FDA
Center for Biologics
Evaluation and Research
Cellular, Tissue and Gene
Therapies Advisory Committee
Meeting #38
March 3, 2005
Cellular Therapies for
Repair and Regeneration of Joint Surfaces
Questions for
Committee Discussion
1. Confirmatory
clinical studies are controlled studies designed to test hypotheses generated
from the exploratory clinical studies. They should provide definitive
information for licensure or marketing approval. The primary endpoint for a
confirmatory clinical study should be a clear, meaningful measure of clinical
benefit. Please discuss the extent to which each of the endpoints listed below
meet this need. Please cite any other endpoints you regard as important for
confirmatory clinical studies. Please note that the list includes some
endpoints that have been regarded as clearly clinically meaningful measures and
others that have been regarded as useful but not definitive measures of
clinical benefit.
a. Changes
in knee function as measured by scoring systems such as the WOMAC function
score.
b. Changes
in pain as measured by scoring systems that take medication usage into account.
c. Changes
in clinical examination findings (e.g., range of motion, patient’s global
assessment, etc.).
d. Changes
in the appearance of the joint surface on arthroscopy and histopathological
appearance of a biopsy sample from the treated site. Please also discuss
whether the potential morbidity entailed by biopsy outweighs its utility as an
endpoint.
e. Changes
in the appearance of the joint surface and joint space on Magnetic Resonance
Imaging or other noninvasive techniques (e.g., X-ray, computerized tomography,
etc.).
2. Confirmatory
clinical studies should provide robust, verifiable evidence of the clinical
benefit afforded by a cartilage repair product. Please discuss the importance
and limitations of the following aspects of clinical study design for sponsors
to consider when designing confirmatory clinical studies. Please highlight
those situations where flexibility may be acceptable and identify any ancillary
considerations that might optimize the clinical study design.
a. The
nature of the control group; for example, active product or active dose
comparator, surgical procedure comparator, historical comparator, etc.
b. The
importance of blinding procedures; for example, complete blinding versus the
use of blinded evaluators or other options.
c. The
duration of the clinical studies, as it relates to assessing short term as well
as long term benefit in time weighted or landmark analyses. Specifically, at
what time points should important endpoints be evaluated in order to assess the
success and durability of a treatment effect?
3. Please
discuss the limitations and capabilities of available animal models for
predicting safety and clinical activity, focusing on the following:
a. How
should questions of dose and allometric scaling (i.e., size and shape of animal
joint versus size and shape of human joint) be explored in animal models?
b. To
what extent do differences between human versus animal anatomy and cell
physiology need to be addressed in an animal model that uses analogous animal
cells to model human chondrocyte function? Which specific interspecies
differences affect the types of conclusions that can be drawn from animal
studies?
c. Are
non-invasive imaging modalities such as ultrasound, CT, or MRI adequate as a
replacement for interim sacrifices in long-term (six to eighteen month) studies
to evaluate for intraarticular toxicity and /or cartilage formation?
d. What
role should biomechanical tests play in analysis of cartilage repair in animal
models?
e. What
role should arthroscopic biopsy play in analysis of cartilage repair in animal
models?
f. Are
tumorigenicity studies needed for cultured chondrocyte cellular products?
4. Please
provide specific comments on the following with respect to a “pivotal” animal
toxicology study that is designed to support a clinical trial of a cellular
cartilage repair product?
a. What
animal model(s) and study duration are needed to support exploratory clinical
trials?
b. What
animal model(s) and study duration are needed to support a licensing
application?
c. Traditionally,
in vivo toxicology studies include measures of systemic toxicity such as
clinical pathology tests and histopathology of major organs. Is this approach
warranted for toxicology studies with the following categories of products:
i.
cellular products?
ii.
modified cellular products that may secrete
molecules capable of producing systemic toxicities (e.g., ex vivo gene
therapy)?
5. For
an allogeneic cellular product for articular repair, what, if any, additional
safety concerns beyond those posed by an autologous product should be addressed
in an in vivo study prior to initiation of clinical trials?
6. Characteristics
of the starting tissue, which could be derived from the involved joint or a
different site, may influence the quality of the cellular product
substantially. Please discuss what criteria should be used for obtaining such
tissue (e.g., anatomic site, pathologic involvement of the tissue to be
collected, etc.). Please discuss the gross characteristics that would be
useful, including those that may be visible at operation before excising the
biopsy, and/or microscopic or molecular characteristics evaluated following
collection but before use.
7. Noting
that cells intended for repair of joint surfaces, when grown in vitro, may not
express characteristics of cells that produce differentiated cartilage, please
consider the following question: What characteristics (e.g., based on analysis
of proteins, extracellular matrix components, mRNA expression levels, cell
surface antigens, cellular morphology, functional properties, or other
parameters) could be used to identify cells that will form stable chondrocytes
in vivo? Where appropriate, discuss characteristics that should be absent from
these products as well as those that should be present.
8. For
licensed biological products, each lot of final product must be tested for
identity, purity, and potency prior to clinical use. Please discuss what
analytical tests and acceptance criteria could be applied to each of these
parameters to provide reasonable assurance of adequate product performance in
vivo.
a. Please
identify the characteristics discussed under question 7 that would be useful in
developing such tests.
b. Given
the capabilities and limitations of animal models discussed previously
(Question 3), please discuss how these models may be used to provide data to
support the in vitro characterization tests.
c. Please
discuss biological activity assays that may be used to measure the potency of
each product lot to ensure product consistency. Are methods based on
determination of viable cells by dye exclusion (e.g., for cells used
immediately after culture) or formation of colonies in soft agar (where time
permits, e.g., if final product is cryopreserved) adequate? If not, please
suggest appropriate alternatives.
9. Many
products in this category consist of cells within a biological or artificial
matrix. What special considerations (e.g., mechanical testing, histological
analysis, spatial distribution of gene expression, etc.) does this present for
product characterization and specifications? Please discuss in terms of product
safety, purity, identity, and potency.