***NORD • NATIONAL ORGANIZATION FOR RARE DISORDERS, INC***
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***100 Rt. 37, P.O. Box 8923, New Fairfield, CT 06812-8925***

***Tel: (203) 746-6518 FAX: (203) 746-6481***

**http://www.rarediseases.org e-mail: orphan@rarediseases.org**

March 14, 2002

Dockets Management Branch

HFA-305

Food and Drug Administration

5630 Fishers Lane

Room 1061

Rockville, MD 20852

RE: Docket No. 01N-0322, OC2001148

> Institutional Review Boards: Requiring Sponsors and Investigators to
> Inform IRBs of any Prior IRB Reviews

Dear Sir or Madam:

The National Organization for Rare Disorders (NORD) represents an
estimated 25 million Americans with more than 6,000 rare "orphan
diseases." Each rare disease, as defined by the [Orphan Drug Act of
1983]{.underline}, affects fewer than 200,000 Americans. Clinical
research is critically important to people with rare disorders because
few of these health conditions are treatable with current therapies.
Therefore, human subject protection rules are of critical importance to
the rare disease community because in many cases the only available
treatment options are investigational.

NORD strongly supports FDA's proposed rule requiring sponsors and
investigators to inform IRBs of any prior IRB reviews. The recent HHS
Office of Inspector General reports have documented instances of "IRB
shopping" that undermines the spirit and intent of human subject
protections. Our goal is to make the system more responsive to the needs
of human research volunteers, and less of a secretive institutional
protection system. We envision a day when scientific investigators will
observe human subject protection rules not because they have to, but
because they want to.

Even more important than "IRB shopping" is the current tendency toward
multi-site clinical trials, and the fact that under our current system
each site can have completely different informed consent documents even
though all human subjects at each site will be participating in the
exact same experiment. There ought to be a way to coordinate IRBs at
each participating site so that all research volunteers will sign
closely related informed consent documents for the same protocol. By
requiring investigators to disclose previous IRB reviews, each IRB will
surely benefit from shared information, and begin to rebuild public
trust in a system that has been shaken by highly publicized scandals.

In answer to your questions:

1.  **We cannot document or quantify the problem of "IRB shopping".**
    However, we can tell you that informed consent documents at
    multi-site clinical trials tend to vary widely, and most often the
    differences appear in legal areas that tend to address the liability
    of the institution. It seems that informed consent documents are
    increasingly evolving into liability protection documents for
    institutions rather than human subject education documents that
    clearly outline possible risks and benefits. Human volunteers can
    hardly make an "informed" decision about participation when a
    multi-site trial stresses unproven benefits and minimizes risks in
    some informed consent documents, while at other sites patients may
    be told the complete opposite. The only way to stop this problem is
    by requiring disclosure and encouraging each site to share IRB
    minutes and consent documents.

2.  **Who should make the disclosures?** If the study is conducted by an
    academic investigator, as a member of the institution's faculty, the
    investigator must seek IRB approval (not the sponsor). However
    commercial clinical trials that are not housed at academic
    institutions sometimes use commercial "National IRBs". In these
    cases, the sponsor usually seeks IRB approval. The sponsor, however,
    is usually the only party that is aware of all IRB decisions and
    recommendations, so the sponsor should be responsible for submitting
    subsequent information about previous IRB reviews to an IRB.

3.  **Who should receive the disclosures?** IRBs should be told that a
    protocol has been reviewed by another IRB, and what that IRB's
    recommendations were. Similarly, an IRB should be told that a
    protocol has been submitted to another IRB even if that IRB's
    decision is still pending.

4.  **What information should be disclosed?** We believe that both
    positive and negative relevant information should be shared by IRBs.
    We particularly urge that IRBs disclose their approved informed
    consent documents. We suggest that institutions post informed
    consent documents on the Internet so that human subjects considering
    participation in a multi-site clinical trial would be able to read
    informed consent documents from other participating sites. The very
    fact that such documents will be disclosed may encourage IRBs to be
    more candid and less deceptive, and to share information and ideas
    with each other so that informed consent documents will be more
    uniform and truthful. Additionally, IRBs should be required to post
    the minutes of their meetings on the Internet so that prospective
    human subjects can understand the points of IRB debate. It is
    essential to rebuild public trust in the IRB system, and
    transparency of the human subject protection process will assure
    that no negative aspects remain hidden from the public.

5.  **We strongly believe that disclosure should be required, including
    requirements for additional reviews, as well as disapprovals,
    requests for changes, etc.** Such disclosure should encourage IRBs
    to communicate with each other, and discourage secrecy that
    undermines public trust. We also believe that informed consent
    documents should be made public so that potential human subjects
    will have access to them. This may result in more uniformity for
    multi-site trials, and indicate that volunteers at site #1 are told
    about the same risks as volunteer subjects at site #2.

6.  **Should information about the basis for a prior decision be
    disclosed?** Detailed information should be shared among IRBs and
    the FDA, but not necessarily the public because of the technical
    aspects of major discussions. Instead, the minutes of IRB meetings
    should be made public so a summary of major decisions will be
    available to the public.

7.  **Researchers and sponsors who do not comply with the rules** could
    be sanctioned through:

    a.  A clinical hold on the experiment so no further subjects will be
        enrolled until the problem is resolved.

    b.  Refer the sponsor/investigator to OHRP.

    c.  Impose other sanctions for violations such as monetary penalties
        for the sponsor or institution.

8.  **Other ways to deal with this problem**: We believe that making
    information public (e.g., putting informed consent documents on the
    Internet, posting IRB minutes on the Internet, requiring sharing of
    IRB data, etc.) should encourage IRBs to learn from each other,
    while keeping the public and the patient community informed. There
    seems to be basic flaws in the current system when one IRB makes
    decisions that conflict drastically with decisions of other IRBs
    reviewing the same protocol. Mandating disclosure will benefit human
    subjects, but it will also enhance the analytical tools of all IRBs
    and help them to make better decisions. Additionally it will share
    important information with other scientists and the general public,
    thereby rebuilding public trust in a system that has been shaken by
    human protection violations.

Very truly yours,

Abbey S. Meyers

President

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