Clinical Trial Policy

Dear Dr Phurough,
Please consider supporting noninvasive objective technologies to guide volume optimization in dialysis patients.Non invasive technologies to assess and guide fluid management in the dialysis population are necessary to prevent cardiovascular and cerebrovascular morbidity and mortality.

Methods that have demonstrated clinical validation in observational studies should be expanded to large well designed randomized clinical trials. Examples of these technologies are listed below.

1. Blood Volume Monitoring

BVM is based on the assumption of the conservation of red blood cell (RBC) mass. During UF, intravascular blood volume is inversely and linearly correlated to hematocrit changes: as fluid is removed, the hematocrit (Hct) rises. Before dialysis, a sterile plastic disposable blood chamber is placed in the circuit between the arterial tubing and the dialyzer. The BVM uses a transmissive photometric technique to measure the Hct on the basis of both the absorptive properties of hemoglobin and the scattering properties of RBC passing through the blood chamber. The BVM visually displays the changes in blood volume and oxygen saturation during HD as fluid is removed from the intravascular compartment. In hypotension-prone HD patients, intradialytic symptoms are often preceded by a drop in blood volume or oxygen saturation prompting an intervention before the patient manifests clinical signs and symptoms of hypovolemia. BVM during HD has been reported in several small studies to allow more timely prediction of impending intradialytic morbid events, improved assessment of dry weight and more effective removal of excess body fluid. BVM is well accepted in the pediatric population. Patel et. al recently reported, the beneficial effects of a non-invasive blood volume protocol on ambulatory blood pressure monitoring (ABPM) comparing clinical parameters before and after its implementation. Their study showed an improvement in ABPM profile, and decreased rate of UF- related morbidity in a group of pediatric patients. We have reported similar improvement of several important clinical parameters in the adult population in the short term.

2. Vector- BIA

Vector-BIA

BIA-Vector is a method for assessing body composition, based on hydration (interstitial fluid) and structure of body compartments. Although the conventional BIA approach has been successfully applied when estimating body fluid volumes in healthy individuals, it cannot be used in dialysis patients since these patients do not have hydration of the fat-free mass at 73%, an assumption required for this approach. Thus, conventional bioimpedance regression methods cannot be expected to be useful in determining dry weight in HD patients. One of several novel bioimpedance methods currently used in the European community to guide volume management, vector-BIA, is a method, specific for the assessment of soft tissue hydration. Clinical information on tissue hydration is obtained directly through patterns of vector BIA distribution, based on direct measurements of the drop in voltage measured as resistance and reactance, standardized by the patient’s height. This approach is currently the most promising for providing patient-specific evaluation of body hydration. This has been tested in various disease groups to assess volume,guide volume optimization and assess nutrition status.

These studies were limited by several methodological limitations including a lack of adequate control groups, selection and dropout bias, and small sample size. It is unlikely that any one of these biases explain the extensive benefits reported, however, their combined effect may be substantial. Given its promise, the potential benefits of a more systematic and objective volume assessment approach must now be established in a rigorous experimental design.

Support of these technologies and others are necessary to more objectively assessing and guiding fluid managment. The result will likely be better outcomes.

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To Whom it May Concern:

Re: Clinical Trial Policy

May 10, 2007

I am writing to lend my support for CMS to provide a clinical trial for the validation of blood volume monitoring to identify ideal dry weights in hemodialysis patients.

Studies have shown that 90% of dialysis patients could be normotensive by lowering dry weight. Experts in the renal community have admitted that we need to focus on dry weights and that we have do a better job of establishing and maintaining dry weights.

Control of dry weights equates to control of blood pressure and thus an increase in survival rates.

Blood Volume Monitoring is a tool that has been shown to effectively determine ideal dry weights in several smaller studies and now needs to be studies on a larger scale. Identifying patients that are carrying excessive fluid can result in reduced fluid-related hospitalizations if this extra fluid is removed and an ideal dry weight is achieved. In addition, identifying patients that are too dry will help prevent inta dialytic morbidities thus allowing patients to have a better treatment and a better quality of life between treatments.

In conclusion, I respectfully request that you provide funding for a study to help show how blood volume monitoring can/will help patient so that they can have the best quality of life possible.

Thank you for your consideration in this matter.

Matthew Haynie

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It is clear that many of the established KDOQI guidelines have improved the adequacy of dialysis in terms of delivered urea clearance Kt/V >1.2, URR >65%, Hgb 11g/dl -12 g/dl.

What is needed are guidelines for the component of adequacy that have been to date overlooked- VOLUME ASSESSMENT AND MANAGEMENT.

The mortality rate of patients receiving chronic hemodialysis (HD) therapy in the United States remains unacceptably high at 15 - 20% per year. [USRDS, 2001] Results from the HEMO Study demonstrated no benefit of either higher dialysis dose or higher membrane flux on morbidity or mortality using three times a week hemodialysis therapy. In contrast, Charra et al., have reported an impressive ten-year patient survival of 75%, associated with excellent control of blood pressure without antihypertensive medication, by maintaining strict control of patient fluid volume. Their results, although observational, suggest that substantial improvements in HD patient outcome can likely be achieved by improving patient fluid status.

What is needed is an objective clinical assessment method for evaluating and guiding volume management. There is evidence in the literature that this will result in better control of BP, cardiovascular and cerebrovascular morbidity and mortality and Quality of life. Well designed, large, controlled, randomized trials are needed. Please consider supporting these trials. Thanking you in advance for the consideration of this request.

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Please find evidence below why particular focus should be given to our dialysis patients. In particular the focus should be targeted on volume and its management. Data from the 2006 USRDS reveals the following.

The number of hospital stay for those on hemodialysis, has not improved since 1999.

Cardiovascular admissions, in contrast, while increasing 8 percent overall, are now 20 percent higher in blacks, 27 percent higher in patients age 20-44, and 53 percent greater in pediatric patients – an issue of great concern. Among dialysis patients age 20-64, overall mortality rates are more than 8 times greater than those found in the general Medicare population.

In ESRD patients, rates of mortality due to heart disease are 169 percent greater for patients age 20-44, and the difference reaches 282 percent in those age 45-64.

Compared to those of transplant patients, mortality rates in the dialysis population are 9.6-13.8 times higher for heart disease, 5.2-6.3 times higher for cerebrovascular disease. No specific geographic patterns for death from cardiovascular disease in all patients are readily evident.

What is interesting is that 92.8% HD patients meet K/DOQI target for delivered Kt/V >1.2 92.0% HD pts meet K/DOQI target for URR >65% 87.6% HD pts meet K/DOQI target for Hgb >11g/dl

The one factor that remains to be addressed is the definition of an optimal fluid status in this population? How do we get to this optimal fluid staus? How do we keep our patients at optimal fluid staus? Will fluid status optimization lead to better quality of life and a reduction in cardiovascular and cerebro-vascular morbidity and mortality. Not enough attention is being paid to these questions.

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We are writing to 1) express our concern regarding the proposed standard related to health disparities and 2) request that any new guidelines include education of beneficiaries regarding clinical trials coverage.

HEALTH DISPARITIES

The CMS standard as stated does not improve upon the existing NIH Revitalization Act of 1993 and the FDA Modernization Act of 1997, which have proven ineffective in bolstering the representation of underrepresented populations to date. Current research demonstrates that underrepresented groups are still not adequately represented in clinical trials:

-According to the Coalition of Cancer Cooperative Groups, 89 percent of participants enrolled in NCI clinical trials between January 2003 and June 2005 were white and;

-Nearly two-thirds of cancer patients are 65 and older, but this age group accounts for less than one-third of those in clinical trials, as referenced in a 2003 study.

Without adequate representation of these populations in clinical trials, researchers cannot learn about differences in safety and efficacy between groups and cannot ensure the generalization of scientific results. This also contributes to health disparities by keeping the newest techniques and drugs out of the reach of disadvantaged groups.

As it stands, we would recommend going back to the initially proposed policy language or modifying the revised standard to have more substantive impact on the problem of disparities in clinical trials and to ensure some mechanism of enforcement.

We recommend the addition (in brackets)to the proposed standard stated below:

“The research study protocol must have explicitly discussed inclusion criteria, considered relevant subpopulations (as defined by age, gender, race/ethnicity, socioeconomic or other factors), [and contain a plan for the retention and reporting of said populations on the trial.]”

Comments: Ideally, the protocol should also contain a plan for assuring that these communities will directly benefit from any outcomes of the trial. If the inclusion criteria can reasonably be expected to have a negative effect on the recruitment or retention of currently underrepresented groups so as to render the clinical trial unable to achieve a representative sample of the target population, the researcher should provide explanation as to why the discriminatory criteria were necessary. If it is discovered during or after a clinical trial that the researcher’s inclusive enrollment criteria failed at achieving a representative sample of the target population, then a written explanation from the researcher will be necessary before further reimbursement will be allowed.

EDUCATION OF MEDICARE RECIPIENTS REGARDING CLINICAL TRIALS BENEFITS

In one study, 60% of respondents who have insurance, cited a fear of having their insurance denied as the reason they decided not to participate in a clinical trial.

We request that Medicare beneficiaries be educated about clinical trial participation and coverage in order to ensure that equitable access to clinical trials is not hindered by misconceptions or lack of information.

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.

Sincerely,

Armin D. Weinberg, PhD
Principal Investigator
On behalf of the Leadership of the Opportunity Team, “Ensuring Healthcare Coverage in Clinical Trials”
EDICT (Eliminating Disparities in Clinical Trials) Project
Chronic Disease Prevention and Control Research Center
Baylor College of Medicine
Houston, Texas

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May 10, 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: NCA Tracking Sheet for Clinical Trial Policy (CAG-00071R)

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 to revise the National 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 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:

The Society of Gynecologic Oncologists (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.

Required changes to protocol design

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 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 three standards proposed to be added to 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 and fulfills 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”.
2) “The research study protocol must have explicitly discussed inclusion criteria and considered relevant subpopulations (as defined by age, gender, race/ethnicity, socioeconomic or other factors)”.
3) “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 population”

There currently exists no mechanism for clinical researchers to comply with any of these three proposed new requirements. To design, develop, and implement such mechanisms will pose a huge burden on the already strained resources needed to develop and implement a cancer clinical trial. With regard to the first requirement to publicize results CMS acknowledges the lack of an existing mechanism and states “CMS will work with other government agencies and the research community to develop routine outlets for release of these results”.

May 10, 2007

BY ELECTRONIC DELIVERY

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 TrialPolicy (CAG-00071R)

Dear Dr. Phurrough:

On behalf of the Almyra, IncI am submitting thefollowing comments to the Centers for Medicare andMedicaid Services’ (CMS) Proposed DecisionMemorandum for Medicare National Clinical TrialPolicy (the Proposed CRP) regarding thereconsideration of its national coverage decision(NCD) on Medicare coverage of clinical trials. Almyra represents a portfolio of start-up medicaldevice manufacturers developing innovative products. Almyra appreciates this opportunity to comment onthe Proposed CRP and recommends that CMS make thefollowing improvements in its final CRP:

I am writing on behalf of the Advanced Medical Technology Association (AdvaMed) regarding the Centers for Medicare and Medicaid (CMS) proposed decision memorandum revising the national coverage decision on the “Clinical Trial Policy” (hereinafter referred to as the “Clinical Research Policy”). 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.

We appreciate CMS’s overall goal in this reconsideration: to ensure that seniors receive timely access to appropriate medical technologies and encourage their voluntary participation in clinical trials. We agree with CMS’s statement that the policy changes in the revised Clinical Research Policy should be directed at removing barriers to this access.

Notwithstanding, we are concerned that the Clinical Research Policy is ambiguous in key areas that we outline in our comments below, and consequently is potentially far-reaching in impact. Given the limited comment period and these ambiguous issue areas, we believe there has not been sufficient time to ensure that the full spectrum of possible issues have been considered by all affected stakeholders. The proposed Clinical Research Policy contains significant shifts in CMS coverage policy toward clinical research and many stakeholders may not be aware of the full ramifications of the proposal. Therefore, we strongly recommend that CMS revise and re-issue its proposal with an extended comment period of at least 60 days in a manner similar to a formal notice of proposed rulemaking. That proposal should clearly delineate the CMS policy’s impact on the various types of studies that would be potentially affected, and specify CMS’s rationale and process for addressing compliance (or approval) of these studies. This would ensure that stakeholders can consider the policy and offer more detailed and thoughtful comments. We appreciate CMS’s efforts to date and the opportunity to continue this important and critical dialogue with the agency to better serve Medicare beneficiaries.

IDE Clinical Trials

At the outset, we are pleased with the clarification that the Clinical Research Policy 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 this distinction is important because the current regulation allowing Medicare coverage of IDE clinical trials is an appropriate means to ensure that beneficiaries have access to medical technologies being studied in IDE clinical trials. In turn, this fosters both innovation and evidence generation.

Recommendations

Regarding the Clinical Research Policy as proposed, we have recommendations for improvements to the Clinical Research Policy in three main areas:

1. Medicare coverage of humanitarian use devices;
2. Non-deemed privately-sponsored research of Medicare-covered items and services; and
3. Other comments.

1. Medicare Coverage of Humanitarian Use Devices

Seniors and disabled Americans who have exhausted traditional treatments for a disease or condition may find that humanitarian use devices provide therapeutic options that would not otherwise be available. As we have stated in our previous comments, Congress and the FDA explicitly have promoted the development of technologies that treat orphan diseases through the humanitarian device exemption approval process.

In the proposed Clinical Research Policy, CMS proposes not to include any separate provision for humanitarian use devices. Rather, CMS proposes that coverage of humanitarian use devices be allowed under the same standards as outlined in the agency’s Clinical Research Policy for other items and services under study and notes that currently Medicare contractors may choose to cover these items at their discretion. We believe that local coverage is appropriate for humanitarian use devices that are not subject to any national coverage decisions because the local coverage process allows for prompt coverage of these medical technologies on a case-by-case basis. We note that the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) had recommended that humanitarian use devices with humanitarian device exemptions that are not subject to any national coverage determination should be subject to the Clinical Research Policy. We do not agree with the MEDCAC’s approach, but rather support CMS’s policy of allowing Medicare contractor medical directors to determine whether to cover these items at their discretion at the local level.

However, CMS states that “the most appropriate coverage of HUDs would be through the “coverage with evidence development” (CED) process in an NCD.” We believe that non-covered humanitarian use devices with a humanitarian device exemption that are being studied in a clinical research context should not have Medicare’s national coverage determination process (through CED) as the only avenue for obtaining coverage. While CMS has made significant improvements in recent years by following the timeframes required by the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, the national coverage process is still nine to twelve months in length. By definition, technologies that have received humanitarian use device designations and humanitarian device exemptions from the FDA involve treatments for small populations with no other viable treatment modality. Given the absence of other viable treatment modalities, allowing aged and disabled Medicare beneficiaries prompt patient access to humanitarian use devices is extremely important. Consequently, we believe that humanitarian use devices should have an expedited means of obtaining coverage under the Clinical Research Policy.

We recommend that CMS adopt the recommendations of the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) as they relate to humanitarian use devices that are subject to a national non-coverage determination, and create an expedited approval process for humanitarian use devices. Specifically, the MEDCAC had recommended inclusion of the following in the definition of “investigational clinical services”:

(For non-coverage NCD) The item has been designated by the FDA as an HUD, has received HDE status and is the investigational item or service in a study that meets the requirements of the policy.

For such humanitarian use devices, we recommend that CMS create an approval process to be conducted in the most expeditious manner possible. Approval under this process would provide for Medicare coverage of the humanitarian use device and the associated routine clinical services (as otherwise defined in the Clinical Research Policy). CMS would review such humanitarian use device studies to ensure that they otherwise meet the requirements of the Clinical Research Policy. Consistent with the Clinical Research Policy language, all other Medicare program rules would apply.

We recognize that CMS is considering its process for addressing non-deemed studies in general, however humanitarian use devices are unique given the absence of alternative treatment modalities for the limited patient populations in need of them. Providing this expedited pathway will provide needed treatment to these seniors and disabled Americans.

2. Privately-Sponsored Research (Non-Deemed) of Medicare-Covered Items and Services

While we recognize that CMS has proposed changes in an effort to update the current Clinical Trial Policy and address numerous issues, the proposed Clinical Research Policy is unclear regarding how the Clinical Research Policy should be reconciled with other existing coverage statutes, regulations, and guidance (or determinations). We believe there are two possible interpretations of how the proposed Clinical Research Policy would apply: (a) as a “safe harbor” providing an opportunity to qualify for additional coverage, without restricting Medicare coverage that might otherwise exist; or (b) as a set of requirements for all studies meeting CMS’s broad definition of “clinical research” in order to obtain Medicare coverage of routine clinical services and investigational clinical services, even if the investigational items or services at issue are currently Medicare-covered. We address these two possible interpretations below and provide recommendations for each.

a. “Safe Harbor” Approach to Clinical Research Policy

Although the current draft contains ambiguities, we interpret the proposed Clinical Research Policy as describing additional situations in which Medicare will cover and reimburse certain costs associated with care delivered to beneficiaries. That is, we read the policy as a kind of “safe harbor” that provides an opportunity to qualify for additional coverage, without restricting coverage that might otherwise exist. If this reading is correct, we recommend that this key distinction be clarified.

The following is an example that we think is illustrative of how the proposed Clinical Research Policy would apply consistent with this interpretation. Medical device companies sometimes sponsor on-label clinical trials of Medicare-covered items or services. A manufacturer may sponsor a study involving the use of its device precisely and carefully in compliance with the labeling that FDA has cleared or approved; and that use of the device is already covered by Medicare whether through a national coverage determination or local policies. The only difference between the use of the product in this study and use of the product outside of the study is that the experience of the patients will be recorded and analyzed.

We read the proposed Clinical Research Policy as not affecting the coverage of that device or the associated routine clinical services in that study because the use of the device and the associated routine care are already clearly Medicare-covered. Thus, resorting to the Clinical Research Policy is unnecessary. If the revised policy is meant to expand coverage in certain circumstances, but is not intended to restrict coverage that is otherwise available in the absence of that policy, we believe this is the way the Clinical Research Policy should apply. We favor this interpretation and recommend that CMS clarify this in its final decision memorandum.

b. Broad Application of Clinical Research Policy Requirements

In the alternative, we recognize that it is possible to interpret the Clinical Research Policy such that CMS does not intend to provide a “safe harbor,” and that CMS is instead setting forth requirements for all “clinical research” to obtain Medicare coverage for the investigational items or services, and the associated routine clinical services, despite being Medicare-covered outside the context of a study. If this is CMS’s intent, we are concerned that this policy may restrict coverage rather than expand it, and lead to a chilling effect on innovation and on-going research and evidence generation efforts by medical centers and other providers. Under this broader interpretation of the Clinical Research Policy, a large amount of privately sponsored research on already Medicare-covered items and services would be swept into the scope of the proposed policy. By imposing additional requirements on these studies of items or services that Medicare considers reasonable and necessary, CMS is creating burdens that do not currently exist. This undermines the stated intent of the policy, which is to expand Medicare patient access to clinical studies, not impose rules, processes and hurdles on researchers.

