FOOD AND DRUG ADMINISTRATION
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CENTER FOR BIOLOGICS
EVALUATION AND RESEARCH
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CELLULAR, TISSUE AND GENE
THERAPIES ADVISORY COMMITTEE
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THURSDAY,
APRIL 10, 2008
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This transcript has not been edited or corrected, but appears as
received from the commercial transcribing service. Accordingly the Food and
Drug Administration makes no representation to its accuracy
The Committee convened at 9:00 a.m.
in the Grand Ballroom of the Hilton Washington DC North/Gaithersburg, 620 Perry
Parkway,
MEMBERS
PRESENT:
WALTER
J. URBA, M.D., Ph.D., Chair
MATTHEW
J. ALLEN, Vet. M.B., Ph.D.
JEFFREY
S. CHAMBERLAIN, Ph.D.
RICHARD
J. CHAPPELL, Ph.D.
KURT
C. GUNTER, M.D., Industry
Representative
LARRY
W. KWAK, M.D., Ph.D.
DORIS
A. TAYLOR, Ph.D.
SAVIO
L.C. WOO, Ph.D.
CONSULTANTS/TEMPORARY
VOTING MEMBERS
PRESENT:
MICHELE
P. CALOS, Ph.D.
KENNETH
R. CHIEN, M.D., Ph.D.
MERI
T. FIRPO, Ph.D.
MARTIN
FRIEDLANDER, M.D., Ph.D.
STEVEN
A. GOLDMAN, M.D., Ph.D.
JOHN
W. McDONALD, M.D., Ph.D.
DANIEL
SALOMON, M.D.
EVAN
Y. SNYDER, M.D., Ph.D.
WILLIAM
TOMFORD, M.D.
GORDON
C. WEIR, M.D.
MEMBERS
NOT PRESENT:
FARSHID
GUILAK, Ph.D.
CONSULTANTS/TEMPORARY
VOTING MEMBERS NOT PRESENT:
SHARON
TERRY, M.A., Consumer Representative
GUEST
SPEAKERS PRESENT:
JEFF
W.M. BULTE, Ph.D.
MELISSA
K. CARPENTER, Ph.D.
JONATHAN
DINSMORE, Ph.D.
OLE
ISACSON, M.D.
JANE
LEBKOWSKI, Ph.D.
FDA
PARTICIPANTS PRESENT:
STEVEN
BAUER, Ph.D.
THERESA
CHEN, Ph.D.
BRUCE
SCHNEIDER, M.D.
CELIA
EXECUTIVE
SECRETARY PRESENT:
GAIL
DAPOLITO
I-N-D-E-X
WELCOME..................................... 5
DR. URBA
INTRODUCTION
OF COMMITTEE.................. 11
INTRODUCTION............................... 15
DR. BAUER
PRESENTATIONS
DR. CARPENTER........................ 27
Developing A Safe Human Embryonic
Stem Cell Product For Diabetes
DR. DINSMORE......................... 57
Safety Considerations for the
Clinical Application of Human
Embryonic Stem Cells
DR. LEBKOWSKI........................ 90
Human Embryonic Stem Cells:
Considerations For Therapeutic
Development
DR. ISACSON......................... 131
Preclinical Evaluation of Human
Stem Cells for Safety and Function:
Examples from Neuronal Transplantation
in Animal Modes of Parkinson's Disease
DR. BULTE........................... 177
Tracking Cells After Administration:
Are They Delivered Correctly,
Where Do They Go, and
What Do They Become?
OPEN
PUBLIC HEARING
AMY COMSTOCK RICK................... 217
Coalition for the Advancement of
Medical Research
CHRIS AIRRIESS...................... 223
DISCUSSION
OF QUESTIONS
QUESTION
# 1.............................. 228
Inappropriate
Differentiation/Tumorigenicity
QUESTION
# 2.............................. 327
Characterization
of hESC-Derived Cellular Preparations
QUESTION
# 3.............................. 357
Patient
Monitoring
Adjourn
P-R-O-C-E-E-D-I-N-G-S
9:00 a.m.
CHAIR URBA: Good morning.
