**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]{.underline} [TEMPORARY VOTING
MEMBERS]{.underline}**

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]{.underline}**

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]{.underline}** 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]{.underline}**

Philippe Menasché, M.D. Rosanna Harvey

John F. Neylan, M.D.

Emerson C. Perin, M.D., F.A.C.C. **[EXECUTIVE SECRETARY]{.underline}**

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.

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

-   

-   

> **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

    -   The appropriate characteristics and properties need to be
        defined for each product and criteria established

    -   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

-   administration

-   

-   

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-   Testing for cell damage due to high-pressure delivery in a small
    gauge needle is critical

    -   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.

    -   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

    -   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

    -   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

    -   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

    -   There are small animal immunosuppressive models available to
        serve as surrogate potency assays

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-   In-vivo potency assays may not be helpful in acute situations

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-   Committee split on whether or not in-vivo bioassays must be
    reproducible between laboratories

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-   Cannot extrapolate from one cell type to another

-   Cannot extrapolate within a cell type if the manufacturing methods
    differ

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:

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-   Appropriate species and disease model to provide proof of concept
    data

-   Appropriate species and disease model to generate pharmacologic,
    physiologic and toxicologic data

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-   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

    -   Academic sponsor-investigators need to adhere to the same
        requirements for preclinical studies as larger corporate
        sponsors

    -   Types of preclinical safety studies may include cell migration
        ("biodistribution") 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.)

    -   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, arrhythmogenesis 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

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-   Potential adverse affects of catheters on viability and
    functionality of a specific cell product

-   Factors contributing to potential adverse events (e.g. clogging,
    cell embolization) by injection via needle catheter into systemic
    circulation or pericardial space

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-   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

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.

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-   Safety issues related to needle based delivery include

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-   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

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-   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

    -   Randomization and masking

    -   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.

Examples of long-term follow-up of cardiac patients receiving cellular
products include:

-   Frequent clinic/office visits

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-   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

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-   The Committee recommended long-term monitoring of left ventricular
    function but stated long-term studies should not be required prior
    to licensure provided there is sufficient preclinical safety data.
    Long-term follow-up should monitor heart damage as a well as
    re/trans-differentiation of cells.

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-   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
monitoring so that 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.**