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@
4 FOOD AND DRUG ADMINISTRATION
5 CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
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..."
21 Gaithersburg, Maryland
22 Thursday, October 9, 2003
2 BRMAC MEMBERS:
3 MAHENDRA S. RAO, Acting Chair
National Institute on Aging
JONATHAN S. ALLAM
5 Southwest Foundation for Biomedical Research
6 BRUCE R. BLAZAR
University of Minnesota
DAVID M. HARLAN
8 National Institute of Diabetes and Digestive
and Kidney Disease
KATHERINE A. HIGH
10 University of Pennsylvania
11 JOANNE KURTZBERG
Duke University Medical Center
ALISON F. LAWTON
13 Genzyme Corporation
14 RICHARD C. MULLIGAN
Harvard Medical School
ANASTASIOS A. TSIATIS
16 North Carolina State University
17 ALICE J. WOLFSON
Wolfson & Schlichtmann
TEMPORARY VOTING MEMBERS:
JAMES F. CHILDRESS
20 University of Virginia
21 LYNNE L. LEVITSKY
Harvard Medical School
1 PARTICIPANTS (CONT'D):
2 TEMPORARY VOTING MEMBERS (CONT'D):
3 ABBEY S. MEYERS
National Organization for Rare Disorders
CAROLE B. MILLER
5 St. Agnes Healthcare
6 W. MICHAEL O'FALLON
DANIEL R. SALOMON
8 The Scripps Research Institute
9 ROBERT S. SHERWIN
Yale University School of Medicine
JANET H. SILVERSTEIN
11 University of Florida College of Medicine
13 JOHN J. O'NEIL JR.
15 University of Miami School of Medicine
16 GUESTS/GUEST SPEAKERS:
17 BERNARD J. HERING
University of Minnesota
19 University of Alberta
20 THOMAS L. EGGERMAN
National Institute of Diabetes and Digestive
21 and Kidney Diseases
1 PARTICIPANTS (CONT'D):
2 GUESTS/GUEST SPEAKERS (CONT'D):
3 JAMES BURDICK
Health Resources and
4 Services Administration
5 FRANCISCA AGBANYO
FOOD & DRUG ADMINISTRATION (FDA) PARTICIPANTS:
JESSE L. GOODMAN
8 Center for Biologics Evaluation
10 Center for Biologics Evaluation
12 Center for Biologics Evaluation
14 Center for Biologics Evaluation
16 Center for Biologics Evaluation
18 Center for Biologics Evaluation
20 Center for Biologics Evaluation
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
8 Center for Biologics Evaluation
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
1 PARTICIPANTS (CONT'D):
2 BRMAC #36 FDA PLANNING COMMITTEE MEMBERS
NICHOLAS I. OBIRI
4 Center for Biologics Evaluation
JOHN ELTERMANN JR.
20 * * * * *
1 C O N T E N T S
2 AGENDA SESSION: PAGE
Conflict of Interests Meeting 11
6 FDA Introduction 16
7 Federal Oversight of Allogenic 37
Moving from Investigational Islet 74
9 Products to Licensed Islet Products
10 Islet Processing: Evolution 135
and Current Standards
Current Status of Islet 172
12 Characterization and Quality
13 Session 2:
14 Laboratory of Stem Cell Biology 412
15 Laboratory of Immunology 426
Laboratory of Biochemistry 458
*Proceedings of CLOSED SESSION at pages
18 421-425 and 472-488 bound separately per
21 * * * * *
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
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
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
22 DR. RAO: I'm Mahendra Rao. I'm
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
20 Again, our center has really borne
21 the brunt of dealing with bioterrorism
22 issues and counter-terrorism. Again, all of
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
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
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
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
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
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
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
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
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
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
1 to the public. We need to be sure we have
2 the right internal expertise and the right
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
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
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
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
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
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
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
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
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
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,
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
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
21 It's always helpful to know how we
22 got here. This is, of course, how we got
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
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
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
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
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
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
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
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,
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.
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
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
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
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
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
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
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,
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
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.
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
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
21 Of course, Dr. Hering from the
22 University of Minnesota is going to talk
1 about characterization and quality
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.
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.
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
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
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
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
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
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
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.
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
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
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
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,
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
22 Now, the only procurement
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
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
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
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
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
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
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
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
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
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
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,
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
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
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
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
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
21 So I leave you with that for
22 today. Thanks for the attention.
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
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
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.
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
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
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.
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
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
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
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
1 appropriate receiving area to receive the
2 source material, and also to do all the
3 processing and documentation that would be
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
21 Whereas, the quality assurance
22 unit would be the unit that uses the results
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
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
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
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
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
21 So I think I can leave you with
22 this point as my take-home message. We are
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
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
21 We would entertain a request for
22 Type C meetings where we would discuss
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
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
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,
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
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
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
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
1 cellular product. The manufacturing process
2 is not licensed; however, a licensed product
3 is dependent upon a specific manufacturing
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
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
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
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
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
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
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
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
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
1 experimental procedures result in
2 experimental products as far as the FDA is
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
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