1
This transcript has not been
edited or corrected, but appears as received from the commercial transcribing
service. Accordingly, the FDA makes no
representation to its accuracyY@
1
2
4 FOOD AND DRUG ADMINISTRATION
5 CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
6
7
8
9 BIOLOGICAL RESPONSE MODIFIERS
10 ADVISORY COMMITTEE (BRMAC)
11 Meeting 36
12"This transcript has not been
edited or corrected, but appears as received from the commercial transcribing
service. Accordingly, the FDA
makes no representation to its accuracy..."
13
14
15
16
17
18
19
20
21 Gaithersburg, Maryland
22 Thursday, October 9, 2003
2
1
PARTICIPANTS:
2 BRMAC MEMBERS:
3 MAHENDRA S. RAO, Acting Chair
National Institute on
Aging
4
JONATHAN S. ALLAM
5 Southwest Foundation for Biomedical Research
6 BRUCE R. BLAZAR
University of Minnesota
7
DAVID M. HARLAN
8 National Institute of Diabetes and Digestive
and Kidney Disease
9
KATHERINE A. HIGH
10 University of Pennsylvania
11 JOANNE KURTZBERG
Duke University Medical
Center
12
ALISON F. LAWTON
13 Genzyme Corporation
14 RICHARD C. MULLIGAN
Harvard Medical School
15
ANASTASIOS A. TSIATIS
16 North Carolina State University
17 ALICE J.
WOLFSON
Wolfson &
Schlichtmann
18
TEMPORARY VOTING MEMBERS:
19
JAMES F. CHILDRESS
20 University of Virginia
21 LYNNE L. LEVITSKY
Harvard Medical School
22
3
1
PARTICIPANTS (CONT'D):
2 TEMPORARY VOTING MEMBERS (CONT'D):
3 ABBEY S. MEYERS
National Organization for
Rare Disorders
4
CAROLE B. MILLER
5 St. Agnes Healthcare
6 W. MICHAEL O'FALLON
Mayo Clinic
7
DANIEL R. SALOMON
8 The Scripps Research Institute
9 ROBERT S. SHERWIN
Yale University School of
Medicine
10
JANET H. SILVERSTEIN
11 University of
Florida College of Medicine
12 CONSULTANTS:
13 JOHN J. O'NEIL JR.
LifeScan, Inc.
14
CAMILLO RICORDI
15 University of Miami School of Medicine
16 GUESTS/GUEST SPEAKERS:
17 BERNARD J. HERING
University of Minnesota
18
JAMES SHAPIRO
19 University of Alberta
20 THOMAS L. EGGERMAN
National Institute of
Diabetes and Digestive
21 and Kidney Diseases
22
4
1
PARTICIPANTS (CONT'D):
2
GUESTS/GUEST SPEAKERS
(CONT'D):
3 JAMES BURDICK
Health Resources and
4 Services Administration
5 FRANCISCA AGBANYO
Health Canada
6
FOOD & DRUG ADMINISTRATION (FDA) PARTICIPANTS:
7
JESSE L. GOODMAN
8 Center for Biologics Evaluation
and Research
9
KATHRYN CARBONE
10 Center for
Biologics Evaluation
and Research
11
RAJ PURI
12 Center for Biologics Evaluation
and Research
13
CAROLYN WILSON
14
Center for Biologics
Evaluation
and Research
15
ANDREW BYRNES
16 Center for Biologics Evaluation
and Research
17
NANCY MARKOWITZ
18 Center for Biologics
Evaluation
and Research
19
STEVEN BAUER
20 Center for Biologics Evaluation
and Research
21
22
5
1
PARTICIPANTS (CONT'D):
2 FDA PARTICIPANTS (CONT'D):
3 AMY ROSENBERG
Center for Drug
Evaluation
4 and Research (CDER)
5 EMILY SHACTER
Center for Drug
Evaluation
6 and Research
7 GAIL DAPOLITO
Executive Secretary
8 Center for Biologics Evaluation
and Research
9
ROSANNA L. HARVEY
10 Committee Management Specialist
Center for Biologics
Evaluation
11 and Research
12 BRMAC #36 FDA PLANNING COMMITTEE MEMBERS:
13 PHILIP NOGUCHI
Center for Biologics
Evaluation
14 and Research
15 CYNTHIA RASK
Center for Biologics
Evaluation
16 and Research
17 DARIN WEBER
Center for Biologics
Evaluation
18 and Research
19 DWAINE RIEVES
Center for Biologics
Evaluation
20 and Research
21 KEITH M. WONNACOTT
Center for Biologics
Evaluation
22 and Research
6
1
PARTICIPANTS (CONT'D):
2 BRMAC #36 FDA
PLANNING COMMITTEE MEMBERS
(CONT'D):
3
NICHOLAS I. OBIRI
4 Center for Biologics Evaluation
and Research
5
RICHARD McFARLAND
6
STEPHEN GRANT
7
SUSAN LEIBENHAUT
8
JOHN ELTERMANN JR.
