Steven A. Wartman, MD, PhD May 9, 2007 President/CEO …

Steven A. Wartman, MD, PhD             May 9, 2007
President/CEO

Board of Directors
                                       Leslie V. Norwalk, Esq.
Michael V. Drake, MD
Chancellor                             Acting Administrator
University of California, Irvine       Centers for Medicare & Medicaid Services
Chair
                                       7500 Security Blvd.
Arthur Rubenstein, MBBCh
Executive Vice President for the
                                       Baltimore, MD 21244
Health System
Dean, School of Medicine
University of Pennsylvania
Chair-Elect                            RE: Proposed Decision Memo for Clinical Trial Policy (CAG-00071R)
Frank B. Cerra, MD
Senior Vice President                  Dear Ms. Norwalk:
for Health Sciences
University of Minnesota
Immediate Past Chair                   On behalf of the Association of Academic Health Centers (AAHC), I wish
John Fernandes, DO, MBA                to comment on the proposed clinical research policy (CRP) of the
President
Oklahoma State University              Centers for Medicare & Medicaid Services (CMS). The AAHC,
Center for Health Sciences             representing 100 academic health centers nationwide, is dedicated to
Antonio M. Gotto, Jr., MD, DPhil       improving the nation's health and well-being by mobilizing and
Stephen and Suzanne Weiss Dean         enhancing the strengths and resources of the academic health center
and Provost, Medical Affairs
Weill Medical College and Graduate     enterprise in health professions education, patient care, and research.
School of Medical Sciences
Cornell University
                                       I would like to take this opportunity to thank the agency for its openness
Jane E. Henney, MD
Senior Vice President and
                                       with the academic health center community, its willingness to engage in
Provost for Health Affairs             dialogue to develop the policy, and its responsiveness to suggestions for
University of Cincinnati
                                       revision, change, and clarification. We applaud the agency for its support
Philip A. Pizzo, MD
Dean, School of Medicine
                                       of medical research and its efforts to advance science through clinical
Stanford University                    trials throughout the nation. The AAHC hopes the collaborative spirit of
Sheldon M. Retchin, MD, MSPH           our comments will contribute to improved policymaking that encourages
Chief Executive Officer VCU Health     and sustains this vital dimension of research.
System, Vice President for Health
Sciences
Virginia Commonwealth University       To ensure that Medicare beneficiaries and hundreds of thousands of
Fred Sanfilippo, MD, PhD               other patients can receive the benefits of improved health as a result of
Senior Vice President and
Executive Dean for Health Sciences     clinical trials, the AAHC has several concerns we believe should be
Chief Executive Officer, OSU Medical   addressed before issuing the final CRP.
Center
The Ohio State University

Larry J. Shapiro, MD                   The AAHC recommends that CMS:
President, Washington University          · Clarify all terminology and ambiguities and provide substantive
Medical Center, Executive Vice
Chancellor for Medical Affairs and           definitions, specifically with regard to the definition of clinical
Dean, School of Medicine                     research;
Washington University
                                          · Modify the definition of therapeutic intent to specifically state that
Andrew A. Sorensen, PhD                      Phase I cancer trials are covered;
President
University of South Carolina              · Provide explicit and detailed instructions on the transition period


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Leslie V. Norwalk, Esq.
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May 9, 2007

       for implementation of the CRP that also include the grandfathering of trials
       now covered under the National Coverage Decision;
   ·   Provide direction with regard to registering multi-site trials;
   ·   Delete reference to the public release of pre-specified outcomes;
   ·   Modify language related to generalizing results to the Medicare population;
   ·   Provide detailed instructions on the implementation of the review and
       approval processes;
   ·   Address the exclusion of IND-exempt studies; and
   ·   Provide clarity on humanitarian use devices.

Further detail on each of these issues is provided below:

Language and Definitions
We appreciate that the new CRP attempts to clarify terminology that has created
unnecessary confusion. However, we still find the document to be fraught with
vagueness and contradiction that needs to be addressed, particularly with regard
to standards for a good clinical trial and the Medicare specific standards.

Clinical research
There is considerable confusion about why the CMS definition of clinical research
differs from that already in use by the Food and Drug Administration (FDA) and
the U.S. Department of Health and Human Services (HHS). How does the CMS
definition now relate to other existing definitions which determine the standards
for clinical trials?