My name is Walter Urba and I'd like to welcome you to the Cell, Tissue
and Gene Therapy Advisory Committee this morning to discuss cellular therapies
derived from human embryonic stem cells and scientific considerations for
preclinical safety testing.
Gail, would you like to read the
statement?
MS. DAPOLITO: Good morning.
I'm Gail Dapolito. I'm the
executive secretary of the committee.
Before I start, we would like to
request that you silence all cell phones and pagers, please.
The Food and Drug Administration is
convening April 10 and 11, 2008, meeting of the Cellular, Tissue and Gene
Therapies Advisory Committee under the authority of the Federal Advisory
Committee Act of 1972. With the exception
of the industry representative, all participants of the committee are special
government employees or regular federal employees from other agencies and are
subject to the federal conflict of interest laws and regulations.
The following information on the
status of this advisory committee's compliance with federal ethics and conflict
of interest laws, including but not limited to 18 U.S.C. Part 208 and Part 712
of the Food, Drug and Cosmetic Act, is being provided to participants at this
meeting and to the public. FDA has
determined that all members of this advisory committee are in compliance with
federal ethics and conflict of interest laws.
Under 18 U.S.C. Part 208 Congress
has authorized FDA to grant waivers to special government employees and regular
government employees who have financial conflicts when it is determined that
the Agency's need for a particular individual service outweighs his or her
potential financial conflict of interest.
Under 18 U.S.C. Part 712 of the
Food, Drug and Cosmetic Act, Congress has authorized FDA to grant waivers to
special government employees and regular government employees with potential
financial conflicts when necessary to afford the committee their essential
expertise.
Related to the discussions at this
meeting, members and consultants of this committee have been screened for
potential financial conflicts of interest of their own, as well as those
imputed to them, including those of their spouses or minor children and for the
purposes of 18 U.S.C. 208, their employers.
These interests may include investments, consulting, expert witness
testimony, contract and grants, gratis, teaching, speaking, writing, patents
and royalties, and also primary employment.
The committee will discuss
scientific considerations for safety testing for cellular therapy products
derived from human embryonic stem cells.
This is of particular matter of general applicability. The agenda also includes several updates.
Based on the agenda and all
financial interests reported by members and consultants, no conflict of
interest waivers were issued under 18 U.S.C. 208(B)(3) or 712 of the Food, Drug
and Cosmetic Act.
Dr. Kurt Gunter serves as the
industry representative for the committee, acting on behalf of all related
industry and is employed by Hospira, Incorporated. Hospira has less than a five percent equity
interest in Novocell. Hospira does not
hold a Novocell board seat and no Hospira employee serves in an advisory capacity
to Novocell. Industry representatives
are not special government employees and do not vote.
In addition, there are many
regulated industry and other outside organization speakers making
presentations. These speakers may have
financial interests associated with their employer and with other regulated
firms. The FDA asks, in the interest of
fairness, that they address any current or previous financial involvement with
any firm whose product they may wish to comment upon. These individuals were not screened by the
FDA for conflicts of interest.
This conflict of interest statement
will be available for review at the registration table.
We would like to remind members,
consultants and participants that if the discussions involve any other products
or firms not already on the agenda for which an FDA participant has a personal
or imputed financial interest, the participants need to exclude themselves from
such involvement and their exclusion will be noted for the record. FDA encourages all other participants to
advise the committee of any financial relationships that you may have with any
firm that could be affected by the discussions.
For topics such as these being
discussed at today's meeting, there are often a variety of opinions, some of
which are quite strongly held. Our goal
is that today's meeting will be a fair and open forum for discussion of the
relevant scientific issues and that the committee discussion proceed without
interruption. Thus, as a gentle
reminder, individuals will be allowed to speak into the record only if recognized
by the Chair and FDA has scheduled a time for public comment during the open
public hearing listed on the agenda at approximately 12:30.
Regarding press inquiries, please,
address all press inquiries to Peper Long and Karen Riley, and they're standing
over here, of the FDA public affairs office.
And, also, the primary spokesman for the FDA is Dr. Celia Witten.
Thank you, Dr. Urba. I'll turn it over to you.
CHAIR URBA: Thank you, Gail.
I'd like to start with an
introduction of the members of the committee.
Dr. Gunter?
DR. GUNTER: Good morning.
