BRMAC Meeting #27

Human Stem Cells as Cellular Replacement Therapies for Neurological
Disorders

July 13-14, 2000

Hilton Hotel, Gaithersburg, MD

**BRIEFING DOCUMENT**

# 

# INTRODUCTION

FDA recognizes that therapies based on stem cell technology may hold
unprecedented potential. Among many conditions for which this class of
products might be considered, serious disorders of the nervous system
are prominent. Conventional treatment for these diseases is often
nonexistent or unsatisfactory. Available preclinical data appear to
provide rationale for the use of cellular replacement therapies in
several CNS indications. Existing evidence suggests that certain types
of pluripotential cells delivered to the CNS may be unusually responsive
to signals from the local environment, and so adopt characteristics
appropriate to the desired clinical effect. In other cases, it may be
possible to supply signals *ex vivo* that will instruct cells to assume
desired characteristics following administration. Accordingly, initial
human safety studies involving stem cells in patients with serious
diseases of the central nervous system are likely to be proposed in the
near future.

# MEETING SCOPE

The purpose of the workshop is to provide FDA with the best scientific
and medical guidance available to facilitate appropriate regulatory
decisions relating to cellular replacement therapies in neurological
disorders. Though there may be important technical considerations
specific to different types of stem cells, FDA believes that many
aspects of the regulatory framework for these cells will not depend on
their source, and that the appropriateness or inappropriateness of
certain sources of cells is beyond the scope of FDA's authority.
Therefore, questions related to this issue are explicitly excluded from
this discussion.

All cellular products present many complex issues not encountered with
other classes of bio-logicals. These products can easily support the
growth of many pathogenic microorganisms and cannot be sterilized.
Moreover, they quite likely will be administered to very sensitive
sites, such as the central nervous system. Thus, efforts to minimize
risks (e.g., stringent microbiological controls) and to justify these
risks (e.g., a rationale for human use supported by appropriate animal
studies) are of special importance. Since these issues are generic to
other types of cellular therapies, they have been considered previously
(see relevant guidance at
[http://www.fda.gov/cber/gdlns/somgene.pdf)](http://www.fda./)). These
issues will therefore also be outside the scope of this workshop.

Production of some pluripotential cells is done with feeder cells of
murine origin. Any such product will need to address special
requirements FDA has implemented to minimize the risks of xenogeneic
source materials, as described in existing guidance
([http://www.fda.cber/guidelines.htm)](http://www.fda.cber./)). Issues
specific to xenotransplantation will thus be excluded from discussion at
this meeting.

FDA therefore needs to identify the novel and significant issues that
must be considered in order to evaluate the risks and benefits of these
novel approaches intelligently. These types of questions generally fall
into three main categories: Product, Preclinical Pharmacology and
Toxicology, and Clinical Trial Design and Analysis. The issues we wish
to focus on are described more fully below and in the accompanying lists
of questions to be posed.

# PRODUCT CONSIDERATIONS

**[Rationale]{.underline}**

A new investigation begins with a solid rationale for the production and
use of the experimental product. An understanding of the concepts on
which both the production and the rationale for clinical use are based
is essential to guide oversight of experiments.

-   What is the basic biology and technology involved in the
    manufacture, formulation, and administration of the therapeutic
    material?

-   Do pluripotential cells of various origins have different
    properties? What are they? Can they be analyzed?

**[Source Controls]{.underline}**

"Source controls" refer to formal criteria for accepting or rejecting
starting materials used in the production of a biologic product, and for
ensuring the ability of a manufacturer to trace a final product to its
source unambiguously. Experience has taught the importance of such
controls repeatedly. They are considered a cornerstone of our regulatory
policy for all biologics.

-   What controls over the source of donor tissue are appropriate?

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-   Will donor screening according to existing blood banking criteria be
    sufficient to address risks from transmissible diseases? Should
    re-testing of donors for HIV following the 'window' period be done
    routinely if the constraints of product manufacture allow this?

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-   Should donors be screened for known heritable neurologic disorders
    (e.g., Huntington's Disease, familial forms of ALS, Parkinson's
    Disease, etc.)? Should positive test results exclude donors? If so,
    under what circum-stances? For example, should the exclusion be for
    all uses of the cells, or only for those presently known to be
    relevant to the proposed use (e.g., Huntingtin gene defect for use
    in the potential treatment of Huntington's Disease)? What should be
    done with the information?

