7171-03.pdf
http://www3.niaid.nih.gov/news/newsreleases/2007/ctu07.htm
Comments submitted to CMS on August 8, 2006 on the CRP by the Association of American Medical Colleges- searchable at the CMS website: https://www.cms.hhs.gov/mcd/viewpubliccomments.asp?id=&cov_id=&state_id=&list_type=&goto=viewpubliccomment&nca_id=186
See for example National Academies of Science/IOM (2002) Responsible Research: A Systems Approach to Protecting Research Participants
http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=10508
21 C.F.R. §312.21(a)(1)
CMS may reconsider whether the CRP should include coverage for adverse events even in these out-of-scope studies; see discussion in Section II.B of this letter.
http://www.pubmedcentral.nih.gov/ and
http://publicaccess.nih.gov/
http://www.who.int/ictrp/results/en/ For those commentors who expressed reservations about results reporting for all Phase I studies, CMS may evaluate some flexibility in implementing this single provision for this preliminary data. However, when results are published, the data should be available by means of open/public access. Please note the comments offered in this section of the letter do not take on the difficult question of how to establish causation of a research related injury unaffected by confounding factors of a complicating illness. These comments address injuries probably caused by the intervention or study procedure itself. See, for example Comments from Genentech to CMS, dated August 9, 2006
Steinbrook, R. (2006) Compensation for Injured Research Subjects. NEJM 354:1871-1873. http://content.nejm.org/cgi/reprint/354/18/1871.pdf

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August 14, 2007

Steve Phurrough, M.D., M.P.A.
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Hubert H. Humphrey Building room 445-G
200 Independence Avenue, SW
Washington, DC 20201

RE: Proposed Decision Memorandum for Second Reconsideration of the Clinical Trial Policy, Renamed the Clinical Research Policy (CAG -00071R2)

Dear Dr. Phurrough:

On behalf of The University of Michigan Health System (UMHS), we would like to thank the Centers for Medicare and Medicaid Services for the opportunity to provide feedback on the proposed reconsideration of the Medicare National Clinical Research Policy (CRP). We take the opportunity to comment seriously, as we believe that the final CRP will have a profound impact on clinical research and academic health centers across the nation. We would like to recognize the leadership of CMS in actively responding to the feedback to date on the original NCD, and making revisions as appropriate. We have reviewed the proposed decision memorandum and have outlined comments or concerns we have below.

Part D, Exclusions from Clinical Research Standards for Medicare Coverage of Items and Services

UMHS would like to comment on one of the criteria for exclusion outlined below:

'Prospective studies in which natural human behavior is observed in a way that does not intentionally or unintentionally change or potentially change the behavior of patients, physicians and other clinical staff, control subjects, healthy volunteers, or caretakers; in which there is no assigned or pre-specified intervention that intentionally or unintentionally changes or potentially changes the behavior of patients, physicians and other clinical staff, control subjects, healthy volunteers, or caretakers; and in which there is no assigned or pre-specified intervention that changes or potentially changes medical care, medical decision-making or any medical treatments.''

UMHS commends the effort to exclude prospective trials that do not influence physician or patient behavior, however the language above makes the exclusion difficult to discern. We believe the language chosen for the proposed NCD does not accurately communicate the true intent of the exclusion. We believe that the focus of the exclusion should be on studies where clinical care is not dictated by the research protocol, rather than studies that potentially change behavior. For example, a prospective observational study in which patient medical records are reviewed for data should be excluded since the clinical care delivered is not altered.

We also believe that randomization should not be considered an intervention that automatically requires studies to comply with the CRP. We would like to present an example to articulate this point. Consider a study where patients/subjects are randomized into two otherwise covered treatments. The physician may change behavior based on the results of the treatment, but this would have happened in the normal clinical management of the patient as well. We do not believe that because the randomization occurred, a beneficiary should lose coverage for otherwise covered benefits. The exclusion language as currently drafted would call into question whether the randomization alone is an intervention, and whether any additional standard of care treatments issued after the intervention changed behavior. The addition of the 'potential' language as written would make it nearly impossible for a study to be excluded because it is the duty of a physician to react appropriately if information is gained that requires a change in treatment.

Additionally, we heard Dr. Phurrough's comments on the CMS Open Door Forum on August 7, 2007 stating that the act of signing an informed consent, in and of itself, may be enough to potentially change behavior, therefore the exclusion would not be available. According to FDA and OHRP regulations, obtaining and documenting informed consent from prospective research subjects is expected unless strict and specific criteria are met. Clearly, the vast majority of studies under consideration would also involve the act of signing an informed consent. Similarly, the existence of a protocol (which CMS has indicated is a requirement of a good clinical trial) could be determined to "potentially" alter the behavior of a provider since protocols are intended to prescribe various treatment approaches. For these reasons, we do not believe an exclusion based on potentially altering behavior is clear, nor logical. If the proposed language is adopted, we again request clarification of the meaning of the term "intervention." We would hope that our example above considering the randomization of patients into two different treatments arms, both accepted as reasonable standard of care, would not be considered an intervention. Similarly, we believe that data collection that involves the addition of a diagnostic investigational clinical service (such as a research MRI, which would not be billed to Medicare) following routine care treatment would not be considered an intervention if it did not influence the clinical management of the patient. In this scenario, the routine care provided prior to the investigational diagnostic service would remain a covered benefit, even if the study did not meet the CRP requirements, so long as it would otherwise be covered by Medicare outside of the trial.

Furthermore, we believe that removing coverage for these types of studies will actually result in the exclusion of Medicare beneficiaries in these trials. With the knowledge that the standard of care services will no longer be covered simply because one additional test is taken, (paid for by the research sponsor) many beneficiaries will opt out of trials, thus preventing them from taking advantage of cutting edge medicine and potentially making study results not generalizable to the Medicare population. We propose amending the exclusion language to state "Prospective studies in which there are no interventions that alter the clinical care the patient would have received outside of the trial, and in which all items/services billed to Medicare are dictated by clinical care are not required to meet the standards of the CRP".