By way of background, many non-governmental entities, including academic medical centers, foundations, and manufacturers, sponsor clinical research on Medicare-covered items and services. This clinical research generates significant evidence on real-world issues relating to clinical interventions for Medicare beneficiaries. We believe it is important that CMS not create additional obstacles to conducting these important research studies because they benefit patients, physicians, and providers, and further inform health care stakeholders with the evidence generated on the medical technologies and procedures studied.

Moreover, for privately sponsored research on Medicare-covered items and services that is “non- deemed” under the Clinical Research Policy, there is no approval process set forth in CMS’s proposal. The proposed decision memorandum for the Clinical Research Policy notes that CMS did not implement the self-certification process for studies without federal funding that had been referenced in its September 19, 2000 National Coverage Determination on clinical trials coverage. CMS proposed in the Clinical Research Policy to eliminate the self-certification process for “non-deemed” studies and CMS states that it is “committed to engaging the public in addressing this issue in the future.”

Given the number and importance of these privately-sponsored studies, and CMS’s acknowledgement that this matter merits further attention by committing itself to engage the public on this issue in the future, CMS should make clear that the scope of the Clinical Research Policy does not apply to privately- sponsored non-deemed studies. We recommend that CMS exclude from the scope of the Clinical Research Policy all privately sponsored clinical research of Medicare covered items and services, including any IDE-exempt studies and non- significant risk IDE studies that may not be covered pursuant to 42 C.F.R. 405.201-405.215, 411.15, and 411.406. These studies would not be required to meet any of the standards or approval processes outlined in the Clinical Research Policy. All human subject protections and patient privacy rules would continue to apply.

Even if there were an approval process for non- deemed studies set forth in the draft, we are concerned that the high volume of these studies would overload CMS, the Agency for Healthcare Research and Quality, or another entity that would be responsible for reviewing and approving the written protocols for these studies. Moreover, as we stated above, we believe that the creation of additional hurdles to the conduct of research that will improve health care for Medicare beneficiaries runs contrary to the overall priority that CMS has placed on evidence- based medicine and evidence-generation in general. CMS should tread carefully to ensure that it does not create disincentives toward such research.

In addition, we note that the proposed scope of the Clinical Research Policy would exclude certain studies or data collection processes because they are “are based on previously collected data, or data collected in such a manner as to not influence current patient management or health outcomes.” These excluded studies appear to include privately-sponsored prospective studies that may involve Medicare- covered items and services—so long as they do not “intentionally or unintentionally change or potentially change the behavior of patients, physicians and other clinical staff, control subjects, healthy volunteers, or caretakers.” Because these studies may be confused with other privately-sponsored, non-deemed studies (the full scope of which we have commented on above), we suggest that the exclusion state clearly that privately-sponsored studies based on, or involving the provision of a Medicare-covered item or service (that meets the specifications of this exclusion language) are not required to meet the standards or approval processes set forth in the Clinical Research Policy.

3. Other Comments

This change will clarify the requirements of the proposed Clinical Research Policy.
* * * * *

Thank you again for the opportunity to comment on the proposed Clinical Research Policy. Given the complex nature of this topic, we 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) of my staff. We look forward to continuing to work with you and your staff on the Clinical Research Policy.

Sincerely,

Ann-Marie Lynch
Executive Vice President

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May 10, 2007

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

Dear Dr. Phurrough:

Re: NCD – Clinical Research Policy CAG-0071R

We commend CMS for providing revisions that help clarify the proposed Clinical Trial Policy, now titled the Clinical Research Policy (CRP). This policy has broad implications for both beneficiaries and the health care industry and deserves thoughtful evaluation by all affected parties.

W.L. Gore & Associates, Inc. (Gore), has designed, built and marketed implantable surgical devices for more than 30 years. From this perspective as a long-term stakeholder with significant experience in the design and conduct of FDA clinical trials, we have four comments:

1) More time is needed for comment. This is a complex issue, and 30 days is inadequate to study, understand and comment on all aspects of the proposed decision memo.

2) Non-deemed, non-IDE trials (“privately sponsored” trials) are not addressed. At minimum, these studies should be explicitly excluded from this proposed policy, subject to seeking further public input. Gore supports AHRQ’s prior recommendation for a self-certification mechanism, or as an alternative, the establishment of third-party reviewers to maintain transparency and allow public scrutiny.

3) Section 5 “Exclusions” should explicitly exempt current on-going and completed research studies in the marketplace. Research studies initiated or completed prior to CRP effective date should:

May 9, 2007

BY ELECTRONIC DELIVERY

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 Trial Policy (CAG-00071R)

Dear Dr. Phurrough:

On behalf of the Medical Device Manufacturers Association (MDMA), a national trade association representing the innovative sector of the medical device market, I am submitting the following comments to the Centers for Medicare and Medicaid Services’ (CMS) Proposed Decision Memorandum for Medicare National Clinical Trial Policy (the Proposed CRP) regarding the reconsideration of its national coverage decision (NCD) on Medicare coverage of clinical trials. MDMA represents hundreds of medical device companies, and our mission is to ensure that patients have access to the latest advancements in medical technology, most of which are developed by small, research-driven medical device companies. MDMA appreciates this opportunity to comment on the Proposed CRP. MDMA and its members supported CMS’ initial NCD in 2000 to cover routine patient care costs for Medicare beneficiaries enrolled in clinical trials. We are pleased that CMS has recognized the importance of enabling Medicare beneficiaries to participate in clinical trials, as the elderly bear a disproportionate burden of disease and other adverse medical conditions in the United States. MDMA supports the efforts of CMS to refine criteria for the coverage of routine patient care costs of Medicare patients enrolled in clinical trials. Medicare patients deserve early access to innovations in medical technology that could contribute greatly to their health and quality of life.

MDMA recommends that CMS make the following improvements in its final CRP:

Leslye K. Fitterman, Ph.D.
Centers for Medicare & Medicaid Services
Leslye.fitterman@cms.hhs.gov

Re: NCA for Clinical Trial Policy (CAG-00071R)

Dear Dr. Fitterman:

These comments are submitted on behalf of the Johnson & Johnson Family of Companies in response to the proposed decision memorandum for the Medicare National Clinical Trial 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.

Our comments are set forth in detail below. The principal conclusions can be briefly summarized as follows:

May 10, 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-00071R)

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.

The proposed Clinical Research Policy that CMS posted on April 10, 2007 reflects significant effort on CMS’ part to clarify and update the Medicare program’s coverage policies for clinical research. We agree with CMS’ statement that the current Clinical Trial Policy presents administrative challenges, which could restrict beneficiaries’ access to study participation, and agree that policy changes should be directed at removing these barriers.

We appreciate the overall context in which CMS has framed this reconsideration – specifically, that the goal of the Clinical Research Policy is to ensure that seniors receive timely access to appropriate medical technologies by encouraging their voluntary participation in clinical trials. This is particularly important with regard to the healthcare of senior women as this remains a population underserved by advancements in disease management and access to appropriate medical technologies. We need to attract senior women for voluntary participation in available clinical trials so that we can better understand the medical needs of this population who make up greater than 50% of Medicare beneficiaries.

We are pleased that the Clinical Research Policy 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 is concerned that the Clinical Research Policy is ambiguous in key areas, and consequently is potentially far-reaching in impact. We are particularly concerned that the Clinical Research Policy, contrary to its stated goal, may actually restrict coverage currently available to beneficiaries. As proposed, it is possible to interpret the Clinical Research Policy to include privately-sponsored research of Medicare-covered items and services, in addition to non-significant risk IDE and IDE-exempt studies. Under this interpretation, such post market and/or privately-sponsored clinical research studies would not be considered “deemed” under the proposed Clinical Research Policy and therefore would not be subject to the “Approval Process” outlined in section 4 of the Clinical Research Policy. As written, it appears that there would be no process by which these non-deemed clinical research studies can obtain coverage for the investigational items or services, and the associated routine clinical services, despite being Medicare-covered outside the context of a study. Even if there were an approval process for non-deemed studies set forth in the draft, we are concerned that the high volume of these studies would overload CMS, the Agency for Healthcare Research and Quality, or whatever entity that would be responsible for reviewing and approving the written protocols for these studies.

If this is CMS’ intent, we are concerned that this policy may restrict coverage rather than expand it, and lead to a chilling effect on innovation and on-going research and evidence generation efforts by academic medical centers and other providers. Under this interpretation of the Clinical Research Policy, a large amount of privately sponsored research on already Medicare-covered items and services would be swept into the scope of the proposed policy. By imposing additional requirements on these studies of items or services that Medicare considers reasonable and necessary, CMS is creating burdens that do not currently exist. This undermines the stated intent of the policy, which is to expand Medicare patient access to clinical studies, not impose rules, processes and hurdles on researchers.

As this clinical research generates significant evidence on real-world issues relating to clinical interventions for Medicare beneficiaries, it is important for CMS to resolve this discrepancy because many non-governmental entities, including academic medical centers, foundations, and manufacturers, sponsor clinical research on Medicare-covered items and services. St. Jude Medical believes it is important to cover this type of research because it benefits patients, physicians, and providers. Without a means for these non-deemed research studies to achieve compliance with Medicare policies and thus receive coverage for these services, these entities may be unwilling to engage in this research at all.

St. Jude Medical recommends that CMS exclude from the scope of the Clinical Research Policy all post market and/or privately-sponsored clinical research studies of Medicare covered items and services. We recommend that these studies not be required to meet the standards or approval processes outlined in the Clinical Research Policy and that all human subject protections and patient privacy rules continue to apply.

If it is CMS’ intent to include post market and/or privately-sponsored research of Medicare-covered items and services under the Clinical Research Policy, we strongly recommend that CMS re-issue its proposal through a formal notice of proposed rulemaking (NPRM) with an extended comment period of at least 60 days. That NPRM should clearly delineate the policy’s impact on the various types of studies that would be potentially affected, and specify CMS’ rationale and process for addressing compliance (or approval) of these studies. This would ensure that stakeholders can consider the policy and offer more detailed and thoughtful comments.

In addition, we note that CMS has already excluded from the proposed Clinical Research Policy “data collected in such a manner as to not influence current patient management or health outcomes,” including “prospective studies in which national 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.” St. Jude Medical recommends strengthening the exclusion language to clarify that the Clinical Research Policy would exclude such observational studies (e.g., registries) that are privately-sponsored.

Other Miscellaneous Comments

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

May 10, 2007

By Electronic Delivery

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

Re: Proposed Decision Memorandum for Medicare National Clinical Trial Policy (CAG-00071R)

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 Medicare National Clinical Trial Policy (to be renamed the Clinical Research Policy) (“the Proposed Decision”), as published on CMS’s website on April 10, 2007. The Cancer Centers, individually listed above, appreciate the opportunity to submit these comments.

I. Introduction

As you are aware, the Cancer Centers have played a pivotal role in improving the detection, prevention, diagnosis, and treatment of cancer. Much of the progress made in understanding the biology of cancer and the treatment of this disease is directly attributable to the work done in the Centers. The Cancer Centers are also at the forefront of the many innovations in cancer prevention and treatment currently under clinical investigation that have been widely publicized in recent years, such as advances in gene therapy, vaccines, and immunotherapy. At any point in time, approximately 20 percent of the Centers’ patients are enrolled in clinical trials. The Cancer Centers’ efforts have contributed to significantly increasing the number of surviving cancer patients, resulting in countless individuals being able to return to productive lives.

As institutions that have been responsible for many transformational advances in cancer treatment, 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 that 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, most recently in response to the tracking sheet posted by CMS on July 10, 2006 that first announced the agency’s reconsideration of the NCD and in connection with our presentation on this topic to the Medicare Coverage Advisory Committee (MedCAC) on December 13, 2006. As described below, although CMS has addressed some of the outstanding issues in the Proposed Decision, there are a number of remaining ambiguities for which we request clarification. We call your attention in particular to our comments below regarding the “deemed” status of the Centers’ trials under the revised policy. We also set out below our recommendations for revising the clinical trial coverage policy in a manner that will further assist Medicare beneficiaries to gain access to these state-of-the-art therapies.

Our specific comments and concerns about the Proposed Decision are summarized below.

II. Discussion

A. General Issues

1. Name Change

The Cancer Centers endorse the proposal to rename the clinical trial policy as the “clinical research policy” (CRP) in an effort to support beneficiary participation in a “full range of qualified, scientifically sound research projects.” As described by CMS, the conventional definition of a trial fails to capture the full range of options available to beneficiaries seeking to participate in clinical studies. We are strongly supportive of efforts to broaden the scope of the Medicare program’s coverage of research studies.

2. Definition of Research

In the Proposed Decision, CMS proposes, for the first time, to define clinical research. The Cancer Centers generally support the proposed definition, but request that the agency 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.”

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. Many cancer prevention trials are also conducted by cancer cooperative groups, which typically do not receive funding from the National Cancer Institute (NCI) 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 (e.g., patients without active malignancy, but at increased/high risk for developing a malignancy) 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

1. Medicare-Specific Standards

a. Therapeutic intent

The Proposed Decision clarifies this issue by proposing a revised Medicare-specific standard that “the clinical research study is not designed to exclusively test toxicity or disease pathophysiology. Research 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.”

We applaud CMS for explicitly including Phase I trials in this standard and for specifically stating that measuring therapeutic outcomes must be one of the objectives of the trial, and not necessarily the primary objective. We are concerned, however, that the Proposed Decision does not provide specific criteria by which to ascertain whether a particular trial satisfies this 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.¹ 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].”² 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 are concerned about potentially conflicting language on this issue included in the Proposed Decision. Specifically, in the general standards for a scientifically and technically sound clinical research study, the first requirement states that “[t]he principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes” (emphasis added). This language could be construed as contravening the Medicare-specific standard stating that measuring therapeutic outcomes must be one of a trial’s objectives. Thus, we request that CMS conform this language in the general standards to the Medicare-specific standard.

b. Trial registration

CMS is proposing to include the following as a Medicare-specific standard: “[t]he research study [must be] registered on the ClinicalTrials.gov website 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 clinical research that the Medicare program is supporting, and applaud CMS for choosing a website for this purpose with which our institutions are very familiar. However, the Cancer Centers have a number of operational concerns regarding this proposed requirement. First, in current practice, trial sponsors and cooperative groups are the “owners” of trial protocols and, as such, typically are responsible for trial registration. Thus, research sites frequently do not have control over when a trial is registered. If a trial is not properly registered before enrollment of the first study subject, it is unfair to penalize the research site (i.e., by denying Medicare payments) for the sponsor’s failure to register the trial. Moreover, withholding Medicare payment may result in some beneficiaries being unable to participate in trials. Particularly in the case of cancer patients, this could mean that beneficiaries may be denied access to potentially life-saving treatments.

Complying with this requirement also may be quite burdensome, 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 current trials are not registered. For example, at one of our institutions, Memorial Sloan-Kettering Cancer Center, only 185 of 456 open protocols are currently registered. Thus, requiring all trials to be registered will require an investment of substantial additional resources. In light of the above, 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. Therefore, 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.

We also request clarification as to whether registrants will be required to update information about a trial on the website. Currently, the ClinicalTrials.gov website has significant amounts of outdated information. For example, a number of trials are listed as open when they are actually closed and eligibility criteria may not be updated when a protocol is amended. If data is not properly maintained on the website, would this be a basis for denial of payment?

We strongly urge CMS to address these important operational issues.

c. Release of study results

CMS is proposing to include in the final revised NCD a requirement that the research study protocol “specif[y] and fulfill[] [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 Cancer Centers request clarification as to the precise obligation that CMS is proposing that research protocols “fulfill.” We interpret this requirement to mean that there is no specific timing requirement for publishing trial results. Rather, 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. CMS officials confirmed this interpretation during a recent BNA audioconference about the Proposed Decision, but we request that this clarification be included in the revised NCD and in instructions to Medicare contractors. Thus, if a study is expected to accrue 100 patients, but after two years only accrues 80 patients yet remains open, we understand and request confirmation that CMS only requires that the protocol initially discuss the expectation of publication and the publication methodology, but that the results would not have to be published by a specific date. 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 can be a significant undertaking, the Cancer Centers would like a clear understanding of what CMS would like to have included before beginning this process. Similarly, we seek clarification as to how publication will be tracked by the agency or contractor, 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? Further, 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 unfair to tie our Medicare payments to publication of results.

This requirement also 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. Further, as CMS acknowledges in the Proposed Decision, the ClinicalTrials.gov website does not have a mechanism for posting trial results at this time. Instead, CMS recommends that results be published in peer-reviewed journals or “public databases.” However, as CMS is aware, publication in a peer-reviewed journal cannot always be guaranteed (e.g., a journal may not be interested in publishing negative results from a study). Moreover, we are aware of only a limited number of public i.e., “sponsor- supported” databases that are currently available to publish trial results.³ Thus, in situations where a trial result cannot be published in a peer-reviewed journal, it would be difficult to comply with this requirement using existing technology.

Finally, the Cancer Centers 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.

d. Health disparities

CMS proposes to include a new Medicare-specific standard that “[t]he research study protocol must have explicitly discussed inclusion criteria and considered relevant subpopulations (as defined by age, gender, race/ethnicity, socioeconomic or other factors).” CMS also states that:

[I]t is not [CMS’s] intention to require a specific enrollment of all subpopulations. It is, however, [CMS’s] intention that all covered study protocols address all populations affected by the technology under investigation with special emphasis on minority and other groups that have experienced disparities in health care due to a lack of quality research data. If convincing evidence indicates that no differences exist between identified subgroups, that information should be noted in the protocol. If that evidence does not exist, then the protocol must discuss how the study intends to address these issues. One option is to power the study to address outcomes in each subgroup separately (emphases added).

The Cancer Centers request clarification as to what the agency is requiring, particularly what is meant by “address all populations,” “address these issues” and “power the study.” The agency seems to be requiring a discussion in the protocol about how certain populations may be affected by the treatment or technology being studied in the trial, but it is unclear if CMS is also requesting that investigators actively recruit subpopulations to enroll in a trial if there are insufficient numbers of these populations.

As we have previously communicated to CMS, we strongly urge the agency not to tie clinical trial qualification to patient demographics or other characteristics. We are very supportive of promoting enrollment in clinical trials from minority and other subpopulations, but patient eligibility for a trial should be based solely on clinical indications. Based on the foregoing, we recommend that this standard be eliminated if the intent is to require trials to recruit enrollees from certain subpopulations in order to achieve a level of representation in the trial. Instead, the requirement should only be to discuss in the protocol investigators’ efforts to recruit subpopulations that have historically experienced disparities in health care and how these subpopulations are affected by the treatment under investigation. Significantly, other federal government agencies, including the Office of Human Research Protection (OHRP) 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.⁴ 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.⁵ Thus, this standard is not necessary because it is duplicative of existing federal regulatory requirements.

e. Medicare populations

A newly proposed Medicare-specific standard is that “[t]he research study protocol contain[] 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 population.”