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-   If the donor can not be identified, will it be appropriate to so
    indicate on the consent form?

**[Process Controls]{.underline}**

It is usually the case that available scientific knowledge is
insufficient to allow definitive characterization of a product by
analytical means alone. Careful control over the manufacturing processes
is therefore essential to produce a safe, effective product
consistently. As scientific understanding and manufacturing experience
accumulate, understanding of the critical process elements improves.
Because stem cell technology is quite new, it is especially important
for FDA to assess the current level of knowledge in this area.

-   What elements of product manufacture are critical to ensure a safe,
    effective, consistent product? Examples of parameters to be
    evaluated might include media and media components, cell density,
    feeder layers, oxygen tension, and so forth.

-   What process parameters remain to be evaluated carefully before
    initiation of human trials?

-   Are tests available to assess the integrity of the manufacturing
    process at intermediate steps? What are they?

**[Characterization and Specifications]{.underline}**

All biological products need to be characterized as fully as current
technology allows. In the area of cellular therapies, this is a special
challenge for two primary reasons. The obvious one is that living cells
are far more complex than most other biological products. This suggests
that evaluation may need to be more involved than for other types of
products. The other concern is that in most‑if not all‑cases, current
understanding of cellular and developmental biology does not allow
definitive conclusions regarding a cell-based product to be based on
analytical procedures alone. This is made especially challenging by the
fact that the therapeutic material will quite likely assume final
characteristics following administration that will be impossible to
assess in the biological product itself. Nevertheless, serious effort
should be directed toward identification of measurable product
characteristics that may be related to product efficacy and safety.
Based on comprehensive characterization studies, a subset of the tests
evaluated can be proposed as product specifications. These may be
modified as experience provides additional insights. As for process
controls, available knowledge in this area must be evaluated.

-   What characteristics of stem cells are related to optimal, mediocre,
    or unacceptable performance?

-   Has evaluation been sufficiently detailed to allow a set of tests to
    be developed that will ensure that the product has consistent
    properties and acceptable performance?

-   What specifications will be useful to establish identity?

-   What specifications will be useful to establish purity? Impurities?

-   What assays can be used to predict desirable performance (potency)?

-   How will the answers to these questions depend on the nature (e.g.,
    autologous, allogeneic germ cell, allogeneic stem cell) and
    manufacture (ex vivo modifications‑genetic, via exogenous growth
    factors, etc.) of the stem cell product?

**PRECLINICAL PHARMACOLOGY AND TOXICOLOGY**

# [Generic Questions]{.underline}

Certain questions apply to all products based on stem cells. Given the
current level of understanding of these products, it is not clear which
of these concerns represent real safety issues. FDA therefore needs
guidance on several questions:

-   What is the potential of stem cells to form tumors? If some types of
    products can form tumors, how frequently does this occur? Should
    potentially tumorigenic cells be engineered to express 'suicide
    genes'?

-   Implanted cells may migrate to sites quite distant from that of
    original implantation. Is this *ipso facto* a safety issue? How may
    this question best be resolved?

# [Cell Fate, Determination, and Specification]{.underline}

The ultimate fate of exogenous cells may depend on both cell autonomous
and cell non-autonomous factors. The balance between these factors may
depend on both the site of administration and the influence of
manufacturing procedures on the competence of the cells to respond to
instruction by local signals from the host tissue. The fate of the cells
following administration is of course the essential factor in
determining the safety and clinical effectiveness of the therapy.
Several questions are germane:

-   What methods or combinations of methods are best (sensitive,
    specific, comprehensive) to assess cell fate? Biochemical studies?
    Immunohistochemistry? Hybridization in situ? Cell marking
    experiments? Others?

-   How long should animals be followed? How long should exogenous cells
    survive in preclinical models to justify the risks of initial human
    experiments?

-   What are the risks of inappropriate fate specification? How serious
    are these risks?

## Proliferation: Non-Neoplastic

-   Is the possibility of inappropriate proliferation of implanted
    cells‑without malignant transformation‑a safety concern?

-   How shall this be evaluated?

-   Should such studies be routine in developing a rationale to support
    initial doses in humans?

It is likely that many of the products under consideration will consist
of more than one cell type. The possibility that each type might behave
differently following administration therefore needs to be considered.

-   How should the issue of product heterogeneity be assessed
    preclinically?

