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June 4, 2002

Food and Drug Administration

Re: Docket No. 01N-0322

To Whom It May Concern:

I believe that the problem of IRB shopping is significant and may be
widespread. There are two obstacles to defining the extent of the
problem. First, there is little communication between IRBs about
specific protocols and the communication that takes place is often
sporadic and anecdotal. Second, IRB shopping often masquerades as
variability in IRB decisions with no attention paid to the expertise of
the different IRBs and the quality of the review. Lacking systematic
data, I am left to appeal to anecdotes from personal experience. Two
recent protocols come to mind. The details cannot be shared as my access
to these protocols are covered under our institutional confidentiality
agreement with the sponsors. One protocol was rejected by our IRB out of
ethical and scientific concerns about the inappropriateness of an
invasive outcome measure in young children. The sponsor never responded
to our concerns. This drug is on the FDA exclusivity list as the subject
of an FDA written request. The second protocol was deferred due to
safety concerns, with a request that one laboratory measurement be
readily accessible to investigators to assure the safety of
participants. In particular, our IRB was concerned that the selected
dose risked the possibility of death in lighter weight subjects. I
believe this protocol is underway at other institutions. I do not know
whether other IRBs shared our concerns, analyzed the issues differently,
or simply ignored the issues. I am deeply concerned that protocols
involving FDA regulated products are subjecting children to unnecessary
invasive procedures or unwarranted risks based on review by IRBs with
inadequate or no pediatric expertise. The alternative is that these
other IRBs had information unavailable to our committee that may
assuaged our concerns. The ability of committees to share information
would work in both directions.

The fundamental ethical principle is that the independent scientific and
ethical review of research protocols should be performed by a committee
that possesses both adequate expertise and all of the relevant
information necessary to make a determination. By not allowing a
committee access to the results of the review of a protocol by other
committees, the current process undercuts public trust. Whether each and
every IRB possess adequate expertise and all of the necessary
information to make an appropriate determination is unknown.

I now turn to some specific comments in response to the questions raised
in the advance notice of proposed rulemaking.

continued

Every institutional review board that reviews a protocol should be
informed of every prior IRB review, as detailed below. In addition,
every institutional review board at an institution where the protocol is
either approved or under consideration should be informed of all
subsequent IRB reviews.

The IRB decision (approved, deferred, rejected) says nothing of the
reasons for the decision. For example, an IRB may require that the
principal investigator attend the meeting or otherwise the protocol will
be deferred. The IRB decision, that is, deferral, says absolutely
nothing about the content of the IRB review (which in this case is
nothing). In order to fulfill the above ethical principle, the reasons
for the IRB decision needs to be disclosed in order to allow a
subsequent IRB to evaluate the importance and relevance of these
reasons. It would be difficult for a subsequent IRB to evaluate and
either accept or reject the decision of another IRB without knowing the
reasons. For example, there may be local variations in the conditions of
research equipoise or differing scientific interpretations of the need
for placebo controls \-- both of which may justify one IRB disagreeing
with another. Absent the reasons, it is nearly useless to know the
decision of another IRB. In addition, the disclosure of the reasons for
a decision cannot be limited to either acceptance or rejection. Reasons
for a deferred protocol should also be disclosed. An IRB may decide to
do for a protocol in order to keep the conversation open with an
investigator and/or sponsor, rather than an outright rejection. If the
investigator chooses not to respond, the IRB decision will remain a
deferral in the absence of institutional policy that renders any pending
deferral as a rejection after a period of time lapses without response.
Finally, the reasons for approval of a protocol may be important as
well, since one IRB may have either ethical or scientific expertise
unavailable to the other IRB which may assuage the specific concerns
that would\'ve otherwise lead to a deferral or rejection.

IRB minutes are well-known to be an inadequate reflection of the issues
raised and discussed within an IRB meeting. This is especially true if
an issue was raised, discussed, and dismissed as not being \"of
concern\". Although IRB minutes can and should be improved in this
regard, the FDA should not close its eyes to the reality that sharing of
IRB minutes will be inadequate. Sharing of minutes alone runs the risk
that an IRB with a specific concern may not know that this same issue
was even discussed by the other IRB. In addition, the letter to the
investigator that is afforded to sponsor may not include all of the
relevant issues. Once another IRB has seen a protocol, both committees
are under the same confidentiality agreement. This agreement would allow
direct communication between the two parties since they have (or should
have) access to exactly the same information. Thus, a sponsor should be
required to inform an IRB of the identity of other IRBs that have
reviewed the protocol, the decision and/or status of the protocol, and a
contact person (telephone and/or e-mail) for that IRB. This would allow
for direct communication between the two committees. This communication
may benefit sponsors, as committees with respected scientific and
ethical expertise may be asked for advice and consultation. Combined
with IRB accreditation and more specific guidance on the interpretation
of existing regulations, such communication will result in a more
effective and efficient review process.

A simple mechanism for facilitating such communication would be to post
the following information on a sponsor\'s web site, with at least
monthly updates: the list of institutions and the responsible IRB at
which a study has been (or is being) reviewed; the status of the
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continued

(approved, deferred, rejected, pending); and the decision date. This
information should be in the

public domain. This would allow the public, including other IRBs, to
review the list of institutions for any given protocol and be able to
evaluate indirectly the quality of the independent scientific and
ethical review.

Finally, as moderator of The IRB Forum at http://www.irbforum.org, I am
aware of isolated instances in which sponsors have brought indirect
pressures on IRB members who have tried to use the list to locate
another IRB that has reviewed the same protocol. In one example, a
member of The IRB Forum simply posted the name of the protocol and
sponsor with the request for other IRBs who reviewed the same protocol
to establish private contact. I later learned that the sponsor became
aware of the request and called the local investigator with the
accusation that the local IRB had posted proprietary information on a
public web site. The only effective response to this fortunately rare
behavior is to allow for direct IRB communication based on public
disclosure of the institutions and/or IRBs who have reviewed or are
reviewing a protocol.

To reiterate, the fundamental ethical principle of independent
scientific and ethical review of all proposed research protocols by a
committee with adequate expertise and access to all of the relevant
information requires sharing of information between institutional review
boards. Personally, I do not believe this requirement would be met by
the use of a central or independent IRB. A full discussion is impossible
in this letter. Suffice it to say, the \"local\" IRB at the Children\'s
Hospital of Philadelphia has access to over 40 members representing a
diverse range of pediatric expertise as well as the ability to seek
consultation from experts within the CHOP investigator community. When
it comes to adequate pediatric expertise, I believe no central or
independent IRB can meet our standards of expertise. Nevertheless, there
are areas where I would welcome the opportunity to draw on the expertise
of other institutional review boards. A proposed rule requiring sponsors
and investigators to inform IRBs of any prior (or subsequent) IRB
reviews is long overdue, ethically appropriate, and would do much to
restore public faith in the research enterprise.

Sincerely,

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Robert M. Nelson, M.D., Ph.D.

Chair, Committees for the Protection of Human Subjects

Associate Professor of Anesthesia and Pediatrics

The Children's Hospital of Philadelphia

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