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
1 Then finally, we'll have a
2
presentation from Dr. Dwayne Rieves about
3
the clinical development of islet products
4
from the FDA.
5 I think that's all I had to say.
6 DR. RAO:
Thank you, Dr. Weber.
7
Our next speaker is going to be Dr. Burdick
8
from HRSA.
9 (Pause)
10 DR. BURDICK:
Thanks. That's far
11
and away the best way to get the obligatory
12
PowerPoint delay down to a minimum.
13 Good morning.
Thanks for the
14
invitation. It's nice to be
here. What I'm
15
going to do today is talk about the initial
16
process of having a pancreas available for
17
what we're all talking about for these two
18
days, and that is the regulatory background,
19
and then a bit about what happens in the
20
actual process of retrieval.
21 Tomorrow, as was said, we'll
22 address some of the
more specific issues
53
1
about islets.
2 By way of perspective, I'll try to
3
go through these slides pretty quickly.
4
They are in your packet, but I'll emphasize
5
a few things. I think it's
important to
6
note an important time in the history of
7
transplantation, which is 1984.
I tell
8 people it was the dawning of the age of
9
Aquarius.
10 It was the year that the drug
11
cyclosporine was approved, and it absolutely
12
revolutionized transplantation.
It's hard
13
to describe what an amazing difference that
14
drug made. There have been many
15
improvements in immunosuppression and in
16
control of infection and other things,
17
preservation, et cetera, since.
18 But that was really the time point
19
at which kidney transplantation became
20
absolutely routine, and transplantation of
21
many other organs became relatively
22
feasible.
54
1 The government clearly saw the
2
fact that this was going to require national
3
activity. The National Organ
Transplant Act
4 was passed in
1984. The other major
5
relevant statutory area deals with specific
6
areas of CNS that I'll mention, in the
7
Social Security Act, 1138.
8 There have been amendments in the
9
usual legislative process, but the overall
10
situation hasn't changed much in concept
11
over the past 20 years. It
created a
12
taskforce which reviewed the situation, made
13
recommendations and is no
longer active.
14
That was a transient thing.
15 Then it established that there
16
would be an organ procurement network and a
17
scientific registry of transplant
18
recipients. These were arranged
as
19
contracts to a non-profit bidder for doing
20
the actual work.
21 The way this was put together
22
involved a very strong join between the
55
1
actual clinical process and the allocation
2
of the organs and retrieval of pre- and
3
post-transplant information, so that it has
4 put in force a
situation in which I think
5
arguably there's more complete national
6
reliable information about this little area
7
of medicine than in anything else in
8
medicine.
9 It has warts and blemishes, but
10
it's very important to know how complete and
11
national that information is.
There's also
12
work on public and professional education,
13
and this is the point at which it became
14
illegal to purchase transplantable organs.
15 The organs you see listed here,
16
the usual ones being transplanted.
But it
17
left this open to the Secretary, and we may
18
need to return to that.
19 The nonprofit entity was the
20
United Network for Organ Sharing.
It is the
21
OPTN contractor. It also
established OPO
22
participation, which is important for us
56
1
today, because the organ procurement
2
organizations are the major technical area
3
where the process of retrieving the pancreas
4
is run, and then obviously, the transplant
5
team, surgeons and nurses, do the actual
6
surgical procedure.
7 OPTN has two or three major
8
activities. In the first place,
it's a
9
membership organization. Members
are the
10
institutions that do transplantation.
And
11
the essence of it is that there is a
12
national system with policies that are
13
generated and evolved, because it's a
14
continuing change from time to time in what
15
the policies will be.
16 They run the organ center. They
17
keep a system and a list, and when an organ
18
becomes available, they are the source of
19
the information about where that organ
20
should go and how to arrange it, as well as
21
the source of the rules about how that will
22
be done.
57
1 Then they also work on improving
2
the supply, improving public and private
3
education, and oversee the collection of
4 data which is
analyzed through the
5
scientific registry.
6 The Social Security Act stipulates
7
that hospitals must have written protocols
8
for identification of donors.
The hospital
9
must be part of the OPTN. The
organ
10
procurement organizations in the hospitals
11
are tied together by regs, and obviously,
12
this deals with the reimbursement ultimately
13
to both; in this case the OPOs and also
14
transplant centers, which is under the CMS
15
process.
16 I should apologize perhaps in this
17
setting slightly for this somewhat
18
HRSA-centric slide to some of the people
19
from other agencies. Clearly, if
we were
20
doing it on the basis of the fraction of the
21
total $500 billion that Secretary Thompson
22
oversees, then this block would be here and
58
1
we'd all be down in the corner, and it's not
2
really fair in any way to have these here.
3 But at any rate, from our point of
4
view, so you understand where things sit,
5
we're in HRSA. We're in the
Office of
6
Special Programs, and that's the Division of
7
Transplantation. Our office
oversees the
8 contracts for the
OPTN, which presently is
9
held by UNOS for the data registry, which is
10
held by a group presently in Michigan,
11
URREA. They are formerly the
contractors
12
for the Dialysis and End Stage Renal Disease
13
Registry.
