Draft of presentation at FDA Part 15 Public Hearing

(prepared 17 June 2002)

Good morning (afternoon). I am Steven Boyce. I am trained as a cell
biologist, and I currently hold positions as Associate Professor in the
Department of Surgery at the University of Cincinnati, as Senior
Scientist and Director of the Department of Tissue Engineering at the
Shriners Burns Hospital in Cincinnati, as Founder and President of
Cutanogen Corporation, a biotechnology development company located on
the campus of the University of Cincinnati Medical Center, and as an ad
hoc reviewer for the Advisory Panel to the General and Plastic Surgery
Branch of CDRH. For more than 20 years, I have conducted preclinical and
clinical studies on a combination of cultured skin cells and biopolymers
for prospective treatment of skin wounds. Clinical studies have been
conducted under Investigational Device Exemption permissions for more
than 10 years. These studies and those of numerous other academic and
corporate laboratories have responded to extensive medical needs for
management and healing of skin wounds. Healing is defined here as
complete closure of a wound with autologous epithelium to result in
permanent, or indefinite restoration of the protective functions of skin
that provide a barrier to physical and biological agents in the
environment, and that retain body fluids to maintain physiologic
homeostasis.

This presentation will emphasize relative risks to patients resulting
from disease processes, whether prospective therapies with cells and
matrices may introduce additional risks, whether a positive
benefit-to-risk ratio may be maintained, and whether the regulation of
these kinds of therapies by either CDRH or CBER may affect the
benefit-to-risk ratio. My remarks are my professional opinion based on
my training and experience, but are not represented to be accurate
interpretations of FDA policy or regulatory jurisdictions of existing
products, or to be all inclusive or exclusive.

The extensive medical needs for wound closure may be divided into three
main categories:

1\) Acute/emergent as occur in traumatic skin loss injuries including
burns over large total body surface areas (TBSA), or toxic epidermal
necrosis,

2\) Acute/elective as occur in reconstructive surgery, and,

3\) Chronic/elective, as occur in skin ulcers of venous stasis, diabetic
or decubitus etiologies.

and two subcategories:

a\) Full-thickness which have no source of epithelial tissue and often
require grafting with split-thickness skin graft to accomplish wound
closure, and

b\) Partial-thickness which have remaining sources of epithelial tissue
and usually will close by proliferation and migration of epithelial
tissue on the surface of the wound if kept clean and protected with
conventional dressings.

Medical risks associated with these categories of wounds are
proportionate with the magnitude of the injury and with the consequent
compromise of the protective functions of skin. In general,
full-thickness wounds present greater risk than partial-thickness
wounds, and large wounds present greater risk than small wounds. In
addition, factors contributing to medical risk include, but are not
limited to: age (old or very young), associated injury (pulmonary
burns), associated disease (e.g., diabetes), personal practices
(tobacco, alcohol), and congenital factors. Therefore, if medical risks
were scaled from high to low, factors contributing to high risks would
include skin wounds with:

1\) emergent etiology,

2\) great magnitude (\>50% TBSA),

3\) full-thickness depth, and

4\) associated injury or disease.

To emphasize this point, (insert plot) data from the 2002 Report of the
National Burn Repository show mortality from burns increases from less
than 1% of patients with burns of less than 10% TBSA, to about 8.5% of
patients with burns of 20-30% TBSA burns, to about 35% of patients with
50-60% burns, to about 66.9% of patients with 80-90%TBSA burns.
Conversely, the predominant majority of patients with chronic wounds may
die [with]{.underline} a chronic wound, but will not die
[from]{.underline} a chronic wound.

Low risks would be the converse of these factors. Incidence and
prevalence of each disease condition must also be considered in risk
assessment of the general population together with the time between
onset of the disease and initiation of treatment.

In response to this variety of medical needs, and this scale of relative
risks, multiple approaches have been designed, tested and implemented to
restore the structure and function of healthy skin. Because healthy skin
consists of two main anatomic components, epidermis and dermis,
replacements for each of these components have been designed and tested.
Although healthy skin provides a multitude of structures and functions
for the human body, the essential properties for stable wound closure
are restoration of the "three B's": epidermal [b]{.underline}arrier,
[b]{.underline}asement membrane, and [b]{.underline}lood supply in
connective tissue. Alternative materials may be acellular polymers,
cells without polymers, or combinations of the two. Healthy epidermis
consists almost entirely of cells (keratinocytes, melanocytes,
immunocytes) with minimal extracellular matrix, whereas natural dermis
is predominantly matrix with low densities of cells (fibroblasts,
endothelial cells, nerve, immunocytes). Consequently, common approaches
to replacement of epidermis have involved cells without matrix, and
delivery of a dermal substitute has included acellular polymers from
either biologic (e.g., collagen) or synthetic (e.g.
poly-lactic/poly-glycolic acids) sources with or without cells. In all
cases, the polymers are a degradable type which have been regulated
historically by CDRH. Furthermore, if cells are contained in the
therapy, they may be from autologous or allogeneic sources with
autologous cells able to persist indefinitely after engraftment, and
allogeneic cells being lost from the treatment site by immune
degradation. The table below summarizes the Cincinnati skin substitute
and some products approved for treatment of skin wounds that are
acellular or cellular, and combinations of polymers and cells. (The
table is not represented to be all-inclusive or exclusive.)