9
JOHN FINKBOHNER
10
SARAH KIM
11
SUSAN ELLENBERG
12
GHANSYAM GUPTA
13
ROBERT MISBIN
14
15
16
17
18
19
20 *
* * * *
21
22
7
1 C O N T E N T S
2
AGENDA SESSION: PAGE
3
Session 1:
4
Conflict of Interests
Meeting 11
5 Statement
6 FDA Introduction 16
7 Federal Oversight of Allogenic 37
Islet Transplantation
8
Moving from Investigational
Islet 74
9 Products to Licensed Islet Products
10 Islet Processing: Evolution 135
and Current Standards
11
Current Status of Islet 172
12 Characterization and Quality
13
Session 2:
14 Laboratory of Stem Cell Biology 412
15 Laboratory of Immunology 426
and Virology
16
Laboratory of
Biochemistry 458
17
*Proceedings of CLOSED SESSION
at pages
18
421-425 and 472-488 bound separately per
request
19
20
21 *
* * * *
22
8
1 P R O C E E D I N G S
2 (8:08 a.m.)
3 DR. RAO:
Good morning, everyone.
4
This is the 36th meeting of the BRMAC.
5 I'm going to just start by asking
6
everybody on the committee to introduce
7
themselves, and to point out that they are
8
going to use the microphone system like
9
you've done before, where you're going to
10
wait for the red light and wait to be
11
recognized by the chairman.
12 We'll start with introductions
13
from the left.
14 DR. SHERWIN:
On the left, Bob
15
Sherwin from Yale. I'm a
professor of
16
medicine there.
17 DR.
LEVITSKY: Lynne Levitsky.
18
I'm chief of the Pediatric Endocrine Unit at
19
Mass. General in Boston.
20 DR. CHILDRESS:
Jim Childress,
21
University of Virginia. I
specialize in
22 Bioethics.
9
1 MS. MEYERS:
Abbey Meyers,
2
President of the National Organization for
3
Rare Disorders, and I have diabetes.
4 DR. O'FALLON:
Michael O'Fallon,
5
biostatistician, Mayo Clinic.
6 DR. ALLAN:
I'm Jon Allan,
7
Southwest Foundation for Biomedical Research
8
in San Antonio, Texas. I'm a
virologist and
9
I study AIDS pathogenesis and animal model
10
systems.
11 MS. LAWTON:
Allison Lawton,
12
Genzyme Corporation, and I'm the industry
13
rep on the panel.
14 DR. KURTZBERG:
Joanne Kurtzberg.
15
I'm a pediatric hematologist at Duke
16
University and run the pediatric bone marrow
17
transplant program.
18 DR. BLAZAR:
Bruce Blazar,
19
University of Minnesota. I'm
involved in
20
pediatric organ transplantation and
21
immunology.
22 DR. RAO: I'm
Mahendra Rao. I'm
10
1
at the National Institute on Aging and I'm a
2
stem cell biologist.
3 MS. DAPOLITO:
Gail Dapolito,
4
executive secretary for the committee.
5 DR.
HIGH: Kathy High. I'm a
6
hematologist at the Children's Hospital in
7
Philadelphia.
8 DR. SALOMON:
Dan Salomon. I'm
9
the director of the Center for Organ and
10
Cell Transplantation, and I'm a transplant
11
physician. I'm also the chair of
the
12
NIH/NCRR Islet Cell Resources Steering
13
Committee.
14 DR. O'NEIL:
Jack O'Neil. I'm
15
with Johnson & Johnson, principal scientist
16
in the Center for Diabetes Advances.
17 DR. BURDICK:
Jim Burdick. I'm a
18
transplant surgeon, and I'm presently
19
director of the Division of Transplantation
20
in HRSA.
21 DR. AGBANYO:
I'm Francisca
22
Agbanyo. I'm from Health Canada,
which is
11
1
the agency that regulates therapeutic drugs
2
in Canada.
3 DR. RASK:
I'm Cynthia Rask. I'm
4
the director of the Clinical Evaluation and
5
Pharmacology/Toxicology at FDA CBER.
6 DR. WEBER:
Good morning. I'm
7
Darin Weber. I'm chief of the
Cell Therapy
8
Branch at the Division of Cell and Gene
9
Therapy in the Office of Cellular Tissues
10
and Gene Therapies.
11 DR.
NOGUCHI: I'm Phil Noguchi,
12
acting director of the Office of Cellular
13
Tissue and Gene Therapies.
14 DR. GOODMAN:
I'm Jesse Goodman,
15
Director of CBER. I guess I have
a conflict
16
of interest in that I used to be at the
17
University of Minnesota.
18 DR. RAO: I
guess, Gail, you need
19
to read the statement.
20 MS. DAPOLITO:
Good morning. The
21
following announcement addresses conflict of
22
interest issues associated with this meeting
12
1
of the Biological Response Modifiers
2 Advisory Committee on
October 9
3
and 10, 2003.
4 Pursuant to the authority granted
5
under the committee charter, the associate
6
commissioner for external relations, FDA,
7 appointed Drs.
Lynne Levitsky, Robert
8
Sherwin and Janet Silverstein as temporary
9
voting members.
10 In addition, the director of FDA's
11
Center for Biologics Evaluation and Research
12
has appointed Drs. James Childress, Michael
13
O'Fallon, Carole Miller, Daniel Salomon, and
14
Ms. Abbey Meyers as temporary voting
15
members.