Establishing a definition of clinical research, while laudable, serves as an example
of the imperative for CMS to work with other federal agencies that sponsor
research to promulgate and use uniform, standard definitions.

A CMS definition for research may be unnecessary. Such a definition risks
excluding important research studies that do not fall within the definition and
thereby may not be covered by the CRP. By falling outside the definition of
clinical research, coverage of the items and services of such studies would be
jeopardized. Rather than imposing a detailed definition of clinical research, we
suggest that CMS state that the CRP addresses clinical research studies that are
reviewed and approved by an Institutional Review Board (IRB). This would be
more in keeping with CMS's goal to cover studies that meet the applicable
standards but not confine covered studies to "clinical trials." We are concerned
that adding a definition of clinical research may continue to sow confusion, create
inconsistencies with definitions of clinical research from other federal agencies,
and may inadvertently restrict coverage.

Alternatively, we believe CMS should stipulate that research meeting the
definitions of research under 45 CFR Part 46 and 21 CFR Parts 50,56 and
satisfying the criteria for "deemed" approval under the CMS policy will meet the
definition of research under the CMS policy.

General Standards
In meeting the general standards for a scientifically and technically sound clinical
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May 9, 2007

research study as outlined on page 33, the AAHC recommends that the standard
requiring that "All research studies have a written protocol" be amended to read:
"All research studies have a written protocol that clearly addresses, or
incorporates by reference, both the general and Medicare-specific standards."
Without this revision, adding the standard for a written protocol is superfluous and
redundant since all deemed studies already require a written protocol under non-
CMS federal regulations.

Medicare Specific Standards
Therapeutic Intent
CMS has proposed: "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 appreciate the clarification of therapeutic intent, which now takes account of
some Phase I trials that previously did not fall within Medicare's definition.
However, the definition may still not permit coverage of some Phase I trials of
diseases that are not chronic, life threatening, or debilitating, but still pose
substantial public health risks, particularly to elderly populations (e.g., treatments
for non-life-threatening respiratory illnesses). In addition, it is still not entirely
clear whether all Phase I trials are considered as having met the therapeutic intent
requirement.

The AAHC recommends that CMS make perfectly clear whether Phase I cancer
trials are considered as meeting the therapeutic intent requirement and whether
they are covered or not covered under this policy. In addition, the wording should
be changed to say that a Phase I study may meet this standard if it studies "acute
conditions that pose substantial public health risks or diseases that are chronic,
life threatening, or debilitating." In this way, trials that study conditions which
include infectious diseases and make significant contributions to science and the
health of Medicare beneficiaries, will not be eliminated from coverage.

Alternatively, if CMS does not add "acute conditions" to this standard, we suggest
that CMS adopt a definition of "chronic, life threatening, or debilitating" consistent
with current definitions of these terms from the FDA and the National Institutes of
Health.

Registering Trials and Transition Provisions
One of the Medicare-specific standards proposed requires that the research study
be registered on the ClinicalTrials.gov website prior to the enrollment of the first
study subject. This requirement raises questions about the transition provisions
for implementing this policy with regard to trials that are underway at the time the
policy becomes effective. Such provisions are not addressed and are greatly
needed.

The AAHC recommends that all research studies which are qualifying clinical trials
under the current Clinical Trials Policy (CTP) and in which subjects have been
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May 9, 2007

enrolled, be conducted according to the CTP until completion of the studies. This
will waive requirements for registration on the website, as well as all other new
standards of the CRP. Any standards that require look-backs or the need to
redesign elements of the protocol or reenrollment of subjects would necessarily
entail suspension of all research activity with respect to Medicare beneficiaries and
re-consenting all participants. This could endanger patients, would be onerous,
burdensome, and harmful to a significant segment of the research enterprise, as
well as Medicare patients searching for new treatments and cures for illness and
disease. In the worst case scenario, Medicare beneficiaries currently enrolled in
clinical trials would have to pay for all trial-related care or be dropped from the
trials. Neither option will benefit the patients.

The AAHC also notes that this requirement does not address trials that are
conducted at multiple sites. In such cases, would each site have to register the
research study? What is the process for ensuring registration? The AAHC urges
CMS to provide direction on registration with regard to multi-site studies. The
AAHC recommends that the provision be amended to ensure that as long as one
site has posted the research study or if the sponsor has registered the trial, then
the research study should be considered to have met this Medicare-specific
standard.