# [Models‑General Considerations]{.underline}

Given the indications being considered, the likely routes of
administration present special concerns. Certain models (e.g., rodents)
may be appropriate for initial preclinical studies, but may not reflect
adequately the anatomical characteristics of humans.

-   Is this the case?

-   Does this represent a consensus in the field?

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-   As before, if not, enumerate the salient viewpoints.

# [Specific Models]{.underline}

It is often the case that the comparison of perceived risk to potential
benefit depends on the adequacy of existing preclinical evidence in the
context of the specific clinical situation under consideration. FDA does
not wish to judge prospectively whether particular indications are
appropriate or inappropriate for initial trials. Nevertheless, it may be
feasible to identify particular clinical indications and eligibility
criteria for which preclinical experimentation has provided especially
favorable prospects. In some of these cases, conventional therapeutic
alternatives may be unsatisfactory. Enumeration of such
clinical/preclinical correlates would be useful.

Moreover, substantial consensus may exist regarding appropriate
preclinical models and experimental paradigms relevant to these clinical
indications. Enumeration of broad areas of consensus could accelerate
product development by facilitating comparisons of different approaches
and by reducing duplication of effort. In these cases, a concise summary
of areas of consensus would be quite valuable. Conversely,
identification of controversial areas, and concise summaries of the
arguments and evidence supporting alternative viewpoints, would be very
useful. Finally, for situations where additional pre-clinical studies
prior to initial clinical trials are needed, there may be agreement on
the nature of these preclinical studies. Enumeration of the appropriate
experiments would also advance the field.

Key questions to be discussed are thus:

-   Can clinical situations be identified for which *existing*
    preclinical and manufacturing information provide strong rationale
    in support of human trials?

-   Does available proof-of-concept data justify initial human trials?
    If not, what further studies are needed?

-   Is the preclinical safety database adequate to justify initial human
    trials? If not, what further studies should be done?

-   Does existing preclinical data support appropriate dosing for
    initial human studies?

-   Conversely, are there disorders or classes of patients for which the
    above information clearly is inadequate?

-   Where information is inadequate to support human trials, what
    additional studies remain to be performed?

-   With respect to these questions, is there consensus in the field or
    not? If not, enumerate the salient viewpoints.

> In certain types of disorders, there may be sufficient information at
> present to recommend particular preclinical models or combinations of
> models and perhaps even experimental paradigms.

### ATTACHMENTS

1.  Stem Cells: A Primer, National Institutes of Health, May 2000-
    <http://www.nih.gov/news/stemcell/primer.htm>

2.  Vogel G. (2000) Can Old Cells Learn New Tricks. *Science*
    **287:**1418-1419.

3.  Barinaga M. (2000) Fetal Neuron Grafts Pave the Way for Stem Cell
    Therapies. *Science* **287:**1421-1422.

4.  van der Kooy D and Weiss S. (2000) Why Stem Cells. *Science*
    **287:**1439-1441.

5.  Gage F. (2000) Mammalian Neural Stem Cells. *Science*
    **287:**1433-1438.

6.  Björklund A and Lindvall O. (2000) Cell replacement therapies for
    central nervous system disorders. *Nature Neuroscience*
    **3(6):**537-544.

7.  Liu S, Qu Y, Stewart TJ, Howard MJ, Chakrabortty S., Holekamp TF and
    McDonald JW. (2000) Embryonic stem cells differentiate into
    oligodendrocytes and myelinate in culture and after spinal cord
    transplantation. *Proc. Natl. Acad. Sci. USA* **97(11):**6126-6131.

8.  Kopen GD, Prockop DJ and Phinney DG (1999) Marrow stromal cells
    migrate throughout forebrain and cerebellum, and they differentiate
    into astrocytes after injection into neonatal mouse brains. *Proc.
    Natl. Acad. Sci. USA* **96:**10711-10716.

9.  Tsai R Y-L and McKay RDG (2000) Cell contact regulates fate choice
    by cortical stem cells. *J Neuroscience* **20(10):**3725-3735.

10. Roy NS, Wang S, Jiang L, Kang J, Benraiss A, Harrison-Restelli C,
    Fraser RAR, Couldwell WT, Kawaguchi A, Okano H, Nedergaard M, and
    Goldman SA (2000) *In vitro* neurogenesis by progenitor cells
    isolated from the adult human hippocampus. *Nature Medicine*
    **6(3):**271-277.