16 Based on the agenda, it was
17
determined that there are no products being
18
approved at this meeting. The
committee
19
participants were screened for their
20
financial interests to determine if any
21
conflicts of interest existed.
22 The agency reviewed the agenda and
13
1
all relevant financial interest reported by
2
the meeting participants. In
accordance
3
with 18 U.S.C. 208, the following special
4
government employees were granted waivers
5
for their participation: Dr.
Bruce Blazar
6
was granted a full waiver that permits him
7 to participate
in the committee discussions.
8 In addition, a limited waiver is
9
granted to Dr. Camillo Ricordi so that he
10
may make a presentation and answer questions
11
regarding his presentation.
12 Dr. David Harlan recused himself
13
from the discussions on human allogeneic
14
islet transplantation.
15 We would like to note for the
16
record that Ms. Alison Lawton is
17
participating in this meeting as a
18
non-voting industry representative, acting
19
on behalf of regulated industry.
20
Ms. Lawton's appointment is not subject
21
to 18 U.S.C. 208.
22 She is employed by Genzyme
14
1
Corporation and thus has a financial
2
interest in her employer.
Genzyme has
3
associations with universities,
4
investigators and research foundations.
5 With regards to FDA's invited
6
guests and consultants, the agency has
7
determined that their services are
8
essential. The following
disclosures will
9
assist the public in objectively evaluating
10
presentation and/or comments made by the
11
participants for the discussions on human
12
allogeneic islet
transplantation.
13 Mr. Jack O'Neil Jr. is employed as
14
a principal scientist at Life Scan Center
15
for Diabetes Advances, Johnson & Johnson.
16 Dr. Francisca Agbanyo is employed
17
as a director, Biologics and Genetic
18
Therapies, Biologics and
19
Radiopharmaceuticals Evaluation Center,
20
Health Canada. Dr. Agbanyo is a
Canadian
21
government official involved in the
22
regulatory oversight of islet cell
15
1
transplantation.
2 Dr. Tom Eggerman, who just joined
3
us, is employed as the director, Islet
4
Transplantation Program, Division of
5
Diabetes, Endocrinology and Metabolic
6
Diseases, National Institute of Diabetes and
7
Digestive and Kidney Diseases.
8 Dr. Eggerman is
participating in
9
this meeting as part of his official
10
government duties. His division
is involved
11
in funding and monitoring a grant in islet
12
transplantation.
13 Dr. Bernhard Hering is employed as
14
the director, Islet Transplantation at the
15
University of Minnesota Medical School.
16
Dr. Hering is directly involved in islet
17
transplantation research.
18 Dr. James Shapiro is employed at
19
the University of Alberta, Clinical Islet
20
Transplant Program. Dr. Shapiro
is directly
21
involved in islet transplantation research.
22 The committee discussions of
16
1
Topic 2, relating to FDA's individual
2
research programs, present no potential for
3 a conflict of
interest. FDA's participants
4
are aware of the need to exclude themselves
5
from the discussions involving specific
6
products or firms that they have not been
7
screened for conflict of interest.
Their
8
exclusion will be noted for the public
9
record.
10 With respect to all other meeting
11
participants, we ask in the interest of
12
fairness that you state your name,
13
affiliation, and address any current or
14
previous financial involvement with any firm
15
whose products you wish to comment upon.
16
Waivers are available by written request
17 under the
Freedom of Information Act.
18 Thank you.
19 DR. RAO: We
have an introduction
20
by the FDA. Dr. Noguchi will
present it.
21 DR. NOGUCHI:
On behalf of CBER,
22
I'd like to welcome all of you, especially
17
1
those in the audience and our advisory
2
committee members to this, I guess it's
3 the 36th meeting
of the BRMAC committee.
4 We are now at a point, and really
5
reviewing a lot of data that has been
6
gathered, a lot of interest that has been
7
gathered since I guess it was March of 2002,
8
when we talked about this before.
9 We feel that its now time to
10
really have the critical discussion to be
11
provided today by all the members of the
12 committee, all the
members of the public and
13
our experts to really see what's going on.
14
It's always nice to really make a critical
15
assessment when it's an appropriate time.
16 I'd like to
also now take just a
17
little bit of time to introduce our center
18
director, Dr. Jesse Goodman. You
know, at
19
CBER, center directors tend to be rather
20
extensive in their stay. I've actually
been
21
here ever since the center has moved from
22
the NIH over to FDA, and I think Jesse is
18
1
now the fourth director.
2 The first one was Dr. Hank Meyer,
3
for about ten years, and Paul Parkman
4
another ten years, Kathy Zoon roughly ten
5
years. We certainly hope Dr.
Goodman will
6
continue in that tradition.
He'll have even
7
less hair when he's finished here.
8 But Dr. Goodman is exceptionally
9
well-qualified. He actually came
to the
10
government in the commissioner's office to
11 head up a program
on infectious diseases and
12
emerging infectious diseases, and has been
13
through a number of different capacities,
14
more recently as deputy director for
15
medicine at CBER.
16 Then as Dr. Zoon moved over to the
17
Cancer Institute, he came and graciously
18
accepted the title of director of CBER.
I
19
know for both him and the rest of us, it's
20
been a very steep and growing learning
21
curve, but we are very proud, myself, to
22
have him here today to give an opening
19
1
introduction of the vision of CBER and how
2
this particular area of cell and gene
3
therapy and tissues really plays into that.