Part E, Covered Items and Services

UMHS would like to comment on the proposed definition of usual patient care of "includes routine clinical services and investigational clinical services in clinical research when the investigational clinical services would be covered outside of the clinical research and the clinical research meets the standards for a clinical research study outlined in this policy." This definition is particularly concerning because of its planned use in a proposed coverage determination stating that "Medicare covers usual patient care in qualified clinical research."

We appreciate the clarification of providing coverage based on whether or not the item/service would have been provided outside of the trial. However, we believe that the coverage determination should also state that Medicare covers items/services that would be covered outside the trial for studies that do not qualify under the CRP. Limiting coverage to only studies that meet the standards for a clinical research study leaves a subset of Medicare beneficiaries that will essentially lose coverage of their routine patient care if they choose to participate in a study that does not comply with the CRP. For example, if a Medicare beneficiary chooses to participate in a pharmacokinetics study that does not have therapeutic intent (and therefore does not comply with the CRP), the routine care provided as part of the trial would be no longer covered. We are concerned about the beneficiaries that may lose their right to coverage they would have had just because they enrolled in a clinical trial. We believe these types of trials are vital to the healthcare industry, as many drugs that now cure and treat our population often began as pharmacokinetic studies. At our own institution, just such a study was performed using a breath test to determine the pharmacokinetics of a standard chemotherapy regimen employing the drug docetaxel in patients with sarcoma. (Hirth J et al. The Effect of an Individual's Cytochrome CYP3A4 Activity on Docetaxel Clearance. Clin Cancer Res ,6: 1255-1258, 2000) Standard chemotherapy was given to treat the sarcoma. Under the proposed language, the standard chemotherapy would not be covered, since the pharmacokinetic study does not, in itself, have therapeutic intent.

We suggest making the distinction that usual patient care (includes investigational services that would have been covered outside the trial) will be covered in qualified trials, and routine clinical services that would have been provided outside the trial will be covered for unqualified trials, so long as the study does not add an intervention to that [routine] item or service. This distinction will ensure that Medicare beneficiaries receive clinically appropriate treatments regardless of which clinical trial he/she participates in. In order to ensure consistency among the CRP, we would also propose changing the language in the introductory paragraph to the CRP to read "Items and services furnished to Medicare beneficiaries in clinical research studies that do not meet the requirements of this policy are not covered, unless such item or service would be covered outside of the trial as medically reasonable and necessary AND the study does not add an intervention to that [routine] item or service."

Part F, Approval Processes

UMHS appreciates and supports the decision to keep the self-certification process to provide an additional method for studies to certify that they meet the standards in the CRP. However, we would like clarification regarding the intended scope for studies that need to go through this process. We supported the general standards for approvals in the April 2007 draft detailed below, but would not support a requirement that all studies must receive self-certification. From participating in CMS's Open Door Forum, we understand that CMS does not want to create separate processes for federal and non-federal research. In most cases, one approach simplifies and streamlines a process. However, federally funded studies are already subject to rigorous approval and oversight mechanisms, and we believe a requirement for these studies to also self-certify would cause unnecessary duplication and delay. Therefore, we would advocate for a separate process where only those that did not meet the general standards are required to use the self-certification process.

I am a hematologist/medical oncologist and have been involved in clinical trials for many years. I have also been a member of IRBs and currently serve on the Biologic Research Association of NY IRB as a reviewer. Frankly, I cannot understand why this new policy has been set up. Almost all the issues you raise are covered in excruciating detail by an IRB and I have no idea why you think you are more fit to make these determinations than a qualified IRA.

I think Medicare should pay for routine care for patients on an IRB approved clinical trial. It is important that the IRB not be biased and safeguards in that regard are reasonable. After approving an IRB Medicare should get out of the way of good research. I agree that only the services that are part of standard patient care should be covered and research costs should be paid thru research support but why you want to get into the difficult job of which research qualifies is beyond me. You are simply going to delay and screw up the system. I should note that because of the many restrictions in this country, the majority of clinical trials in my field are being done in Europe and Asia. We are losing money and prestige and our patients are getting delayed access to new treatments already and you are going to make it much worse. What for?

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Dear Dr. Phurrough:

Thank you for the opportunity to comment on the proposed Clinical Research Policy. We appreciate CMS' efforts to consider additional comments from stakeholders.

B&D Consulting's Health & Life Sciences Practice group offers advisory and advocacy services to health care providers, pharmaceutical companies, medical device manufacturers, industry groups and voluntary health associations. We respectfully submit the following comments for your review.

We commend the Centers for Medicare and Medicaid Services for proposing definitions of research, administrative and investigational services. These clarifications will allow providers to accurately categorize study protocol activities and will ensure compliance in submission of Medicare claims.

We urge CMS to further clarify the distinction between the Clinical Research Policy and the regulations governing coverage of IDEs with its contractors. While the proposed memo notes that "This policy is not applicable to, and does not change Medicare coverage according to the regulations on category A and category B investigational device exemptions (IDE) found in 42 CFR 405.201-405.215, 411.15 and 411.406," we believe that additional guidance from CMS to its contractors is required.

Presently, some Contractor Medical Directors appear to be uncertain about which policy governs the coverage of services associated with the study of an investigational device. Some medical directors are unsure which of these two policies to consider and many merge elements of the two policies when evaluating IDE studies for coverage. Additionally, the documentation required by contractors for submission of an IDE coverage request varies widely and leads to confusion among applicants.