  ----------------- ------------------ ------------------ ---------------------
  ***Component***   ***Acellular***    ***Allogeneic***   ***Autologous***

  Both                                 Apligraf, Orcel  Cincinnati Skin
                                                          Substitute

  "Epidermis"                                             Epicel

  "Dermis"          Integra,          DermaGraft        
                    Alloderm                             
  ----------------- ------------------ ------------------ ---------------------

Depending on the magnitude and depth of the skin wound, either
allogeneic or autologous cells may result in permanent closure of an
open wound. For example, materials containing allogeneic cells have been
demonstrated to promote closure of chronic wounds of limited size, but
allogeneic cells will not close an extensive, full-thickness burn. At
present, only autologous cells can provide direct structural and
functional restoration by transplantation to the diseased site, whereas
allogeneic cells act indirectly to deliver cytokines and extracellular
matrix that stimulate healing by autologous cells of the recipient. In
either case where intact, metabolically active cells are applied, the
mechanisms of healing are clearly biologic. The biologic contribution to
the mode of action of a combination material can be easily quantified in
controlled preclinical studies that compare the combination material to
the acellular vehicle. Acellular materials alone have been demonstrated
to promote dermal repair by recruitment and ingrowth of surrounding
tissue, or by combination with a split-thickness skin autograft.
However, the composition of the material may be derived from processing
of a natural tissue (i.e., AlloDerm), or by extraction of purified
compounds that are fabricated with specific structural and biochemical
characteristics that can be distinguished from natural tissue (i.e.,
Integra). The former is considered a processed tissue, while the latter
is considered a medical device.

The Cincinnati model of cultured skin substitute has been used
successfully to treat and close burns of greater than 50% TBSA in dozens
of patients, and has demonstrated clinically significant reduction of
donor site requirements to complete wound closure. At the time of
surgery, this material consists almost entirely of cells, and acts by
delivering to the wound functional epidermal barrier, basement membrane
and angiogenic factors that stimulate vascularization and biological
engraftment of the transplanted cells within 5 days after surgery. These
properties result almost entirely from cellular processes that, at
present, cannot be duplicated by acellular chemical reactions performed
in the laboratory, or by the use of recombinant compounds administered
individually or in combination. The effectiveness of this material
reduces greatly the life-threatening risks of extensive, full-thickness
burns, by restoration of the protective functions of healthy skin. The
same benefits have been demonstrated in a limited number of cases of
giant congenital nevus which also may involve large TBSAs, and require
full-thickness excision followed by closure with autologous skin grafts.
This material may also be prepared with allogeneic cells, and has been
used to successfully treat chronic wounds. The general processes for the
fabrication of this material involve banking of cells by
cryopreservation, and banking of a sterile, degradable substrate by
storage in desiccated conditions. The collagen-based substrate used in
this material is virtually identical in composition and performance to
several kinds of implantable collagen materials that are known to be
very safe and efficacious, yet the substrate's use in this combination
material cannot currently be approved by a 510k mechanism. If the
substrate were not combined with cells, most probably it would not be
considered a Class III device, but rather a device of lower risk due to
the extensive experience and known safety and efficacy of similar
materials.

In addition to the relative risks of disease etiology described above,
risks may result from the sources of starting materials or the
processing of the proposed material. If polymers or cells are derived
from allogeneic sources, the standards established by the American
Association of Tissue Banks have provided very high assurances of safety
from disease transmission (microbial or viral), determination of donor
suitability, processing and tracking of tissues, and facilities
accreditation. These standards together with FDA's requirements for
facilities registration and inspection, and the developing Good Tissue
Practices (GTPs) provide a very positive benefit-to-risk ratio to
recipients of transplanted tissues from allogeneic sources.
Historically, assurances that acquisition and/or processing of
allogeneic tissues does not present additional risks to patients has
been sufficient to allow release of tissue for transplantation without
the need for pre-market approval or multi-center study. However, if
additional processing of tissues occurs to isolate or derive an
acellular or cellular component from allogeneic tissue, then the
additional processes may be subject to review to assure that biological,
chemical or physical risks are not introduced from processing.
Furthermore, those processes may denature or degrade the structure and
function of the original tissue, to an extent that compromises its
efficacy. Demonstration that processing of tissues does not introduce
risks, or degrade efficacy may be advisable to assure that the processed
material provides the safety and efficacy of the natural tissue. These
assurances can be provided by direct comparisons between the processed
tissue and the natural tissue in preclinical studies to determine
whether or not efficacy is maintained.