4 Dr. Goodman.
5 DR. GOODMAN:
Good morning. I do
6
thank everybody for being
here. I thank
7
Phil for the kind introduction.
Actually, I
8
feel very privileged to be at CBER and to be
9
here today.
10 I'll use just a few minutes of
11 everybody's time in
a little bit of
12
opportunity to say a couple of things about
13
what's happening at FDA in general and at
14
CBER, and how working on this new technology
15
really fits into our vision of bringing safe
16
and effective products to people.
17 Also, I just want to share that
18
Dr. McClelland, the commissioner, is very
19
interested also in this subject and this
20 meeting, and
he's sorry that he couldn't be
21
here today with us to say hi at least.
22 Anyhow, as some of the pictures I
20
1
put on the opening slide show, this is
2
diabetes review, as a very important disease
3
and a very high priority.
Obviously, even
4
if you look at this week's "JAMA," we're
5
having a huge diabetes epidemic.
6 Those of us who do medical care
7
certainly understand the epidemic of
8
complications of diabetes and organ damage.
9
Of course, what we are here about is islet
10 cell transplantation and the potential for
11
that to address at least some of these
12
problems. Obviously, many of
these
13
problems, we could also prevent.
So that's
14
a whole other area.
15 I'd just
like to, for the members
16
of the committee and others, just sort of
17
give a little overview of just where this
18
fits in the spectrum of what we're facing at
19
FDA and CBER in general.
20 We are dealing with constant
21
related challenges, many of which are quite
22
acute and urgent at times; vaccine safety
21
1
and availability; blood safety and
2
availability. We have advisory
committees
3
that help us with this.
4 Many emerging infectious disease
5
issues. It seems that just when
we've done
6
what we need to do to have things moving on
7
one, SARS or Monkeypox comes along.
These
8
also, I think, as you think forward in
9
cellular therapy, the areas that the BRMAC
10 is concerned
on, are things that as these
11
things become incorporated more into medical
12
practice, you're going to need to be
13
thinking about as well.
14 Human tissue cell products and
15
gene therapy are very high priorities for
16
us. As you know, Kathy Zoon,
working with
17
Phil, moved this into the status of a new
18
office recently, and this signifies the
19
importance.
20 Again, our center has really borne
21
the brunt of dealing with bioterrorism
22
issues and counter-terrorism.
Again, all of
22
1
this is urgent. All of this is
24/7, and
2
all of it, I think, requires us to work in
3
better and new ways to try to bring products
4
along.
5 Well, Dr. McClelland has put forth
6
a vision through a strategic plan, and
7
again, these are very broad areas, the plan
8
is quite detailed, but I just thought, for
9
those who haven't heard them, I'd share them
10 with you: Science-based risk management,
11
which simply means exactly what we often do
12
in advisory committees, looking at the
13
information and making the best possible
14
decisions, being sure that we're paying
15
attention to the consumer and the patient in
16
terms of information, patient safety, that
17
the products are used wisely and safely.
18 Counter-terrorism has made it up
19
there, as you can see, for the reasons that
20
I said.
21 Then attention to a strong FDA,
22
and this has been a particular challenge for
23
1
everyone, of course, with the fiscal
2
restraints that we're all under.
But also
3
it's a challenge just for the government in
4
general to have personnel processes and
5 infrastructure
which enable us to deal with
6
important issues like this.
7 Part of the strength of FDA is in
8
our processes, whether it's review, science,
9
administrative processes to enhance the
10
availability of new technologies.
This is
11
something that I really believe in and
12
Dr. McClelland does as well. I
think where
13
all of these, and particularly these are
14 very pertinent
to CBER's mission, and our
15
actions do support this plan.
16 I'd just like to identify a few
17
other general areas which I think are
18
emerging as high priorities and ways of
19
getting there for our center in general, and
20
again it fits very well with what you're all
21
doing here today.
22 I think we really, as a center
24
1
actually within FDA, we've really been very
2
active in seeking outside collaboration and
3
input, whether it's in the science that
4
people do or whether it's in our review and
5
regulatory work. But we want to
do that
6
more. That involves doing things
like
7
bringing issues to groups like you, getting
8
input, perhaps sometimes even when there is
9
not a regulatory decision at that time, but
10
to help move a field along and help be sure
11
we're getting the best information to move
12
in the right direction.
13 Again, this doesn't just include
14
science, but includes the public, et cetera.
15
We need to really, as per a strong FDA,
16
strengthen the base for and performance of
17
CBER and its collaborative science.
Again,
18
I'm trying to extend the vision of science
19
not just to include laboratory science, but
20
epidemiologic, clinical science and
21
expertise, risk science.
22 We want to try to identify what
25
1
are the stumbling blocks to product
2
development and new technologies; you know,
3
which ones are fixable, which ones aren't,
4
and can we help be a partner in removing
5
those. Part of this is enhanced
6
interactions with all kinds of partners,
7
ranging from our colleagues at NIH, other
8
regulatory authorities. So we
have HRSA
9
here today on the organ transplant front,
10
and other partners.
11 Again, in all of this to the
12
degree that we can get input, look at what
13
we do, have it be focused, have a lot of
14
transparency, it's helpful.