My name is Kurt Gunter and I'm the industry representative, non-voting.
DR. WOO: Savio Woo, I'm professor and Chairman of the
Department of Gene and Cell Medicine at the Mt. Sinai School of Medicine in
DR. WEIR: Gordon Weir,
DR. CHIEN: Ken Chien, I'm the director of the
DR. SNYDER: Evan Snyder, professor at the Burnham
Institute for Medical Research and director of the Stem Cell Program and Stem
Cell Research Center.
DR. SALOMON: Dan Salomon, molecular and experimental
medicine, The Scripps Research Institute; and director of The Scripps Center
for Organ and Cell Transplantation.
DR. FRIEDLANDER: Martin Friedlander, professor in the
Department of Cell Biology at The Scripps Research Institute; and also chief of
the Retina Service in the Department of Ophthalmology at The Scripps Clinic.
DR. TOMFORD: Bill Tomford, I'm an orthopedic surgeon at
DR. CHAPPELL: Rick Chappell, professor of the Department of
Biostatistics at the University of Wisconsin Medical School.
DR. CALOS: Michele Calos, professor in the Department of
Genetics at Stanford University School of Medicine.
MS. DAPOLITO: Gail Dapolito, Center for Biologics.
CHAIR URBA: Walter Urba, medical oncologist, Child's
Research Institute,
DR. GERSON: Stan Gerson, professor of medicine,
DR. KWAK: Larry Kwak, chairman of the Department of
Lymphoma and Myeloma at
DR. TAYLOR: Doris Taylor, professor of medicine and of
physiology; director of the Center for Cardiovascular Repair, University of
DR. FIRPO: I'm Meri Firpo, also from the
DR. GOLDMAN: I'm --
MS. DAPOLITO: Dr. Goldman, could you turn your -- yes.
DR. GOLDMAN: I'm back on?
Steve Goldman, I'm the professor of neurology/neurosurgery at the
DR. ALLEN: Matthew Allen, I'm associate professor of
Small Animal Surgery at the
DR. CHAMBERLAIN: I'm Jeff Chamberlain, professor of neurology
at the University of
DR. SCHNEIDER: Bruce Schneider, medical officer of the
Center for Biologics, FDA.
DR. CHEN: Theresa Chen, Center for Biologics, FDA.
DR. BAUER: I'm Steve Bauer, branch chief of the Cell and
Tissue Therapy Branch, FDA.
DR. WHITTEN: Celia Whitten, office director of the Office
of Cell, Tissue and Gene Therapies at FDA.
CHAIR URBA: Thank you.
We'll start out with an introduction from the FDA given by Dr. Steven
Bauer, Chief of the Cell and Tissue Therapy Branch of Cellular and Gene
Therapies of CBER.
DR. BAUER: Well, good morning, everyone.
Members and guests of the Cell,
Tissue and Gene Therapy Advisory Committee, on behalf of my colleagues at the
FDA, we welcome you and thank you for your participation in this meeting.
My introduction will describe the
background, goals and focus for today's meeting. This meeting is being convened to provide the
Food and Drug Administration with scientific insight regarding safety issues in
the development of cellular therapies derived from human embryonic stem
cells. No specific products will be
discussed for regulatory review purpose.
Invited speakers will present
information that focuses on scientific issues concerning development of these
types of products. Members of the
committee will be requested to consider this information and provide a response
to FDA questions.
Could I have the next slide?
The Office of Cellular, Tissue and
Gene Therapies is charged with oversight of all cell-based therapies. FDA has convened a number of advisory
committee meetings over the previous years to discuss scientific issues related
to development of cell therapies.
This slide lists selected recent
advisory committee meetings and a recent workshop related to cell therapy
products. These meetings have provided
significant feedback about the scientific issues involved in the development of
quite a few novel cell therapy products, many of which use stem cells from a
variety of sources.
Information from these meetings is
posted on the CBER website where it can be accessible to researchers and the
public, as well as FDA. Also of likely
interest to many of you in attendance today is an upcoming NIH research
symposium on clinical applications of cell therapies on May 6th this
year. We expect continued activity and
discussion as these therapies advance in their development.