In addition to the administrative burden posed by varying documentation requirements by contractors, Medicare beneficiary access to investigational care using new technologies may be compromised as coverage decisions for the same IDE study can, and do, vary among contractors. Geographic variation in coverage presents a barrier to care, as it should not be reasonably expected that if a Medicare beneficiary's local medical director denied coverage for a study that beneficiaries should relocate or travel long distances to seek care at an investigational site that has received approval. We believe that if the policies were made clear by CMS to its contractors, coverage variations could be reduced or eliminated.

The proposed Clinical Research Policy requires that "the research study protocol explicitly discuss[es] how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit form the intervention." To the extent that the results of IDE studies will be used to demonstrate health outcomes and to support Medicare's consideration for coverage of items and services post-market, studies must be powered sufficiently to inform that coverage determination. Thus, any limits to study participation for Medicare beneficiaries reduce study effectiveness and may compromise the ability for sponsors to receive a positive National Coverage Determination.

Thank you again for this opportunity to comment and for the Agency's engagement of all stakeholders in developing the Clinical Research Policy.

Sincerely,

Elizabeth A. Spurgin
Vice President

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Dear Sirs:
The proposed policy change in CMS coverage for clinical trials is a serious blow to the progress we have made in fighting cancer. Just as the public is seeing the benefit of decades of research that has resulted in a decrease in cancer death rates, your office is proposing to halt the progress by restricting clinical trial participation. This is also at a time when our population is aging and thus will be more likely challenged by a cancer diagnosis. This would qualify as a double knock out punch to such efforts. Much research has concluded that clinical trial care does not cost more than standard care. However, the time and effort by the research team is never compensated, thus always paid for by institutiona and not passed on to providers. The regulations proposed are duplicative, and they would restrict participation in trials. The regulations would add layers of cost and effort to a study. Many patients are worried about the cost of their care and would not enter a trial where Medicare would state, "we will determine later if your bill is paid- only if the trial got our regulations right." The NIH and FDA are looking out for the health of our citizens by numerous regulations of trials. CMS does not need to add to its job the evaluation of trials.

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August 10, 2007

Steve Phurrough, M.D.
Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Department of Health and Human Services
Mailstop: C1-09-06
7500 Security Blvd.
Baltimore, MD 21244

RE: Proposed Decision Memo for Clinical Trials Policy (CAG-00071R2)

Dear Dr. Phurrough:

On behalf of the 1,100 members of the Society for Gynecologic Oncologists (SGO), we offer the following comments on the Centers for Medicare & Medicaid Services' (CMS') Proposed Decision Memorandum for second reconsideration of the National Clinical Trial Policy (hereinafter renamed the, 'Clinical Research Policy').

The SGO is a national medical specialty society of physicians who are trained in the comprehensive management of women with malignancies of the reproductive tract. Our purpose is to improve the care of women with gynecologic cancer by encouraging research, disseminating knowledge which will raise the standards of practice in the prevention and treatment of gynecologic malignancies and cooperating with other organizations interested in women's health care, oncology and related fields. With over 1,100 members, the SGO is the leading organization of physicians who care for women with cancer in the United States.

Clinical Research Standards: SGO appreciates the opportunity to provide comments to the Centers for Medicare and Medicaid Services (CMS) as it reconsiders its national coverage decision on coverage of the routine costs of qualifying clinical trials. The SGO commends CMS for proposed changes to the CRP that may increase the participation of women with gynecologic cancers in clinical trials including the decision to rename 'routine costs to 'routine clinical services' and include in the definition of covered services the administration of non-covered chemotherapeutic agents.

However, we are concerned that some of the proposed changes are in conflict with the principal goal of the revised NCD for Clinical Research Policy -to reduce the barriers to Medicare beneficiaries to participate in clinical trials. The following two proposed standards that would be included in the 'Medicare-specific standards for clinical research studies,' are likely to decrease access for Medicare beneficiaries to cancer clinical trials as a result of the additional burden placed on the cancer centers, cancer clinical trials cooperative groups, and individual investigators who design and develop research protocols and conduct cancer clinical trials.

1) The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. However, a full report of the outcomes must be made public no later than three (3) years after the end of data collection.

The SGO is very concerned that rigid deadlines regarding the publication of clinical trial results included in this standard will make it very difficult to conduct research for clinical trials that have as part of their protocols periods for long-term follow-up or survival endpoints. This is very much the case with adjuvant chemotherapy trials.

Also, for those who are principal investigators on trials that are being run through federally funded clinical trials cooperative groups, the timing of the availability of the data for publication is dependent on the statistical center and the priority relative to the other studies that are being done at the same time.

SGO urges CMS officials convene a meeting of the leaders of all the federally funded clinical trial/research cooperatives to discuss the feasibility of these publication requirements and the impact that including activities such and timelines such as these will have on getting a protocol approved by the federal agency prior to the cooperative being able to start the study.

2) 'The research study protocol contains a discussion of how the results will generalize to the Medicare population to infer whether Medicare patients may benefit from the intervention. In particular, the protocol describes the potential impact of age-specific and other factors on outcomes and whether the research study is powered sufficiently to draw conclusions with respect to the Medicare populationn

The SGO understands the desire to provide Medicare beneficiaries greater understanding regarding the results of clinical trials and that clinical services provided during a trial that is covered by Medicare should produce results that can be demonstrated to be relevant to the Medicare population. Since cancer is a leading cause of morbidity and mortality for both men and women older than 65 years of age in the U.S., the results of any cancer clinical trial are obviously applicable to Medicare beneficiaries as a whole. There needs to be the ability as part of the self-certification process to have CMS recognize that certain studies involving diseases of the elderly automatically meet this standard.