14 Also, we oversee the contract for
15
the National Bone Marrow Registry, in
16
coordination with the Secretary's wonderful
17
recent initiatives on improving public
18
education about the need and value of being
19
in favor of donating organs.
20 The regulation includes a lot of
21
specifics and a lot of delegation to the
22 contractor. This is ultimately,
59
1
fundamentally, and dominantly a community
2
activity, but it is very clearly done with
3
input from and ultimate regulatory authority
4
exercised by the Secretary and the DOT and
5
the HHS in general.
6 Some rather specific things are in
7
the final rule. The
configuration
8 membership
requirements at least are
9
partially specified. How
transplant
10
programs behave once they become members;
11
the necessity for data collection; are all
12
things that we work together from the
13
government and with the community, which
14
essentially is the OPTN contractor by proxy,
15
to optimize the process.
16 You can see the contractors have
17
the responsibilities, including an important
18
website, public information, which is a very
19
valuable place to go for anyone for some of
20
the background information that you might
21
want.
22 Now, the only
procurement
60
1
organization is the technical source of the
2
pancreas in terms of much of the process.
3
They are the ones that are in the hospitals,
4
involved with the patient families, arrange
5
for where and when the retrieval will happen
6
and how it will go. This is
through the
7
organ center arrangements for what organs
8
will be transplanted where.
9 We could go into the process in
10
more detail, but I don't think it's
11
necessary for these purposes.
12 Both the oversight of all of the
13
technical things and the actual logistic
14
arrangements are the Organ Procurement
15
Organization, and these are 60-some
16
nonprofit organizations throughout the
17
country generally representing several
18
transplant centers. And their
activities
19
are closely overseen and specified both
20
within the final rule by implication from
21
NOTA and also by the CMS oversight as the
22
pair.
61
1 The OPOs are looking at all the
2
organs, and I think that's important to keep
3
in mind. This process of having
a pancreas
4
for islets is inextricably tied to the
5
process for having a heart and a liver and
6
kidneys et cetera to be transplantable as
7
well.
8 So a fairly general medical
9
assessment; most important perhaps are the
10
infectious disease things, which work
11
remarkably well. The big issue,
12
particularly with these things, is the
13
timeframe, because as you probably know, a
14
heart needs to be transplanted,
15
revascularized in the recipient within about
16
five hours of cessation of blood supply in
17
the donor.
18 Kidneys,
especially with some
19
aids, can go up to 48 hours, but it's
20
preferable to have a liver in within 8 to 12
21
or 14 hours.
22 The pancreas, there's some
62
1
discussion, but generally a vascularized
2
pancreas graft, the results are a bit better
3
if they can go in within 12 hours or a
4
little more.
5 So you
need to be able to get all
6
of this stuff back quite quickly, and it's
7
done. In transmission of
infectious
8
disease, with some terrible, very prominent
9
disasters notwithstanding, it has been
10
extremely uncommon and the control of that,
11
I think, works very well.
12 Again, given the process, it's
13
probably not as close to 100 percent as it
14
would be if you had months to
deal with each
15
individual organ before it were
16
transplanted. But it does work
very well.
17 This is something again that's
18
national. It's uniform. We have the data
19
across the country, so it's really there for
20
study and evaluation and thought, the
21
processes we are talking about.
22 Obviously, pancreas function is
63
1
checked, although the pancreas transplant
2
surgeon, considering a whole organ, pays
3
little attention to any of these, because in
4
general, there are all sort of reasons they
5
don't correlate very well with what's going
6
to happen in the recipient.
7 Well, there is a shortage, but
8
with pancreas transplantation, it's an even
9 more complex
shortage, because it's not only
10
the number of patients on the list versus
11
the number of pancreases available, but it's
12
the general status of the field.
13 Pancreas transplantation has not,
14
although it is quite successful and it is
15
something that's done on a regular basis,
16
well over 1,000 per year in recent years
17
being done in this country, it's not worked
18
out with quite the same reliability and
19
success as some other organs, for various
20
physiological reasons.
21 So there's less general sense of
22
purpose and mission and need and value for a
64
1
pancreas transplantation, I guess I would
2
summarize, across the country than there is
3
for the kidney or heart or liver.
4 This means that decisions are
5
often made paying less attention to whether
6
the pancreas will be transplanted or not.
7
This is not to say that there isn't a
8
perfectly available and robust process for
9
achieving just the right removal techniques
10
for a process such as a very excellent islet
11
cell transplant treatment that works very
12
well on almost all patients and for which
13
there's a great need for very good
14
pancreases to be removed in just the right
15
way. That process is available
to be
16
facilitated.
17 We are going to talk more about
18
things related to allocation.
There's a lot
19
of research going on with the pancreas right
20
now, because the field in general is still
21
early. So there are some
financial issues
22
that probably we'll just put off until
65
1
tomorrow.
2 But at any rate, one of the issues
3
for islet transplantation right this minute
4
is that there are not as many pancreases
5
retrieved as might be. Again, I
think that
6
this is going to be driven by the results.