There is considerable interest in
development of cell therapy products derived from stem cells due to their
ability to self renew and proliferate in tissue culture while maintaining
pluripotency. The FDA has considerable
experience in the evaluation of investigational cell therapy products. Nevertheless, the use of cellular therapy
products derived from embryonic stem cells prevents specific safety questions
that the committee will consider today.
This slide shows several biological
properties of embryonic stem cells and how those properties result in
particular safety concerns. As this
diagram, where my pointer is, illustrates, these cells have the ability to self
renew and proliferate in tissue culture while maintaining pluripotency. The pluripotency is suggested by these
downward arrows and the upward arrow suggests
the self renewal. But these
properties allow production of large numbers of undifferentiated stem cells.
And as illustrated here, the cells
maintain their capacity to differentiate, and they can be induced to
differentiate along specific cell lineages under carefully controlled
laboratory conditions. As they
differentiate, they proceed through immature stages and finally differentiate
into mature, functional cells. Today we
will be discussing cell products that are intended to be more mature than stem
cells, as indicated in this rectangular area.
The immature stem cells have the
ability to generate teratomas, which may contain differentiated cells
originating from all three embryonic tissue types: endoderm, mesoderm, and ectoderm. Although this characteristic provides
evidence of pluripotency, it also raises a potential safety concern,
tumorigenicity, as shown by this arrow.
When administered to animals in sufficient numbers, these cells give
rise to teratomas comprised of either differentiated or undifferentiated cell
types depending on the micro environment at the site of administration.
Because cells that are more mature
do not pose the same risk of teratoma formation, current efforts are focused on
using cells that are downstream or more mature than embryonic stem cells. Nonetheless, cell therapy products derived
from human embryonic stem cells could be heterogeneous in their composition and
include cells that have differentiated to variable degrees. Residual undifferentiated stem cells may
become teratomas, some of which may become malignant.
A related potential safety concern
is that residual undifferentiated stem cells and partially differentiated cells
may have the ability to migrate from the site of administration. Since they will contain the capacity to
proliferate and differentiate further, such cells may undergo inappropriate
differentiation and form ectopic tissue which could potentially have tumor-like
effects or disrupt function at unintended sites.
One of the FDA's major
responsibilities is to assess potential risks and benefits and take steps to
reduce potential risks to subjects who are enrolled in investigational clinical
trials. Safety assessment is based in
part on the preclinical safety studies performed by a sponsor, and the design
and conduct of the studies are critical to evaluating whether it is reasonably
safe to conduct the proposed clinical investigations.
This slide quotes from Title 21 of
the Code of Federal Regulations, Part 312, which describes safety assessment
studies. As pointed out here, adequate
information about the pharmacological and toxicological studies should be
provided. The kind, duration and scope
of animal and other tests required varies with the duration and nature of the
proposed clinical investigations.
So the preceding slides provide some
of the background that leads us to the focus for today. Namely, safety issues regarding the use of
cellular therapy products derived from human embryonic stem cells. The goal of the meeting is to obtain expert
advice regarding product characterization, preclinical testing, and design of
clinical studies both to enhance recipient safety and improve the assessment of
therapeutic activity in clinical trials of such products.
We will have discussion from our
advisory committee members and additional experts on the panel. These members received a briefing document
assembled by my colleagues and me from the Office of Cellular, Tissue and Gene
Therapies. This document is available on
FDA websites. The document contains
additional and more detailed background information and some specific questions
for discussion.
In the next few slides I will
highlight the issues we would like to focus on today.
The topic of inappropriate differentiation,
including tumorigenicity, is of a particular interest to us, especially with
regard to the animal models that could be used for preclinical safety
assessments. We are seeking the
committee's perspectives on issues related to the selection of animal species,
animal models, and design of animal studies that are relevant to clinical
trials.
The physiological environment and
the anatomical location where cellular products are administered, as well as
where the cells end up, may have a significant influence on safety. Therefore, the site of cell implantation and
the fate of cells after administrations are topics for discussion today.
Another topic is related to cell
dose extrapolation, in particular as it relates to the composition and purity
of the cell product. As I mentioned
earlier, these products may be heterogeneous in their composition and contain
some undifferentiated stem cells.