The SGO has significant concerns that CMS' proposed additional Medicare-specific standards, including but not limited to mandating whole new sections of clinical trials protocols be developed with no guidance as to acceptable standards of compliance, will decrease Medicare beneficiaries' access to cancer clinical trials

Self-Certification Process for Clinical Research:

SGO commends CMS for providing a better defined process for all clinical research seeking coverage of the 'Usual Patient Caree

I am absolutely opposed to the proposed changes in clinical trial policy to the Medicare program. These changes would result in limited access of Medicare patients to clinical research and set a precedent that quite likely would be followed by private insurance agencies. The effects would go beyond limiting access to clinical trials for Medicare patients; this would further strain the medical research community in general, where funding is already severely restricted resulting. This would be disastrous for our society's ability to contribute to the advancement of medical knowledge and therapies through clinical research. I echo the comments by Dr. Joseph Bailes on behalf of ASCO and request that the current proposal be withdrawn with a return to the original 2000 clinical trials policy.

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Thank you for the opportunity to comment on CMS' Proposed Clinical Research Policy. We would like to offer three comments/questions for further clarification.

1. During the Special Open Door Forum on the Proposed CRP National Coverage Determination (CRP NCD)held Tuesday, August 7, 2007, Dr. Phurrough made two remarks about the CRP NCD and clinical trials of IDE devices. First, he stated that the CRP NCD would have "minimal" effect on IDE device studies. Later in the Open Door Forum, he stated that "IDE studies are excluded from this policy."

The proposed policy clearly states that the CRP will not affect the IDE coverage rules outlined in 42 CFR Part 405 Subpart B, so certainly the possibility of local Medicare coverage decisions will still exist through that path. However, the CRP does not state that the IDE trials can only qualify for coverage through the rules outlined in 42 CFR Part 405 Subpart B, and can not alternatively quailify for national coverage through the CRP process. Can you please clarify?

2. The second issue we'd like clarified is the "investigational clinical services that would otherwise be covered" being provided outside of qualified clinical research. Here's a scenario to make the question clearer. Suppose company A sells surgical mesh (let's call it mesh A) to be used for ventral hernia repairs. Suppose company B also sells a surgical mesh (Mesh B) for the same indication. Both devices are cleared by the FDA for this indication, and ventral hernia repair utilizing surgical mesh is a well-recognized treatment that is covered by Medicare. Now suppose company A wants to sponsor a clinical trial comparing outcomes when using mesh A vs mesh B for the repair of ventral hernias. Assuming the enrollees will include some Medicare beneficiaries, would the trial sponsor/PI need to go thru the self-certification process to get the trial listed by Medicare as a qualifying trial, so that Medicare beneficiaries enrolled in the study would be covered? Or, since these services would be covered outside of a clinical trial, would they be covered whether or not the trial goes thru the self-certification process?

3. Dr. Phurrough stated in the Open Door Forum that if a study was found, after self-certification, to not meet the criteria outlined in the policy for a qualifying trial, Medicare would not require payback of paid claims if the claims were properly coded with the NCR and IDE number. We would like to have this statement published in a CMS document.

Thank you for your assistance,

Respectfully,
James Gardner, MD, MBA
Director of Reimbursement/Medical Science Officer
Cook, Inc.

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I am urging CMS to reconsider its policy. The access to clinical trials is the only way we are going to make progress in the fight against cancer and this policy, which strips away a patient's ability to afford treatment on protocols while going even further to make them not eligible for protocols is impractical and will do more to discourage BOTH investigators and patients from participation in trials. I urge withdrawl of what will be a burdensome and unethical policy, which will result in less research and less progress, a larger bureaucracy and in the end, much more suffering.

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I commend Dr. Bailes on his comprehensive assessment of the proposed policy and potential implications. I have a few additional comments/concerns which I would like to address.

Although I understand the effective date of the revised policy will be the day it is posted (October 17, 2007). I would graciously ask CMS to add parameters around this date. Specifically, those studies that have already begun the IRB process (at atleast 1 site, not all sites) prior to the effective date should be grandfathered into the old policy. As you are aware, the administrative implementation of the proposed policy will take time to implement which will cause potential compliance problems/enrollment issues if sponsors do not have adequate time to implement the changes.

I could not agree more with Dr. Bailes and many other community members who feel that removing the "automatically deemed" process is not only unnecessarily duplicative but also has very little, if any, value. Please reconsider this and keep the language as it was stated in the 2000 policy for those studies that are automatically deemed qualified. This also ties into the next comment.

As you are aware, industry sponsors are required to post trials on www.clinicaltrials.gov and are also required to post the results of marketed drug products w/in a year of study completion on www.clinicalstudyresults.org. Changing this to all studies, not just those that are marketed, exposes confidential information to competitors. Please reconsider the proposed the language used in bullet 11, page 4. I would suggest removing it entirely or have it only apply to marketed products.

Finally, as previously mentioned, please reword the language used in bullet 9, page 4 to address the Phase I studies in patients with life- threatening conditions.

Thank you for your time and consideration to the above mentioned items.

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As the leading medical society for physiciansinvolved in cancer treatment and research, theAmerican Society of Clinical Oncology (ASCO) submits these comments in strong opposition to theproposed changes in the clinical trial policy ofthe Medicare program, now renamed the Clinical Research Policy. If adopted as proposed, the newpolicy will impose substantial impediments toresearch as well as needless additional expensefor the research enterprise, in both the publicand private sectors. The proposal represents asignificant retreat from the enlightened policydeveloped by the Medicare program to implementPresident Clintonn's June 2000 executive memorandum.

After six years of providing coverage of routinepatient care costs in high quality clinicaltrials, as determined by the peer-review andoversight mechanisms of respected federal scienceagencies like the National Institutes of Health(NIH) and the Food and Drug Administration (FDA),the Centers for Medicare & Medicaid Services (CMS)now proposes to create a burdensome, duplicativeand impractical bureaucratic scheme that willdiscourage provider participation in clinicalresearch and greatly add to its cost, whileproviding no tangible benefit. It also willlikely result in fewer Medicare beneficiaries participating in clinical trials' compromisingthe overarching goals of the clinical researchpolicy that CMS reaffirmed in its July 2006reconsideration announcement. The current policyhas worked well, enhancing participation ofMedicare beneficiaries in high quality clinicalresearch without adding significantly to the costof care or compromising in any way the quality ofthat care.

