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DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
Food
and Drug Administration
1401 Rockville Pike
Rockville, MD 20852-1448
Center for Biologics
Evaluation and Research
Biological Response
Modifiers Advisory Committee
SUMMARY MINUTES
Meeting #34, February 28,
2003
Holiday Inn, Silver Spring,
Maryland
COMMITTEE MEMBERS TEMPORARY
VOTING MEMBERS
Daniel R. Salomon, M.D., Chair Barbara
Ballard
Jonathan Allan, D.V.M John Coffin,
Ph.D.
Bruce R. Blazar, M.D.* Kenneth Cornetta,
M.D.
David M. Harlan, M.D. John French, Ph.D.
Katherine A. High, M.D. Warren Leonard,M.D.
Joanne Kurtzberg, M.D. Crystal Mackall,
M.D.
Alison F. Lawton Abbey
S. Meyers
Richard C. Mulligan, Ph.D. Thomas Murray, Ph.D.
Mahendra S. Rao, M.D., Ph.D. Bruce E. Torbett, Ph.D.
Anastasios A. Tsiatis, Ph.D. Linda Wolff, Ph.D.
Alice J. Wolfson, Esq.
GUEST
SPEAKERS FDA
PARTICIPANTS
Claudio Bordignon, M.D. Philip Noguchi, M.D.
Marina Cavazzana-Calvo,
M.D., Ph.D. Raj
Puri, M.D., Ph.D.
Adrian Thrasher, M.D., Ph.D. Cynthia
Rask, Ph.D.
Carolyn
Wilson, Ph.D.
NIH REPRESENTATIVES COMMITTEE MANAGEMENT SPECIALIST
Amy Patterson, M.D. Rosanna
L. Harvey
Stephen M. Rose, Ph.D.
EXECUTIVE
SECRETARY
*not attending Gail
M. Dapolito
The summary minutes for the February 28, 2003
meeting of the Biological Response Modifiers Advisory Committee were approved
on .
I certify that I attended the February 28, 2003
meeting of the Biological Response Modifiers Advisory Committee and that this
report accurately reflects what transpired.
_________________________ ________________________________
Gail Dapolito, Executive Secretary Daniel R. Salomon, M.D.,
Chair
FDA BIOLOGICAL RESPONSE
MODIFIERS ADVISORY COMMITTEE
SUMMARY MINUTES
MEETING #34, February 28,
2003
The Biological Response Modifiers Advisory Committee
(BRMAC) met on February 28, 2003 at the Holiday Inn, Silver Spring, MD. In open session, the committee discussed
adverse events recently identified related to a retrovirus gene therapy for the treatment of patients
with X-linked severe combined immunodeficiency (X-SCID). The committee also discussed safety issues
related to retrovirus gene therapies for ADA-SCID and other retrovirus gene
transfer trials using hematopoietic stem cells
Daniel Salomon, M.D., Chair, called the meeting to
order and introduced the members, consultants, guests and guest speakers. The executive secretary read the conflict of
interest statement into the public record.
This statement identified members and consultants of the committee with
an appearance of a conflict of interest, who were issued waivers to
participate. Copies of the waivers are
available from the FDA Freedom of Information Office.
The FDA provided 1) a review of the consensus points
from the BRMAC meeting on October 10, 2003 when the committee initially
discussed this issue, 2) an update on the FDA actions taken in response to the
October 10, 2003 BRMAC meeting and the subsequent notification of another
adverse event in the French trial, and 3) a review of recommendations from
other federal or international committees who have deliberated on these events.
Guest experts provided presentations to the
committee on:
The Chair then commenced the open public hearing. The committee heard comments from the audience representing
· American Society of Gene Therapy
· Stop ALD Foundation
· Citizens for Responsible Care in Research
The committee also heard data from preclinical and clinical studies at Beth Israel Deaconess, Harvard Medical School on retroviral gene therapy to treat several types of cancer in adults.
BRMAC #34 Summary Minutes
February 28, 20003
Following the open public hearing, the committee
engaged in a discussion of the following issues:
1)
Ethical
issues and informed consent related to the confirmation of a second adverse
event in the French trial. The
committee did not propose any changes to the October 10, 2002 committee
consensus on informed consent for retrovirus gene transfer trials to treat
X-SCID.
2)
Differences
in what is known at this time vs. at the previous meeting (October 10,
2002). The most important difference
being that at this meeting it is known that a second adverse event occurred,
indicating this event is not random.
3)
Distinguishing
characteristics of the patients in the French X-SCID trial that may have
contributed to leukemogenesis in two patients.
The committee listed several factors that need to be considered
including, the age of the 2 patients, extent of cell proliferation during the
ex-vivo expansion, cell dose administered, kinetics or T cell reconstitution,
vector (integrations),
transgene and time on study.
