FDA
BIOLOGICAL RESPONSE MODIFIERS ADVISORY COMMITTEE
SUMMARY MINUTES
Meeting #26, March 20-21,
2000
The
26th meeting of the Biological Response Modifiers Advisory Committee was held
at the Holiday Inn, Bethesda, Maryland on March 20-21, 2000. Four
topics were included on the agenda:
1) Islet Transplantation; 2) Chairman's Summary Report of the January
13, 2000 meeting of the Xenotransplantation Subcommittee of the BRMAC, 3)
administrative update, 4) update of CBER research programs in the Division of
Cellular and Gene Therapies and the Division of Therapeutic Proteins. A closed session was held on March 21. This portion of the meeting was closed to
permit discussion and review of trade secret and/or confidential information, 5
U.S.C. 552b (c) (4). The public meeting
was attended by approximately 75 persons.
On
March 20, the meeting, was opened to the public and called to order at 9:10
a.m. by Daniel Salomon, M.D., Committee Chair.
A conflict of interest statement was read into the public record which
stated that members with the appearance of a conflict of interest based on
their work with products which could be affected in the future were given
waivers to participate. Copies of the
waivers are available from the FDA Freedom of Information Office. A copy of the agenda and roster are
attached.
The FDA provided a brief introduction to the
islet transplantation issues proposed for discussion on day 1 of the meeting.
The
committee heard presentations from several experts in the field of islet
transplantation. These presentations
addressed islet transplantation as an alternative to whole organ pancreas
transplantation; methods and techniques employed in recent islet transplant
protocols; and quality standards for
islet preparations.
The
committee also heard presentations from two major funding organizations of
islet transplantation research, the National Institutes of Health and the
Juvenile Diabetes Foundation International.
The FDA provided a regulatory perspective for the manufacture of islets
for transplantation.
The
chair then commenced the open public hearing.
There were no requests for public comment. At this time the committee began deliberations of questions posed
to the committee by FDA regarding issues related to the manufacture of pancreatic
islets.
Pancreatic
Islet Product Questions
1. Organ Quality - Source
Material for Islets.
The
committee was asked to discuss recommendations for pancreata exclusion criteria
including restrictions on minimum and maximum donor age; diseases or other
conditions. The committee was also
asked to discuss appropriate serum markers in addition to, or as an alternative
to serum lipase.
The
committee discussed issues related the
use of pancreata from donors <14
years of age. There was no consensus by
the committee on the use of younger donors.
While younger donors may provide a larger source of organs, some
problems could exist with this use of islets from younger donors, including
decreased cell number, difference in secretory capacity and difference in the
time necessary for younger islets to increase insulin production. The committee stated that at this time there
are no data to support rigid age criteria
but if the age limits are expanded there could be the need to modify
guidelines and adjust laboratory techniques.
There
was no consensus by the committee on exclusion criteria for malignancy, prior
diabetes history or acute pancreatitis.
While the committee discussed the importance of using the best criteria
to produce safe and effective islets, in general there are no data to exclude
pancreata from pancreatitis donors, cancer donors or donors with a prior
history of type II diabetes. The committee suggested that the same criteria used for normal
pancreatic organ donation be adopted
for early clinical islet trials.
The
committee agreed on the need for a safe product and that efforts should be made
to obtain the highest quality islets available. There was a concern expressed that islet transplant programs not
adversely affect the ability of patients to obtain high quality whole
pancreata. The committee stated for the
public record that the FDA should join with islet purification centers and UNOS
to address whole organ vs islet programs.
2. Appropriate Types of Identity
and Potency Testing
The
committee included issues related to identity testing and potency in the same
discussion. The committee discussed 3
separate levels of testing. The
committee stated that the following criteria for islets should be measured:
within 2 hours of purification there should be a determination of sterility
(gram stain and endotoxin negative), islet integrity (determined by
diphenylthiocarbazone positive staining) and islet number (at least 5000
IE/kg). There should also be a
reasonable volume to contain the islet mass obtained (e.g. less than 10ml) and
viability should be greater than 95% as determined by vital dye exclusion.
Within
24 to 48 hours of transplantation, follow-up testing should include a measure
of insulin content and a dynamic test of insulin release. These assays could include glucose
stimulated insulin release, and insulin biosynthesis assays.
The
committee also discussed additional assays that could be performed for further
research purposes, including gene expression arrays; expression of apoptosis
markers and confocal microscopy for stimulated Ca++ fluxes.
The
committee also discussed the value of a true in vivo potency assay, for
instance, transplantation in a diabetic SCID mouse model.