Origin of the Policy

Throughout the second half of the 19900's, ASCO andmany other cancer-related organizations advocatedfor comprehensive policy to require third-partypayers to cover patient care costs in clinicaltrials that met certain standards for peer reviewand oversight and general quality of the research. We argued, and a number of legislative proposalsreflected, that the best way to determine thequality of clinical trials in an efficientmannerr'i.e., without individualized auditing andanalysis of each trial and trial sitee'was to relyon the peer-review and oversight mechanismsalready in place under the auspices of federalagencies like NIH and FDA.

Thus, when President Clinton issued his June 2000executive memorandum requiring Medicare coverageof patient care costs in clinical trials, theMedicare program looked to its sister agencies toidentify trials worthy of coverage. As a result,and in order to make the review process asstraightforward as possible, Medicare 'deemedd'coverage for trials sponsored by federal fundingagencies like NIH (as well as NIH-funded centersand cooperative groups) and for trials reviewed byFDA under an investigational new drug (IND)application or designated by FDA to be 'IND-exempt..'

The self-certification process which CMS nowproposes to make the centerpiece of the policy wasnever implemented in the initial policy. In fact,CMS proposed eliminating the process in its July2006 reconsideration announcement. The core of theoriginal policy was coverage of the deemed trialsoverseen by NIH and FDA, and self-certificationwas reserved for the limited number of trials thatdid not qualify for deemed coverage. It isillogical, to say the least, that the cumbersomeand untested self-certification process nowproposed in the Clinical Research Policy wouldreplace the policy of deemed coverage that hasworked well for Medicare beneficiaries seekingtreatment for their cancer in the context of aquality clinical trial.

Problems with the Proposed Policy

The proposal seems to abandon the deemed coverageof the original policy, replacing it with anuntried self-certification process. In order toobtain Medicare coverage under the new policy, thesponsor or principal investigator must certifythat each of 13 separate criteria has beensatisfied. In contrast to the current policy,where any 'deemedd' trial is automatically coveredwith no further paperwork or other burden, the newpolicy will require specific review of each of the13 criteria and '[d]iscussion as to how the studymeets each of the standards in [the] policy..' This approach poses a number of challenges toclinical researchers, including uncertaintyregarding the intent of CMS with respect tosubjective elements of the criteria; the quantumof justification required to satisfy CMS; and theconsequences of failing, in a post-hoc analysis,to meet CMSS's unspecified requirements.

Facing such uncertainty, there is a very realchance that institutions and investigators engagedin research in both the public and private sectorswill eschew Medicare coverage, with the resultthat Medicare beneficiaries will once again besystematically excluded from participation incancer clinical trials. Those sponsors andprincipal investigators who do not forsakeMedicare coverage entirely will be subject tosignificant new and additional burdens that willsubstantially delay the initiation of clinicalresearch studies. The paperwork imposed by thenew policy is basically duplicative of whatresearch institutions already must provide toother Federal agencies and institutional reviewboards (IRBs), so it adds no value, but the burdenof complying with new Medicare requirements willbe expensive and will contribute to delays inprotocol activation and accrual. At both academicinstitutions and large pharmaceutical companies,compliance officials will be concerned about theprospect of false claims liability throughretrospective claims review, prompting additional review and oversight beyond that envisioned by the proposed policy. All of this will occur in the context of woefully under-funded support for research sponsored by the NIH and its centers and cooperative groups, so that this public-sector research will be even more at risk than others.

The criteria themselves are unworkable. Forexample, by what standard or measure does aninvestigator determine, for the purpose ofcertifying compliance, that the study is 'well-supported by available scientific andmedical informationn' and that it 'does notunjustifiably duplicate existing studies??' Theseare overwhelmingly subjective criteria that offerno useful information regarding a given clinicaltrial. At the same time, the proposed policyleaves unanswered or unclear certain issues ofconcern to cancer clinical researchers and cancerpatients, including the coverage status of phase Itrials. The ninth criteriaa'that the study 'is notdesigned to exclusively test toxicity or diseasepathology in healthy individualss' seems to be anobvious reference to phase I clinical trials, butthey are not identified as such, contributing togeneral confusion.

Other criteria seem to have been selected withoutconsideration of ongoing parallel initiativesregarding the same issues. For example, the veryspecific requirements for public release of allpre-specified outcomes do not take into accountthe current efforts by Congress to passlegislation requiring clinical trials registries,including reporting of results. The requirement that CMS seeks to impose here would, in someinstances, be inconsistent with the pendinglegislative standards, which are more likely thannot to become law. Moreover, the CMS criteriaseem unmindful of confidentiality protections thatFDA regulations afford to data supporting pendingnew drug applications.

The criteria seeking analysis of howsubpopulationss'presumably including not onlyMedicare patients but also racial and ethnicminoritiess'are or are not affected by the studyprotocol seem unnecessarily burdensome and alsosomewhat irrelevant. Most clinical trialsprotocols address these issues prior to, or aspart of, the peer review process and review byIRBs. If CMS concludes, after approval of theprotocol by NIH or FDA reviewers and by IRBs, thata research study does not adequately discuss these 'subpopulationn' issues, will CMS deny Medicarecoverage? And how will CMS otherwise use theinformation provided in these self-certifications? It is somewhat ironic and troubling that CMS,ostensibly in support of Medicare beneficiariess'inclusion in clinical trials, would imposeunneeded criteria that will in diminish thelikelihood that beneficiaries will participate insuch trials.