In this respect, FDA's Guidance on minimally-manipulated autologous
tissue ("MAS"; e.g., Epicel, Carticel) may not make adequate
considerations of the risks associated with loss of efficacy from
isolation, proliferation and implantation of cells without a matrix.
Combination materials for skin repair with autologous cells may provide
greater analogy to native skin by providing both epidermal and dermal
components, and by regenerating epidermal barrier and basement membrane.
The development of these functional phenotypes of skin increase skin
repair and decrease patient risk, but FDA has historically considered
combination materials to have greater risk than grafts of single cell
types. However, under the MAS Guidance, clinical comparison of isolated
cells to the prevailing standard of care may not be required. In my
opinion and experience, the greater the anatomic and physiologic analogy
to natural skin of combination materials (i.e., Cincinnati skin
substitute) increases the benefit-to-risk ratio to patients more than
single cell types without matrix (i.e., Epicel). And as stated above, if
the composition of a device matrix is similar to an existing, approved
material, then the matrix component should be reviewed under a 510k
mechanism because its composition and performance are predictable and of
limited risk. From this perspective, combination materials made with
autologous cells should be able to follow the general path to market
that is permitted by the MAS Guidance which is under the jurisdiction of
CBER with a parallel 510k review of the matrix by CDRH. Regulatory
requirements that extend farther than this result in unnecessary delays
to entry of new therapies into clinical care, without identification of
additional risk, except the lack of a precedent in clinical practice.

In comparison, current FDA standards for materials containing living
cells combined with a matrix also require assurances of safety, but if
reviewed under the jurisdiction of CDRH require multi-center (pivotal)
studies for pre-market approval. Because most of the combination
materials for skin repair have no predicate and have been considered
devices, each has been classified by default as a Class III (Signifcant
Risk) device. Although the assumption that combination materials are
high risk provides a conservative position that may provide maximum
protection to patients, without determination that a risk from the
therapy exists, this conservative position may reduce availability of
the therapy to patients whom are at greater risk from their disease
condition (i.e., extensive burns). The Class III device designation
requires demonstration of clinical efficacy in multi-center (pivotal)
studies to gain marketing approval, and cGMP manufacturing. However,
because the primary mode of action is cellular, the assignment of
jurisdiction to CDRH provides more limited consideration of the
biological origins and actions of the cellular components, and may
require more stringent conditions for manufacturing under cGMP than for
tissue processing under GTP standards. Assuming that all cellular
products are handled in Class 100 biological safety cabinets, incubated
in Hepa-filtered incubators, and handled by trained staff wearing
protective clothing, more important to the material safety than the
manufacturing environment is the composition and origin of the reagents
through which the cells pass during processing.

Environmental controls provide assurances of minimum contaminations of
cellular materials for transplantation, but more important may be the
animal cells or tissue derivatives through which the cells for
transplantation may pass. Although it is fair to say that all
laboratories that fabricate cellular products for transplantation would
prefer pharmaceutical-grade reagents for all processing steps, some
reliance on animal by-products to promote expression of definitive
tissue phenotypes (i.e, epidermal barrier or basement membrane) remains,
because all of the physiologic requirements and molecular mediators for
generation of tissue substitutes are not understood. In addition to the
fundamentally-biological activity of the cells for transplantation,
molecular mediators of cellular proliferation and tissue morphogenesis
are also biologic agents, and not devices. Therefore, review of these
issues is also more appropriate by CBER than CDRH.

In summary:

1\) Combination materials of cells and polymeric matrix usually consist
of mostly cells, and act predominantly by cellular mechanisms, either
direct as with autologous cells, or indirect as with allogeneic cells.
The contribution of the cellular component can be determined in
preclinical studies that compares the combination material to the matrix
alone.

2\) Risks associated with combination products made with autologous
cells should be considered no greater than minimally manipulated
autologous tissue. In fact, risks are less because biologic analogy to
the natural tissue is usually greater.

3\) For combination products with allogeneic cells, standards of the
American Association of Tissue Banks and the developing Good Tissue
Practices of the FDA provide adequate assurances of tissue safety to
patients to maintain a very favorable benefit-to-risk ratio for most
disease conditions.

In conclusion:

1\) If the primary mode of action of a combination of cells with matrix
is cellular, then the jurisdiction should be under CBER, not CDRH. If
the primary mode of action is the matrix, then CDRH should have
jurisdiction. The acellular matrix component should be reviewed by CDRH.

2\) If the jurisdiction for combination products containing cells and a
device matrix is under CBER, then pre-market approval should require
safety assurances and facilities requirements as in tissue banking
(registration, GTPs), but not include mandatory multi-center trials to
demonstrate efficacy in comparison to a prevailing standard of care. If
autologous cells are used in the material, the MAS Guidance should be
followed for the cellular component. If allogeneic cells are used, then
tissue banking practices should become the reference standard. Process
controls and release criteria that are specific to the material should
be required to provide assurances of safety.

3\) Any additional procedures or reagents not typically used in tissue
banking (animal cells or by-products) should be reviewed for
consideration of safety before marketing approval, and most frequently
these will be biologic.

Thank you for your attention, and for the privilege of making this
presentation.

Below are flow diagrams in which general practices and FDA jurisdictions
are suggested for combination materials with a primary mode of action
that is from living cells:

For combination products with ***autologous cells***:

Acquire, process and release like MAS under CBER. Matrix approval by
CDRH

For combination products with ***allogeneic cells***:

Aquire, process, release and tracking like tissue banking (microbial and
viral testing, GTPs) under CBER. Matrix approval by CDRH.

Legend: