Center for
Biologics Evaluation and Research
Biological
Response Modifiers Advisory Committee
SUMMARY MINUTES
Meeting #37, March
18-19, 2004
Hilton Hotel, Silver Spring, Maryland
COMMITTEE MEMBERS TEMPORARY VOTING MEMBERS
Mahendra S. Rao, M.D., Ph.D., Chair Jeffrey S. Borer, M.D.
Jonathan S. Allan, D.V.M. Susanna Cunningham, Ph.D.
Bruce R. Blazar, M.D. Jeremy N. Ruskin, M.D.
David M. Harlan, M.D. Michael D. Schneider, M.D.
Katherine A. High, M.D. Michael Simons, M.D.
Joanne Kurtzberg, M.D.
Alison F. Lawton*
James J. Mulé, Ph.D. FDA PARTICIPANTS
Richard C. Mulligan, Ph.D.* Ellen Areman, M.S., SBB(ASCP)
Thomas H. Murray, Ph.D. Kimberly Benton, Ph.D.
Anastasios A.Tsiatis, Ph.D. Jesse L. Goodman, M.D., M.P.H.
Alice J. Wolfson, J.D. * Stephen Grant, M.D.
*Not Participating D. Nick Jensen, D.V.M., M.S.
Richard McFarland, Ph.D., M.D.
Philip Noguchi, M.D.
Raj Puri, M.D., Ph.D.
GUESTS/GUEST SPEAKERS Cynthia Rask, M.D.
Richard O. Cannon, M.D. Dwaine Rieves, M.D.
Stephen E. Epstein, M.D. Mercedes Serabian, M.S., D.A.B.T.
Silviu Itescu, M.D.
Robert J. Lederman, M.D. COMMITTEE MANAGEMENT SPECIALIST
Philippe Menasché, M.D. Rosanna Harvey
John F. Neylan, M.D.
Emerson C. Perin, M.D., F.A.C.C. EXECUTIVE SECRETARY
Stephen M. Rose, Ph.D. Gail Dapolito
Doris A. Taylor, Ph.D.
Norman Vinter, Ph.D.
The summary minutes for the March 18-19, 2004 meeting of the Biological Response Modifiers Advisory Committee were approved on _________________________.
I certify that I attended the March 18-19, 2004 meeting of the Biological Response Modifiers Advisory Committee and that this report accurately reflects what transpired.
__________________________ __________________________
Gail Dapolito, Executive Secretary Mahendra S. Rao, M.D., Ph.D., Chair
FDA
BIOLOGICAL RESPONSE MODIFIERS ADVISORY COMMITTEE
SUMMARY
MINUTES
MEETING # 37, March 18-19, 2004
The Biological Response Modifiers Advisory Committee (BRMAC) met on March 18-19, 2004 at the Hilton Hotel, Silver Spring, MD. In open session, the committee discussed issues related to the design of early phase clinical trials of cellular therapies for the treatment of cardiac diseases.
On March 18, Mahendra Rao, M.D., Ph.D., Chair, called the meeting to order and introduced the members, consultants and guests. 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 financial conflict of interest, for whom FDA issued waivers to participate. Copies of the waivers are available from the FDA Freedom of Information Office.
The FDA provided an introduction and regulatory perspective related to preclinical and clinical development and manufacturing issues for cellular products for the treatment of cardiac disease. Guest experts provided presentations related to 1) clinical and preclinical studies of cellular products for cardiac diseases and 2) cardiac catheter delivery systems.
During the Open Public Hearing
the Committee heard comments from individuals of the public, including
presentations from researchers at the School of Veterinary Medicine, University
of California-Davis and representatives of Genzyme, Gen Vec and Viacel. and
GenVec. Viacel also commented- should we list?
The FDA asked the Committee to discuss and make recommendations related to manufacturing, preclinical testing and pilot clinical design questions.
The Committee discussed manufacturing questions related to:
· Intrinsic safety concerns for cellular products for the treatment of cardiovascular diseases and the testing that should be performed to ensure administration of a safe product
· Elements of product identity and characterization necessary to generate meaningful data about safety and efficacy
The Committee agreed on the following outline for the discussion of manufacturing issues:
· Would focus on issues specific to a particular cell type as it is applied to administration of the cellular product into the heart
· Would not focus on issues generic to manufacturing of all cellular products and other Biologics, i.e. testing for adventitious agents, GMP requirements
· Would not include discussion of allogeneic cells due to the fact that autologous cells have been administered in the majority of ongoing or previously conducted clinical trials
·Would distinguish between
cells manufactured using in vitro culture
(such as skeletal myoblasts and mesenchymal stem cells) and cells manufactured
without in vitro culture (such as bone
marrow and peripheral blood progenitor cells)
FDA BIOLOGICAL
RESPONSE MODIFIERS ADVISORY COMMITTEE
SUMMARY
MINUTES
MEETING
# 37, March 18-19, 2004
·
Would distinguish between cells manufactured using in
vitro culture (such as skeletal myoblasts and mesenchymal stem cells) and
cells manufactured without in vitro culture (such as bone marrow and
peripheral blood progenitor cells)
In a discussion of cellular products manufactured using in vitro culture prior to administration, the Committee generally agreed on the following:
· Cultured cells should be tested for the appropriate characteristics and properties periodically during culture and when prepared for administration, and
o The appropriate characteristics and properties need to be defined for each product and criteria established
o Appropriate methodologies need to be developed and optimized to determine these characteristics and properties
· More information should be obtained regarding the composition of cellular products administered to patients
Critical information includes cell subtypes present
in the product, differentiation,
karyotype stability,
serum requirements/exposure, residual culture materials in the
final product, cell passage
number/doubling time, cell density, and formulation for
oadministration
· Testing for cell damage due to high-pressure delivery in a small gauge needle is critical
o Large cell types such as myoblasts and mesenchymal stem cells are more likely to be damaged by small gauge needles
· More data are needed on the characteristics of the cells prior to and following administration to monitor cell survival, differentiation, etc.
o Studies to date suggest that most injected cells die shortly after administration. Therefore, trials need appropriate endpoints that will provide biologic information about the cells that are administered and the cells that survive in order to establish the appropriate characteristics of the desirable cell populations.
· Drug-biologic interactions should be characterized prior to the start of clinical trials
o Drugs the patient receives concomitantly or prior to the collection or administration of cellular product may affect cell survival, differentiation, and/or other properties.
· Dose-response and cell death rate should be evaluated
o Once
the desirable cell populations are defined and characterized, manufacturing
techniques should be developed to maximize their survival. When manufacturing
is optimized it will be possible to obtain data on the minimum cell dose necessary
for clinical benefit
FDA BIOLOGICAL RESPONSE
MODIFIERS ADVISORY COMMITTEE
SUMMARY MINUTES
MEETING # 37, March 18-19,
2004
· The Committee also discussed cells that are manufactured without in vitro culture and generally agreed on the following: Cell populations should be characterized by phenotype
o Need to characterize contaminating subpopulations and determine whether they may cause adverse events.
· Cells should be tested for viability and sterility prior to administration
The Committee also discussed issues that were relevant to cellular products manufactured with or without in vitro culture, and generally agreed on the following:
· Surrogates for potency assays are needed that are representative of in vivo the function(s) of the cells
o There are small animal immunosuppressive models available to serve as surrogate potency assays
§ In-vivo potency assays may not be helpful in acute situations
§ Committee split on whether or not in-vivo bioassays must be reproducible between laboratories
· Cannot extrapolate from one cell type to another
· Cannot extrapolate within a cell type if the manufacturing methods differ
FDA
BIOLOGICAL RESPONSE MODIFIERS ADVISORY COMMITTEE
SUMMARY
MINUTES
MEETING #
37, March 18-19, 2004
The Committee summarized that at this time it is difficult to provide conclusions related to manufacturing issues without a better understanding of the product and offered a broad recommendation for overall consistency and facility quality in the manufacture of cardiac cellular products.
The Committee discussed preclinical questions related to
the identification and use of appropriate animal models to:
· Assess the safety of cellular therapies for cardiac diseases:
o Appropriate species and disease model to provide proof of concept data
o Appropriate species and disease model to generate pharmacologic, physiologic and toxicologic data
· Assess safe starting dose prior to initiating clinical trials
· Assess acute and chronic toxicity of cellular therapies for cardiac diseases
The Committee generally agreed:
· It is critical to perform preclinical safety studies prior to initiating clinical studies
o Academic sponsor-investigators need to adhere to the same requirements for preclinical studies as larger corporate sponsors
o Types
of preclinical safety studies may include
cell migration (“biodistribution”) studies studies
(karoytyping or mouse assay).
FDA BIOLOGICAL RESPONSE
MODIFIERS ADVISORY COMMITTEE
SUMMARY MINUTES
MEETING # 37, March 18-19,
2004
· Selection of a preclinical model depends on the clinical population under investigation (i.e., chronic CHF, acute MI, etc.)
o Safety studies in animals should mimic the clinical trial design as closely as possible
§ There is no perfect animal model of heart failure for human cardiac diseases
§
Large animal models (ex. pigs, dogs, non-human
primates) can provide information on the safety and effectiveness of delivery
systems, arrhythmiogenesis and potentially safe
starting doses for the Phase 1 clinical trial
§ Small animal models (ex. immunocompromised rodents) can provide information regarding the ability of the human cellular product to target the myocardium, as well as potential safety issues of the human product
There was discussion among the Committee and participants regarding time of follow-up in animal models in that it was thought that the length of follow-up should be sufficient to identify both potential acute (administration-related) and chronic toxicities (related primarily to the action of the cellular products), although a consensus on a specific timeframe for length of study was not reached.