Consequences of a Policy Change

Establishment of the Medicare clinical trialspolicy in 2000 is a welcome example of agovernment initiative that can be shown to havemade a measurable difference for patients. Priorto adoption of the coverage policy, a study by theSouthwest Oncology Group found that Medicare-agepatients were significantly under-represented inclinical trialss'Medicare patients constituted 25%of the groupp's accrual to clinical trials, whereasthey comprised 63% of the population of all cancerpatients. After adoption of the Medicare clinicaltrials policy in 2000, participation by Medicarepatients increased to 38%, at least for those withsupplemental insurance.

To the extent that the proposed policy rolls backthe relatively straightforward qualification forMedicare coverage through 'deemedd' status andsubstitutes a burdensome, complex and uncertainprocedure for self-certification, there willundoubtedly be fewer clinical trial opportunitiesfor Medicare beneficiaries. This would beextremely unfortunate for cancer patients anddetrimental to our ability to determine how bestto treat cancer in the elderly. The 2000 clinical trials policy was one of the finest moments forthe Medicare program, embodying a forward-lookingand patient-friendly posture that the program doesnot often achieve. The proposed policyessentially reverses all that has beenaccomplished since adoption of the original policyin 2000 at a time when the prevalence of cancer inthe Medicare population is rapidly increasing.

Conclusion

The current proposal should be withdrawn, and theoriginal 2000 clinical trials policy, which hasserved cancer patients well, should be reaffirmed. Otherwise, Medicare beneficiary participation inclinical trials will inevitably suffer, togetherwith progress against cancer.

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Latino groups must be included in clinical trials and also seperately identified. Though we share one language our cultures vary as much as our diets and locations. Do not include our numbers as one group. This will serve no one. There are other underrepresented and disadvantaged members of our society who have never gained any benefit from clinical trials which did not include them. Programs must be tailored to appeal, not to the clinician, but to the study patient, with guidance from the clinician. Cultural competance may be learned prior to the design stage and is critical to developing a program with excellent retention.

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Re: Proposed Decision Memo for Clinical Trial Policy (CAG-00071R2)

Dear Dr. Phurrough:

On behalf of the Association of Academic Health Centers (AAHC ), I am pleased to provide comments on the Proposed Decision Memorandum for Second Reconsideration of the Clinical Trial Policy, Renamed the Clinical Research Policy (CAG-00071R2) issued by the Centers for Medicare & Medicaid Services (CMS) on July 19, 2007. I wish to applaud the agency for seeking to improve and clarify issues and for addressing many of the concerns raised by the academic health center community during the first reconsideration of this policy last year.

The AAHC, a national, non-profit association representing more than 100 of the 133 academic health centers nationwide, is dedicated to improving the nationnn-s health care system by mobilizing and enhancing the strengths and resources of the academic health center enterprise in health professions education, patient care, and research.

A second reconsideration of the clinical trial policy (CTP) is essential given the enormous impact of clinical trials not only on Medicare beneficiaries but also on all people suffering from illness and disease. Our hope is to ensure that clinical research and the advances that emerge from this vital endeavor continue and thrive in the U.S. with the help and support of CMS.

With regard to the proposed changes:

- The AAHC is pleased to note that clinical research has been defined to align with the definition in human subjects regulations and the NCD renamed to clinical research policy (CRP) to include all clinical research.

- The AAHC is also pleased with the clarification of the definition of routine clinical services and the examples provided.

- Finally, the AAHC applauds the agency for clarifying usual patient care as including routine clinical services and investigational clinical services in clinical research when the investigational clinical services would be covered outside of the clinical research.

The AAHC appreciates the benefits that the new CRP will provide the academic health center enterprise in enrolling increasing numbers of Medicare beneficiaries. However, the AAHC would caution that overall the proposed policy and standards does place increased, if not excessive, administrative burdens on institutions, sponsors, and principal investigators (PIs) that when taken together could slow the pace and growth of clinical research in the U.S.

To ease the transition from the current Clinical Trial Policy to the new Clinical Research Policy (CRP) and to enhance the final policy:

- The AAHC recommends that all federally-sponsored studies that have undergone review at the federal level (e.g., under IND or FDA approvals) would be viewed as satisfying the standards represented by bullets 1-6.

- The AAHC recommends that CMS provide illustrative examples of how each standard should be addressed.

To facilitate analysis, discussion, and implementation, the AAHC strongly recommends that the policy be reformatted to ensure a user-friendly document, which includes standards clearly numbered and placed in a rational order that takes account of the billing process and the implementation needs of institutions.

The AAHC asks that the following specific issues be carefully addressed by CMS.

New Proposed Standards for Clinical Research to Support Medicare Coverage of Items and Services
The AAHC would appreciate some clarification and change in some of the specific new standards for clinical research to support Medicare coverage of items and services. With regard to:
Standards bullet #3: The research study does not unjustifiably duplicate existing studies.

- The AAHC recommends that CMS clarify what is meant by -the research study does not unjustifiably duplicate existing studies...-

- The AAHC recommends that existing studies be defined as -published studiesss- so as not to create confusion in the research community given there are concerns about what CMS is seeking in the extent and breadth of documentation for this standard.
Standards bullet #6: The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46. If a study is FDA-regulated, it also must be in compliance with 21 CFR Parts 50 and 56.

- The AAHC recommends that CMS accept the submission or representation of an approval by a registered IRB of an institution holding a Federal-wide assurance as adequately addressing this standard.

o Standards bullet # 8: The research study has a written protocol that clearly addresses, or incorporates by reference, the Medicare standards.

- The AAHC does not know what is meant or intended by this standard. It appears that CMS should list this standard which addresses the written protocol and notes that -the research study has a written protocol that clearly addresses, or incorporates by reference, the Medicare standards,,,- either -firsttt- or -lasttt- in this list. As currently drafted, this standard is misplaced and thus repetitive, asking again for the protocol to address all the Medicare standards previously dealt with. What is CMS envisioning with this standard? Clarification is needed given the many differing views in the academic health center community on how to operationalize this standard.