4)
Pre-clinical
models. The committee and members of
the public mentioned several factors that need to be considered in evaluation
of animal models including, the age of the animals, the immune competence of
the animal and the length of time animals are maintained and followed.
5)
Retroviral
vector-mediated insertional mutagenesis.
The committee noted that this will be an inherent risk of all trials
using retroviral vector-mediated gene therapy and recommended that further
research be undertaken to determine the number of vector integrants that can be
statistically predicted to have a reduced risk of insertion into known
oncogenes.
6)
Retrovirus
gene transfer (gamma-c transgene) as first-line therapy for patients with
X-SCID/Jak3 deficiency/IL-7 deficiency.
The committee discussed alternative therapies and alternative gene
therapy approaches for patients with X-SCID.
Given the current evidence and until new data are available (in 18-36
months), the committee in a unanimous vote (19 yes, 0-no, 0-abstain) advised
that the FDA only allow gene therapy trials (using a retroviral vector, with
the gamma-chain transgene) in patients with X-SCID, when there are no effective
alternative therapies available.
BRMAC #34 Summary Minutes
February 28, 2003
7)
Retrovirus
gene therapy to treat patients with ADA-SCID.
The committee discussed whether disease differences in ADA-SCID vs.
X-SCID affect the safety of retroviral gene therapy to treat ADA-SCID. Several viewpoints were presented by members
of the committee:
a.
There
is an effective FDA-approved drug therapy for ADA-SCID, PEG-ADA, therefore,
only patients failing drug therapy be considered for retrovirus gene
therapy. The committee also
acknowledged that the typical alternative for patients failing PEG-ADA is a
bone marrow
transplant, however the committee was not sure
whether BMT should also be tried prior to retrovirus gene therapy.
b.
Patients
on PEG-ADA lose the advantage of in-vivo selection provided by retroviral gene
therapy. Therefore, PEG-ADA treatment
should be suspended in patients who receive retroviral gene therapy, in order
to
provide the in-vivo selective advantage of the
therapy.
c.
There
are not sufficient data on the important biological parameters that could
affect insertion and cell growth to make a recommendation on the use of
retrovirus gene therapy in ADA-SCID patients.
d.
Some
committee members stated ADA-SCID is a sufficiently different disease and
should be considered differently for retrovirus gene therapy. Other stated the principle is the same as
for X-SCID, namely risk/benefit analysis.
7.
Other
retrovirus gene transfer studies using hematopoietic stem cells (HSC). Again the committee expressed varying
viewpoints:
a.
There
are no data to predict if the same adverse event is or is not a significant
risk in other HSC retrovirus gene therapies.
b.
It
is difficult to extrapolate data on adverse events from one trial to all
studies using the same vector and target cells, as different transgenes and
different clinical indications may prove to be important variables regarding
relative risk of tumorigenesis.
The committee voted 18-yes, 1-no, 0-abstain advising
the FDA to remove the clinical hold on retroviral gene therapy trials in
hematopoietic stem cells after case-by-case review with the following
provisions:
BRMAC #34 Summary Minutes
February 28, 2003
there is appropriate
risk/benefit to the therapy
there are appropriate
consent form documents
the risk/benefit of
alternative therapies is considered
The dissenting member encouraged the FDA to request
an analysis from sponsors of the probability of a similar adverse event
(leukemogenesis) occurring in the individual trials.
8.
The
committee requested the FDA publicly disclose (for example, posting on a
website) information on future agency measures related to HSC retrovirus gene
transfer trials currently on hold.
Publicly available information should also include updated data on
questions of concern to the committee, including cell dose, vectors,
integration sites and clonality. The committee members recognized however, that
they did not specifically address, at this meeting, the questions prepared by
the FDA related to cell dose, vector and several other issues
9.
The
committee also noted the importance of a number of other issues that they did
not have time to adequately discuss:
a.
The
committee encouraged the scientific community to develop retroviral vectors
with improved design to reduce the risk of insertional tumorigenesis, such as
deletion of retroviral vector enhancer elements and use of insulator elements
or suicide genes.
b.
The
committee acknowledged the critical importance of cell dose relative to vector
integration sites to the safety of retroviral gene therapy.
c.
The
committee advised that investigators participating in gene therapy clinical
trials provide documentation of their familiarity with best practices for
informed consent.
This completed the committee discussion and the Chair officially adjourned the meeting.
For more detailed information concerning the open session presentations and committee discussion summarized above, please refer to the meeting transcripts available on the FDA website at http://www.fda.gov/ohrms/dockets. Please submit all external requests to the FDA Freedom of Information Office.