7
As the results become clearly better, and
8
it's clear that the OPO will be able to have
9
the pancreas as an organ that gets a
10
reimbursement for the clinical process, as
11
is true for other organs, et cetera, that
12
will drive excellent and more complete
13
retrieval from donors that become available.
14 We're still left with the main
15
problem of the disparity between donors and
16
recipients. About a fifth are actually
used
17
for organ transplantation.
18 Of course, there are other
19
problems. This is one of the
biggest
20
problems. Presently, this is the
21
allocation. It involves two
things. One is
22
first, it will go to a whole organ if there
66
1
is an appropriate recipient identified in
2
the center that feels that that client is
3
appropriate for whole organ transplantation.
4 If that isn't the case, it goes
5
for islet transplantation if possible, and
6
if that doesn't happen, which is quite
7 uncommon now as yet, then it goes perhaps
8
for research or is discarded.
9 That situation, with a large
10
fraction not going to treat a patient in any
11
way, or perhaps even going for research, is
12
one of the reasons for the relatively lower
13
retrieval rate.
14 It's also true that facilitated
15
placement, for one purpose or another, is
16
stipulated in the OPTN policies if initial
17
placement of the organ isn't fairly rapid.
18 It's important to remember that
19
the OPO begins the placement process
20
actually hours before the organ is taken out
21 of the donor, in almost
all cases. In fact,
22
facilitated placement can start if it looks
67
1
like retrieval will be starting within about
2 an hour. That's part of the policy for how
3
to best find a place where this will be an
4
effective donation.
5 I think the procurement process is
6
unlikely to turn out to be a big issue for
7
people, but it certainly is going to be an
8
issue if it changes either the logistics or
9
the cost.
10 I think the criteria are going to
11
have to be studied and developed for exactly
12
what the limits are for an appropriate
13
organ, and I'm going to talk more about
14
what's going on in the OPTN about that right
15
now.
16 Because of its intrinsic
17
relationship to organ transplantation in
18
general, as you can guess, it's very much a
19
major interest in the OPTN, and it's
20
something that the OPTN will continue to
21
play a major role in.
22 The preservation method, I think,
68
1
is interesting. Presently, we
use what's
2
called the University of Wisconsin solution,
3
which is designed particularly for liver
4
preservation, but seems to work well for all
5
the abdominal organs; again, something that
6
will come up as an issue in the specifics of
7
how the glands are taken care of.
8 I think probably I should
9
summarize with a couple of points for
10
tomorrow's discussion, and for further
11
thoughts about how this is going to play out
12
from the point of view of the FDA regulation
13
particularly.
14 One is that the process of getting
15
the pancreas to the point at which the
16
consideration for preparing islets is made,
17
and the oversight of what happens afterwards
18
in the recipient, which is something the
19
OPTN will continue to be part of, because of
20
the involvement with organ transplantation
21
in general, are robust. There's
a long
22
successful history now in the country of
69
1
dealing with this, and it has very clear and
2
active federal oversight.
3 It does, however, involve deeming,
4
if you will, some of that process to the
5
individual medical approaches worked out
6
through the contractor's policies, and
7
that's something that people thinking about
8
the details of regulatory language should
9
understand.
10 Now, the second thing I'll say,
11
and probably more importantly for tomorrow's
12
discussion, just for people to be thinking
13
about, is the concept of product or device,
14
which to some degree gets down to the issue
15
of ownership.
16 I'm sure Jim
Childress is going to
17
give us the real word on this, so I don't
18
want to go too far on this. But
I think
19
it's important to understand that an organ,
20
a kidney or a heart, is in an interesting
21
situation after it's been removed from the
22
donor.
70
1 While it's still in the donor,
2
it's owned by the donor. I don't
think
3
lawyers would have a problem with that.
4
Once it's been revascularized in the
5
recipient, the recipient owns that organ,
6
and again, I don't think there's too much
7
trouble with that.
8 In the meantime, the OPO that
9
packs it up and carries it off, the OPO that
10
receives it to be taken to the hospital
11
where it'll be transplanted, is exercising
12
stewardship. That organ is not
really owned
13
by anybody.
14 Now, if you're talking about
15
products or devices, you're thinking about
16
something that essentially can be owned, and
17
I think that's an issue to be dealt with in
18
this interface question of the islets, which
19
is one of the sort of interesting parts of
20
this.
21 So I leave you with that for
22
today. Thanks for the attention.
71
1 DR. RAO:
Thank you, Dr. Burdick.
2
Any burning questions?
3 MS. MEYERS:
I'm somewhat
4
confused, because when we talk about organ
5
transplantation, the FDA really doesn't
6
regulate organ transplantation, you know.
7
There's no GMPs that a facility has to live
8
up to, et cetera. It's really
run by these
9
contractors to the government.
10 Now here, we're talking about
11
these cells, and we're talking about what
12
appears to be setting up GMPs and the whole
13
manufacturing process, and I'm wondering
14
under what legal authority FDA has to
15
regulate these -- while it looks like it's
16
going to end up regulating these cells
17
whereas it doesn't really regulate the whole
18
pancreas.