Standards bullet #9: The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Studies of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life-threatening as defined in 21 CFR 312.81(a) and the patient has no other viable treatment options.

- The AAHC recommends that CMS change this standard to read: -The clinical research study is not designed to exclusively test toxicity or disease pathophysiology. Research studies, including some Phase I trials with protocols that commit to measuring therapeutic outcomes as one of the objectives, may meet this standard if studies are for acute conditions that pose substantial public health risks or diseases that are chronic, life threatening, or debilitating...- Such wording would ensure that Phase I cancer trials that are so significant for Medicare beneficiaries are covered.

Standards bullet #11: The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. However, a full report of the outcomes must be made public no later than three (3) years after the end of data collection.

- The AAHC strongly urges that CMS include a statement that clearly specifies that this policy should not require any standards to be met that cannot be met before services are rendered.

- The AAHC recommends that CMS should delete the portion of this standard requiring fulfillment of the method and timing of public release of all pre-specified outcomes.

To: Centers for Medicare & Medicaid Services

Cc: Maria Hardin, NORD Vice President Patient Services
Diane Dorman, NORD Vice President Public Policy

Date: July 25, 2007

RE: Comments on Proposed Decision Memo for Clinical Trial Policy (CAG-00071R2)

We read with great interest the CMS Proposed Decision Memo for Clinical Trial Policy. We thank CMS for formulating clear and understandable guidelines that should be very helpful to Medicare beneficiaries and service providers who are investigating which components of clinical research Medicare will reimburse for. We are especially grateful that CMS has clarified that this policy will apply to all clinical research, and will not be limited to protocols restricted to specific diseases or certain clinical trial sites.

The National Organization for Rare Disorders (NORD) represents the needs of individuals with more than 6,000 rare diseases that each affect fewer than 200,000 people in the United States. Combined together, this amounts to an estimated 25 million Americans. Because their diagnoses are unusual, people with rare 'orphann' diseases often fall through the cracks of the healthcare system. Most rare diseases are still untreatable or unsatisfactorily treated so clinical research may be their only hope for amelioration.

We provide the following comments on the Proposed Decision Memo that was issued on July 19, 2007:

- Previously, all of the HCFA and CMS statements issued on Clinical Trial Policy limited eligibility to investigational treatments when the research was sponsored by a federal government department such as NIH, CDC, VA, DOD, etc. We are delighted that the 2007 statement includes privately-funded trials. We urge CMS to issue new rules that clearly include privately-funded trials that meet CMS standards, including mandatory registration on the ClinicalTrials.gov website and mandatory publication of study results within a reasonable time period.

- CMS proposes that study sponsors and/or clinical investigators self-certify that their study complies with CMS standards. CMS will list the study as certified on your website, in the Federal Register, and on the ClinicalTrials.gov website. We agree this is an acceptable alternative to submitting a complicated application that would take months for CMS to review and approve. However, this section should include a provision for CMS to de-certify or refuse to certify any protocol that clearly raises questions or might violate ethical research standards.

- Local Coverage Determinations (LCDs) raise questions for patient advocates because Medicare, which is a national program, sometimes operates like several regional programs when local carriers are free to make decisions to exclude things that are covered by other Medicare carriers in different areas of the country. We urge CMS to require local carriers to conform to national CMS coverage standards for clinical trials. It is unreasonable to expect Medicare beneficiaries to move to a different state if they want reimbursement for something that is denied by their local Medicare carrier.

- Humanitarian Device Exemptions: Drugs to treat rare diseases are known as 'orphan drugs..' Medical devices to treat rare conditions are known as 'Humanitarian Devices..' When FDA grants a Humanitarian Device exemption it means the device is approved for marketing in the United Sates. Therefore, CMS should clearly mention that Humanitarian devices are not listed under the clinical trial policy decision because they are not considered to be investigational. They are approved by the FDA for marketing, according to the FDA Office for Orphan Products Development (OOPD). Decisions about coverage of Humanitarian Devices should not be left to local contractors; National CMS policy should prevail in all areas of the United States.

We hope these comments will be helpful in CMS deliberations about the clinical trial proposal. We urge you to issue rules that will implement the policy quickly.

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Thank you for taking the time to readdress this policy. The current NCD defines 1 requirement for medicare coverage of routine costs that I do not believe is adequately addressed in the proposed decision. Specifically, the current NCD states that the "The trial must not be designed exclusively to test toxicity or disease pathology. It must have therapeutic intent."

This language, are you are aware, has very imporant implications for Phase I research studies in cancer patients.

In the Proposed Decision Memo dated April 10, 2007, it specifically mentioned the public, MedCAC and AHRQ's thinking regarding the "Therapeutic Intent" language. This was described as "some Phase I studies whose protocols commit to measuring therapeutic outcomes as one of the objectives, may meet this standard only if the disease being studied is chronic, life threatening or debilitating."

I commend the agency and public for recognizing this sub group of patients and hope that the final decision coverage will also mention this important group of patients. Limiting coverage on this group will only further delay drug development.

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The clinical trial policy and the clincal research policy both state the following:
The three requirements above are insufficient by themselves to qualify a clinical trial for Medicare coverage of routine costs. Clinical trials also should have the following desirable characteristics; however, some trials, as described below, are presumed to meet these characteristics and are automatically qualified to receive Medicare coverage:
4. The trial design is appropriate to answer the research question being asked in the trial;
5. The trial is sponsored by a credible organization or individual capable of executing the proposed trial successfully;
7. All aspects of the trial are conducted according to the appropriate standards of scientific integrity.