15 Okay, just other major areas: As
16
you know, we have a new office and we really
17
appreciate what Phil and many of the others
18
in this room have done getting that going
19
under very challenging circumstances.
20 This is a key office in this
21
technology facilitation. I mean,
so much of
22
the promise of medicine is stuff that is
26
1
brought to your committee and are things in
2
these therapeutic areas.
3 I mentioned emerging infectious
4
diseases, but you may not realize we have
5
several issues. The protection
of blood
6
cell vaccine tissue safety is the most
7
obvious one, and it's the one we always deal
8
with every Friday afternoon at
5:00.
9 But also, we have a role in
10
products for prevention. We have
been very
11
active in trying to facilitate development,
12
for instance, of West Nile, SARS vaccines,
13
et cetera, as well as in treatment and
14
diagnosis, and tried to have a more systemic
15
approach to this also, not just in CBER, but
16
across FDA.
17 We have needs, based on what's
18
gone on in the world and what's gone on with
19
our products, to strengthen our emergency
20
response in crisis management.
We have some
21
external metrics that we work on with
22
industry that also involve increasingly the
27
1
support for our activities. So
we have the
2
User Fee Act's prescription drugs which
3 affects our
licensed biologic products, and
4
now a medical device User Fee Act.
5 Again, some people here may not
6
realize it, but quite a number of devices
7
involved in the safety of the blood supply
8
or in preparing cellular therapies such as
9
centrifuge and cell separators, et cetera,
10
are handled within CBER, and ideally, that
11
works by having us have a consistent view of
12
them as part of a product and a product
13
development and a system.
14 Then in all of this, we view our
15
primary function for the American public in
16
terms of safety and efficacy of our
17
therapies, and we want to see that we manage
18
our review process with high quality and
19
with consistency, and with the incredible
20
variation of products which FDA faces and
21 the incredible
creativity that's out there
22
in the academic and industrial world, this
28
1
is a very challenging thing to do.
2 So we do a
lot of innovative
3
technology in public health, and that's
4
really a big part of our vision at CBER.
5
These issues are uniquely focused within our
6
center. Looking at how we view
our mission
7
and our goals, certainly we want to protect
8
and improve public and individual health in
9
the U.S., and also where feasible, globally.
10
So we want to be good global partners.
11 We
want to facilitate development
12
approval and access to safe and effective
13
products and promising new technologies. We
14
want to strengthen CBER as a preeminent
15
regulatory organization for biologics, and
16
one that performs in an excellent manner
17
here and performs in an excellent manner
18
with our international partners.
19 So what about what we're here
20 today
about? It is about trying to find
21
safe and effective promising new
22
technologies. As a general goal,
we really
29
1
see ourselves having a role in assisting
2
product development in nascent fields across
3
industries. How can we help?
4 Examples are what we have had to
5
do in bioterrorism preparedness, gene
6
therapy, new areas like tissue engineering,
7
stem cells, cell therapies, new vaccine
8
technologies, and even in areas like blood,
9
which will seem to the clinician as quite
10
traditional and staid, there's a lot of
11
potential in terms of oxygen carriers,
12
pathogen inactivation, better pathogen
13
detection.
14 Well, how can we help? Most of
15
the ferment and most of the ideas are coming
16
from everyone, from industry, et cetera.
17
But our guidance, our standards, our
18
outreach, our policy can be creative.
19
Looking at safety and efficacy, we need to
20
find the best pathways to do that.
21 We need to work with the other
22
partners to improve our risk communication
30
1 to the public. We need
to be sure we have
2
the right internal expertise and the right
3
partnerships.
4 So based on those kinds of
5
priorities and that kind of vision, I think
6 we're here today to
learn about and get
7
input about, and also hopefully provide some
8
helpful thinking about islet cell
9
transplantation.
10 Again, you guys, hearing about all
11 of you and hearing about
some of our guests
12
here, you know, you truly are the experts.
13
I'm not really here to tell you any of this,
14
but what are some of the issues here?
15 Well, this is
the perfect example
16
of a promising technology, where if we can
17
work well with partners, we can perhaps play
18
a facilitating role at sorting out how is
19
that promise best directed and how is it
20
best evaluated.
21 This addresses a major unmet
22
public health need. We know that
even with
31
1
increasingly sophisticated treatments for
2
diabetes, we've got a long way to go, and
3
there are patients who nonetheless develop
4
serious complications.
5 There's a real need here to help
6 define and
guide product development in
7
regulatory pathways. We may not
have all
8
the information we need to know how to do
9
that right. But we have to do
our best.
10 We have to assure safety and
11
effectiveness, but hopefully not inhibit
12
availability of effective therapies, and
13
based on limited information, set up a
14
system or standards that inhibit future
15 improvements or
innovation. These are all
16
very fine balancing acts.
17 So what are some of the issues
18
that I think, I'm sure, are going to come
19
up? I've seen them in some of
the
20
materials. They are just the
ones that came
21
to me in thinking about this.
22 Organ availability, the variations
32
1 in short-term
outcomes that have been
2
observed in some of the studies in different
3
centers, centers, the quality of the
4
materials, the procedures themselves.
This
5
is the focus of a lot of today's discussion.