19 DR. NOGUCHI:
Abbey, thank you for
20
that question. That is at the
heart of some
21
of the continuing discussions that we have.
22
But I think the way we would look at it is
72
1
that products can be manufactured from a
2
variety of different sources.
3 This is an unusual situation,
4
where we are getting material from one
5
source that has really had a large degree of
6
oversight by another agency. We
are looking
7
at this as, once it has been delivered to a
8
place where it's manufactured, that is where
9
FDA oversight begins for that particular
10
process. We are not directly
addressing the
11
question of ownership. I think
the question
12
that has just been raised is an important
13
one, for which, quite frankly, we don't have
14
a good answer at this time.
15 But part of it is trying to say
16 that we believe that
in some cases, a whole
17
organ may or may not be used for
18
transplantation, but that does not
19
necessarily mean that then it should be not
20
looked at as a source of material that could
21
be further manufactured for a product that
22
may be beneficial to a human recipient.
73
1 I'm not sure if I'm quite getting
2
to the question you're asking, but what we
3
are saying is that we believe that cellular
4
therapies, and this is a part of that,
5
albeit that the islet is a collection of
6
cells, is something that we have
been
7
regulating actually for quite a number of
8
years, as Dr. Weber noted, for just
9
about 15, perhaps 20 years on a very
10
irregular basis, but on a more regular basis
11
since the year 2000.
12 The other question you're asking,
13
though, is a more complicated one.
It's
14
about how does the government really deal
15
with something where different things come
16
into something that eventually is used in a
17
human in a way that we consider at FDA that
18
to be a manufactured product.
19 MS. MEYERS:
What you're saying is
20 that these cells
will be delivered through
21
some manufacturing site that will then
22
process it or do something to it, and that
74
1
manufacturing site will then send the cells
2
out to whatever facility; rather than a
3
whole organ moving from one hospital to
4
another hospital and no manufacturing.
5 DR. NOGUCHI:
Essentially, right.
6
Many of them may not be shipped further than
7
the place of manufacture, and some will.
8
You know, that's still to be developed.
9
Most of the experience has been they are
10
shipped to a place where that facility then
11
for that university or for the hospital will
12
prepare the cellular islet transplant.
13 DR. RAO:
That's a really
14
important topic, and we should hold it
15
because that might be a segue into the
16
discussion as we begin.
17 Our next speaker is going to be
18
Dr. Nicholas Obiri.
19 DR. OBIRI:
Good morning. I'm
20
Nicholas Obiri. I'm with the
division of
21
manufacturing and product quality over at
22
CBER.
75
1 It's my role today to provide an
2
overview of the facilities and good
3
manufacturing practices and expectations for
4
a biologics license application to
5
manufacture allogeneic islets.
6 I'll begin
with a quick overview
7
of the regulatory authority that FDA has to
8
regulate this product. I'll
review the
9
general design principles for a facility
10
that manufactures the product, and I will go
11
over measures that should be in place to
12
maintain control of the facility.
13 Because of the particular
14
relevance of aseptic processing to
15
allogeneic islet manufacture, I'll talk
16
about a few aspects of aseptic processing.
17 FDA's authority to regulate this
18
is product actually is rooted in this act,
19
the Public Health Service Act, Section 351
20
of it, which basically says that FDA shall
21
license biological products when certain
22
conditions are met.
76
1 Another regulation that we need to
2
refer to, which is particularly relevant
3
here, is the Title 21 of the Code of Federal
4
Regulations, Part 601 of its Section 3(d).
5 It basically says that in order to
6
license a product, a biologic, it has to
7
have these attributes in terms of quality,
8
but in addition to that, it has to be
9
manufactured in a facility that meets
10
certain standards. Now the standards are
11
defined in these regulations here.
12 Just to illustrate what I'm trying
13
to say, if we say that the qualities that a
14
product should have would make it acceptable
15
to FDA, or we should just refer to it as a
16
quality product, then in order to get a
17
biologics license to make allogeneic islets
18
or any other biologic, you'd have to
19 demonstrate ability
to manufacture a quality
20
product; i.e., a product that meets those
21
attributes I showed in the previous slide.
22 Then, not only that, but a
77
1
facility in which you made that product has
2
to meet such design standards.
In addition
3
to the design standards for the facility,
4
you also have to have the manufacturing
5
operations reflect these attributes.
In
6
other words, the operations within the
7
facility should have these characteristics.
8
I will return to this slide at a later
9
point.
10 But for right now, I do want to
11
start with a discussion of the facility. In
12
other words, we are talking about a facility
13
that would be a compliant facility.
It
14 would be one that
meets all of the
15
requirements that are defined by the
16
regulations I referred to earlier, and these
17
regulations are otherwise known as the good
18
manufacturing practices, or GMPs.
19 Such a facility should be
20
appropriately designed. It
should have a
21
controlled environment within the facility
22
where the operations are occurring.
It
78
1
should have provisions for using only
2
equipment that's properly qualified, and
3
there should be adequate measures to control
4
cross-contamination, and there should also
5
be adequate measures to ensure that there is
6
no mix-up of patient material.