3. Viability, Number and
Size of Islet Preparations
The
committee discussed lot release specifications for islet viability and
recommendations for appropriate measures of viability. There was some consensus among the committee
that while it is hard to set absolute criteria for viability, 70% viability as
determined by fluorescent dye exclusion would be acceptable. An islet preparation of 50% viability would
not be recommended for transplant.
In
further comments the committee stated there are insufficient data available to
recommend a maximum volume/dose that may safely be transplanted. As
the maximum tolerated dose is unknown the committee recommended
monitoring hepatic portal pressure during transplantation or keeping the volume
under 10ml.
4. Purity-Composition of Islet Preparations
There
was a brief discussion by the committee about the effect of exocrine tissue
which might be present in islet preparation.
The committee stated that there is no evidence that exocrine tissue
associated with islets is associated with immunogenicity problems. On the other hand, the significant post
transplant death of many cells in the nonislet pancreatic tissue associated
with the islets might well result in inflammatory cytokine release and other
immune effects that should be the subject of further research. Moreover, it is
also known that animals and human patients can be chimeric with donor-derived
cells in tissue compartments distant from the transplant site after islet
transplantation, which might also have effects on the immune response, positive
or negative.
5. Demonstration of Control in Islet Processing
The
committee agreed new investigators/islet transplantation centers will need to
obtain training and to demonstrate proficiency in procurement and
processing. New investigators/islet
transplantation centers will ultimately need to demonstrate (possibly by an
independent assessment) they can reproducibly meet purification standards for
at least 10 consecutive preparations with at least 90% sterility after
processing and 70% viability from sterile, non-clinical grade pancreata.
This
completed the discussion of islet manufacturing issues.
The
committee began a discussion of the Chairman's Summary Report of the January
13, 2000 meeting of the Xenotransplantation Subcommittee of the Biological Response
Modifiers Advisory Committee.
The
report of the FDA Xenotransplantation Subcommittee was presented to the
committee by the subcommittee chair.
The report outlined the recommendations of the subcommittee regarding
FDA policy on blood donor deferral and the risks posed by different types of
xenotransplantation products.
The
committee received an update from the FDA regarding further recommendations
made by the Blood Products Advisory Committee on the issue of additional questions to be included in the
current blood donor questionnaire.
Members of the Xenotransplantation Subcommittee present voiced concerns
regarding a recommendation by the BPAC on questions pertaining to close
contacts of xenotransplant recipients that did not agree with the recommendation
of the Xenotransplantation Subcommittee.
Following
a brief discussion of the report the committee voted unanimously 10 yes, 0 no
to approve the report as written.
At
this time, the meeting was adjourned at approximately 6:15 p.m., March 20,
2000.
The
meeting was reconvened at 8:00 a.m., March 21, 2000. The committee received information on the proposed future
direction of the Biological Response Modifiers Advisory Committee. It was proposed by FDA that future committee
discussions focus on early product development issues. Committee members expressed a concern that
as these types of discussions are less focused than product approval
discussions the committee might lose some enthusiasm for the topics brought
before them. It was emphasized by the
FDA that the direction of the BRMAC would be expanded and the committee would
continue to be involved in future product approval issues but also would have a
major role in early development policy discussions.
Following
this discussion, the committee was provided updates of several CBER research
programs in the Division of Cellular and Gene Therapies and the Division of
Therapeutic Proteins. Individual
research programs from the Laboratory of Cytokine Research and the Laboratory
of Chemistry were briefly summarized for the committee.
At
this time the committee held a brief closed session. The meeting was closed to allow for discussion of confidential issues as warranted under 5 USC
552b(c) (6).
The
meeting was then reopened to the public.
The topic for day two was Preclinical and Clinical Issues in Allogeneic
Islet Therapy. A brief introduction by
FDA to the topic was followed by an open public hearing. There were no requests for public comment.
The
FDA perspective on animal models of islet therapy was provided and the
committee heard two expert presentations on non-human primate and other animal
models of islet transplantation. The last presentation provided the FDA
perspective of clinical issues concerning islet therapy.
At
this time the committee began deliberations of questions posed to the committee
by FDA regarding issues related to preclinical and clinical issues in
allogeneic islet therapy.
1. Immunosuppression
The
committee was asked to consider what
additional animal studies should be done to optimize the immunosuppressive
regimens.