Public release of pre-specified outcomes
The AAHC supports efforts to ensure unbiased recording of research and public
dissemination of health outcomes that advance clinical awareness of new and
innovative therapies. However, requiring that the outcomes of Medicare-covered
research studies be publicly released may prevent beneficiaries from receiving
coverage for reasonable and necessary treatment during a research study if the
individual health care provider does not have control over decisions about public
release of results or the timing of such a release.

In addition, the proposed policy does not make clear what is considered
"fulfillment" of plans for public release of health outcomes. Often, sponsors are
responsible for releasing results, which may or may not be posted on a sponsor's
website. Results may also be released through publication in peer reviewed
journals; the timing of such publications is not within the researcher's control and
not all studies are published. Given that publication of a study's results can rarely
be supervised by a research site and that no central repository for such
information currently exists, the AAHC recommends that this fulfillment standard
be deleted.

Generalizing the results to the Medicare population
The AAHC understands the desire to determine the impact of age-specific and
other factors on research outcomes and the importance of knowing as much as
possible about the benefits of studies for Medicare beneficiaries. However,
the AAHC must point out that there is no clear sense of how to determine what
threshold CMS is seeking when it requests that the research protocol describe
"whether the research study is powered sufficiently" to draw conclusions with
respect to the Medicare population. We recommend that this terminology be
deleted given that it can only create confusion for all concerned. The AAHC
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May 9, 2007

requests the use of simple, direct, and unambiguous language in this and all other
standards.

The AAHC would recommend that CMS state precisely whether it desires the
research study to be designed to provide results that can be generalized to the
principal Medicare population (persons 65 years or older) or whether it is sufficient
to have a general discussion in the protocol that identifies whether
the study does or does not hope to seek conclusions about the Medicare
population.

The AAHC recommends adding a statement that the protocol include a brief
discussion of benefits to Medicare beneficiaries when such benefits are known or
can reasonably be expected. We strongly encourage a study in which the design
may not be tailored to reach specific conclusions about the Medicare population
not have its coverage jeopardized.

Routine clinical services
The AAHC is very pleased the term routine clinical services has replaced the
ambiguous and confusing term, routine costs, in the new policy.

Approval Process
The processes for meeting the general standards are described in an ambiguous
and unclear manner. The term "approval process" likely is part of this confusion.
It appears that the term "approval process" merely refers to CMS having deemed
certain types of research studies to meet the general standards, because the
research studies have been through an "approval process" that would assure CMS
that the research study meets the general standards. While this is
understandable from a policy perspective, the term "approval process" is
misleading.

Rather than highlighting the "approval process" that the deemed studies have
been subjected to, the AAHC suggests that CMS merely refer to the studies that
have been through acceptable approval processes as "deemed studies." This is a
term with which the industry is familiar. To the extent that the general standards
are designed to replace the "highly desirable characteristics," this would minimize
re-educating the industry on this new term, given that the current term--
deemed--is sufficient and still used within the proposed CRP.

The AAHC also recommends that CMS establish a certification process to inform
investigators, providers, and sponsors that "health care research centers or
cooperative health care research groups" funded by HHS, the Veterans
Administration, or the Department of Defense have met all regulation
requirements. The AAHC suggests that CMS post a list or create a registry of
organizations that meet all the CRP criteria as a funded "health care research
center or cooperative health care research group."

Another ambiguity which should be clarified in the CRP is the posture assumed by
CMS and the Agency for Healthcare Research and Quality (AHRQ) related to
deemed studies under the policy. In the past, CMS has acted in the role of third-
Leslie V. Norwalk, Esq.
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May 9, 2007

party payor with respect to routine clinical services provided in the context of a
clinical trial. The proposed CRP's new requirements reflect obligations heretofore
reserved for the role of a sponsor of research. Indeed, the terminology used in the
proposed policy "conducted or supported by" is the very definition of sponsored
research. Thus, we would like some clarity before implementation of this policy
given the questions that emerge at this time. Is CMS and/or AHRQ acting as a
sponsor of research under this policy? If so, the AAHC recommends that these
agencies clearly adopt and develop the regulatory infrastructure mandated by HHS
regulations, which, for example, include receipt of reports of unanticipated
problems and adverse events related to human subjects. If this is not clarified,
we fear that CMS and AHRQ will receive and/or be overwhelmed by such reports.