7 There should be provision for
8
controlling incoming raw materials, and
9 there should also
be an independent quality
10
assurance or quality control staff.
11 There should also be appropriate
12
provision for keeping up with the records
13
and making sure that all documentation is up
14
to date.
15 So just to spend a little more
16
time on the design attributes of the
17
facility, the design should be influenced by
18
the nature of the source material.
For
19
example, if we were starting with a solid
20
material like a pancreata, for example, then
21
one would expect that a facility would be
22
designed in such a way that there's
79
1
appropriate receiving area to receive the
2
source material, and also to do all the
3
processing and documentation that would be
4 required.
5 Now if, on the other hand, we were
6
talking about static materials that would be
7
a vial of frozen cells, then we probably
8
wouldn't need to have an elaborate design
9 for a receiving
area.
10 The design should also be
11
influenced by what the purpose of the
12
facility is. Is it going to be a
single
13
product facility or is it going to be a
14 multi-product
facility?
15 Critical manufacturing areas
16
should be designed into the facility.
For
17
this kind of product, one would anticipate
18
that aseptic processing would occur.
19
Therefore, the facility should be made of
20
materials that will be appropriate for that
21
kind of processing. Just as an
example, the
22
interior surface of the material should be
80
1
made up of materials that are smooth and
2
solid, being able to resist the cleaning
3
agents that would necessarily have to be
4
used to maintain a high level of sanitation
5
within the facility.
6 For this class of products in
7
particular, I think it's well-agreed that
8
the processing should be well-defined and
9
well-characterized. So the
manufacturing
10
process, would need to be such that it is
11
built into the facility so that the design
12
of the facility should provide for a proper
13
flow of personnel and the process.
14 Just as an example, one can
15
anticipate that the initial processing of
16
the material would occur in a particular
17
part of the facility. While the
design
18
should provide for a situation in which
19
there is a defined location for that kind of
20
processing; not only that, but any
21
subsequent processing of the materials that
22
are likely to be more refined should occur
81
1
in a segregated area from the more crude
2
initial processing.
3 This scheme would allow for a
4
situation in which not only
does the
5
manufacturing process flow from the upstream
6
manufacturing areas to the downstream
7
manufacturing areas, but you would also have
8
a natural flow of personnel.
This
9
arrangement would ensure that there is very
10
minimal chance for cross-contamination.
It
11
would also make it very unlikely that you
12
would have product mix-up.
13 So I want to
switch gears just a
14
little bit. I've talked
primarily up to
15
this point about the facility, the physical
16
facility. As I indicated at the
beginning,
17
especially when we are looking at that
18
regulation, we not only have to have control
19
of the physical facility; we also have to
20
have control of the environment within the
21
facility which governs the manufacturing
22
operations.
82
1 So I'm going to go on now and talk
2
about the measures that should be taken to
3
ensure that we maintain environmental
4
control within the facility.
5 The single most important system
6
that would ensure control of the
7
environmental conditions within the facility
8
would be the heating, ventilation and the
9
air conditioning system, commonly referred
10
to as HVAC. That system is
critical,
11
because it has to be able to provide a
12
HEPA-filtered air in the manufacturing
13 areas. By that I mean high efficiency
14
particulate filtered air.
Because the
15
environment in the facility has to be of the
16
cleanest standard, has to meet the highest
17
standard of cleanliness with regard to the
18
air quality, as much as possible.
19 It should provide then for the
20
ability to control the air supply to the
21
area, and also be able to create conditions
22 or areas within
the facility where critical
83
1
operations can occur.
2 It should provide for the ability
3
to use a pressure cascade to protect the
4
product, and this should be possible by
5
allowing very critical operations, such as
6
situations in which we have to open the
7
exposed product to the environment; that
8
kind of operation should be performed in an
9
area of high pressure surrounded by an area
10
of low pressure.
11 The HVAC system should be able to
12
provide for the ability to use a pressure
13
sink to protect all the manufacturing areas
14
and personnel.
15 Because of its importance, we
16
should have a very well-defined process or
17
procedure or program to qualify the HVAC
18
system, because we need to be able to
19
confirm that the equipment itself, that's
20
the hardware of the HVAC, its control and
21
the circulation system, we have to be able
22 to ensure that
they meet expected
84
1
performance quality.
2 This is usually done by monitoring
3
the environment. Again, remember
that the
4
environment is provided by the HVAC.
So in
5
order to do the qualification of the HVAC,
6
we would have a program of environmental
7
monitoring where we monitor conditions
8 within the
facility under non-operational
9
conditions as well as under operational
10
conditions.
11 So in addition to having a clean
12
environment within the facility, we also
13 want to ensure
that all of the materials,
14
the reagents that come into the facility,
15
meet a minimum standard. For
example, we
16
would expect that pharmaceutical-grade
17
reagents and supplies, such as water,
18
processed air, and utility gases would meet
19
these minimal standards.
20 Again, the manufacturing process
21
has to be validated. This
validation would
22
be based on data. Actually, data that is
85
1
gathered by the manufacturer. We
would
2
expect that there would be demonstration of
3
the ability of the manufacturer to make this
4
product on a consistent basis.