More specific guidance is offered in the clinical research policy about the criteria that are required of an organization or individual, which demonstrate the capability of executing a proposed trial successfully and with appropriate standards of scientific integrity. Still the determination will be challenging. For example if the American Heart Association might not qualify as a sponsoring organization would a contract-research organization (CRO) or a site-management organization (SMO) managing clinical trials for manufactures be considered credible organizations with sufficient expertise to design and carry out clinical trials with scientific integrity? The probability of an organization other than the ones identified in 2000 in every instance or always meeting the three criteria above seems unlikely. Will individual protocols need to be scrutinized in order to asertain for example in the case of a non-inferiority trial if the margin is appropriate, (i.e. smaller or equal to the smallest or largest value that would be clinically relevant)?

Ref: Bodenheimer T, Uneasy alliance clinical investigators and the pharmaceutical industry NEJM 2000; 342: 1539 - 1543 LeHenanff A, GiraudeauB, BaronG, RavaudP, Quality of reporting o noninferiority and equivalence randomized trials JAMA. 2006; 295: 1147 - 1151

The proposed clinical research policy identifies standards crafted to update the 2000 CTP with input from other Federal Agencies that conduct health research, the MedCAC, and AHRQ. We[CMS] are proposing that they be established as standards of a clinical research study in this revised Clinical Research Policy: The principal purpose of the research study is to test whether a particular intervention potentially improves the participants' health outcomes. The research study is well-supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use. The research study does not unjustifiably duplicate existing studies.

Making the distinction between the first two bullets above and the third may difficult. One proposal to help make the distinct under some circumstances is offered below. A clinical trial of a drug, which is not intended to be reported to the FDA as a well-controlled study in support of a new indication and is already legally marketed in the United States 21 CFR 312.2(b)(1) (i-ii) would be redundant or the subject of studies already performed. Therefore, is the investigation of a marketed drug not reported to the FDA a clinical trial that unjustifiably duplicates existing studies? If this is correct such a clinical would not qualify for Medicare reimbursement of the associated cost. The text of the CFR follows:

part 312 can be found at 69 FR 13717, Mar. 24,2004.Subpart A-General Provisions
§ 312.1 Scope.
§ 312.2 Applicability.(a) Applicability. Except as providedin this section, this part applies to allclinical investigations of products thatare subject to section 505 of the FederalFood, Drug, and Cosmetic Act or to thelicensing provisions of the PublicHealth Service Act (58 Stat. 632, asamended (42 U.S.C. 201 et seq.)).(b) Exemptions. (1) The clinical investigationof a drug product that is lawfullymarketed in the United States isexempt from the requirements of thispart if all the following apply:(i) The investigation is not intendedto be reported to FDA as a well-controlledstudy in support of a new indicationfor use nor intended to be usedto support any other significant changein the labeling for the drug;(ii) If the drug that is undergoing investigationis lawfully marketed as aprescription drug product, the investigationis not intended to support asignificant change in the advertisingfor the product;(iii) The investigation does not involvea route of administration or dosagelevel or use in a patient populationor other factor that significantly increasesthe risks (or decreases the acceptabilityof the risks) associatedwith the use of the drug product;(iv) The investigation is conducted incompliance with the requirements forinstitutional review set forth in part 56and with the requirements for informedconsent set forth in part 50; and(v) The investigation is conducted incompliance with the requirements of § 312.7.(2)(i)

The proposed payment of the investigational device does not seem to be in complete concordance with the FDA proscription of charging for the investigational drug as outlined in 21 CFR 312.7(2)(d)(1). Will the investigational item always be paid if it is covered outside the trial? Another suggestion is may the reporting of enrollment numbers within defined periods be a qualifying requirement of clinical trials? The purpose of the reporting would be to avoid unduely prolonging the trial thereby violating 21CFR 312.7(c) in the case of investigational new drugs? The text of the CFR follows:
§ 312.7 Promotion and charging for investigationaldrugs.
(a) Promotion of an investigational newdrug. A sponsor or investigator, or anyperson acting on behalf of a sponsor orinvestigator, shall not represent in apromotional context that an investigationalnew drug is safe or effective forthe purposes for which it is under investigationor otherwise promote thedrug. This provision is not intended torestrict the full exchange of scientificinformation concerning the drug, includingdissemination of scientificfindings in scientific or lay media.Rather, its intent is to restrict promotionalclaims of safety or effectivenessof the drug for a use for which itis under investigation and to precludecommercialization of the drug before itis approved for commercial distribution.
(b) Commercial distribution of an investigationalnew drug. A sponsor or investigatorshall not commercially distributeor test market an investigationalnew drug.
(c) Prolonging an investigation. Asponsor shall not unduly prolong an investigationafter finding that the resultsof the investigation appear to establishsufficient data to support amarketing application.
(d) Charging for and commercializationof investigational drugs'
(1) Clinicaltrials under an IND. Charging for an investigationaldrug in a clinical trialunder an IND is not permitted withoutthe prior written approval of FDA. Inrequesting such approval, the sponsorshall provide a full written explanationof why charging is necessary in orderfor the sponsor to undertake or continuethe clinical trial, e.g., why distributionof the drug to test subjectsshould not be considered part of thenormal cost of doing business.
(2) Treatment protocol or treatmentIND. A sponsor or investigator maycharge for an investigational drug for atreatment use under a treatment protocolor treatment IND provided:
(i)There is adequate enrollment in theongoing clinical investigations underthe authorized IND;
(ii) charging doesnot constitute commercial marketingof a new drug for which a marketingapplication has not been approved;
(iii)the drug is not being commerciallypromoted or advertised; and
(iv) thesponsor of the drug is actively pursuingmarketing approval with due diligence.FDA must be notified in writing in advanceof commencing any suchcharges, in an information amendmentsubmitted under § 312.31. Authorizationfor charging goes into effect automatically30 days after receipt by FDA ofthe information amendment, unless thesponsor is notified to the contrary.

Respectfully

Patrick Price MD FACS

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