Low levels of undifferentiated cells
are of concern, but total cell doses for animal studies are lower than total
doses proposed for human studies. Does
this difference in absolute numbers of potentially tumorigenic cells alter the
ability of the animal studies to predict patient safety in clinical trials?
Finally, study duration is important
to discuss since engraftment and duration in animals should be sufficient to
address concerns about inappropriate differentiation and tumorigenesis.
Another topic for discussion is
product characterization. The
sensitivity, specificity, robustness, accuracy and precision of assays used for
characterization of these products must be sufficient to provide a reasonable
assurance of safety. Assays used as
process controls and for lot release should be capable of detecting and accurately
measuring low levels of undifferentiated stem cells or other cellular
impurities. These may present an
unacceptable risk because of their ability to form tumors, differentiate inappropriately, or present
other safety concerns.
As this slide shows, we are also
asking the committee to discuss issues related to patient monitoring and other
aspects of clinical trial design that will help assure safety in recipients of
these products. What tools exist for
monitoring the infused cells during clinical trials? Where do the cells localize and in what
amounts? Can we detect inappropriate
cellular differentiation and function in the recipient?
An important clinical issue relates
to cell dose levels. Given the potential
risks of these products, data supporting a reasonable possibility of efficacy
may need to be particularly strong.
Clinical design parameters should
permit evaluation of potential clinical benefits even where possible in early
studies. Such expectations of and
proposed evaluations of potential therapeutic action are generally based on
preclinical demonstrations of proof of concept, and specific requirements for
such data will vary among products in clinical indications.
I have discussed the focus of this
meeting and described some of the issues on which we are seeking the
committee's insight and perspectives. To
add to the basis for discussion, we have asked some guest speakers to address
different aspects of the issues.
This morning we will have
presentations from our guest speakers. Dr. Melissa Carpenter, Dr. Jonathan
Dinsmore, Dr. Jane Lebkowski, Dr. Ole Isacson, and Dr. Jeff Bulte. This will followed by an open public hearing
in the afternoon and then the panel discussion of FDA questions.
We value the expertise, insight and
perspectives that our panelists and guests bring to this meeting and the
opportunity for open discussion. Thank
you to the members of the committee, our guest speakers, and Gail Dapolito and
other FDA staff who have helped organize this meeting. Thank you.
CHAIR URBA: Thank you, Dr. Bauer
(Applause.)
CHAIR URBA: Any questions from the committee?
(No audible response.)
CHAIR URBA: If not, thank you. We'll move on to our first presentation from
Dr. Carpenter, Developing A Safe Human Embryonic Stem Cell Product For
Diabetes.
DR. CARPENTER: Okay.
I'd like to start by thanking the committee for the opportunity to speak
today. And what I'd like to talk about
is utilizing human embryonic stem cells for the treatment of diabetes and talk
about the safety issues surrounding that.
What I want to start with is by
reminding you that in the case of diabetes, cell therapies have already been
pretty well tested. What we know about
diabetes and about cell therapies for diabetes is, that if you implant primary
islet cells into these patients, you will see a positive effect.
This has been done, perhaps most
recently and most notably, in the Edmonton Protocol, and in this case what it's
done is that primary islets are isolated from donor pancreases and put into the
liver of diabetic patients. The result
of this is that these patients have, in many cases are completely insulin
independent, which is a profound effect in the diabetes population.
Now, there are hindrances to
this. These grafts ultimately do fail
and the patients are on complete immunosuppression. But the point of starting with a slide like
this is to tell you that islet cell therapy or
cell replacement therapies can have a profound effect on the patients
and now it's a question of being able to do this in a manner which is going to
be safe using human embryonic stem cells.
So that's where we go next.
So how do we do this kind of a
therapy with a human embryonic stem cell product knowing that we're going to
have an effect on these patients that could be positive?
Well, there's two aspects to this,
and a lot of what I'll be discussing today is characterizing the cell product
in vitro. But then, also, you're going
to want to evaluate the cell product in vivo and this is going to take a number
of different aspects. You're going to
want to be looking at the efficacy, the stability, any potential toxicity, and
tumorigenicity.
So what does it look like when
you're talking about characterizing a cell product? And, specifically, I'm going to be talking
about the work that we're doing at Novocell for diabetes as an example for
this.