5 Because of the nature of this
6
particular class of product, we would expect
7
the manufacturer to demonstrate ability to
8
carry out aseptic processing.
9 So the validation of the process
10
would encompass not only the ability to
11
manufacture the product on a consistent
12
basis, but it would also be expected that
13
qualified equipment would be used in that
14
manufacture. At the same time,
we would
15
expect the manufacturer to demonstrate an
16
ability to maintain control over other
17 facility systems while
making the
18
consistency lots.
19 In order to achieve this, of
20
course, you would also expect that all of
21
the staff that would be used in this process
22
would be properly trained and qualified.
86
1 So I've talked about several
2
different things that should be in place in
3
order to make a quality product.
One might
4
wonder how does one keep track of all of
5
these things. That's the reason
there
6
should be a quality system. A
quality
7
system is a system that should be in place
8
in the facility that should have these
9
attributes.
10 There should be provision for
11
vendor audit, and this would be the
12
suppliers of the reagents and the materials
13
that are used for manufacture.
The vendors
14
should be qualified with regard to integrity
15
as well as with regard to the quality of the
16
materials that they supply.
17
There should be
provision for
18
material qualification. All
materials that
19
are going to be used for manufacture should
20
be properly qualified. There
should be
21
provision for an oversight of the process,
22
and there should be provision for a change
87
1
control. By this I mean a
well-thought-out
2
procedure that would be used for making
3
changes in the manufacturing process or with
4
regard to equipment after the initial
5
qualification or validation has occurred.
6 I should also mention that after
7
licensure, FDA does not expect changes in
8
the manufacturing process or some of the
9
critical processes. But when
those changes
10
are necessary, there is provision or
11
requirements for how the agency should be
12
notified about those changes.
13 There should also be provision for
14
personnel training. I think it's
obvious
15
that people that are going to be involved in
16
the manufacture of this kind of product
17
would need to be properly trained and be
18
well-versed in the use of complex equipment.
19 However, what should not be
20
overlooked is the need for these personnel
21
to have GMP training also. So
usually one
22
would expect that there would be initial
88
1
training of all staff on GMP issues, but
2
also a regular updating of that training.
3
It's also very important that that training
4
be documented.
5 There should be provision within a
6
quality system for investigation of
7
deviations, recalls, product complaints and
8
the Med Watch Program.
9 So I said I would return to this
10
slide and I think from the previous things
11
that I have said, you can see what I mean by
12
saying that to make a quality product, which
13
would meet all of the attributes that are
14
required by the law, then it is FDA's
15
expectation that these features would be
16
obvious in the manufacturing facility.
17 So we would need a facility that
18
meets certain minimal design standards, but
19
in addition to that, that the manufacturing
20
operations within the facility also manifest
21
these features.
22 We would expect them to use
89
1
qualified equipment. We would
expect that
2
the manufacturing process be validated.
We
3
would expect that the components and the raw
4
materials would be qualified, and we would
5
expect that the environment within the
6 facility would be
under control.
7 We would also expect that there
8
would be a quality unit that assures that
9
all of these standards are met.
In some
10
places, it would be a quality assurance
11
unit. In some places, it would
be a quality
12
control unit. In many places,
you'd have
13
both of them; you'd have both a quality
14
control unit as well as a quality assurance
15 unit.
16 One might look at it as that the
17
quality control unit would carry out all the
18
tests that need to be performed on the
19
product, as well as on the intermediate
20 reagents.
21 Whereas, the quality assurance
22
unit would be the unit that uses the results
90
1
generated by the QC unit to reject or accept
2
the product.
3 So with this setup in place in a
4
well-designed facility, we would expect to
5
be able to make a quality product.
6 I did say that I would say a few
7
words about aseptic processing.
I am
8
putting up this definition, which I think
9
talks about what I have in mind here.
It's
10
a processing approach in which a product
11
manufacturer goes under environmental and
12
processing conditions that assures minimal
13
opportunity for contamination from the
14
environment or personnel.
15 Because of its nature, terminal
16
sterilization would not be a physical option
17
for allogeneic islets.
Therefore, the final
18
product has to be assembled by introducing
19
the aseptically-produced or processed final
20
formulation of islet cells into a sterilized
21
container and then filled with a sterilized
22
closure system in a high quality
91
1
environment.
2 In order to do that, it would be
3
necessary for all open manipulations and
4
connections that have to be made, they have
5
to be made under aseptic conditions.
So
6
aseptic processing would involve trained
7
personnel and qualified personnel.
It must
8
be validated.
9 Typically, aseptic processing
10
would be validated through media challenges.
11 Basically what this
means is that we would
12
simulate the entire manufacturing process,
13
except that we would substitute media for
14
the product, and then we would incubate that
15
media, and hopefully there will be no
16
microbial growth after a period of
17
incubation.
18 So aseptic processing typically
19
occurs in a Class 100 environment.
A
20
Class 100 environment is just the highest
21
quality environment that one would expect to
22
see in a manufacturing facility.