We understand from CMS’s statements at the audio conference that the agency does not intend to impose a quota on the number of Medicare beneficiaries in a trial. As described above with respect to health disparities, we strongly urge CMS not to tie clinical trial qualification to patients’ enrollment status, demographics, or other characteristics. We are strongly supportive of promoting enrollment in clinical trials from all sectors of society, but patient eligibility for a trial is based on clinical and other indications that are not normally related to the type of insurance an individual carries or other socioeconomic factors. Rather, access to a trial should be available to all eligible patients.

We also are uncertain as to what is being expected of our researchers based on this language. Specifically, it often may be difficult, if not impossible, to generalize the results of a trial to the Medicare population. First, our investigators typically are unaware of the type of insurance an individual carries. In fact, they are encouraged not to take into consideration trial participants’ insurance coverage in making decisions about the trial.⁶ Second, many clinicians believe it is not possible to make such generalizations about the entire Medicare population based on a study sample size e.g., for many Phase I studies, there are a small number of participants (typically 30 to 50) enrolled in the trial. Third, it is unclear precisely what “discussion” CMS wants researchers to include in the protocol, particularly in situations where the trial results cannot be generalized to the Medicare population. In this regard, we find it peculiar that CMS is requesting that this analysis of how the trial results can be generalized be addressed in the protocol, rather than after the trial has been completed. We assume that CMS would not make an adverse payment determination based simply on a study’s applicability to the general Medicare population. For example, if the protocol suggested that the study only had a modest expected benefit for elderly patients, this should not be grounds for denying Medicare payment. We request that the agency confirm this interpretation in the final NCD.

C. Approval Processes

1. Deemed Trials

CMS is proposing to include within the definition of “deemed trials” all “[s]tudies reviewed and approved by health care research centers or cooperative health care research groups … funded by [HHS, the Veterans Administration, or the Department of Defense] ….” Based on our discussions with CMS and statements made by agency officials at the December 2006 MedCAC meeting, it is clear that CMS’s intent is to include as “deemed” all trials conducted by research institutions, such as the Centers, that receive federal funding from one of the designated agencies. However, the language in the Proposed Decision introduces some ambiguities in this regard. In particular, we are concerned about the requirement that the federal agency review and approve “the applicant research centers’ … subcontract and subgrant funding requirements, selection procedures and oversight methods, and determine[] that those processes provide the same level of protocol review as provided by the supporting Federal agency.” Typically, the Cancer Centers receive a core grant from NCI to support all of their research activities. Significantly, the NCI 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 Institutional Review Board and then assure ongoing internal oversight of all the scientific and research aspects of the trial. We request that CMS confirm that federal guidelines such as the NCI core grant guidelines, or comparable processes, satisfy the standard of federal review and approval of the Centers’ protocol review processes. In the event that such guidelines do not satisfy this standard, we strongly urge CMS to adopt a more flexible approach in defining deemed trials. It is difficult to imagine a group of institutions that exercise more rigorous oversight over their clinical trials than the Cancer Centers. If the Centers do not satisfy this standard, we submit that CMS would be hard-pressed to identify any such institutions.

D. Covered Services

1. Routine Clinical Services

The Cancer Centers generally support the proposed definition of routine clinical services. Under the existing NCD, routine services are 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, routine clinical services include “[i]tems and services that are available to Medicare beneficiaries outside of a clinical study, other than items or services that meet the definition of investigational clinical services ….” Thus, it is clear that any item or service that is covered outside of the trial would be covered in the trial, even if it could not be characterized as “conventional care.” This would be a significant improvement over the existing definition.

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 “[i]tems and services provided solely for purposes of obtaining data for study analyses that are not intended or indicated for patient management will not be included in [the] definition [of routine services]” (emphasis added). 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.

2. Investigational Clinical Services

The Cancer Centers are generally supportive of the proposed definition of investigational clinical services. Based on a previous meeting with CMS, we understood that the current policy would cover investigational items or services that are covered by Medicare outside the trial. The Proposed Decision confirms this interpretation, stating that “the 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 … then [it is not investigational and it is] appropriate to cover these items and services within a covered research study even if they are the item under investigation.” 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 coverage status simply because it is being provided in a trial. We would appreciate CMS’s confirmation of this important principle.

E. Additional Issues

1. Medicare Advantage Plans

The Cancer Centers seek clarification with respect to billing for clinical research items and services to Medicare Advantage plans. Specifically, the original NCD provides that “[f] or the initial implementation, Medicare contractors will pay providers directly on a fee for service basis for covered clinical trial services for beneficiaries enrolled in [Medicare Advantage plans]” (emphasis added). To date, we understand that CMS has not changed this policy. The current policy creates financial barriers to clinical trial participation for Medicare Advantage beneficiaries because billing to the contractor, rather than the Medicare Advantage plan, makes the beneficiaries responsible for the traditional fee-for-service 20 percent co-insurance. The Cancer Centers request that the agency clarify in the final revised NCD whether these claims should be billed directly to the Medicare Advantage plan or to the Medicare contractor. We propose that CMS consider permitting the claims to be billed to the Medicare Advantage plan so as to encourage Medicare Advantage beneficiaries to enroll in trials.

2. Retroactivity

In the aforementioned audioconference, we understand that CMS officials stated that the revised final NCD would not be retroactive. Thus, the new NCD would become effective 60 days after the comment period closes and would only apply to trials commencing after that date. Therefore, we would not have to amend trial protocols that are currently in place (or are under development, but not yet finalized), which would be extremely burdensome, complex, and potentially violative of our contracts with trial sponsors. We request that CMS clarify in the final revised NCD and in its instructions to contractors that the new NCD is not retroactive and will only affect trials that commence after the new NCD is published.

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.

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

1 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.

2 Letter from Empire Medicare Services to Ropes & Gray, LLP (May 5, 2006).

3 See, e.g., Eli Lilly and Company Clinical Trial Registry website, available at http://www.lillytrials.com/.

4 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.

5 See, e.g., R01 and R21 grants, Public Health Services Grant Application, PHS 398, Section E.

6 Significantly, in order to participate in the Medicare program, we are not permitted to discriminate against Medicare beneficiaries in any of our operations. See, e.g., 58 Fed. Reg. 46,270 (Sept. 1, 1993) (“[A] hospital may not refuse to provide a covered service to a Medicare beneficiary if it provides that service to other patients”); 60 Fed. Reg. 45,778, 45,789 (Sept. 1, 1995); 59 Fed. Reg. 45,330, 45,343 (Sept. 1, 1994); see also Termination Of Provider’s Agreement Withholding A Segment Of Services From Title XVIII Medicare Patients, HCFA Ruling No. 78-19 (“[n]o Medicare patient may have withheld from him services ordinarily provided by the health care institution to its patients generally if the institution is to qualify or remain qualified as a provider of services”).

Less

May 10, 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

Re: Clinical Research Policy CAG-00071R

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.

We appreciate the opportunity to provide comments on the Centers for Medicare and Medicaid Services (CMS) proposed National Coverage Determination (NCD) for the Medicare National Clinical Trial Policy (renamed the Clinical Research Policy). Our comments below draw from a long history in working directly with CMS on numerous NCDs involving our products. We have also worked collaboratively with the agency and its contractors during the clinical research phase of many of Medtronic’s lifesaving and life-enhancing technologies, typically through the existing regulations defining coverage of Category B Investigational Device Exemptions (IDE) trials.

Medtronic supports CMS’ overarching goal of ensuring that Medicare beneficiaries receive timely access to appropriate medical technologies by encouraging their voluntary participation in clinical trials. Medtronic also supports CMS’ goal to increase Medicare beneficiary access to quality clinical research thereby improving the available evidence for better physician and patient decision-making. Manufacturers increasingly appreciate the value of evidence-based approaches and the need to invest in robust clinical and economic evidence to ensure appropriate adoption of their therapies by patients, providers and payers.

Although Medtronic is supportive of CMS’ overarching goals for the Clinical Research Policy (CRP), we are concerned that the CRP is unclear in critical areas – particularly, as described below, regarding privately-sponsored studies of Medicare-covered services – and consequently the policy may be interpreted in a manner that has far-reaching, unintended consequences to beneficiary access to quality clinical research. Given the brief comment period and the lack of clarity in the CRP, we believe there has not been sufficient time to ensure appropriate input from all stakeholders. The proposed CRP, if broadly applied, has the potential to produce a sweeping shift in policy concerning clinical research. Because of the ambiguous nature of the CRP, many stakeholders may not recognize the potentially far-reaching scope or the full implications of the proposal on beneficiary access to clinical research.

Given the potential adverse impact on ongoing and planned clinical research and beneficiary participation in clinical studies, Medtronic strongly recommends that CMS re-issue its proposal in a manner similar to the formal notice of proposed rulemaking process with an extended comment period of at least 60 days. In this new proposal, the scope of the policy as it relates to the various types of clinical research should be clearly delineated, and CMS’s rationale and process for addressing compliance (or approval) of these studies should be openly specified. Such a proposal would allow stakeholders to be appropriately informed as to the scope and intent of the policy, thereby ensuring a more open and deliberate process for policy development, providing for more suitable input from all stakeholders involved, and ensuring the implementation of the most appropriate policy.

Regarding the CRP as proposed, we have recommendations for enhancements to the policy in the following areas:

Dear Drs. Fitterman and Phurrough:

Novo Nordisk Inc. (Novo Nordisk) appreciates the opportunity to comment on the Medicare Clinical Research Policy contained in the Proposed Decision Memorandum issued April 10, 2007 (CAG- 00071R). We applaud CMS in reconsidering this policy that affects a wide range of vital clinical research. As Medicare is the largest purchaser of healthcare in the United States, and Medicare coverage and payment policy is often a guidepost for private payers, we urge CMS to proceed carefully and thoughtfully in finalizing the proposed Clinical Research Policy.

Novo Nordisk is a healthcare company and a world leader in diabetes care. The company has the broadest diabetes product portfolio in the industry, including the most advanced products within the area of insulin delivery systems. In addition, Novo Nordisk has a leading position within areas such as hemostasis management, growth hormone therapy and hormone replacement therapy. Novo Nordisk manufactures and markets pharmaceutical products and services that make a significant difference to patients, the medical profession and society.

General Comment

The proposed Clinical Research Policy should be further revised to enable CMS to meet its stated goal of encouraging Medicare beneficiary participation in clinical research studies that will add to the knowledge base about the appropriate use of products in the Medicare population for improvement of health outcomes. The proposed policy erects barriers to this goal because to obtain Medicare coverage and payment, manufacturers and other researchers will be required to meet three separate standards (i.e., General Standards for a Scientifically and Technically Sound Research Study, Medicare- Specific Standards, and, where applicable, National Coverage Determination Standards) for clinical research. Adding these standards to the current regulatory requirements will increase the administrative burden on research sponsors, principal investigators, physicians and others healthcare providers. Given these significant concerns, we encourage CMS to consider ways to ease the administrative burden and suggest one way to do so would be to rely on generally recognized scientific standards of clinical research rather than imposing separate standards for Medicare coverage.

Further, manufacturers customarily provide complimentary research-related items and services to study participants. The financial burden on Medicare beneficiaries of 20 percent co-insurance for Medicare covered clinical research will be a significant deterrent to beneficiary participation. We urge CMS to work with the Office of the Inspector General to devise a mechanism to relieve this potential obstacle to beneficiary enrollment in research studies.

1. Investigational Clinical Services

Proposed definition: and services that are being investigated as an objective within the study.

Medicare coverage would be subject to the following condition: The item or service in a clinical research study is an item or service that is currently available to the Medicare beneficiary outside the study (i.e., the item or service is covered under § 1861(a)(1)(A) of the Act).

Comment: Although and redefine those clinical services that are eligible for Medicare coverage and reimbursement during clinical research, it is unclear what services are included in the definition. We suggest that CMS clarify that if items or services are covered by Medicare, the same items or services furnished during a clinical research study, or that are the subject of a study, would also be covered and reimbursed by Medicare.

Further, implementation creates practical difficulties for manufacturers and sites when conducting blinded clinical trials. For example, in a blinded drug trial, principal investigators will not know what patients receive placebo and study drug. In this situation, it is unclear how a clinical site would determine how to submit claims for Medicare payment without unblinding the trial and jeopardizing clinical trial results.

2. Phase I Release of Study Results When Clinical Research Involves Debilitating or Life Threatening Illness

Comment: The Proposed Decision Memorandum does not define “debilitating or life threatening” and we encourage CMS to provide further guidance on this determination. A number of diseases may potentially be life threatening, but are manageable with sufficient therapy or treatment.

The Proposed Decision Memorandum does not impose a stringent requirement as to when Phase I study results need to be released in a public database or via publication, and we appreciate this flexibility. Manufacturers may be placed at a competitive disadvantage by the premature release of Phase I study results. Thus, we encourage retention of this concept in the final policy.

3. Clarification of Generalizable to the Medicare Population

The Proposed Decision Memorandum would add the following Medicare-Specific Standard: 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 population.

Comment: CMS’s interpretation and application of “generalizable to the Medicare population” is unclear. The Proposed Decision Memorandum suggests that a discussion of any potential benefits, potential impact and other factors on outcomes, and whether research is sufficiently powered. However, the proposed policy does not explain whether Medicare will rely on generally accepted scientific standards for sufficiently powered research or on some other standard to assist manufacturers in ensuring that clinical research is sufficiently powered to meet Medicare requirements. It would be helpful for the Proposed Decision Memorandum to include guidance or references to powering standards or other useful tools for manufacturers interested in meeting this requirement.

We also suggest that CMS confirm that local or national Medicare coverage would not be denied for items or services that were the subject of clinical research that Medicare later determines was not sufficiently powered to meet the proposed “generalizable to the Medicare population” requirement. We suggest that CMS revise the Proposed Decision Memorandum to explain that clinical research that meets FDA or other recognized scientific standards for sufficient powering of studies of items or services that may be used to diagnose or treat a Medicare covered illness or condition also satisfy Medicare “generalizable to Medicare population” requirements.

4. Clinical Research Policy’s Impact on Current Study Protocols or Ongoing Clinical Trials and Clinical Research

Comment: The Proposed Decision Memorandum will have significant impact on clinical trials and other research whose protocols have already been approved internally or have already begun. We suggest that the final National Coverage Decision explain how CMS expects to address this impact.

Specifically, we urge Medicare to apply any changes under a final National Coverage Decision prospectively. One suggestion is that the new policy apply only to clinical research that has not already been approved or submitted for approval to an Institutional Review Board or other internal body as of the effective date of the final National Coverage Decision. Of course, subsequent new clinical research for which an entity seeks Medicare coverage and payment would be covered by the revised policy.

5. Clarification of Why Clinical Study of Part D Drugs or New Indication for Part D Covered Drugs Are Not Included on Proposed Clinical Research Policy

The Proposed Decision Memorandum states: This policy is not applicable to and does not propose any changes to Medicare policies for coverage of prescription drugs under Medicare Part D.

Comment: We suggest that the final policy clarify that clinical research on drugs that currently meet the definition of covered Part D drugs, or drug, biologicals or other products that have the potential for coverage under the Medicare Part D benefit are subject only to meeting any FDA- approval requirements and general principles of good scientific practice generally recognized in the scientific community for clinical research. The policy in the Proposed Decision Memorandum does not explain how clinical research on covered Part D drugs or drugs that would potentially be eligible for coverage under Part D would be affected by the policy.

In addition, although we are aware of difficulties in applying the proposed policy to Part D drugs provided in a trial setting when they are available to beneficiaries outside of the trial, we encourage CMS to reconsider this position in recognition of the vital role self- administered outpatient prescription drugs and biologicals play in the health outcomes of Medicare beneficiaries.

6. Proposed Clinical Research Policy Does not Explain What are the “appropriate standards of scientific integrity”

General Standards for a Scientifically and Technically Sound Clinical Research Study: Seven Highly Desirable Characteristics All aspects of the research study are conducted according to the appropriate standards of scientific integrity.

Comment: We suggest that the final National Coverage Decision clarify that Phase IV data collection and registries that adhere to general principles of scientific practice recognized in the scientific community provide sufficient assurances that the research study has been conducted according to appropriate standards of scientific integrity. The Proposed Decision Memorandum fails to define or provide guidance on what Medicare would determine is “appropriate standards of scientific integrity.” General principles of good scientific practice generally recognized in the scientific community should be sufficient. Moreover, the clinical research practices that are conducted to avoid violation of fraud and abuse laws provide sufficient incentive to ensure that clinical research is based on accurate verifiable data. A separate, insufficiently defined Medicare-specific standard will not assist manufacturers or Medicare in meeting the goals of increasing Medicare beneficiary participation in clinical research or expanding the knowledge base to improve health outcomes for Medicare beneficiaries.

7. Effect of Clinical Research Policy on Medicare Coverage of Items and Services

Comment: We suggest that CMS clarify that FDA-approved or cleared items or services will not be denied Medicare coverage should clinical research on the products not meet all of the standards under a final Medicare Clinical Research Policy. The Proposed Decision Memorandum does not explain whether items or services that have been FDA- approved or cleared using clinical trials or other research that does not meet all three proposed Clinical Research Policy Standards would be covered by Medicare. For various reasons, financial and otherwise, clinical research on FDA- approved or cleared items and services may not have met the General, Medicare-Specific and National Coverage Determination Standards under the Proposed Decision Memorandum. However, assuming the items or services are used to diagnose or treat a Medicare covered illness or condition, FDA clearance or approval should provide sufficient assurances that clinical research on the products has adhered to scientific and technical principles. Medicare coverage should not be denied for an approved indication outside of the research setting due to additional Medicare-specific standards for coverage during clinical research on these products. The burden of meeting separate Medicare-specific standards will also limit or delay beneficiary access to promising new treatments.

Conclusion

Novo Nordisk thanks CMS for the opportunity to comment on the development of the Clinical Research Policy and looks forward to partnering with you on this issue in the future in order to provide Medicare beneficiaries with access to the highest quality care. Should you have any questions or like additional information, please feel free to contact me at the number below.

Sincerely,

A. Paige Keener, Esq.
Director, Medicare & Medicaid Policy
Novo Nordisk Inc.
pkee@novonordisk.com
202-626-4536

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May 10, 2007

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: Proposed Decision Memorandum for Medicare National Clinical Trial Policy (CAG- 00071R)

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 April 10 as part of the agency’s reconsideration of the current National Coverage Decision (NCD) on this policy.

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.

Over the nearly seven years that Medicare’s current Clinical Trial Policy has been in effect, 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 the current NCD, we urge the agency not to lose sight of the overarching goal of supporting beneficiary access to clinical trials and continued medical innovation.

Summary of Key Comments:

The goal of a patient-centered policy requires support for broad beneficiary access to the clinical benefits of promising research. We are concerned that some of the proposed changes, in particular those affecting research conducted under rules for Investigational New Drug (IND) studies and IND-exempt research, could have the unintended consequences of discouraging patient access, reducing Medicare beneficiaries’ enrollment in research studies, and delaying medical research. Both types of studies are carefully regulated by FDA – and both represent an important means for Medicare beneficiaries to secure access to promising innovations, and for generating better evidence on how particular medicines affect the Medicare population specifically.

PhRMA requests that, until CMS has clarified its procedures for determining whether such research meets the requirements of the Medicare Clinical Research Policy, the agency maintain the current status of IND and IND-exempt research as automatically qualifying for coverage of routine clinical care. CMS should ensure that its process avoid creating new barriers to access, such as delays in obtaining approval or the potential for inconsistent policy among Medicare carriers.

In addition, in order to avoid disruption to ongoing research, CMS should clarify that the new policy will only apply to new studies, and that current research that qualifies for coverage under the current Clinical Trial Policy will continue to qualify for coverage under the new Clinical Research Policy. This should apply to any study that currently has an approved Investigational New Drug application or is IND-exempt with Institutional Review Board approval. This will ensure that changes in the policy do not disrupt ongoing trials in which Medicare beneficiaries are receiving Medicare coverage of routine clinical care.

PhRMA also requests that CMS describe clear, open and transparent procedures for studies spurred by the Agency’s Coverage with Evidence Development guidance. We address this recommendation in more detail below.

Specific Comments:

1) Retain “Deemed” Status, In Its Current Form, for IND and IND-Exempt Studies

Steve Phurrough
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services

Subject: CAG-00071R: Proposed Decision Memorandum for Medicare National Clinical Trial Policy

Dear Dr. Phurrough:

The Council on Governmental Relations (COGR) is an association of more that 170 research universities and their affiliated academic medical centers and research institutes. COGR concerns itself with the influence of government regulations, policies, and practices on the performance of research conducted at its member institutions. We are pleased that the Centers for Medicare and Medicaid Services (CMS) has responded to concerns from the research community and opened a reexamination of the National Clinical Research Policy (CRP).

We encourage your careful review and consideration of the comments submitted by the Association of American Medical Colleges (AAMC). Representing US medical schools and the major teaching hospitals, AAMC’s comments represent the opinion of many of the major performers of clinical research in the United States.

We are particularly concerned about those features of the CRP that might limit Medicare beneficiaries from participation in appropriate clinical trials. In addition to the clarifications and resolution of conflicts between the general Good Clinical Trial and Medicare-Specific Standards described by AAMC, we believe that CMS should reconsider the exclusion of most IND exempt studies. We support the proposal advanced by the Medicare Evidence Development and Coverage Advisory Committee (MedCAC) to consider entities such as “professional societies, private foundations, academic health centers and university scientific review panels” as entities with delegated approval authority for IND-Exempt studies. The entities identified by MedCAC could serve as approval bodies for all clinical studies, and not be limited only to IND-exempt studies. As AAMC notes, the exclusion of most IND exempt studies may prove an unnecessary impediment to useful research.

In addition, we urge CMS to reconsider the decision to delete self-certification as an option. Without an alternative process for approval of studies, CMS’s decision may prove a disincentive for many valuable, small, investigator-initiated studies that have no other approval mechanism and hold potential benefit to Medicare beneficiaries. Research institutions have effectively reviewed and monitored studies through the time-honored, federally mandated review mechanism embodied in an Institutional Review Board (IRB). These Boards are responsible for assessing the risks and benefits of clinical research studies as part of their obligation to protect human subjects, and ensure the highest levels of research standards to all clinical studies conducted by research organizations.

In addition to potential limits on the participation of Medicare beneficiaries in research clinical trials, we echo the concerns expressed by AAMC and others in the need for clarifying and acknowledging the constraints on the method and timing of the public release of study outcomes. As others have noted, the ability to “fulfill” the method and timing can be constrained by a variety of factors including the timing and certainty of publication in a journal, the nature of agreements with study sponsors, or participation in a multi-site trial. The deletion of the requirement for fulfillment would alleviate the concerns.

Finally, we share AAMC’s concern that this revision does not resolve the questions concerning the relationship between this policy and the Medicare Secondary Payer Rule for Medicare beneficiaries and Medicare Advantage enrollees. The CMS interpretation of the rule as it applies to clinical research agreements poses a significant stumbling block for enrolling Medicare beneficiaries and Advantage enrollees in clinical trials.

Thank you for the opportunity to comment on the proposed revisions.

Sincerely, Anthony P. DeCrappeo President

Paper copy to follow by USPS

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May 10, 2007

Leslie Norwalk
Interim Administrator
Centers for Medicare & Medicaid Services
Hubert H. Humphrey Building, Room 443-G
200 Independence Ave, SW
Washington, DC 20201

SUBJECT: CAG-00071R - Proposed Rule

Relating to Medicare Payments for Clinical Trials

Dear Interim Administrator Norwalk:

On behalf of the University of California (UC), Office of the President, and the UC’s five academic medical centers (AMCs) located in Davis, Los Angeles, Irvine, San Diego, and San Francisco, we are writing regarding Proposed Rule CAG-00071R (“Clinical Research Policy”). Through this rulemaking UC is pleased that CMS is revising its policy on payment for items and services for Medicare beneficiaries who participate in clinical trials and appreciates this opportunity to provide comments.

Together, the UC health sciences and services programs are the nation’s largest health sciences and medical education training program, the fifth largest healthcare delivery system in California, the leading provider of certain specialty services and medical procedures, world leaders in clinical discoveries, and one of the state’s largest providers of care to Medicare patients. Annually, the AMCs provide patient care services valued at over $4 billion. In alignment with their patient care work, the AMCs also play a critical role in a number of broad public-policy goals, including the education of health professionals and the advancement of medical science through cutting-edge research. Specifically, UC medical centers offer services that are essential to the health and well being of Medicare beneficiaries including a broad-array of highly specialized services, such as cancer centers, geriatric and orthopedic centers of excellence, organ transplant programs, and world class primary and preventive care.

Our specific comments on the rule are as follows:

1. Name Change

UC supports CMS’s proposal to change the prior National Coverage Decision for Clinical Trials to Clinical Research Policy, thus acknowledging the importance of permitting Medicare beneficiaries access to a broad range of scientifically qualified studies.

2. Definition of Clinical Research

UC supports CMS’s efforts to clarify the definition of “clinical research,” however, we recommend that the Common Rule’s definition of “research” serve as the foundation for the Clinical Research Policy’s definition of the term “clinical research.” In addition to this foundational definition, we propose the following modifications to the term “clinical research”:

The phrase “clinical research” means:

“research conducted with human subjects with diagnosed disease and/or healthy controls that tests hypotheses relating to disease, injury or illness in order to analyze the mechanisms of human disease, therapeutic interventions, diagnostic tests, prevention, and/or the development of new healthcare technologies. Examples of clinical research that are supported under the Clinical Research Policy, include, but are not limited to:

May 10, 2007
VIA FedEx and Electronic-Mail to
CAGinquiries@cms.hhs.gov
Steve Phurrough, M.D., M.P.A.
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, Maryland 21244-1850
RE: Proposed Decision Memo for Clinical Trial Policy (CAG-00071R)
Coverage Pathway for Humanitarian Use Devices under Humanitarian Device Exemption
Dear Dr. Phurrough:

On behalf of ABIOMED, the developer, manufacturer and marketer of the AbioCor® Implantable Replacement Heart (AbioCor®), we are pleased to submit comments on the above- captioned Proposed Decision Memo for Clinical Trial Policy (the “Decision Memo”). Our comments are focused on the need, within the Clinical Research Policy (CRP) , for CMS to articulate clearly the pathways for coverage of Humanitarian Use Devices (HUDs) marketed pursuant to an U.S. Food and Drug Administration (FDA)-approved Humanitarian Device Exemption (HDE). Specifically, we request that the Centers for Medicare and Medicaid Services (CMS) provide for coverage of an HUD, as an investigational clinical service, where the HUD is marketed under an FDA-approved HDE and is subject to FDA-approved post-approval study. Our rationale for making this request and recommended language to incorporate into a Final Decision Memo are provided below.

I. Background on ABIOMED and the AbioCor® Implantable Replacement Heart

ABIOMED, Inc. (“ABIOMED”) is a publicly traded company that develops, manufactures and markets medical products designed to assist, recover or replace the pumping function of failing hearts. The company has devoted over 20 years in the development of the AbioCor®, a total replacement heart in collaboration with many medical and scientific professionals, the Food and Drug Administration, the National Institutes of Health, and patients and their families committed to advancing the options of care for those who suffer from end-stage cardiac failure. The AbioCor® implantable replacement heart is the world’s first completely self-contained, internal replacement heart. The AbioCor® sustains the body’s circulatory system and mimics the function of the human heart. The complete system consists of an internal thoracic unit, an internal rechargeable battery, an internal miniaturized electronics package and an external battery pack, handheld alarm monitor and sophisticated computer console. The thoracic unit of the AbioCor®, weighing approximately two pounds, includes two artificial ventricles with corresponding proprietary artificial valves which provide a seamless blood path, as well as a motor-driven hydraulic pumping system.

AbioCor® was designated as a Humanitarian Use Device by the FDA’s Office of Orphan Product Development in September 2003. In September 2006, ABIOMED obtained approval of an HDE to market AbioCor®. The device— “[I]s indicated for use in severe biventricular end stage heart disease patients who are not cardiac transplant candidates and who

UPMC Cancer Centers and the University of Pittsburgh Cancer Institute (UPCI) appreciate the opportunity to provide comments addressing the proposed Clinical Trial Policy (CAG-00071R). UPMC Cancer Centers and UPCI strongly support Medicare’s actions, including the National Coverage Decision (NCD), which work to reduce barriers and improve access for Medicare beneficiaries to qualified research. In an effort to further improve clinical research access by Medicare beneficiaries we would like to call attention to a few concerning issues in the proposed final NCD.

In addition to our comments on the proposed NCD, we would like to 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 the CMS organization responsible for the creation of the Clinical Research NCD continue to actively engage CMS as a whole to resolve the coverage issues currently affecting Medicare Advantage. 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 an NCD. Further, the Balanced Budget Act made provision for the resolution of Medicare Advantage’s coverage for trial participants.

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. 35079422.109(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.”

Unfortunately neither provision was fully recognized, and rather than substitute payment structure involving a change in coverage was implemented. Please take this opportunity to incorporate all of the necessary changes in CMS’ 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.

General Standards

CMS has proposed several changes to the standards that define qualifying clinical research. The previous seven highly desirable characteristics have been renamed and an additional criterion requiring a written protocol has been included. The Medicare Specific Standards have been expanded with inclusion of four new requirements and the removal of two unnecessarily duplicative statements. Overall, the new terminology adds clarity to the structure of the requirements; however, some of the requirements themselves are confusing or problematic.

The newly formed “general standards for a scientifically and technically sound clinical research study” are good examples of the attributes constituting well-designed clinical research. If CMS believes that it is necessary to define these standards, we will not argue. Our issue with the inclusion of the general standards is that they are unnecessary unless an alternate means of acquiring qualifying status becomes available. According to the proposed rule the only means established to confirm meeting the general standards is through the deeming process. As a result the general standards would only serve as guidance to the organizations able to invoke a deemed status for clinical research. We believe that these standards are already fully considered and accounted for by the organizations listed in the section on deemed status and therefore are unnecessary. If an alternate means of qualifying research for coverage becomes available, the standards could be added at that time and made relevant to the new deeming process.

Medicare Specific Standards

The Medicare Specific Standards in the proposed NCD include requirements intended to increase transparency and derive value to the Medicare population. While in theory the requirements appear benign, we believe that in practice some of the additional requirements will negatively impact clinical research.

Specifically, the third Medicare Specific Standard, which requires the scheduled release of outcomes to the public, is problematic. This proposal is a very late entry into this proceeding and we would ask that CMS first evaluate to determine if there truly is problem of access to study results (both complete and incomplete) within the scientific community, prior to adding the requirement to the proposed NCD. Further, due to the already sensitive and risk-charged process of product development, the end result of this type of policy could be to cause an overall decrease in both number and size of industry sponsored research studies. A more responsible scientific practice than open reporting would be to continue allowing the scientific community to review and evaluate complex data for validity prior to making it publicly available while maintaining an option for public reporting when appropriate.

The fourth and fifth requirements, to document in the protocol inclusion criteria for subpopulations and the generalizeability to the Medicare population respectively, would be more appropriately included as general standards for a scientifically and technically sound clinical research study. Further, since the Medicare population is composed of subpopulations, the successful completion of requirement four would make it unnecessary to document requirement five specifically. Both requirement four and five represent good guidance for clinical research that we believe is unnecessary to state or to attempt to verify as part of this NCD. It would be more effective to implement this guidance through the channels of the deeming agencies, who we believe are already sensitive to the issues.

IND-Exempt Studies

The decision to stop allowing IND-Exempt trials deemed qualifying status is confusing and counterproductive. IND-exempt trials are reviewed by the FDA, an identified deeming body, and determined to be good clinical research. The proposed Clinical Research NCD will force investigators to insist that the FDA track proposed studies under the IND designation if coverage for IND-Exempt studies is no longer available. The result will be a dramatically increased workload at the FDA which will slow approval of new studies and decrease the agencies ability to oversee existing studies. At the very least the proposed Clinical Research Policy should continue to cover IND-Exempt studies until an alternate approval process can be developed.

Grandfathering

There is no discussion of the effect of the proposed policy on clinical research studies currently in operation. The proposed policy includes several new requirements involving additions to the original protocol and a requirement for registration prior to subject enrollment. The new requirements would exclude the many of the research studies currently in operation from attaining qualifying status unless some form of grandfathering is implemented.

Final Thoughts

The proposed NCD does an effective job of clarifying Routine Clinical Services, Investigational Clinical Services, and the approval process. It is also clear that Medicare contractors are responsible for insuring that the requirements associated with approval are met. It is our hope that the local contractors will, in a timely manner, develop guidance on the documentation and processes which provide for successful compliance with this NCD. We are also encouraged but skeptical about CMS’ statement to continue pursuing options for certification beyond the deeming process and increasing coverage for areas not currently covered (orphan drugs, and research involving medical procedures).

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 the work done in clarifying existing components of the NCD as well as extending the coverage to a more diverse array of clinical research. As noted above we are concerned about how some of the new policy elements will manifest in practice and the decision to no longer cover IND-Exempt studies. 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,

Ronald B. Herberman, M.D.
Director, University of Pittsburgh Cancer Institute
and UPMC Cancer Centers

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May 10, 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: [CAG-00071R] Proposed Decision Memo for Clinical Trial Policy

Dear Dr. Phurrough:

The Medical Imaging and Technology Alliance (MITA), a division of the National Electrical Manufacturer’s Association (NEMA), is pleased to submit comments regarding the proposed revisions to the national coverage determination (NCD) Clinical Trial Policy, to be renamed the Clinical Research Policy . As the leading trade association representing companies whose sales comprise over ninety percent of the global market for medical imaging, we are pleased to provide the Centers for Medicare and Medicaid Services (CMS) with our perspective on ways to enhance participation from Medicare beneficiaries in clinical trials by expanding Medicare coverage to include certain investigational products and services.

Medical imaging encompasses X-ray imaging, computed tomography (CT) scans, radiation therapy, diagnostic ultrasound, nuclear medical imaging including positron emission tomography (PET) and magnetic resonance imaging (MRI). Imaging is used both to diagnose and treat patients with disease and offers physicians the ability to view soft tissue and organs, often reducing the need for costly and invasive medical and surgical procedures. In addition, imaging equipment is used in some procedures to guide physicians as they carry out a medical or surgical intervention to ensure high-quality clinical results for the patient.

Because imaging has become a standard of modern care for virtually all major medical conditions and diseases, including cancer, stroke, heart disease, trauma, and abdominal and neurological conditions, it is necessary to perform clinical trials to ensure enhancements of these life- saving technologies are properly researched. Imaging clinical trials differ from drug and biological trials because the underlying research focuses on understanding how specific imaging tests can be used to diagnose, screen, direct treatment pathways, monitor disease progression as well as develop incremental improvements on existing technologies. It is important for CMS to understand the adverse effects on patient access to imaging services if certain provisions in this NCD are not defined in a clear manner.

MITA asks CMS for clarification regarding the following issues:

• Unjustifiably duplicate existing studies
• Therapeutic outcomes
• Treatment of non-deemed studies
• Investigational Device Exemption (IDE)

Unjustifiably Duplicate Existing Studies

CMS outlined general standards for a scientifically and technically sound clinical research study. One of the criteria listed was that “a research study does not unjustifiably duplicate existing studies.” MITA asks for clarification regarding the use of the term unjustifiably. We feel it is unwise to restrict the proposed policy to exclude all duplicate existing studies, and seek guidance to determine what CMS considers a justifiable duplicate study. Many imaging studies build upon existing bodies of evidence to determine if intricate imaging scans are more accurate or if combination studies enhance diagnoses. We understand the Agency’s intentions to limit duplicate clinical studies, however the objective of this standard should not be to create guidelines that limit access to innovative technologies for patients, nor should it foreclose reasonable methods of developing efficiencies on how imaging technology is studied.

Therapeutic Outcomes

CMS proposes as one of the Medicare- specific standards for clinical research studies, “Research studies…whose protocols commit to measuring therapeutic outcomes (emphasis added) as one of the objectives, may meet this standard only if the disease being studied is chronic, life-threatening, or debilitating.” We ask that CMS clarify the definition of the term “therapeutic outcomes.” As you know, many imaging studies do not focus solely on researching therapeutic intent but also concentrate on enhanced diagnostic interventions, leading to overall better patient care. It is important for future imaging studies that therapeutic outcomes continue to encompass diagnostic interventions.

Treatment of Non-Deemed Studies

NEMA seeks guidance on the treatment of research studies involving Medicare-covered items and services, wherein the studies do not qualify for coverage under the Clinical Research Policy deemed status, CED coverage, or the IDE provisions noted below. Such studies may include, for example, post-market clinical evaluations sponsored by private organizations. According to the Clinical Research Policy, there appears to be no process for securing coverage for these non-deemed studies. We recommend that CMS develop a process for reviewing and approving such studies in the future.

NEMA believes that it is important to support this research which generates significant evidence on the diagnostic and treatment interventions appropriate for Medicare beneficiaries. Absent a process for addressing these non-deemed studies, sponsors and participating institutions will be less likely to undertake such research.

Investigational Device Exemption (IDE)

Finally, we thank CMS for verifying that this national coverage determination is not applicable to, and does not propose to 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. MITA agrees with CMS that the current policy of allowing Medicare coverage of IDE clinical trials remains an appropriate measure and does not expand standing coverage or payment policies. CMS local carrier medical directors have the in-house expertise to determine appropriate coverage of IDE clinical trials that best affects Medicare beneficiaries in their respective geographic regions, thereby allowing continued access to life-enhancing technologies.

Conclusion

In providing coverage of routine clinical trial costs, as well as investigational services and items which are reasonable and necessary to diagnose and treat Medicare beneficiaries, CMS provides an excellent opportunity for improved data collection for the population which is most affected and in need of new therapies. We urge CMS to ensure future imaging studies are not restricted due to limited opportunities for enhanced clinical research. We strive to continue working with CMS on these matters under the proposed Clinical Research Policy.

Respectfully submitted,

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May 10, 2008

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

Re: CAG-00071R: Proposed National Coverage Decision for Clinical Trial Policy

Dear Dr. Phurrough:

The American Association of Neurological Surgeons (AANS), the Congress of Neurological Surgeons (CNS), and the American Society of Interventional and Therapeutic Neuroradiology appreciate the opportunity to comment on the proposed revisions to the Medicare National Clinical Trial Policy, published on April 10, 2007. While we commend the Centers for Medicare and Medicaid Services (CMS) for clarifying aspects of its Clinical Trial Policy, we are disappointed that the agency failed to develop a new coverage policy for Humanitarian Use Devices (HUDs). Currently CMS has no national policy concerning Medicare coverage for HUDs those devices that have been granted a Humanitarian Device Exemption (HDE) by the Food and Drug Administration and we had hoped that the agency would develop such a policy as part of the Clinical Trial Policy NCD process.

In the Clinical Trial Policy “tracking sheet” issued in July 2006, CMS indicated that it would include policy for the coverage of HUDs as part of the Clinical Trial Policy (to be renamed Clinical Research Policy) proposed NCD. We were therefore surprised to see that this new proposed policy did not include a separate provision for HUD coverage. Instead, CMS recommends that HUDs be covered only through the Coverage with Evidence Development (CED) process in an NCD. We disagree with this decision. We believe that devices approved by the FDA under a humanitarian device exemption (HDE) should have a special pathway for Medicare coverage consideration.

We would like to see CMS develop a policy to cover HUDs for which there may not be an NCD but for which the device is included in clinical research such as a registry that meets CMS approval. The FDA HDE approval process allows devices for treatment of rare and orphan diseases for unique and small patient populations for which large trials are difficult or impossible to conduct. We believe CMS can design a coverage path that will permit Medicare beneficiaries to receive coverage for these potentially life-saving devices in a timely manner and assure that a reasonable level of data collection is conducted through a registry or other means deemed fitting by CMS.

Our contention that HUDs should be covered is consistent with the position we expressed to CMS on September 8, 2006 in our comments regarding proposed coverage for Intracranial Stenting and Angioplasty (CAG-00085R2). We continue to believe that coverage for this device and other devices approved by FDA under a HDE should be provided for Medicare patients. Delay in access to these devices represents a potential loss of life for those Medicare patients who need these devices. We believe covering HUDs is the right thing to do, as some of the patients who are appropriate candidates for these devices would die if left untreated.

We thank you for the opportunity to comment on this important proposed decision memorandum and we urge you to include a separate provision in the final NCD outlining a plan to cover HUDs.

Sincerely,

Jon H. Robertson, MD, President, American Association of Neurological Surgeons

Douglas Kondziolka, MD, President, Congress of Neurological Surgeons

Gary M. Nesbit, MD, President, American Society of Interventional and Therapeutic Neuroradiology

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Thank you for the 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). I am submitting comments on behalf of ASBMT and the NMDP.

ASBMT is the American Society for Blood and Marrow Transplantation, an association of 1,500 clinicians and investigators promoting research, education and clinical practice in the field of blood and marrow transplantation and related cellular therapy.

NMDP is the National Marrow Donor Program, established in 1987 to facilitate unrelated donor allogeneic transplants. The NMDP maintains a registry of more than 6 million adult volunteer donors in the United States and a listing of more than 50,000 cord blood units. It has coordinated more than 25,000 allogeneic transplants and conducts research as a partner of the Center for International Blood and Marrow Transplant Research (CIBMTR) and The Blood and Marrow Transplant Clinical Trials Network (BMT CTN).

ASBMT and NMDP strongly endorse CMS interest in re-examining support of clinical trials. We view clinical trials as fundamental to advancing stem cell transplantation as effective and often curative therapy for a variety of hematologic malignancies, inherited diseases and blood disorders. Improvements in outcomes resulting from clinical trials in transplantation have positioned transplantation therapies as part of the armamentarium in treating Medicare beneficiaries with certain diseases. Investigation of the utility of stem cell transplantation in a variety of other diseases has been hampered, however, by the present policies which limit funding of clinical trials. ASBMT and NMDP jointly support most of the proposed policy changes, but have concerns about several. Those concerns are addressed below.

PROPOSAL 4 – REGARDING MEDICARE-SPECIFIC STANDARDS

ASBMT and NMDP believe that research studies must be vetted through a peer review process, and only scientifically sound data should be offered to the public. Peer review has been an effective method for verifying the authenticity as well as outcomes of clinical research. Premature release of data (whether encouraging or disappointing) that has not been reviewed could be misleading for both the public and the scientific community.

For research that is not published through peer review, an alternative might be to require a summary paragraph in the federal registry of clinical trials addressing certain elements listed in the proposal. These should include accrual information as well as any unanticipated toxicity.

We applaud the mention of the health care disparities among many subpopulations. Transplant services are needed within all groups. However, we are concerned that the proposed policy changes would exclude from clinical research studies Medicare beneficiaries younger than 65 years of age. We believe that all Medicare beneficiaries should be allowed to participate in clinical research studies. Younger beneficiaries may have diseases that are not common in the general Medicare population, but inclusion in clinical trials may benefit the general population.

Furthermore, some older beneficiaries may meet criteria for therapies such as reduced intensity allogeneic transplantation, autologous transplantation or newer applications of cellular therapy. Medicare recipients should not be denied the opportunity to participate in trials that advance therapeutic outcomes addressed by these treatment modalities. A focus that is limited to those 65 years of age and older would undermine the intent of the clinical research policy to address health care disparities among all Medicare beneficiaries.

PROPOSAL 6, REGARDING DEEMING AND SELF-CERTIFICATION FOR QUALITY CLINICAL TRIALS

ASBMT and NMDP are concerned that removal of the self certification process may result in a disincentive for patients to enroll in non-qualified trials. In addition the proposal to remove IND-exempt studies is alarming. A majority of the advances in hematopoietic stem cell transplantation have occurred in IND-exempt studies. Such studies have examined questions regarding new uses of drugs in therapy, supportive care, transplant indications or even patient selection. Exclusion of IND-exempt studies would serve as a major obstacle to clinical research and patient access to state-of-the-art transplant care. An alternative would be to develop criteria for self- certification and establish local review committees that can determine if a study meets the criteria of both the General Standards for a Scientifically and Technically Sound Research Study and the Medicare-specific standards.

The IDE issue has an additional dimension that needs attention. In the case of cellular therapies such as hematopoietic stem cell transplantation and immunotherapy, the FDA in some instances considers cellular processing procedures and products a biologic – for example, the infusion of Natural Killer (NK) cells – and these fall under IND review. For other indications, the agency considers the processing procedure and products a device – for example, CD3 depletion of an allogeneic cell product – and therefore these fall under IDE review. The FDA subjects both INDs and IDEs to rigorous review. Medicare beneficiaries should not be denied coverage for trials involving IDEs.

Attention also should be given to appropriate “grandfathering” of patients currently enrolled in clinical trials.

We would be pleased to assist CMS in the development of criteria for the inclusion of IND-exempt studies.

Thank you again for the opportunity to submit these comments. Please let us know if you have any questions or need clarification.

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End stage renal disease has been a funded, supported, and monitored for over 40 years. As the guardian of the patients being served by this benefit, it is important to bring to your attention the lack of forward direction being required and applied by our health care system in America. European patients have been monitored and successfully achieved a higher level of well being and physical wellness by concentrating not only on the clearance of the toxins (urea) but by focusing on the undeniable need for fluid management of their patients. We, as a society who considers ourselves on the cutting edge of technology, have fallen terribly short of the goal to lengthen and improve the quality of our patients' life. Because it has not been a required and monitored aspect of our treatment, this part of dialysis has been sorely and inaccurately handled in the daily care.

Subsequent problems with the lack of fluid management and control has resulted in a continued escalation of hospitalizations and cardiac deterioration in a population of patients that is only going to increase beyond the 600,000 mark in the next 10 years due to the population of the baby boomers and the rising numbers of diabetics and hypertensive patients.

We need you to focus, to demand, to hold accountable a standard that has already been proven as a significant outcome tool to protect our patients, lengthen and strengthen their lives and decrease the abhorant rise in medical care, particularly the acute level of care.

Their are already FDA approved standards and equipment for managing this need for fluid removal. We as caregivers have made efforts to manage this without success because their has not been a standard set, a bar to reach, a society who is watching over this problem

Please focus on this and improve the outcome on all levels. It is imperative. Thank you

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We thank the Center for Medicare Services (CMS) for providing the research community with the opportunity to comment on Proposed Decision Memo for Clinical Trial Policy (CAG-00071R) and recognize the need for CMS to develop consistent and operationally effective standards for determining when a clinical research study is qualified to be reimbursed by CMS. We welcome a number of the proposed revisions, however we caution against implementation of the decision as currently written without further clarification.

We were particularly struck by three revisions that appear to run counter to CMS’s stated intent to allow Medicare beneficiaries to participate in research studies, to encourage the conduct of research studies that add to the knowledge base, and to allow beneficiaries access to have access to emerging treatments that may have a health benefit. The three revisions of concern are 1) the addition of a definition of clinical research to be covered, 2) the elimination of IND exempt trials from deemed status, and 3) the elimination of self certification.

It is our belief that in revising the definition of research, CMS intended to expand coverage beyond clinical trials to all research designs involving human subjects. However, in broadening the scope of the decision CMS may have unduly created a coverage exemption for standard care procedures that would be covered if a beneficiary were not in a research study. Specifically, we are concerned that beneficiaries who volunteer for observational outcome studies of specific interventions, experimental and quasi-experimental studies of primary and secondary prevention strategies, delivery of care modalities, or health services research will be excluded from CMS reimbursement if those studies are IND exempt, not federally funded, or have no Federal review mechanism. Because this may have a profound and detrimental effect on clinical research, we request specific clarification regarding clinical research in this category. Two key examples of this situation are as follows.

Consumers Union, the independent, non-profit publisher of Consumer Reports, congratulates and strongly supports CMS’s proposal to require the registration of all clinical trials prior to the enrollment of the first study subject, and that the research protocol specifies and provides for the public release of all pre-specified outcomes to be measured, including release of outcomes if outcomes are negative or the study is terminated early.

Thousands of Americans have suffered, and many have died, because drugmanufacturers have repeatedly hidden and distorted clinical trial data and results. We strongly support CMS’s efforts to prevent the abuses of the past, and to use better scientific methods in Medicare’s coverage decisions. We believe your efforts will help promote evidence-based medicine and our understanding of what medicines and procedures are truly effective and safe—and worth paying for. A key to this process is requiring that all trials—including their principal endpoints—be registered, and that the results of those trials, whether good or bad, are added to the public, scientific database.This proposal will help researchers understand areas of study that are unproductive and even harmful to trial participants, and in the long run, it will help promote effective and less costly research on new drugs, procedures, and devices.

Fellow citizens who participate as basically human Guinea Pigs in clinical trials deserve to have their contribution added to the sum of human scientific knowledge. We believe it is fundamentally wrong to ask people to participate in trials and not to share that trial, and that trial’s results, with the world’s scientific community. Some will say such sharing of scientific knowledge is interfering with their commercial rights. We hope you will reject that argument. Trials that are supported by public money, either directly through NIH grants, or indirectly through tax code subsidies, should be part of the public domain.

On other issues, we hope you will do more to promote diversity—race, age, and sex in the clinical trial populations. All too often, trials are conducted largely on relatively healthy, middle-aged Caucasian men. That is not the population that is most likely to eventually use the medicine! We are a diverse nation, and for the sake of understanding safety and effectiveness of drugs, we need a diverse clinical trial population.

On the issue of self-certification, we strongly believe that self-certification by industry is not sufficient. We have seen in the case of Ketek and in a series of reports by Bloomberg News, the quality and honesty of some of these trials has been somewhere between criminal and unacceptable. There is too much money in play to entrust the lives of trial participants to those whose fiduciary duty is not to science, but to their stockholders.

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Steve Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Blvd., Room C1-12-04
Mail Stop C1-09-06
Baltimore, MD 21244

Re: CAG-0071R – Proposed Decision Memorandum for National Clinical Trial Policy

Dear Dr. Phurrough:

The Accelerated Community Oncology Research Network (ACORN) is a network of 30 community oncology sites who conduct research trials collaboratively with the aim of achieving a more efficient research process. Our goal is to advance the science of oncology care as rapidly as possible in order to bring needed improvements in treatment options to our patients.

The proposal by CMS to no longer support IND-exempt trials will have detrimental effects on the scientific process in oncology, and will hurt Medicare patients in particular. We design and conduct many investigator-initiated trials through the ACORN network. All trials using medication are submitted to the FDA as part of the IND process. After careful review of the study protocol, most, but not all, of these trials have been judged to be IND-exempt by the FDA. That is not to say that these studies are not scientifically important, but that they do not require an IND according to current federal guidelines. All of these trials still undergo review and approval by an IRB. All investigators follow federal regulations and ICH GCP throughout the conduct of the study.

This determination by CMS would effectively deny clinical trial participation for IND-exempt studies to Medicare patients. Therefore, our ability to evaluate which approved drugs are optimal for use in older adults will be reduced. There is a need to study treatment regimens specifically in the context of their efficacy in older adults, as mandated by federal regulations on this topic. Chemotherapy regimens in particular are noted to have substantial toxicities that may be much more poorly tolerated among older adults than in younger populations. ACORN has conducted investigator-initiated trials aimed specifically at determining the efficacy and safety of certain cancer treatments for geriatric patient populations, and in some cases these trials have been classified as IND-exempt by the FDA. These treatments are approved by the FDA on the basis of studies showing their efficacy in a group of patients primarily composed of younger patients, and it is can be unclear how useful these treatments will be in older adults.

Therefore, withdrawing coverage for IND-exempt trials will hurt Medicare beneficiaries directly by decreasing their ability to enroll on a clinical trial, as well indirectly by reducing the number of trials that might have brought clarity to optimizing treatment for cancer in older adults.

ACORN is committed to conducting clinical trials in oncology that contribute directly to improvement in clinical care for patients with cancer. We strongly recommend that CMS continue to provide coverage to beneficiaries who may enroll in an IND-exempt clinical trial.

Sincerely,

Lee S. Schwartzberg, MD, FACP
President, Accelerated Community Oncology Research Network

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

May 9, 2007

By Electronic Submission

Steve Phurrough, MD
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 Medicare National Clinical Trial Policy (CAG-00071R)

Dear Dr. Phurrough:

Genentech, Inc. (“Genentech”) appreciates the opportunity to submit the following comments in response to the revisions proposed by the Centers for Medicare & Medicaid Services (“CMS”) to the Medicare National Clinical Trial Policy (“NCD”).

As you are aware, 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 has recognized that there is considerable confusion in the clinical research community and among beneficiaries about the scope of Medicare coverage for clinical trials, and that the current NCD has not been as effective as it could be in encouraging Medicare beneficiaries to participate in clinical trials. Genentech welcomes many of CMS’ proposed changes outlined in the April 10, 2007, Proposed Decision Memorandum (“Proposed Decision”), such as clarifying “therapeutic intent” and defining “routine clinical services.” Other revisions proposed by CMS, however, are inconsistent with the principal goal of the NCD, which is to reduce the barriers to beneficiaries’ participation in clinical research studies. Some of CMS’s proposed revisions also conflict with the Agency’s limited role in regulating clinical trial design and conduct. Instead, changes to the NCD should seek to expand the opportunities for Medicare beneficiaries to participate in clinical trials by reducing the barriers to participation rather than by enacting vague and confusing new requirements on clinical trial sponsors and study sites. Any general or Medicare-specific standards in the CRP should be standards that can be evaluated at the beginning of the trial, so that charges appropriately billed to Medicare are not subsequently deemed to be improper.

It also is important that the final CRP apply prospectively only to new clinical studies and not retrospectively to ongoing studies. Grandfathering existing clinical studies will ensure that Medicare coverage rules for those studies do not change in the middle of the study.

Specifically, in revising the proposed NCD, CMS should:

I run the clinical cancer research program at a tertiary care community hospital and also serve as PI for the St. Louis-Cape Girardeau CCOP. I speak for all of my colleagues when I say that I wholeheartedly agree with the comments submitted by ASCO. The IND exempt trials need to be covered by Medicare, and CMS needs to work closely with the FDA to refine this policy. These trials are large part of our cancer research program and we need to make them available to Medicare patients.

We also are very troubled by the refusal to address the Medicare Advantage issue. We have many patients in these plans who are unable to participate in clinical trials because of the financial disincentive.

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On behalf of the University of Arkansas for Medical Sciences (UAMS), please find our comments in response to the April 10, 2007 request by CMS for public comments regarding the Proposed Decision Memo for Clinical Trial Policy (CAG-00071R). UAMS is a state institution with a large clinical research program involving both industry-sponsored and investigator-initiated research.

The Proposed Decision Memo for Clinical Trial Policy provides clarification in a number of areas. However, as written, it creates uncertainty and in some cases impractical complications for research which is already subject to strict and ever increasing regulation. The final Clinical Research Policy will have a significant impact on the conduct of research.

I.1. Definitions

Proposed Definition: “Clinical research is the observation of events in groups of individuals who share a particular characteristic, such as a symptom or illness; or who have the same treatment or diagnostic test provided for a symptom or illness. Inferences are made based on comparisons of predefined health outcomes among groups. Procedures are in place to assure that the rights, safety, and wellbeing of research study participants are protected. Research studies need to conform to all applicable Federal regulations concerning human subject protection and privacy including 45 C.F.R. Part 46 and Parts 160 and 164.”

Comment: The federal regulations which govern research provide definitions for “research” (45 CFR 46.102(d)) and “clinical investigation” (21 CFR 50.3(c)) which are vastly different from that proposed by CMS. This difference, by itself, creates confusion and uncertainty. However, we assume the intent of providing a definition within this policy is to specify a particular subset of research that should be subject to evaluation under the standards of the Decision Memo. With that assumption, we turn to the proposed definition.

The first sentence of the proposed definition states “Clinical research is the observation of events in groups of individuals who share a particular characteristic, such as a symptom or illness; or who have the same treatment or diagnostic test provided for a symptom or illness.” Section IV.A.2 of the memo recites, “[M]any researchers have a very narrow definition of ‘clinical trial’ and as such many studies that CMS would like to support may not be included. By proposing a change to the name of the policy to the CRP, we hope to signal our continued support of beneficiaries’ participation in the full range of qualified, scientifically sound research projects.” Rather than provide support for research, the overly broad definition of clinical research casts a wide net which would, for example, subject clinical services later reviewed under a “study” to the evaluation of the standards of the Decision Memo. This definition fails to include any requirement that the research study provide any type of clinical intervention for a subject. In fact, it would seem to only encompass studies which make observations, rather than clinical intervention, such as focus group studies or retrospective chart reviews. In addition, the latter part of this definition seems to expressly exclude studies that involve both a control group and an intervention group, as these two groups would not receive the same treatment or diagnostic test. Much valuable clinical research would be excluded if these types of studies are not included.