The
committee stated at the current time, there are insufficient data from
preclinical studies to justify a particular immunosuppressive regimen in
clinical trials. Some committee members
suggested there are current clinical data from which to base future clinical
trials, others suggested that non-human models be recommended for new
immunomodulatory agents or combined regimens which have never been used in
humans. It was generally agreed that a justification of any given
immunosuppressive or tolerance inducing strategy should be based on multiple
preclinical models including but not limited to specific islet transplantation
models and at least some nonhuman primate work.
Some
members recommended, if possible, data be obtained from an autoimmune animal
model of diabetes along with more clinically analogous models such as pigs or
monkeys that have been rendered diabetic.
However, some on the committee were not convinced that autoimmunity had
any major role in the success or failure of allogeneic human islet transplants,
particularly under immunosuppression.
The
committee was asked which patients would be most appropriate to include in
studies of islet-only therapy.
There
was no consensus from the committee on the question of patient selection. Some eligibility criteria suggested by the
committee included hypoglycemia unawareness, metabolic instability, and early
secondary diabetic complications with a creatinine cut-off. Psycho-social factors should be considered
and it would be important for patient eligibility to be assessed by an
independent diabetologist. Reference
was made to standards employed for selecting patients for pancreas transplant
but some felt that islet administration is less risky and could potentially be
employed more broadly.
Some
of the committee stated that the risk/benefit ratio will be different for each
individual, therefore, the only recommended required standard eligibility
criteria should be the patient’s informed consent. Others stated that an
informed consent was an imperfect document and subject to real or perceived
bias introduced by the investigators. Therefore, some felt that it was critical
to have independent members on a selection committee to make sure that protocols
were well based on the science and medicine. The potential positive role of the
FDA IND process in this issue was acknowledged by some.
2. Donor-recipient matching
The
committee was asked to discuss preclinical or clinical data which address the
immunogenicity of islet preparations, the minimum criteria (HLA disparity, etc)
to be used for donor-recipient matching and the collection of data on
donor-recipient matching.
The
committee stated HLA matching should not be required but data on HLA typing
should be collected from clinical trials.
There was no consensus among the committee on the need for
cross-matching of blood groups. The
committee stated that animal models, other than non-human primates, could
provide preclinical immunogenicity (e.g. relative to whole pancreas transplant)
data, however there are no data at this time that indicate that HLA antibodies
adversely affect the outcome in islet transplantation.
3. Route/Site of Islet Product Administration
The
committee was asked to discuss direct contact of islet preparations with portal
circulation, safety considerations of intraportal injection of islets, other
routes of administration (immunoprivileged sites) and animal models to evaluate
route/site of administration of islet
preparations.
There
was consensus by the committee that current preclinical and clinical data
suggest portal infusion of islets, employing the current best islet
preparations and recently improved methods of infusion, is safe. There was a suggestion that alternative
sites of administration be considered that would allow insulin to be released
into the portal vein and not directly into the liver or systemic
circulation.
The
committee stated that preclinical data need to be obtained to evaluate other
routes/sites of administration.
4. Outcome Measures
The
committee was asked to discuss issues related to activity measures in early
clinical studies including the appropriateness of specific measures (C-peptide,
Hemaglobin A1c, glucose tolerance, insulin usage, hypoglycemic episodes and
patient diaries); other potential endpoints, and criteria to determine loss of
graft function. The committee also
discussed issues related to efficacy endpoints in phase 3 trials.
The
committee discussed activity measures that would evaluate function. Recommendations were made for all centers to
perform daily glucose monitoring, as
well as measure glucose disappearance and insulin release. Periodic activity measures of Hb1Ac and
C-peptide were recommended.
The
committee stated there are not sufficient current data to set criteria for
determining loss of graft function, particularly in partial function
transplants, therefore, it is important to obtain information on as many
activity measures as possible in early trials.
There
was no consensus by the committee on potential endpoints for phase 3 trials of
allogeneic islet products. The
committee stated there is not
sufficient available information to recommend which patients should go into
Phase III trials. Some areas of concern
include patients with severe hypoglycemia and ketoacidosis. Cardio-vascular complications are
significant risk factors in allogeneic transplants and there need to be
parameters in this regard also.
Additionally, while there are some data from current clinical trials
there are no preclinical or clinical data on the long term consequences of the
immunosuppressive regimens used in these early clinical trials.
This
completed the discussion of issues related to allogeneic islet therapy for the
treatment of diabetes. The meeting was
adjourned by the chair at 4:00 p.m., March 21, 2000.
For more detailed
information concerning the open session presentations and committee discussions
summarized above, please refer to the meeting transcripts. Transcripts may be obtained through the FDA
Freedom of Information Office or accessed through the Internet
(http:www.fda.gov)
Attachments