The
92
1
conditions in a vial safety cabinet fulfill
2
that requirement, but when operations are
3
being performed in this kind of environment
4
there should be appropriate environmental
5
monitoring.
6 For example, viable and non-viable
7
airborne particulates should be monitored.
8
Aseptic processing may also occur in a
9
closed system. A manufacturer
may define a
10
system as closed, but we would expect that
11
such a claim would be supported by
12
validation data.
13 An example of a closed system
14
would be, for example, a system of
15
fermenters or a system of bags that are
16
aseptically put together, for example, using
17
sterile connecting devices. So
as I said
18
again, it's very important that there should
19
be data that supports the claim of a closed
20
system.
21 So I think I can
leave you with
22
this point as my take-home message.
We are
93
1
saying that we should design compliance into
2 the facility
plans. It's advisable to seek
3
CBER input prior to construction.
I also
4
think that might be cost-effective in some
5
instances.
6 We should establish a thorough
7
qualification or validation program, and we
8
should maintain an effective quality
9
assurance or quality control unit to assure
10
maintenance of quality standards and
11
regulatory compliance.
12 We should maintain an aggressive
13
approach to compliance with aseptic
14
processing requirements.
15 I just want to leave this up as an
16
additional resource that may be helpful.
17
The division of manufacturing and product
18
quality would welcome an opportunity to
19
answer questions that manufacturers may
20
have.
21 We would entertain a request for
22
Type C meetings where we would discuss
94
1
facility issues. It's usually
helpful if
2
the manufacturer has specific questions that
3
they want to ask.
4 In the preparation for obtaining a
5
biologics license, one of the things that
6
have to be done would be a pre-operation
7
inspection. We would also be
very happy to
8
discuss details of those inspections with
9
you.
10 I'd like to acknowledge my
11
colleagues at the Division of Manufacturing
12
Quality, as well as John Eltermann, the
13
director, Dr. Finkbohner, the deputy
14
director, for useful discussions and
15
contributions that they made to this
16
presentation.
17 Thank you very much.
18 DR.
RAO: Thank you, Dr. Obiri.
19
Before we go on to the next speaker, I'd
20
like to take this opportunity to welcome two
21
additions to the committee. I'd
like to ask
22
them to just briefly introduce themselves,
95
1
Dr. Eggerman and Dr. Mulligan.
2 DR. EGGERMAN:
I'm Tom Eggerman.
3
I'm a program director for Islet
4
Transplantation in the Diabetes Institute,
5
and I'm very glad to be here.
Thank you.
6 DR. MULLIGAN:
I'm Richard
7
Mulligan from Harvard Medical School.
I'm a
8
member of the BRMAC and I'm a researcher in
9
the area of stem cells and gene transfer.
10 DR. RAO: Our
next speaker is
11
Dr. Wonnacutt, who will sort of carry on on
12
the next aspect of looking at quality
13
control and looking at some of the product
14
issues.
15 DR. WONNACUTT:
Thank you,
16
Dr. Rao. My name is Keith
Wonnacutt, and
17
I'm in the Office of Cellular Tissue and
18
Gene Therapies, and I'll be talking about
19
processing and product quality issues.
20 As an overview for what I'm going
21
to be talking about, first I'll talk a
22
little bit just about the FDA regulation of
96
1
islets, and then go into specific issues
2
related to islet product quality, how source
3
materials relate to that manufacturing
4
process, and product testing all contribute
5
to product quality, and the questions that
6
the FDA has surrounding these areas.
And
7
then conclude with issues related to islet
8
comparability.
9 So the first part, FDA regulation
10
of islets. As Darin mentioned in
his talk,
11
in September of 2000, the FDA issued a Dear
12
Colleague letter which stated, "The purpose
13
of this letter is to inform or remind you of
14
how the Food and Drug Administration
15
regulates allogeneic pancreatic islets for
16
transplantation. These cellular
therapies
17
are regulated as biological products subject
18
to licensing under Section 351 of the Public
19
Health Service Act."
20 So what is actually licensed? The
21
FDA licenses products. In this
case, what
22
would be licensed is the final islet
97
1
cellular product. The
manufacturing process
2
is not licensed; however, a licensed product
3
is dependent upon a specific manufacturing
4
process.
5 In the absence of extensive
6
product characterization and manufacturing
7
process, the manufacturing process helps to
8
define the product. So in order
to obtain a
9
license for a biological product, the
10
sponsor has to submit a biologics license
11
application.
12 The data that's needed to support
13
this application is prescribed in the regs,
14
which state "the manufacturing shall submit
15
data derived from non-clinical laboratory
16
and clinical studies which demonstrate that
17
the manufactured product meets prescribed
18
requirements of safety, purity and potency."
19 So how do we ensure safety, purity
20
and potency? The way we do that
is by
21
applying quality standards to the products.
22
During pre-clinical development, before we
98
1
start in humans, although not necessarily
2
required, good laboratory practices or GLPs
3
contribute to product quality.