The definition then lists procedures that need to be in place and regulations to which the study must conform. It is to be expected that the protocol will address these procedures and that the IRB and Investigator comply with all applicable laws and regulations. However, these requirements should not be included as part of a definition of research. In fact, these requirements are more appropriately addressed in the general standards for a sound clinical research study.

Recommendation: We recommend that the definition of clinical research read 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 and which is carried out using appropriate controls and data safety standards.

Some examples of the types of clinical studies that might be supported follow, but this list should not be considered an all-inclusive list:◦ Randomized controlled trials and other comparative clinical studies of effectiveness and comparative effectiveness; and◦ Clinical studies of diagnostic tests, including measurements of sensitivity and specificity, and impact on physician decision making and patient outcomes.

II.1. Definitions Medicare Specific Standards for Clinical Research Studies

Proposed standard: “The research study protocol specifies and fulfills 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.”

Comment: As an academic medical center and a state institution, we certainly support the public release of study results, regardless of outcome. However, we are troubled by the statement “and fulfills”. Publishing in a peer reviewed journal is beyond the control of the investigator, no matter how dedicated the academic medical center may be to get the results to the public. CMS states that it would also be acceptable to publish in a sponsor supported database, but once again, this is a format that is not within the control of the investigator. Stating that publishing must be fulfilled also raises a concern as to whether procedures that were appropriately billed during the study could be deemed inappropriate if the methods and timing of the results are not met. This requirement is impractical and unnecessary.

Recommendation: We recommend that CMS delete “and fulfills” from the proposed standard or in the alternative provide for a form of public release within the control of the investigators, for example on a public website.

III.1. Definitions Medicare Specific Standards for Clinical Research Studies

Health Disparities proposed standard: “The research study protocol must have explicitly discussed inclusion criteria and considered relevant subpopulations (as defined by age, gender, race/ethnicity, socioeconomic or other factors).”

and

Medicare Populations proposed standard: “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 population.”

Comment: The typical protocol discusses inclusion/exclusion criteria focused primarily on the disease and related factors. The vast majority of these studies are open to any population with the specific disease being studied, including the Medicare population, regardless of race/ethnicity, gender or socioeconomic factors. In studies such as these, requiring an explicit statement that relevant subpopulations have been considered and a statistical power analysis significantly increases the burden on institutions and will likely result in a decrease in studies for the Medicare population. Further, the goal of the Executive Order was to remove barriers to the Medicare population to participate in clinical trials. These requirements run counter to the Executive Order.

Recommendation: Revise standards to provide coverage for studies which are open to all relevant populations without requiring explicit statements or power calculations.

IV.4. Approval Processes

Proposed Language: “Studies conducted under an Investigational New Drug (IND) when the FDA has reviewed the protocol and the IND has not been put on hold.”

Comment: As written, the proposed language would seem to eliminate any IND study that had ever been placed on hold. It is assumed that if a study had been put on hold and later the hold was lifted, the study would qualify.

Recommendation: For clarity, we recommend that the language read, “Studies conducted under an Investigational New Drug (IND) when the FDA has reviewed the protocol and the IND research activities are not halted due to a current clinical hold.”

Clarification Request: Also, the FDA allows for subjects to remain on therapy under a clinical hold if it is in the interest of patient safety (21 CFR 312.42). We seek clarification for this situation.

V.4. Approval Processes

Proposed change: Remove the following options for “deeming” studies: IND Exempt Studies

Comment: By removing IND Exempt studies from the “deemed” status, CMS states that its intention in the policy is to stipulate the conditions under which Medicare will judge whether a trial is being conducted under scientifically and technically sound principles. Examination of whether a study is scientifically and technically sound is described by the federal requirement that IRBs review studies to ensure that risks are minimized by using procedures which are consistent with sound research design. CMS’ statement that IND Exempt studies do not have FDA oversight is not entirely correct. For example, the FDA regulates this type of research by establishing the requirements that must be met to qualify as IND Exempt. One of those requirements is that IND Exempt studies must obtain IRB approval and informed consent from the subject, as described in 21 CFR parts 56 and 50. In addition, IND exempt studies may involve drugs that are lawfully marketed as prescription drug products, all of which are subject to FDA regulation and oversight.

Additionally, the FDA has issued guidance encouraging the use of the IND exempt process for qualifying studies in the area of cancer research. The FDA felt it was appropriate to allow the investigators and IRBs the ability to determine that based on the scientific literature and generally known clinical experience, there is no significant increase in the risk associated with the use of the drug product and that the study otherwise meets the requirements for IND exemption described at 21 CFR 312.2(b)(1).

Recommendation: Based upon the required IRB review, FDA oversight of prescription drug products, and the FDA’s guidance encouraging the use of the IND exempt process specifically in the area of cancer research, there is ample assurance that IND Exempt studies are scientifically and technically sound. We recommend CMS retain IND exempt studies in the deemed qualified category. In the alternative we recommend CMS retain IND exempt status for oncology studies.

We very much appreciate your consideration of these comments. If you have any questions please contact me.

Sincerely,

Robert W. Bishop, J.D.
Vice Chancellor for Institutional Compliance

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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 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.

**Proposal 4, regarding the Medicare-specific standards

PLEASE MAKE VOLUME MANAGMENT A POINT OF FOCUS: Below I have outlined evidence that suggest the need to focus on volume and the managment of Volume;

2006 Annual Data Report - Chapter 6 The number of hospital days has decreased somewhat steadily over time for those on peritoneal dialysis; for those on hemodialysis, the number has varied little since 1999. Cardiovascular admissions, in contrast, while increasing only 8 percent overall, are now 20 percent higher in blacks, 27 percent higher in patients age 20-44, and 53 percent greater in pediatric patients – an issue of great concern. Morbidity & Mortality. pg 136. Among dialysis patients age 20-64, overall mortality rates are more than eight times greater than those found in the general Medicare population;…

Rates of mortality due to septicemia are similar in the ESRD and general populations. In ESRD patients, however, rates of mortality due to heart disease are 169 percent greater for patients age 20-44, and the difference reaches 282 percent in those age 45-64.

Pg 138.Compared to those of transplant patients, mortality rates in the dialysis population are 9.6-13.8 times higher for heart disease, 5.2-6.3 times higher for cerebrovascular disease,…No specific geographic patterns for death from cardiovascular disease in all patients are readily evident. It does appear, however, that rates in the eastern half of the country are generally higher.

92.8% HD pts meet K/DOQI target for delivered Kt/V >1.2 92.0% HD pts meet K/DOQI target for URR >65% 87.6% HD pts meet K/DOQI target for Hgb >11g/dl

(My comment: If the targets are being met, why the increase in cardiovascular admissions, mortality etc? – Fluid is an independent risk factor for cardiovascular mortality per Jaeger & Mehta, 1999)

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6. Summary

Novartis appreciates the opportunity to submit comments on CMS Clinical Trial Policy and we hope that the CMS finds our comments helpful in producing a final set of clear regulations that provides Medicare beneficiaries with increased access to clinical studies. In review, Novartis:

1. We need a focus on preventing cardiovascular morbidity and mortality in the hemodialysis(HD) population. a. Specifically, we need more objective measures to help the clinician assess and guide fluid status in these patients. The sensitivity and specificity of the physical exam in these patients is poor. There exist validated, FDA approved technologies, for example, that that can help assess and guide management. More than 20 million Americans have chronic kidney disease (CKD) - a number that continues to grow at a rate of seven percent annually. This growth is influenced in part by diseases associated with the aging population such as diabetes and hypertension, two leading causes of end stage renal disease. This is particularly true for our patients , who have a disproportionately high prevalence of chronic diseases including diabetes, hypertension and who fall into the older age group particularly in this city. By the year 2010, an estimated 650,000 Americans will require dialysis or kidney transplantation, with direct Medicare costs of well over 48 billion dollars annually.

In HD patients, both volume over-hydration and under-hydration are independent risk factors for increased cardiovascular morbidity and mortality. Chronic hypervolemia in these patients contributes to hypertension, left ventricular dysfunction and left ventricular hypertrophy (LVH); independent risk factors for increased cardiovascular and cerebrovascular morbidity and mortality in the dialysis population. Furthermore, LVH is predictive of an increased incidence of myocardial infarction, congestive heart failure (CHF and sudden death in HD.

Conversely, hypovolemic HD patients, are also at risk since they may develop symptoms of volume depletion such as profound fatigue, dizziness, nausea, vomiting, muscle cramping (abdominal, extremity), syncope, dyspnea and intradialytic hypotension, MIs and stroke. In a multicenter, study in which over 1000 patients were followed for two years, authors found that intradialytic hypotension after HD were significant and independent risk factors for two year mortality.

Correction of hypervolemia or hypovolemia requires accurate assessment of the HD patient's fluid volume; however, this remains difficult to achieve with the clinical exam alone. Dialysis patients may not exhibit signs of overt volume overload since edema is not usually detectable until the interstitial fluid volume has risen to 30% above normal (4-5 kg of body weight).

On the other hand, the patient may not have achieved his or her dry weight, yet may still experience intradialytic episodes of hypotension, syncope or such symptoms as cramping, dizziness, fatigue, nausea and vomiting. We are in need for more objecvtive methods to assess and guide volume management in dialysis.

2. We need well designed, randomized, controlled, clinical trial that address:i) volume/fluid assessmentii) volume/fluid managemnt

3. We need guidelines for acuracy of hemodialysisthat address not only molecule clearance but equally focuses on definitions of volume status and gold standard methods to guide volume control.

4. We need educational tools to make clinicians and support staff aware of this problem. Poor fluid fluid management negatively impacts on cardiovascular disease, anemia, nutrition, quality of life, hospitalizations and hospital stay, death and has negative economic consequences.

5. We need to join hands with the cardiology community in this matter.Thank you for allowing us to voice our concerns.

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My name is Dr. Robert Dowling and I am a Professor of Surgery at the University of Louisville, Louisville, Kentucky, and the Director of Mechanical Circulatory Support. Along with Dr. Laman Gray, I served as the Principal Investigator for the AbioCor total replacement heart clinical trial between 2001 and 2004, performing 7 of the 14 implants at Jewish Hospital. During this time, we feel we have become one of the most experienced surgical and medical team for the replacement of the human heart and have agreed to resume implantation of patients in 2007 in accordance with the Post-Market Study accompanying the designation of the AbioCor as an HDE in 2006. On behalf of Jewish Hospital, we welcome the opportunity to provide comments on this important policy decision before the Centers for Medicare and Medicaid Services. My comments concern the Decision Memo for Clinical Research Policy (the “Decision Memo”) and specifically, the need to establish a clear, viable, efficient and timely pathway for coverage of Humanitarian Use Devices (“HUD”s). Specifically, we request that the Centers for Medicare and Medicaid Services (CMS) provide for coverage of an HUD, as an investigational clinical service, where the HUD is marketed under an FDA-approved HDE and is subject to FDA-approved post-approval study. Furthermore, we recommend that a FDA post-market study be considered a “deemed” clinical study that otherwise meets the general standards for a scientifically and technically sound clinical research study.

The importance of providing a viable coverage pathway for HUDs such as the AbioCor under an HDE cannot be over-emphasized. At Jewish Hospital alone, we see patients on a weekly basis with end-stage heart failure where transplantation is not an option. Some of these patients are likely to benefitfrom this technology. We have learned that the AbioCor will extend patients lives for months, if not years. Although more evidence is needed before full coverage is warranted, we believe that providing coverage for the item and routine clinical services in the post-market study is well within the intent of CMS in revisiting the Clinical Research Policy. We also believe that this was the intent of the Medicare Coverage Advisory Committee (MCAC) which was reflected in their recommendation that the HUD coverage pathway be available. The post-market study will provide CMS additional data for analysis for future coverage decisions. We strongly recommend that CMS articulate this policy within the Clinical Research Policy and that the post-market study be a “deemed” clinical research study allowing for covered items and services.

I look forward to working with CMS to resolve this important issue and continue providing life saving technologies such as the AbioCor to patients with chronic heart failure.

Regards,
Robert D. Dowling, MD
Professor of Surgery
University of Louisville School of Medicine

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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 revisions to the Medicare National Clinical Research Policy (CRP). As an academic institution active in clinical research, we are pleased to be able to provide our perspective on the CRP, which we believe will continue to have a profound impact on academic health centers around 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 believe the revised CRP is a step in the right direction, and have outlined comments or concerns we have below.

Proposal 4, regarding the “Medicare-Specific standards.”

UMHS would like to comment on the following proposed Medicare-specific standards:

May 9, 2007

Steve Phurrough, MD, MPA
Director
Coverage and Analysis Group
Center for Medicare and Medicaid Services
Hubert H. Humphrey Building, Room 445-G
200 Independence Avenue, SW
Washington, DC 20201

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

Dear Dr. Phurrough:

AABB (formerly known as the American Association of Blood Banks) appreciates the opportunity to comment on the Center for Medicare and Medicaid Services’ (CMS) proposed revisions to the Medicare National Clinical Research Policy. AABB is a professional association dedicated to advancing transfusion medicine and cellular therapies. AABB’s members include approximately 1,800 institutions, including hospital-based blood banks and laboratories, transfusion services and blood and bone marrow collection facilities, as well as approximately 8,000 individuals involved in blood, bone marrow, cord blood and peripheral blood stem cell collection, processing, storage and infusion.

Clinical research plays a critical role in promoting quality care for patients requiring transfusions as well as those battling certain cancers and other life-threatening conditions treated with hematopoietic stem cell transplants. It is important that CMS’ clinical research policy be designed and implemented in a manner so as not to discourage patients from participating in high quality clinical trials. Although AABB supports the overall goals of CMS’ proposed policy as well as many of the proposed edits to this policy, the association has several significant concerns regarding the latest proposal. Prior to its implementation, AABB urges CMS to amend and/or clarify the revised policy to address the following issues.

Release of Study Results

AABB agrees that it is extremely important that the public have access to critical outcomes information. However, the association is concerned that if outcomes are released without going through an appropriate peer-review process, the released information may mislead the public and compromise good research. Long-accepted peer- review practice offers the best means of verifying the scientific legitimacy of outcomes information. Therefore, AABB recommends that CMS amend its proposal to state that research studies should undergo a peer review process and all data found to be scientifically sound must be made available to the public. This requirement should only apply to the principal organization in a multi-site trial, not to each individual site.

Medicare Populations

AABB believes that CMS’ proposal requiring the protocol to discuss how results will generalize to the Medicare population is problematic and may deter Medicare beneficiaries from participating in potentially life-saving clinical trials. First, this proposal appears to focus almost exclusively on elderly Medicare beneficiaries, and not the population of Medicare beneficiaries who are under age 65, but are disabled. These individuals – a population that includes ill patients requiring hematopoietic stem cell transplants and/or blood transfusions – must not be shut out of Medicare-covered clinical trials.

In addition, CMS should be careful not to deny Medicare beneficiary access to trials that even though they are not easily generalizable to the 65-year or older Medicare population offer these patients the best possible care. For example, studies involving hematopoietic stem cell transplantation may be restricted to patients under 65 or 67 due to related toxicities to older patients.

AABB requests that CMS amend its proposal to allow the researcher to state the reasons why a particular study may not be generalizable to the entire Medicare population.

Routine Costs

AABB recommends that CMS further refine its definition of routine costs to distinguish between events that are research-related and those that are due merely to the underlying disease or standard treatment. AABB urges CMS to add language stating that a research-related injury is defined as “something that would not reasonably be expected outside of participation in the study.”

Approval Processes

AABB is concerned that CMS’s proposal to no longer allow for coverage of IND-exempt studies could significantly deter Medicare beneficiaries from participating in valuable clinical trials. Such investigator-initiated trials help answer discrete, yet important, questions involving new combinations or dosages of potentially life-saving drugs. Over the next few years, there will be several cellular therapy products licensed as biologicals. As more such products are approved and this practice of medicine continues to evolve rapidly, a growing number of patients will be treated with IND-exempt off- label use of cellular therapy products. Medicare beneficiaries, including those battling cancer and other non-malignant life-threatening conditions, should have access to these promising new treatments. AABB requests that CMS not eliminate this important deemed coverage for IND- exempt studies.

Rather than eliminating self certification, AABB recommends that CMS allow for self-certification based on the following set criteria. These criteria should include establishing local Protocol Review Committees consisting of clinical investigators, biostatisticians and basic scientists. This process would determine if the study met both the “General Standards for a Scientifically and Technically Sound Research Study” and the “Medicare-Specific Standards.”

In addition, AABB recommends that CMS amend its proposed language prohibiting coverage for studies conducted under an IND “when the FDA has reviewed the protocol and the IND has not been put on hold.” This language should be edited to instead read “when the FDA has reviewed the protocol and the IND is currently not on hold.” It is not uncommon for FDA to put an IND on hold pending receipt of requested information and then release the hold. Once an IND is no longer on hold, the trial should be eligible for Medicare coverage.

Finally, AABB is very concerned about the need for Medicare coverage of trials under an investigational device exemption (IDE). Although we recognize that this issue may not be covered under this particular clinical research policy, AABB believes that the IDE issue requires attention. In the case of cellular therapy (bone marrow/stem cell transplant and immunotherapies), FDA in certain instances considers cellular product processing procedures and the resultant product as a biologic (i.e., the infusion of Natural Killer (NK) cells) and therefore these fall under the IND review mechanism. For other indications, the agency considers the processing procedure and the resultant product a device (i.e., CD3 depletion of an allogeneic cell product) and therefore these fall under the IDE review mechanism. FDA subjects both INDs and IDEs to rigorous review. Medicare beneficiaries, therefore, should not be denied coverage for trials involving IDEs.

Thank you for the opportunity to comment on this important coverage policy that will significantly impact Medicare beneficiary access to high quality cellular therapy and transfusion medicine related care. If you have any questions or require further information, please contact Theresa Wiegmann, Director, Public Policy at 301-215-6554 or Theresa_L@aabb.org.

Sincerely,
Karen Shoos Lipton, JD
Chief Executive Officer
AABB

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May 9, 2007

CLC COMMENTS RE CMS PROPOSED DECISION MEMORANDUM ON MEDICARE NATIONAL CLINICAL TRIAL POLICY

RE: CAG-00071R

The undersigned members of the Cancer Leadership Council (CLC) represent cancer patients, providers and researchers throughout the nation. We are writing to express our deep concern over the proposal to change the “deemed status” of IND exempt trials, eliminating their automatic coverage by Medicare under the 2000 National Coverage Determination (NCD) on clinical trials.