Exceptions
CMS states that should the agency find that a study no longer qualifies for
coverage, Medicare payment would be denied under 1862(a)(1)(E) of the Social
Security Act. Again, this situation raises critical questions about the transition
period, how currently open studies would be handled, and how this process (and
others) would unfold. The AAHC requests that clear and detailed guidance and
clarification be given on this issue.

Furthermore, this provision is critically important for the requirement to publish
results of the study. Generally, billing to CMS for services by health care providers
is contemporaneous with delivery of service. If the condition for publication of
results will not be fulfilled for several years after the time of service, then the
billing provider becomes at risk for return of all CMS payments related to the trial
and possibly allegations of fraud. Waiting to bill CMS for services until the trial is
completed will lead to stale claims that are not allowable. In the current health
care climate, providers may likely chose to forego research activity altogether
rather than assume a risk out of their control.

IND-exempt clinical trials
The majority of IND-exempt studies are investigator-initiated studies that take
place in academic health centers. Most of these studies would not qualify for
coverage under the proposed CRP. Excluding such trials, which may be directed
at new combinations or uses of approved drugs and often involve new scientists
and physicians, would be highly detrimental to the U.S. research establishment.
If CMS refuses to pay for medically necessary services during investigator-initiated
studies, there will be a dramatic drop in this type of study. The long-term effects
of this rule will exacerbate current workforce problems, discourage students and
researchers from entering into or remaining in the medical research arena, and
severely limit researcher participation in investigator-initiated trials that provide
many benefits to furthering science and improving health.

Investigator-initiated IND-exempt studies play an important role in the public
health of the country as they enable dissemination of innovative therapies. Many
of these trials are studies of off-label uses of FDA approved drugs that
investigators have already seen to be effective in the non-research context of their
clinical practice. However, in order for the outcomes to be discussed in most peer
reviewed journals, the results must be verified in an organized clinical trial.
Leslie V. Norwalk, Esq.
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May 9, 2007

Withdrawing coverage for these types of research studies not only will discourage
Medicare beneficiaries from enrolling in the research study because the services
may be covered outside the research study, but also will thwart the ability of
clinicians to bring to the public's attention safe and effective off-label uses of FDA
approved drugs.

CMS acknowledged these same concerns in the comments to the proposed rule
and noted the need to develop solutions to address them. Thus, the AAHC is
concerned that CMS decided to change the current policy covering such trials
when time and again the agency has recognized the benefits to be gained from
such trials and the benefits and consequences of a changed policy are yet to be
determined.

Given that the benefits of such trials far outweigh any arguments to the contrary,
there appears to be little reason to deny coverage of IND-exempt trials. The
burden of changing policy more than once will be clearly excessive and very
disruptive and costly to all stakeholders. We recommend that CMS not change
such coverage until sufficient time is spent in gathering information and assessing
the best way to proceed.

Humanitarian Use Devices
Finally, the AAHC would like to recommend that CMS provide some clarity
regarding Humanitarian Use Devices (HUDs) related to clinical trials. The current
policy creates confusion for IRBs and investigators. It would help greatly if CMS
could provide some explicit language about coverage for these devices. Is
coverage for HUDs decided by the local medical director? Is there any change
regarding coverage for HUDs with the new CRP? We believe that CMS could
provide additional comments in this area and confirm when such coverage exists.

Thank you for considering these recommendations. Please note that we have a
broad consensus on these issues and were guided by comments from a wide
range of institutions with a steering committee chaired by Samuel J. Tilden, MD,
JD, LLM, Deputy Provost for Human Subjects Research, Research Compliance
Officer, and Professor of Pediatrics at the University of Alabama at Birmingham.

We look forward to continued work and collaboration with CMS regarding the
publication of the revised Clinical Research Policy. Please know that the AAHC is eager
to offer its assistance to CMS as a bridge to the academic health center community.

Sincerely,


Steven A. Wartman, MD, PhD
President/CEO


cc: Dr. Steve Phurrough
    Ms. Patricia Graves
    Dr. Leslye K. Fitterman