4 During investigational stages in
5
the clinic of drug development, GMPs are
6
required, but they are applied in a way that
7
allows for development of the product early
8
and control of the product late in
9
development. Full compliance
with good
10
manufacturing practices are required for a
11
licensed product.
12 During this process development,
13
we expect that the characterization of the
14
product will be constantly improving,
15
although we expect that a threshold of
16
product characterization would
be met prior
17
to beginning pivotal studies so that the
18
manufacturer understands and can control
19
what is being given to the patients.
20 So specifically, how do we control
21
product quality, and what goes into current
22
good manufacturing practices? In
the
99
1
squares here, I've just listed some of the
2
major points involved in the current good
3
manufacturing practices, as outlined in the
4
regulations. They would include
things such
5
as organization and personnel, buildings and
6 facilities,
packing and labeling, control of
7
components, manufacturing controls,
8
laboratory controls, records and reports,
9
holding and distribution.
10 All of these things ensure the
11
safety, purity and potency of the product.
12 Now, LaVelle Edwards, who was the
13
BYU football coach at my alma mater, used to
14
say practice doesn't make perfect, but
15
perfect practice makes
perfect. When we
16
talk about controls, I would apply this to
17
that and say controls don't make quality
18
products, but quality controls make quality
19
products.
20 So my talk will focus on what are
21
the aspects of quality control that will
22
lead to a quality product, especially in
100
1
terms of the source material, the
2
manufacturing, and the product testing.
3 So this leads me into the second
4
major section of my talk. The
control of
5
the source material relates directly to the
6
first CMC question that we're proposing to
7
the panel today. It deals with
the quality
8
control of the source material, or the
9
cadaveric organs.
10 Source material control is
11
difficult in the case of islets because the
12
islet source material is variable.
The
13
source material for islets are cadaveric
14
organs and cannot be controlled in a
15
traditional way, because each
organ is
16
unique in terms of organ size, donor age,
17
extent of fibrosis and autolysis.
18 Also, organ procurement procedures
19
may vary. This was part of what
Dr. Burdick
20
was talking about: Ischemia
time, transport
21
media, organ core temperature, these are all
22
things that may vary with the organ, and
101
1
it's not within the FDA's purview to control
2
some of those things.
3 So a key component for ensuring
4
the control of a validated islet
5
manufacturing process is the use of
6
predefined acceptance criteria for the
7
source material. The acceptance
criteria
8
should ensure that only suitable donor
9
organs, or organs with maximal potential for
10
yielding adequate numbers of
islets are used
11
for islet manufacturing, while unsuitable
12
organs are excluded from further
13
manufacture.
14 Of course, as Dr. Burdick points
15
out, we have to balance this
with the idea
16
that we want to be as inclusive as possible
17
because of the shortage of the organs.
So
18
what could go into the acceptance criteria
19
for the source material or the donor organs?
20
Donor suitability determination, such as
21
viral testing, organ characteristics,
22
harvesting conditions and transport
102
1
conditions, are all things that may
2
contribute to source material control.
3 So our first question is what
4
would be appropriate for a license
5
application? Please discuss the
data needed
6
for developing predefined acceptance
7
criteria for source organs.
8 The second area I'd like to talk
9
about is manufacturing controls.
10
Specifically, the quality control of the
11
manufacturing process. First,
our
12
expectations. In order to
produce a product
13
that is consistent in safety, purity and
14
potency, the manufacturing process should be
15
standardized and validated.
16 In-process testing should confirm
17
the consistency of this process, and for
18
licensed products, the process by which they
19
are made should not be experimental and
20
should be shown to produce a safe and
21
effective product.
22 I'd just like to point out that
103
1 experimental procedures
result in
2
experimental products as far as the FDA is
3
concerned.
4 So what about manufacturing
5
changes? We know that
manufacturing changes
6 can impact product
safety, identity, purity,
7
potency, consistency and stability in
8
unforeseen ways. Therefore, the
product
9
used in pivotal trials should be
10
representative of the product that is
11
intended to be licensed.
12 In the case of allogeneic islets,
13
there is a lot of change, or differences, in
14
the processing. Investigators
frequently
15
customize an islet isolation procedure based
16
on a given donor organ's characteristics to
17
optimize the yield of islets.
18 There are many variations in islet
19
isolation methods, both within centers or a
20
single manufacturer and across centers.
21
Examples of manufacturing variations include
22
digestion time and temperature; the use of
104
1
additives such as DNase and protease
2
inhibitors; issues with critical digestive
3
enzyme, which is usually liberase; and
4
culturing islets prior to transplantation.
5 All of these things can be varied
6
and do vary from manufacturer to
7
manufacturer. Also, all of these
are many
8
times used to optimize the yield of the
9
islets. So here at the FDA, we
agree that
10
some flexibility in the manufacturing
11
process is acceptable, if it's conducted
12
using predefined criteria or algorithms
13
within a validated manufacturing protocol.
14 These predefined criteria would
15
establish conditions that would allow for
16
processing variations based on the
17
characteristics of each donor organ.
18 So in terms again of a licensing
19 application or for
a license, is it
20
reasonable to expect that criteria or