Many CLC members have worked for years not just to achieve the Medicare policy on clinical trials but also to obtain passage of state legislation modeled after that policy. We are very disappointed to see that the Centers for Medicare & Medicaid Services (CMS) has deleted an important element of the policy, coverage for IND exempt trials, without offering a satisfactory justification. The Food and Drug Administration (FDA) has made a science-based decision that IND exempt trials do not require the same level of oversight as other trials, and CMS should respect that decision. These trials offer important treatment options for many patients, and they also provide incremental advances in our knowledge of how chemotherapy drugs may be best utilized. It is not insignificant that, as CMS acknowledges, every comment submitted on this topic advocated retaining the automatic coverage of IND exempt trials.

CMS committed to the development of a self- certification process for these trials, but no such process has emerged. We feel that it is not an acceptable response for CMS simply to abandon coverage for IND exempt trials without further consideration of methods for assuring that these trials are appropriately covered – though we firmly believe that FDA’s judgment on this issue should be controlling.

Finally, this category of trial has special – perhaps unique – significance for cancer treatment, and we urge CMS to seriously consider continuing the “deemed” coverage status of IND exempt cancer trials, even if a decision is made to eliminate coverage of other IND exempt trials.

Sincerely,
Cancer Leadership Council

cc: Leslie Worwalk, Acting CMS Administrator
Leslye Fitterman, Ph.D., Lead Analyst

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As an Oncology nurse that has been involved in clinic resaerch for the past 5 years there are several issues with the "proposed decision memo" that I would like to bring to your attention.

First, the requirement that a study by listed on ClinicalTrials.gov before a Medicare patient can be enrolled. There are many studies that I am involved with where the sponsoring drug company does not want others to know what they are doing. By requiring to place the study on the government web site, you expose potentially confidential information to public view. I have handled multiple requests for insurance carriers who want information about clinical studies that one of their patients may be participating in, but we are prevented from sharing anything contained in the protocol because it is considered "confidential".

Second, along with information about "inclusion criteria" it is just as important to list the "exclusion crietria". For example, a potential patient may have the right kind of cancer to participate in a study, but if they had a heart attack 3 months ago, that might render them ineligible. The patient needs to have both the "inclusion" and "exclusion" criteria if they are searching the web for a potential study.

Third, the requirement of the protocol to contain a discussion of how the results will generalize to the Medicare population, may be an impossible hurdle for a protocol. A protocol could provide a theory of the impact on Medicare patients, but it would only be a theory or guess. The results of the study will provide you the impact by age range once the study has at been completed(or you could get a "snapshot" of that information at each data analysis point.

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May 9, 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

Dear Dr. Phurrough,

Thank you for the opportunity to comment on the proposed changes to the national coverage decision (NCD) governing the Centers for Medicare and Medicaid Services’ (CMS) Clinical Trial Policy (to be renamed Clinical Research Policy). America’s Health Insurance Plans (AHIP) is the national trade association representing the private sector in health care. AHIP’s member companies provide health benefits to more than 200 million Americans. We are pleased to submit these comments on behalf of our members.

Proposed Revisions to the Clinical Trial Policy

We support CMS’s effort to provide a clear statutory linkage to registries and clinical trials that take place under the aegis of CMS’s coverage with evidence (CED) policy. In addition, many of the elements of the proposed revisions to the Clinical Trial Policy will be very positive steps to clarify the characteristics of high quality research in which routine clinical services should be covered by Medicare, such as the requirement for generalizing study results to the Medicare population and the definition of routine clinical services. However, we have great concern that the effort to broaden the types of research eligible for consideration of coverage includes a change to “Medicare-specific standards” that represents an inappropriate shift in the understanding of the boundaries between early, developmental research and clinical research intended to assess therapeutic outcomes. The language we are concerned about is the proposed change in Medicare-specific standards for coverage of routine costs:

“The clinical research study is not designed to exclusively test toxicity or disease pathophysiology. Research 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.”

AHIP strongly opposes a change from the current standard requirement which states that coverage can only be considered for costs within research studies that have “therapeutic intent.” We believe the proposed new language would lead to coverage for the costs of studies seeking early information on toxicity, dosing, and basic physiological response to new, unproven interventions. The costs for these studies have always, and appropriately, been borne by manufacturers, and we do not believe they should be shifted to Medicare or the private sector. The proposed language presents several specific risks:

May 7, 2007

Steve Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd., Room C1-12-04
Mail Stop C1-09-06
Baltimore, MD 21244

Re: CAG-0071R – Proposed Decision Memorandum for National Clinical Trial Policy

Dear Dr. Phurrough:

The Community Oncology Alliance (COA), a non-profit organization whose mission is to foster and protect high quality, affordable and accessible cancer care, would like to offer the following as it relates to the solicitation for commentary on the proposed decision memo for clinical trials.

As you may be aware, a large percentage of clinical trials are conducted in the community oncology clinic setting where 84% of cancer care is delivered; in fact, the community setting provides the basis from which most clinical trials flourish. COA’s primary concern is the potential effect on beneficiary access that will result from The Centers for Medicare & Medicaid Services (CMS) decision to exclude clinical trials exempt from the investigational new drug application (IND) process. CMS cites its inability to develop self-certification validation criteria as the reason for the elimination of the IND-exempt trials. In the interest of affording Medicare beneficiaries the utmost in affordability and access to current and prospective cancer therapies, COA urges CMS to recant its decision to abandon coverage on such trials while the agency continues to develop what it considers to be appropriate guidelines. And remember also, that the Food and Drug Administration (FDA) has already furnished clear and concise guidelines to determine the appropriateness of trials for the IND-exempt process, which is firmly adhered to.

Please consider in your decision-making, the rationale behind COA’s request that coverage for IND-exempt trials remain. When treating cancer, there are a limited number of pharmaceuticals and established chemotherapy protocols. Often times, the conventional methods of treating cancer do not produce the desired effect; that is, the remission or potential cure, hence the multitude of clinical trials that are initiated each year. These trials, often times, commence at the urging of those very physicians who are searching for novel ways of treating disease, resistant to standard treatment regimens. It is precisely in employing these trials that we learned that a drug with an FDA approved indication for colon cancer, also works in treating lung cancer. A substance designed to treat breast cancer, now working in tandem with one specifically for colon cancer, saves lives that would have been lost. And even today, an announcement that a drug given to cancer patients to preserve bone density, thru clinical trials, reveals a staggering benefit on preventing further bone degradation due to osteoporosis, in a simple 15 minute once-a-year infusion.

We know that it is not the intention of CMS to limit access to clinical trials for Medicare beneficiaries. In reality, it has become extremely difficult to recruit beneficiaries to clinical trials. And, with the added exclusion of IND-exempt trials and the development of a new Clinical Research Policy (CRP) with limiting criteria, we fear the number will degrade even further.

Additionally, the cost of actually performing a clinical trial is escalating. For every one hundred patients asked to consider participation in a trial, less than one-third choose to do so. This process is initiated by the physician after patient evaluation and case review. A clinical trials coordinator then usually sits down with the potential candidate, verifying eligibility, fielding questions by the patient and his or her family members and ordering further studies necessary prior to enrollment in the prescribed trial. This process culminates 67% of the time with a negative decision to participate, even though the clinic has already expended countless dollars, without the benefit of a candidate. Should CMS go forward with these additional policy constraints, community oncologists predict an increase in costs to conduct these trials and a shrinking pool of candidates to participate in these trials, resulting in a reduction versus and increase in such trials. A recent Annual Report from the President’s Cancer Panel suggested that funding should be provided to employ a research nurse who would travel among community physician practices to assist with documentation. This, in and of itself, would alleviate some of the time and cost burdens in enrolling beneficiaries in a clinical trial.

Also commented on in the President’s Cancer Panel report were the myriad of federal and state regulations which, in today’s world, are proving to be an impediment rather than an inducement to increase the pace in which innovative breakthroughs in science can be developed. And too, this same regulatory structure actually thwarts the community oncologist from enrolling his or her patients into clinical trials due to the innumerable layers of paperwork necessary to achieve acceptance into the trial.

COA asks that CMS take into consideration when developing a CRP, avoidance of any criteria that would otherwise deter Medicare beneficiaries from participation. Such limits might include specific locations where trials may be conducted, thereby eliminating those with an inability to travel, the additional burden of costs associated with adverse trial outcomes not paid for by Medicare and specific demographic, minority or clinical characteristics. Further, it is strongly recommended that clinical trials currently in place remain unaffected by the implementation of such newly developed CRP. Consideration should also be given to the inclusion of Phase I studies where the disease studied is chronic, life threatening or debilitating. COA urges CMS to develop policies and procedures that encourage rather than discourage participation by our senior population.

COA urges CMS to look carefully at the number of trials taking place in the community oncologists offices and to consider an advanced directive which makes our Medicare population aware not only of the availability of these trials, but of the accessibility of participating in such right in their home towns at the community oncology clinic in their locale. We are confident that a heightened level of awareness and an ease of access will produce a positive enrollment and thus a positive outcome.

In closing, COA is pleased to have been given the opportunity to share its observations with CMS. We are hopeful that you will carefully consider these remarks, along with those of other cancer organizations, patient foundations and industry groups, with the ultimate goal of developing policies that will provide affordable, accessible, quality cancer care to all Americans.

Very truly yours,

COMMUNITY ONCOLOGY ALLIANCE

Frederick M. Schnell, MD
President

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Steve Phurrough, M.D., M.P.A.
Director
Coverage and Analysis Group

May 8, 2007

RE: Proposed Decision Memorandum for Medicare National Clinical Trial Policy

Dear Dr. Phurrough:

On behalf of Partners HealthCare System, Inc. (Partners), I appreciate the opportunity to comment upon the Centers for Medicare and Medicaid Services’ (CMS) Proposed Decision Memorandum for Medicare National Clinical Trial Policy.

Partners HealthCare is an integrated health system founded in 1994 by Brigham and Women’s Hospital and Massachusetts General Hospital. In addition to its two academic medical centers, the Partners system also includes community and specialty hospitals, community health centers, a physician network, home health and long-term care services, and other health-related entities. A principal teaching affiliate of Harvard Medical School, Partners is one of the nation’s leading biomedical research organizations with approximately $1 Billion in research funding.

I very much appreciate recognition of the administrative challenges posed by the 2000 Clinical Trial Policy and CMS’s attempts to clarify its position for all providers. We believe many of the changes proposed by CMS will increase beneficiary access to participation in clinical research studies. However, we also believe that certain of the proposed changes will hamper wider implementation of standard cost saving therapies, greatly restrict beneficiary access, and suppress innovative care.

To that end, Partners would like to provide comments on the following specific CMS proposals to inform the final CMS Clinical Research Policy:

On behalf of the Association of Academic Health Centers (AAHC), I wish to comment on the proposed clinical research policy (CRP) of the Centers for Medicare & Medicaid Services (CMS). The AAHC, representing 100 academic health centers nationwide, is dedicated to improving the nation’s health and well-being by mobilizing and enhancing the strengths and resources of the academic health center enterprise in health professions education, patient care, and research.

I would like to take this opportunity to thank the agency for its openness with the academic health center community, its willingness to engage in dialogue to develop the policy, and its responsiveness to suggestions for revision, change, and clarification. We applaud the agency for its support of medical research and its efforts to advance science through clinical trials throughout the nation. The AAHC hopes the collaborative spirit of our comments will contribute to improved policymaking that encourages and sustains this vital dimension of research.

To ensure that Medicare beneficiaries and hundreds of thousands of other patients can receive the benefits of improved health as a result of clinical trials, the AAHC has several concerns we believe should be addressed before issuing the final CRP.

The AAHC recommends that CMS:

May 8, 2007
Steve Phurrough, MD, MPH
Centers for Medicare & Medicaid Services
Office of Clinical Standards and Quality
Director, Coverage and Analysis Group
C1-09-06
7500 Security Boulevard
Baltimore, MD 21244-1850

Re: Comments on National Clinical Trial Policy, CAG-0071R

Dear Dr. Phurrough:

On behalf of the more than 71,000 Fellows who are members of the American College of Surgeons (College), I am pleased to comment on the clinical trial policy. The College wants to comment on revision number eight, titled “Investigational Clinical Services”, in the list of ten revisions that are proposed for the Medicare National Clinical Trial Policy.

The College welcomes the policy change which would cover an item or service in a clinical trial that is eligible for coverage outside the trial. We never saw the logic of excluding an item of service when it is provided in a clinical trial. Indeed, under the existing policy, a person might forego participating in a clinical trial designed to capture meaningful clinical information because the item or service would not be covered.

We also support the policy change which would cover items or services that have been covered contingent upon the collection of additional data or “coverage with evidence development.” This expansion will bring the additional resources of the clinical trial, such as assurances the data would be reviewed with rigor, to the collection of additional data. We view this as an entirely appropriate extension of the policy that an item or service is covered both within and outside of a clinical trial.

Finally, we want to compliment the Centers for Medicare & Medicaid Services (CMS) for taking the time and effort to do a thorough review and revision of the clinical trial policy, including consulting with the Medicare Coverage Advisory Committee (MedCAC) and the Agency for Healthcare Research and Quality (AHRQ). We believe the revisions will result in improved coverage of clinical trials as required by the Executive Memorandum issued in June, 2000.

Sincerely,
Thomas R. Russell, MD FACS
Executive Director

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The following comments are submitted on behalf of the Association of American Medical Colleges:

RE: Proposed Decision Memo for Clinical Trail Policy (CAG-0071R)

The Association of American Medical Colleges is a nonprofit association representing 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 AAMC is pleased that CMS is revising its policy on payment for items and services for Medicare beneficiaries who participate in clinical trials and appreciates this opportunity to provide comments. We welcome the Agency’s consideration of the many viewpoints expressed about this policy and the thoughtful proposals that have been put forward for comment.

As part of the process for reviewing this proposal, the AAMC spoke to many of the individuals at our member institutions who will be charged with implementing the clinical research policy (CRP). These discussions have led the AAMC to conclude that the new policy, although containing many commendable features, requires additional changes and clarifications, described below, that will allow CMS to issue a clear, understandable policy that can be implemented without institutions having fears of inadvertently submitting an incorrect bill to Medicare for the items and services covered by the CRP.

I. Conflict Between Standards for a Good Clinical Trial and Medicare-Specific Standards and Clarification of Regarding Phase I Studies

For a trial to qualify for Medicare coverage, it must first meet the eight “standards for a good clinical trial.” Once these standards are met, a trial must meet a minimum of 5 Medicare- specific standards (or more if the trial is being conducted under the coverage with evidence development process). The first requirement for a good clinical trial is that:

The first Medicare-specific standard appears to be contradictory to this, as it says that:

The AAMC requests that CMS clarify whether a study that has “measuring therapeutic outcomes as one objective” could also have as its “principal purpose” to test whether a particular intervention potentially improves the participant’s health outcomes. If not, then the policy would not allow for the coverage of any Phase I studies. CMS could provide clarity to this issue by revising the first general standard for a scientifically and technically sound clinical research study as follows:

The AAMC also requests that CMS clarify that the requirement in the Medicare-specific standard that the “disease is chronic, life threatening, or debilitating” only applies to Phase I trials. The language suggested by AHRQ provides more precision, and should be considered for inclusion in the final CRP:

II. Need for Grandfathering Certain Trials— Registration on ClinicalTrials.gov and Protocol Discussions

The AAMC strongly supports the registration of all clinical trials on ClinicalTrials.gov. However, the proposed CMS requirement is mandates that the registration occur “prior to the enrollment of the first study subject.” The AAMC also supports the three proposed requirements related specifically to the contents of the protocol (though with modifications that will be discussed below). However, AAMC suggests the need for CMS to grandfather trials under two different circumstances:

1. On-going trials not registered on ClinicalTrials.gov. Trials that currently are being paid under the 2000 national coverage decision, but are not registered on ClinicalTrials.Gov should be grandfathered because it will be impossible for them to meet this standard since the first study subject already is enrolled. If these trials suddenly becomes ineligible for Medicare coverage, both the institutions where the studies are being conducted and the study participants will face hardship. Institutions negotiated payment with sponsors based on the reasonable belief that some of the costs of these trials could be billed to Medicare. Should this anticipated payment disappear, it is possible that some of these trials could not continue, to the detriment of those already enrolled in them. An alternative would be for CMS to require that on-going trials that meet the standards of the 2000 NCD be registered on ClinicalTrials.Gov within 60 days of the effective date of the CRP if they wish to remain eligible for Medicare payment.
2. Protocols that have been submitted to an IRB, but are not yet approved as of the effective date of the CRP. The development of a protocol to the point where it is submitted to an institutional review board (IRB) is a long and intensive process. Protocols submitted prior to the effective date of the CRP may not contain the required elements regarding release of all pre-specified outcomes; discussion of inclusion criteria and considered relevant subpopulations; or a discussion of how the results will generalize to the Medicare population. If, as of the effective date of the CRP, the studies have been submitted to an IRB, they should qualify for Medicare payment as long as they would have qualified under the 2000 NCD. Only studies submitted to an IRB on or after the effective date of the CRP should be required to comply with its requirements.

To minimize problems related to on-going studies and studies already submitted to an IRB, the AAMC further suggests that the effective date of the CRP be at least 30 days after the final policy is published on the CMS website.

Finally, CMS indicates in the proposed CRP that it will ‘review adherence” to the requirement for registration on ClinicalTrials.gov. The AAMC requests that CMS clarify whether CMS intends to audit only that a trial actually is registered, or whether adherence depends on the inclusion of certain information on the ClinicalTrials.gov site. If the latter, please specify the information that must be included in the registration for the purposes of a CMS audit.

III. Method and “Fulfillment” of Timing and Public Release of All Pre-Specified Outcomes

The AAMC strongly supports the requirement that trials qualifying for Medicare payment must publicly release all pre-specified outcomes and encourages our members to commit to such release of all trial results. Rapid communication of results is particularly important in the case of either clear problems with the trial that leads to termination, or the determination of a clear benefit. The AAMC suggests that when a termination occurs public release of the reasons for the termination decision should occur within no more than 7 days of the termination.

Of concern to the AAMC is the requirement for “fulfillment” of the public release of information. The sponsor may be responsible for release of the results, and thus it may not be possible for the hospital to control whether or when such release is made. It also is possible that a journal will not accept publication of the study results, or that publication may be delayed. Institutions should not face the possibility that Medicare will request the return of “overpayments” for a clinical trial if, for reasons outside of their control, the public release is not “fulfilled.” The AAMC recommends that CMS delete the requirement for “fulfillment.”

While study results can be posted on the web, CMS acknowledges that there is no site that is supported by either the government or a neutral private party. At this time such posting is most likely to occur on a sponsor’s website and would not be subject to review by outside bodies. It would be preferable if there were a governmental or other neutral-party repository where information is made publicly available. The most direct way to accomplish this would be to authorize and enable ClinicalTrials.gov to develop this capability. The AAMC would be happy to work with CMS and other federal agencies on the establishment of such a site.