6
I'm not sure as much is known about patient
7
variables.
8 There are acute adverse event
9
outcomes that we need to consider in any new
10
therapy, and there are, as I said, all these
11
issues of product characterization:
The
12
quality, the quantity. And again
I think we
13
know less on a more sophisticated level
14
about the functionality of quality and how
15
to measure it.
16 Very important, as one thinks
17
about moving forward beyond some of the
18
really incredibly exciting promise that
19
we've heard about, is the issue of long-term
20
outcomes; to what extent do we restore
21
normal metabolic function.
Again, what are
22
the predictors of doing that or not doing
33
1
that? How can we do better? What are the
2
adverse effects of cell therapy?
3 We don't know much long-term.
4
Immunosuppression, I think we're starting to
5
have a pretty good database from lots of
6
other kinds of transplantation in terms of
7
long term and organ effects, benefits and
8
just the real outcomes that matter to human
9
beings in terms of morbidity, mortality,
10
quality of life.
11 Probably the people who do this
12
are thinking about it, but you don't see too
13
much thinking about who are the patients
14
most likely to benefit, early versus late
15
treatment? How do you assess
efficacy? We
16
deal with this frequently with exciting new
17
products: Are there ways to look
at
18
historical data? Are there
issues that
19 require control
groups?
20 What can be the pathways to
21
clinical success, and a somewhat different
22
question, to licensure? How much
data would
34
1
one want to see? How much
benefit does one
2
need to see to adopt a therapy like this?
3 The world of clinical medicine is
4
filled with examples, both where promising
5
new technologies are documented and
6
effective technologies have been adapted too
7
slowly.
8 But it's also filled with examples
9
where things that seem promising have been
10
adapted on a widespread basis, only to be
11
found not to really have the effect we
12
thought they would.
13 You know, autologous breast cancer
14
transplantation is a reasonable example of
15
that.
16 So I think no matter what you all
17
do and what this community does, we need to
18
think about how do you do long-term
19
assessment and how do you improve these
20
technologies as they move forward.
21 So anyhow, your input and the
22
broader community as well is very welcome
35
1 and
critical. We're going to hear it today.
2
I won't be able to be here for all of it,
3
but I'll find out about it.
We're really
4
going to work together with you and the rest
5
of the appropriate communities to try to
6
refine and develop this promising advance.
7 We'll try to do our part and
8
synthesize this information and provide the
9
best possible guidance to help this along.
10
I think the good thing is that we do have a
11
common goal here, which is to get therapy to
12
people. But a lot of our role is
to be sure
13
it's safe and effective, and we all want to
14
see better outcomes and quality of life.
15 Another point that really hit me
16
in thinking about this, and I think you
17
folks in this field should think very
18
carefully about, is what we learn, and
19
hopefully the successes that are achieved,
20
but also, as always, the things that we
21
didn't succeed in are going to be critical,
22
not only for these patients with diabetes,
36
1
but I think this a first event, potentially,
2
in the development of cellular therapies for
3
a variety of diseases.
4 There's a lot
of complexities here
5
from the clinical, the scientific and the
6
regulatory point of view that the more
7
thoughtful we are about this and the more we
8
learn from it, the better.
9 So with that, anyhow, I probably
10
took far too long and you knew this all
11
already, but I wanted to indicate how
12
important we thought this was and how
13
seriously we take outside input in this
14
area. So thanks.
15 DR. RAO:
Thank you, Dr. Goodman.
16
It's very useful to reemphasize the fact
17
that what we discuss today may have general
18
application related to all other stem cell
19
therapies as well.
20 We're going to have four speakers
21
from the FDA which will sort of set the base
22
for questions and issues. I'm
going to
37
1
request that if possible, unless it's a
2
burning question, that you hold it towards
3
the end because there will be overlapping
4
things which might possibly be
answered by
5
the subsequent speakers.
6 But if you need to ask a question,
7
just feel free to press the button.
8 DR. WEBER:
Good morning,
9 everyone. Thank you, Mr. Chairman and
10
members of the committee, and the support of
11
Dr. Goodman and Dr. Noguchi for supporting
12
this meeting this morning.
13 My task is to provide basically a
14
kind of an introduction to the topic as well
15
as some of the overview of FDA's regulatory
16
issues for allogeneic islet transplantation,
17
in about ten minutes or less. So
I'm going
18
to go fairly rapidly to try to give you a
19
sense of what we're trying to accomplish
20
today.
21 It's always helpful to know how we
22
got here. This is, of course,
how we got
38
1
here from the FDA's perspective.
We'll
2
discuss some of the goals of this meeting,
3
what we hope to get out of the meeting from
4 the FDA's side.
5 I'll briefly mention some of the
6
federal agencies who are involved in the
7
U.S., as well as provide an introduction to
8
the FDA's questions, and then set up the
9
stage, if you will, for the discussion
10
that's going to follow by introducing the
11
speakers.
12 Again, this is a cartoon. It
13
represents a timeline again from the FDA's
14
perspective. We certainly
acknowledge that
15
there's been a lot of research going on in
16
this field outside the purview of the FDA.
17
So I'll just recognize that. But
what I'm
18
trying to tell you here is that
for a
19
ten-year period between 1990 and 2000, the
20
FDA received a total of ten islet INDs for
21
allogeneic islet transplantation, which was
22
somewhat indicative of not a lot of rapid
39
1
progress being made in this field.
2 I think, as you all know, a lot of
3
that changed in the year 2000, for a variety
4
of reasons shown here. As Phil
indicated,
5
back in March of 2000, we had another
6
advisory committee, another BRMAC meeting on
7
the same topic. That meeting was
primarily
8
focused on some of the fundamental
9
regulatory issues for regulating this
10
therapy under IND, so we talked about
11
pre-clinical models; we talked about some of
12
the fundamental manufacturing information as
13
well as clinical issues that should be
14
included in an IND.
15 Of course, that was in many ways
16
an anticipation of the publication of
17
Dr. Shapiro's group, the Edmonton Protocol,
18
in "The New England Journal" in July
19
of 2000.
20 Then, subsequent to that, FDA sent
21
a follow-up letter; basically a Dear
22
Colleague letter to all the organ transplant
40
1
centers in the U.S., basically reminding
2
them that in fact, this therapy is regulated
3
by the FDA, and if you want to treat
4
patients, you would need to submit an IND.
5 So in many ways for the FDA, I
6
think this was a threshold year.
Of course,
7
subsequent to that and prior to this time,
8 there's been a lot of funding in this area
9
by many different organizations.
Obviously,
10
the JDRF is a major player, the Juvenile
11
Diabetes Research Foundation, and of course,
12
various institutes at the NIH.
13 I think it's fair to say it's
14
borne quite a bit of fruit. If
you can see
15
it here, the graphics show a little detail
16
here.
17 What I'm just trying to show here
18
is prior to 2000, which is right about here,
19
there is a low level of activity, and then a
20
real significant jump since that time.
We
21
have received about 28 islet INDs
22 since 2000, which
represents obviously a
41
1
significant work load for the FDA as well as
2
tremendous interest in the community for
3
this therapy.
4 So that brings us to today and
5
what some of the goals of this meeting are.
6
Honestly, we, from the FDA, have wanted to
7
talk about expectations, manufacturing data
8 and clinical
evidence that we would like to
9
see in a BLA, a Biologics License
10
Application, that would subsequently lead to
11
the approval for this therapy for Type One
12
Diabetes.
13 Of
course, in that context, we
14
want to get advice and perspectives from you
15
folks on the committee in terms of
16
discussing the data that you think should be
17
provided in a BLA.
18 Certainly, it's very important for
19
us to do this is in a public forum, to get
20
input and feedback from stakeholders who
21
obviously have a strong interest in this
22
therapy.
42
1 So this slide just gives you a
2
plethora of acronyms of various federal
3
agencies in the U.S. who are involved.
4 HRSA, of course,
is the Health Resources
5
Service Administration. They
are, of
6
course, involved in organ procurement and
7
allocation in the U.S.
8 Of course, the FDA is interested
9
in the regulatory oversight of chemical uses
10
of pancreatic islets.
11 Of course, our NIH colleagues, who
12
are involved with basic research as well as
13
clinical research for islet transplantation.
14
I think we have been very fortunate at FDA
15
to have a very good collaborative working
16
relationship with our colleagues.
Many of
17
them are here, and Dr. Eggerman's on the
18
committee as well.
19 Last, but not least, of course, is
20
the role that the Centers for Medicare and
21
Medicaid will play in terms of reimbursement
22
issues. I just wanted to point
out,
43
1
obviously, the whole issue of reimbursement
2
is something that's really beyond the scope
3
of the FDA and it's something we're not
4
going to talk about today at this meeting,
5
but we just want to acknowledge, obviously,
6
it's an important issue that is going to
7
have to be addressed in a different forum.
8 So now,
moving into the more
9
specific questions the FDA would like to
10
discuss in terms of islets as a license
11
product in terms of the manufacturing
12
issues; obviously, islets would need to be
13
prepared in a well-established manufacturing
14
process. We'd need a document
record of
15
manufacturing consistency to support a
16
license application.
17 Of course, the islets would have
18
to be prepared in a facility that is meeting
19
current GMP, or good manufacturing
20
practices, as well as, of course, complying
21
with the lot release test requirements for
22
these biological products.
44
1 So the FDA presentations this
2
morning will cover this. Mr.
Wonnacutt will
3
talk about the first and the third bullet,
4
and Dr. Obiri from the FDA is going to be
5
talking about the manufacturing issues.
6 So as a sneak preview, if you
7
will, in terms of the questions we're going
8
to ask, these are just paraphrased, and the
9
committee has a little more detail about the
10
background to these questions.
11 But, obviously, there's an
12
interest from the FDA in all aspects of
13
manufacturing as well as the delivery of the
14
product to the patients. So we
certainly
15
recognize that source organs are a
16
challenge, obviously, coming from a
17
cadaveric organ, coming from the organ
18
procurement system that's overseen by HRSA.
19 So we'd obviously like to have a
20
discussion concerning the use of basic
21
manufacturing experience data that's
22
currently being collected under IND that
45
1
would help establish pre-defined acceptance
2
criteria for these source donor organs, the
3
idea being only to include high-quality
4
organs while excluding unsuitable organs for
5
islet processing.