The Committee discussed device delivery questions related to:
· Potential interactions between cellular products and cardiac catheters
o Potential adverse affects of catheters on viability and functionality of a specific cell product
o Factors contributing to potential adverse events (e.g. clogging, cell embolization) by injection via needle catheter into systemic circulation or pericardial space
· Effects of spread of cells in the myocardium and systemic exposure
The
Committee recommended in-vitro and in-vivo testing of new catheters and of
catheters approved for other indications..
Committee members recognized there are catheter systems currently in use
that are very precise and accurate and can be manipulated safely when used in
the manner described in the “Instructions for use”, however the committee stated animal and ,
FDA BIOLOGICAL RESPONSE
MODIFIERS ADVISORY COMMITTEE
SUMMARY
MINUTES
MEETING #
37, March 18-19, 2004
however the committee stated
animal and bench safety data are needed when these systems are
proposed for use in novel sites, for delivery of novel product, or for other
off label use. The Committee agreed
data should not be extrapolated from one type of catheter/delivery system to
another.
The Committee recognized that cell damage could occur
· Due to contact of cellular product with catheter polymers
·
Due to mechanical perturbation of heart by manipulation
of catheter/needle
FDA BIOLOGICAL RESPONSE MODIFIERS ADVISORY
COMMITTEE
SUMMARY MINUTES
MEETING # 37, March 18-19,
2004
· When cells are delivered through a small gauge needle at high pressure.
o Safety issues related to needle based delivery include
§ significant loss of cells either in the left ventricular chamber or into the myocardial vasculature
§ arrhythmias
In light of these risks, the Committee recommended a conservative approach to clinical studies of cellular products for cardiac diseases that include in-vitro and preclinical studies prior to initiating clinical studies, therefore preclinical studies should be designed as follows:
· Must be able to monitor events to assess the risk of micro-emboli, particularly if delivering to arteries or veins
· Follow-up of a month should be sufficient to detect device related injury in an animal model
The Committee discussed clinical questions related to
design elements of early-phase clinical trials of cellular products for cardiac
diseases including:
· Potential population groups
· Appropriate frequency and duration of patient follow-up
· Appropriate use of control groups in early clinical studies
o Randomization and masking
o Use of placebos
The Committee highlighted two potential populations groups:
· Patients with acute myocardial infarction (MI)
· Patients with chronic heart failure
The Committee stated these groups need different monitoring. Acute MI patients can be monitored by non-invasive means such as echocardiograms. Patients might be monitored several times during the first 2 weeks following treatment, then potentially every 3 months and every 6 months. Patients with chronic heart failure will need more intensive monitoring.
Some Committee members suggested patients with currently
implanted intracoronary devices might be an appropriate population for initial
studies. Other members stated
intracoronary devices might interfere with the ability to evaluate surrogate
markers such as MRI assessment.
FDA
BIOLOGICAL RESPONSE MODIFIERS ADVISORY COMMITTEE
SUMMARY
MINUTES
MEETING #
37, March 18-19, 2004
Examples of long-term follow-up of cardiac patients receiving cellular products include:
· Frequent clinic/office visits
· Non-invasive measures such as periodic echocardiograms, radionuclide angiography, exercise capacity
FDA BIOLOGICAL RESPONSE MODIFIERS ADVISORY
COMMITTEE
SUMMARY MINUTES
MEETING # 37, March 18-19,
2004
· Autopsy of patients who die
· Monitoring left ventricular function
o The
Committee recommended long-term monitoring of left ventricular function but
stated long-term studies should not be required prior to licensure providiedprovided there is
sufficient preclinical safety data.
Long-term follow-up should monitor heart damage as a well as
re/trans-differentiation of cells.
· Systemic inflammation markers
There was consensus among the Committee members that in order to determine the definitive safety of cellular products for cardiac diseases, clinical studies should be double blind, randomized trials. The Committee strongly agreed that a control group is necessary to determine if adverse events are due to the therapy or the natural history of heart disease.
The Committee also stated that monitoring plans should be
pre-specified in the clinical protocol.
The Committee recommended appropriate monitoringmonitoring bedesigned
so that a short-term benefit does not mask
long-term failure.
This concluded the Committee discussion and the Chair adjourned the meeting.
For more detailed information concerning the open session
presentation 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 Freedom of
Information Office.