IV. Generalizing the Study to the Medicare Population

The AAMC agrees that it is important that any study that merits payment by Medicare by one that may be of benefit to the Medicare population which includes both the aged and the disabled. Therefore, it is reasonable that the study protocol contain such a discussion. However, CMS also is proposing that:

The AAMC is concerned that this sentence imposes a further requirement on study design, i.e. that sufficient Medicare patients be enrolled such that a valid scientific conclusion can be reached based on analysis of only the Medicare patients. The consequence of such a requirement would be the need for a far greater number of subjects potentially causing sponsors to exclude Medicare patients in order to control study costs. General Standard 4 already addresses study design: “The research study design is appropriate to answer the research question being asked in the study”. To avoid unintended and unnecessary exclusion of Medicare patients from studies which can benefit them, AAMC supports using the MedCAC recommended revision instead:

“The protocol must contain a discussion of how the results will generalize to the Medicare population to infer whether Medicare patients benefit from the intervention and whether the results are generalizable to Medicare beneficiaries.”

V. Routine Clinical Services

The AAMC appreciates the changes that CMS has made to this requirement. Payment for “routine clinical services” rather than “routine costs” adds much clarity to this policy.

VI. Deemed Studies

CMS lists five types of studies that will be “deemed” to have met the eight standards for a good clinical trial. The second type of “deemed study” is one that is reviewed and approved by a health care research center or cooperative health care research group, funded by a Federal agency, provided that:

It will not be possible for hospitals to determine if this review and approval has occurred as there is no place they can turn to find this information. This puts them at risk for incorrectly billing Medicare if they submit bills for any studies that would fall into this category. If CMS retains this requirement, it should consider entering into agreements with the relevant Federal agencies to require that they report the results of this review and approval to a web site that will be publicly accessible to any institution that needs to know if a study qualifies under this deemed category.

VII. IND-Exempt Trials

The AAMC is sympathetic to the concern expressed by CMS that many IND-Exempt trials do not have an “external process for ensuring that the standards of this Medicare policy are met.” We also recognize that many IND-Exempt trials involve new combinations of drugs or new uses of drugs that may be of direct benefit to the Medicare population. The exclusion of most IND- Exempt studies from Medicare payment may be an impediment to much useful research. In its recommendation, MedCAC suggested that “CMS develop a mechanism to certify other entities to deem research studies,” such as “professional societies, private foundations, academic health centers, and university scientific review panels.” The AAMC supports this idea as an alternative to the elimination of most IND- Exempt studies from Medicare coverage and would be pleased to work with CMS and others to implement it.

VIII. Medicare Secondary Payer Rule and Medicare Advantage Enrollees

The AAMC remains concerned that even with revisions and clarifications to the clinical trials policy, the outstanding questions regarding the interaction of this policy with the MSP rules remain an impediment to the enrollment of Medicare beneficiaries. That is equally true of the inherent disadvantages to Medicare Advantage enrollees who may wish to participate in a clinical trial but could be discouraged by the stiff out-of-pocket costs that they would incur. We urge all relevant parts of CMS to work in concert to produce a clinical research policy that addresses all remaining concerns and removes barriers to the enrollment of Medicare beneficiaries in clinical trials.

Sincerely,
Robert M. Dickler
Senior Vice President
Division of Health Care Affairs

David Korn, M.D.
Senior Vice President
Division of Biomedical and Health Services Research

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This policy is unfortunately watered down with respect to acheiving its stated goals of gaining knowledge of how medical products and therapeutics impact the medicare population as a whole.

Many Phase IV studies, post marketing commmittment studies and registries are designed with a safety focus in mind. Excluding Medicare patients from these only because they have a safety objective in mind seems futile as there are potential learnings about safety that may beneifit the entire Medicare population.

It is unlikely that many sponsors will be willing to have clinical trial data results posted on Clinical Trials.gov only for the chance to have small deferment in costs to enroll Medicare patients. The major risk to pharmaceutical companies in posting data on Clinical Trial.gov is feared data trolling by plaintiffs attorneys for amunition to support new or ongoing litigation. The cost faced by companies to rebut the misuse of such freely posted data is far in excess of any advantage of CMS support for Medicare beneficiary participation.

I would propose that the requirement for data posting be eliminated and that Medicare participants be permitted to participate in observational studies (with the exception of phase 1 studies) that have safety objectives.

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The American Society of Clinical Oncology (ASCO), with more than 24,000 members worldwide, is the leading medical society for physicians involved in cancer treatment and research. ASCO has a longstanding interest in cancer clinical research and was heavily involved in the negotiation of terms for the National Coverage Determination that is now under review.

When the current clinical trial policy was finalized in September 2000, it reflected the contributions not just of ASCO and various patient advocate organizations, but also those of cancer research experts from the Food and Drug Administration (FDA) and the National Cancer Institute (NCI). An important feature of the 2000 policy was the decision to extend coverage of patient care costs to so-called “IND-exempt” trials as designated by FDA. Those trials were included among those that would enjoy “deemed status”—that is, they were automatically considered to be qualified for coverage. This decision was based on substantial input from both FDA and NCI. The Centers for Medicare & Medicaid Services (CMS) contemplated development of criteria for self-certification to validate IND-exempt trials, but, by its own admission, has failed to develop the self-certification process that would enable continuation of coverage for IND-exempt trials.

ASCO is very disturbed to see that CMS is proposing to abandon coverage for IND-exempt trials, a move that we believe has the potential to create havoc in both clinical cancer research and quality cancer care for beneficiaries. We urge reconsideration of this policy change, at least as it applies to clinical cancer studies and perhaps to studies in other therapeutic areas as well.

The Role of IND-Exempt Trials

The concept of exempting certain investigational new drug (IND) applications from submission to FDA is well established in FDA regulations. 21 CFR§312.2(b)(1). Thus, FDA exempts from compliance with IND regulations a study that:

While IND-exemption is available for any class of drug, the exemption is particularly important for oncology drugs. This is, in part, because there is a strong culture of clinical research in oncology, with hundreds of investigator-initiated trials commenced every year. These trials are undertaken not with an intention to change labeling or advertising practices or otherwise to advantage a pharmaceutical sponsor, but rather to seek answers to discrete questions about dosing or usage of already marketed drugs. Many of these trials are developed by investigators at NCI designated cancer centers and undergo rigorous scientific review before implementation.

In addition, oncologists have the clinical skills to enable them to judge the potential risks involved in relatively limited changes of the sort contemplated by IND-exempt studies. As FDA noted in one of several Guidances issued to encourage the use of IND-exemptions in oncology:

Subsequent to the 2000 National Coverage Determination, FDA issued this 2004 Guidance emphasizing, as in previous Guidance, that studies meeting the definition of IND-exempt under the regulations should not be submitted to FDA. The 2004 Guidance stated that “[d]espite the Agency’s attempts to clarify its policy on IND exemptions, many cancer drug IND applications that the agency determines are exempt from IND regulation are still being submitted unnecessarily.” Indeed, hundreds of unnecessary INDs are submitted annually.

Undoubtedly FDA’s policy is based not only on assessment of need for direct agency oversight, but also on the desire to conserve agency resources by limiting active agency review to studies where such scrutiny is necessary. Officials at FDA are also cognizant of the importance of IND-exempt studies in the practice of oncology and no doubt sought to avoid unnecessary burdens on the conduct of such studies. CMS’s proposal to eliminate “deemed” coverage status for IND-exempt trials will pose threats to patient access to the full range of cancer clinical trials, as well as challenge the administrative efficiency of FDA and the well-being of this sector of the clinical cancer research enterprise.

Proposed CMS Policy Change

Although CMS reports that “[a]ll the comments CMS received on this topic advocated continued “deemed” status for IND-exempt trials,” the proposal is to delete this category of automatic coverage. The rationale for this decision is that “IND Exempt trials do not have FDA oversight and thus have no external process for ensuring that the standards of this Medicare policy are being met.” Apparently, there remains a theoretical possibility for coverage of these trials, but the process for securing coverage is not articulated. In fact, CMS states that it “agrees with the need to explore alternative processes for approving other types of studies such as IND Exempt studies,” yet there appears to be no willingness to delay the change in coverage while such exploration is underway.

ASCO Objections to Policy Change

ASCO believes the proposal to discontinue “deemed”coverage status for IND-exempt trials is extremelymisguided and has been developed withoutappropriate consultation:

1. FDA has determined that this category ofstudies, at least in oncology, is little differentfrom the general practice of oncology, involvingrelatively small modifications of the labeledrecommendations. As FDA notes, this practice isfamiliar to oncologists and poses little or norisk to patients. Collecting data on patientoutcomes in such situations can only be considereda plus, and the notion of penalizing physiciansfor doing so is perverse.
2. Contrary to CMS’s assertion, it is not accurateto suggest that there is no FDA oversight forIND-exempt trials. FDA has formulated criteriaindicating which trials should be consideredexempt, and this regulatory judgment reflectsmeaningful oversight by the agency. Moreover, inthe case of hundreds of studies a year, the IND isactually submitted to FDA for review before FDAdetermines that it should be IND-exempt anddeclines to accept it for further review.
3. CMS made a commitment in 2000 to develop aself-certification process for authorizingIND-exempt trials. ASCO did not believe suchself-certification was necessary because we agreewith FDA that these trials have sufficient generaloversight from FDA and specific oversight from thelocal IRB and, in many cases, from scientificreview boards. Nevertheless, self-certificationwas regarded as necessary by CMS, and CMSundertook the obligation to develop such aprocess, so it is inappropriate for CMS simply todrop the effort precipitately, leaving no optionfor clinical researchers and patients involved inIND-exempt trials. At the very least, “deemed”coverage of IND-exempt trials should continueuntil a self-certification process can be implemented.
4. A decision of this magnitude, reversing apolicy developed in consultation with FDA, shouldnot have been abandoned without renewedconsultation with that agency, and we see noevidence that such consultation has occurred.
5. If CMS goes forward with the proposed policychange, there is no question that FDA will beunnecessarily burdened with requests for INDs thatare considered exempt at present. Clinical cancerresearchers and their patients will be leftuncertain as to whether their treatment shouldcontinue in IND-exempt studies. Both cancertreatment and cancer research will suffer,particularly with respect to Medicarebeneficiaries, who will be particularlydisadvantaged compared to non-Medicare patients.

Additional Issues

On a related matter, ASCO strongly objects to the refusal of CMS to address in a comprehensive and coordinated manner the secondary payer and Medicare Advantage issues referenced in so many comments. The clinical trials policy is not just a policy of the Coverage and Analysis Group of CMS, but rather of the agency as a whole. As internal managers of the clinical trials policy, the Coverage and Analysis Group should accept responsibility to interface with other parts of CMS that may be exerting a negative impact on that policy, whether through inaction, lack of clear direction, or otherwise. When the policy is opened for comment and potential revision and substantive comments are submitted, the process requires meaningful response, not deferral to other offices in the agency. It is note worthythat the deferred issues have a significant impact on access for underserved populations, which should be a special concern of the clinical trials policy. We urge reconsideration of these issues, with a coordinated response to the submitted comments.

ASCO also disagrees with the definition of “investigational clinical services” in that it may conflict with the Medicare statute regarding coverage of off-label uses of marketed cancer drugs. The definition of “investigational clinical services” is “those items and services that are being investigated as an objective within the study.” Many investigator-initiated studies (whether under an IND or IND-exempt) are undertaken with marketed drugs, exploring new uses beyond those referenced in the labeling. To the extent that these studies involve indications (specific cancers) that are either approved by FDA or included in one of the accepted medical compendia, Medicare is required to cover them. 42U.S.C. §1395x(t)(2). The definition should be revised to note that it is subject to this statutory requirement.

CONCLUSION

CMS should withdraw its proposal to eliminate “deemed” coverage for IND-exempt trials. If necessary, CMS should limit the policy so as to maintain “deemed” status for IND-exempt clinical cancer studies, even if it changes the policy with respect to other therapeutic areas.

Sincerely,

Joseph S. Bailes, MD
Co-Chair, ASCO Government Relations Council

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Please consider the case study application of the current proposed policy that follows in reference to these questions:

I am generally in favor and enthusiastic about theproposed amendments to the Clinical Research NCD.I am especially glad that CMS proposes to coveritems/drugs, etc. being researched if they areALREADY a covered benefit outside of the trial.

My main concern, however, is the proposal tocontinue refusing payment for scans, labs, etc.,that are required by the trial but not of discretetherapeutic benefit. The reason is oppose this isthat such information gained from these"research-only" diagnostics is necessary to figureout whether or not the investigationalintervention is in fact an improvement overcurrent practice. If Medicare refuses to pay forthese tests, etc., other insurers will followsuit, and this will have the net effect ofblocking access to clinical trials not only forMedicare beneficiaries, but for many privatelyinsured patients, as well.

In truth, most of these studies required solelyfor the research benefit are usually paid for bythe study sponsor, but there are some exceptions,for instance, an NCI-sponsored intergroup trialinvestigating the prevention of renal cell cancerrecurrence in resected patients. We have hadparticular trouble with getting patients on thistrial due to insurance and Medicare non-coveragefor the required scans.

I propose that CMS at least cover theseresearch-required diagnostics forgovernment-sponsored trials (NCI in particular) inthe event that the trial sponsor does not orcannot provide for that service.

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Now, 411.15 is CFR location of most of the so-called "statutory exclusions" found at 1861(a)(2-22) (eyeglasses, routine foot care, etc). 411.15 applies to Category B IDE devices only at 411.15(o) which states that CMS does not cover experimental devices (not defined) except FDA Category B devices used within an FDA clinical trial. If you are citing 411.15 to mean that Cat B devices related to any of the diverse exclusions at 411.15 are not covered when they are in the form of a Cat B device, it is very similar to the statement that "statutory exclusions" are not covered and should be more explicit. If you mean to refer only to 411.15(o) then do so.

On the other hand, 411.406 is the general CMS program integrity warning that payment will be recouped if the provider could have been aware that a service was not R&N by local community standards or CMS communications (411.406 is considerably amplified by HFCA ruling 95-1). 411.406 is not at all specific to devices and the citation is confusing at the end of a sentence about IDE, and not at all specific to this NCD as a whole; 411.406 could apply to almost any statement CMS makes, that CFR 411.406 (and for that matter all other CFRs) applies.

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The proposed NCD is an improvement in clarity. There are two ways in which the implementation would be made easier for both investigators and contractors.

(1) Be crystal clear regarding the exclusion of Category B related trials and registries. Although the authors probably feel point #8 regarding IDE is clear, I suggest the policy explicitly say that Cat A&B rules entirely "override" the Clinical Trials NCD, even when many parts of the NCD seem to apply (e.g. an NIH funded trial). In short, if the object of investigation is Cat A/B device, no further reading of the NCD inclusion and exclusion rules need be carried out at all. I would put a cross-reference to this right in the definition of clinical research, because for the purpose of this NCD Cat A/B devices are excluded entirely.

(2) I think there is still the possibility in the proposed NCD that some clinical trials may "enter" the domain of the NCD but not be able to get approval in Section 4. Hypothetical - the California Heart Foundation funds a randomized trial of two fully FDA approved artery stents which are already fully covered by the Carrier/FI. This trial seems to enter the Clinical Trials Policy, because it is defined as clinical research, but the trial cannot be 'approved' because it is not an NIH, VA, etc funded trial. I believe the trial does not need to be submitted at all since both arms are already fully covered, and the trial is exempt from the NCD under Point #7, LCDs. (Is this what CAG means?) Perhaps the investigator and contractor would not be sure a priori if it both arms are already covered or not (there is often no written LCD). CAG should ensure that the NCD operates to handle such a situation in the way CAG wants. If both arms are covered, and, the NCD should not change that coverage of both routine and observed services, be sure that the trial does not "enter" the domain of the NCD without being able to "get out" again. I urge you to be as clear as possible, even if the resulting statement is a little redundant to what the policy "implies."

I believe the NCD could be asborbed more easily if it was a little more operational in style. "The following clnical trials are covered by this policy [Clinical research etc]." "However, the following types of clinical trials are always exempt from consideration under this NCD: [Both arms covered by LCD or 1862a1A], [Category A or B devices - separate rules will apply instead of the rules of this NCD], [Simple non comparative case reports...]. The investigator may wish to confirm with a contractor that his trial meets an exemption." These additions would also reduce continuing confusion in Medicare Advantage about covering the "device" in a trial. Under the NCD, the MA plan is responsible for routine costs; under the Cat B rules, the FFS contractor is. The result is a big difference. Many people outside of CMS find the distinction puzzling and let's make it as crystal clear as possible.

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According to the proposal, on page 3, the current policy:

". . . limits the payment for items and services provided to Medicare beneficiaries in qualified trials to routine costs. In general, the policy defines 'routine costs' as those items and services that would generally be available to Medicare beneficiaries outside the trial. Among other things, it also excludes items and services that are the subject of the investigation even if they are covered outside the trial."

The new policy on pg. 26, if I am reading it properly, would not change this because it states that CMS will pay for:

"Items and services that are available to Medicare beneficiaries outside of a clinical study, other than items or services that meet the definition of investigational clinical services."

Elsewhere in the proposed policy, you say comparative effectiveness studies would be covered under the policy. Yet the proposed policy would make it very difficult for Medicare beneficiaries to participate in these crucial comparative effectiveness studies (which could save the agency a lot of money) because it won't pay for already approved drugs.

This came up recently in the proposed Avantis/Lucentis comparative effectiveness trial for macular degeneration sponsored by NIH. CMS normally pays for Lucentis for beneficiaries because it is an FDA approved drug. But it will not pay for it if the beneficiaries participate in the clinical trial.

I think you should amend the policy so it will allow CMS to pay for items like drugs that would normally be covered outside the clinical trial if they are being tested as the comparator arm in a cost effectiveness study.

Not to do that is a penny wise, pound foolish decision, it seems to me.

Sincerely,
Merrill Goozner
Director, Integrity in Science Project
Center for Science in the Public Interest

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Excellent policy, 2 small points:
1. There are some Cat B IDE Trials in which an existing device is being used for a new indication as opposed to the classic device of an improved existing device for an existing indication. Trial for a new indication in which it may or may not work is fundamentally a clinical trial. Cat B IDE may be NONCOVERED by the local contractor and often are if the unproven indication creates a lack of medical necessity ("investigational"). Recommend adding to the list of deemed trials "Any Category B IDE that is not approved by the contractor for payment under the IDE benefit."
2. With respect to "routine costs", you are INCLUDING the cost of administration of the trial item (e.g. administration of chemo agent.) This would appear to indicate that an outpatient procedure (e.g. a cathetirization to place an investigational stent equivalent) OR an invasive procedure (implantation of an investigational pacing device) OR even an entire inpatient stay(intracranial implantation of an investigational device) would be covered. If this is your intent, please state this. If not, it is reasonable to determine that the investigation object and the direct cost of administration/insertion is NOT covered. In other words, this point is ambiguous and additional clarification in one direction or the other would improve the contractor's ability to follow your intent.Thank you

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