6 Moving down the manufacturing
7
scheme here in terms of dissociation
8
enzymatic and mechanical dissociation to get
9
islets; obviously, for a license
10
application, you're going to need a
11
well-controlled manufacturing process.
12 We also realize that the FDA is
13
going to have to be balanced by the need for
14
some flexibility in the manufacturing, and
15
again, recognition of the source material
16
here.
17 So again,
we would like to have a
18
discussion about the use of data being
19
collected under INDs that again can help
20
predetermine under what conditions various
21
reagents can be used in terms of helping to
22
optimize the yield of islets. A
lot more
46
1
detail about this will be discussed by
2
Mr. Wonnacutt in his presentation.
3 Of course, lot release testing,
4
making sure the product has a quality in the
5
safety characteristics before it's delivered
6
to the patient. One particular
type of lot
7 release in terms of
islet potency; basically
8
the idea is that an assay that can be
9
predictive of the ability of the islets, in
10
this case, to perform as expected.
11 So there's a variety of assays
12
being done. Many of them are
retrospective,
13
meaning the results are only available after
14
the patient receives it under the IND.
Of
15
course, for a licensed product, we need a
16
prospective assay, an assay that's available
17
prior to transplantation.
18 So I think there's a lot of
19
opportunity for discussion on this issue.
20 So the fourth manufacturing
21
question is dealing with comparability.
22
That deals with all different aspects of the
47
1
manufacturing process. Comparability,
2
product comparability in terms of
3
recognizing that at different academic
4
centers, islets are being prepared in
5
slightly different methods, in different
6
ways.
7 So how can we show comparability,
8
whether the product really is the same or
9
really is different, based on how it's
10
prepared? So what should be some
of the key
11
criteria, some of the key measures for
12
ensuring comparability?
13 So that could lead to a discussion
14
of various analytical assays, bioassays,
15
preclinical and even clinical studies that
16
would show comparability or would not show
17
comparability.
18 So transitioning into Day 2, the
19
clinical considerations, obviously, approval
20
of this product, of course, is going to be
21 based on data
from domestic or foreign
22
studies that are from well-controlled,
48
1
well-designed studies. They are
going to be
2
performed by qualified investigators.
And,
3
of course, conducted in accordance with
4
ethical principles.
5 So basically, good clinical
6
practices is what we are talking about here.
7 Of course, the
data has to be safe and
8
demonstrate efficacy.
9 So the clinical question is,
10
again, this is just a preview, now we have
11
an islet product and some of the questions
12
to come when you deliver that to the
13
patient, who are the right patients, what
14
are the right measures or outcomes?
15 So this is paraphrasing. So the
16
questions tomorrow will focus on outcome
17
measures, the basic importance and
18
limitations of various outcome measures
19
listed here. For example,
insulin dependent
20
hemoglobin, et cetera.
21 Then the
second question we'd like
22
to have discussed concerns a clinical
49
1
development plan as well as appropriate
2
risk-benefit assessments, things like safety
3
data, the nature and extent of long-term
4
clinical data, historical controls,
5
extrapolating results from a subset of
6
patients, et cetera.
7 All right, so in the last couple
8
of minutes of this talk, I just wanted to
9
remind you of the format.
Basically, it's
10
three parts. Day One consists of
the
11
discussion of manufacturing issues for
12
allogeneic islet transplant.
13 Then late afternoon, we're going
14
to provide an update on research programs.
15
I just wanted to point this out.
This is
16
something that is distinct and not part of
17
the discussion of islet transplantation, but
18
it's an open, public forum. If
you are
19
interested in hearing about it, please stick
20
around. There is a closed
session here.
21 Then tomorrow, of course, we'll be
22
focusing on the clinical issues.
50
1 So the speakers we've lined up:
2 Dr. Burdick from
HRSA is going to following
3
my talk and giving an overview of organ
4
procurement in the U.S., particularly with a
5
focus of the pancreas, of course.
6 Then from the FDA, the general
7
theme of talking about moving from
8
investigational to licensed islet products,
9
what do you need to do from the IND to a
10
license.
11 So Dr. Obiri will be speaking on
12
facilities and GMP issues, and Dr. Wonnacutt
13
about the processing and product quality.
14 Then we're real fortunate to have
15
some experts in the field. Of
course,
16 Dr. Ricordi from
the University of Miami is
17
going to talk about, I think, a historical
18
perspective as well as the current standards
19
for this therapy, for preparation of the
20
product.
21 Of course, Dr. Hering from the
22
University of Minnesota is going to talk
51
1
about characterization and quality
2
standards.
3 Again, the idea here is to provide
4
information that will help provide context
5
for the questions we're asking the committee
6
to discuss.
7 So again, switching to Day Two,
8
Dr. Shapiro is here from the University of
9
Alberta and will give us a talk on clinical
10
islet transplantation and his experience at
11
Edmonton as well as a part of the immune
12
tolerance network, the multi-center study,
13
as well as other studies that he has
14
information on.
15 Then Dr. Burdick has kindly agreed
16
to come back and talk more about allocation
17
issues for pancreas in the sense of how that
18
might impact distribution of islets.
19 Then Dr. Childress from the
20
University of Virginia is going to give us a
21
discussion on ethical considerations for
22
this therapy.
52