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










         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













         1     PARTICIPANTS:


         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




                     JAMES F. CHILDRESS

        20           University of Virginia


        21           LYNNE L. LEVITSKY

                     Harvard Medical School














         1     PARTICIPANTS (CONT'D):




         3           ABBEY S. MEYERS

                     National Organization for Rare Disorders


                     CAROLE B. MILLER

         5           St. Agnes Healthcare


         6           W. MICHAEL O'FALLON

                     Mayo Clinic


                     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


        12        CONSULTANTS:


        13           JOHN J. O'NEIL JR.

                     LifeScan, Inc.


                     CAMILLO RICORDI

        15           University of Miami School of Medicine


        16        GUESTS/GUEST SPEAKERS:


        17           BERNARD J. HERING

                     University of Minnesota


                     JAMES SHAPIRO

        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

                     Health Canada




                     JESSE L. GOODMAN

         8           Center for Biologics Evaluation

                     and Research


                     KATHRYN CARBONE

        10           Center for Biologics Evaluation

                     and Research


                     RAJ PURI

        12           Center for Biologics Evaluation

                     and Research


                     CAROLYN WILSON

        14           Center for Biologics Evaluation

                     and Research


                     ANDREW BYRNES

        16           Center for Biologics Evaluation

                     and Research


                     NANCY MARKOWITZ

        18           Center for Biologics Evaluation

                     and Research


                     STEVEN BAUER

        20           Center for Biologics Evaluation

                     and Research
















         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


                     ROSANNA L. HARVEY

        10           Committee Management Specialist

                     Center for Biologics Evaluation

        11           and Research




        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):





                     NICHOLAS I. OBIRI

         4           Center for Biologics Evaluation

                     and Research


                     RICHARD McFARLAND


                     STEPHEN GRANT


                     SUSAN LEIBENHAUT


                     JOHN ELTERMANN JR.


                     JOHN FINKBOHNER


                     SARAH KIM


                     SUSAN ELLENBERG


                     GHANSYAM GUPTA


                     ROBERT MISBIN













        20                       *  *  *  *  *

















         1                      C O N T E N T S


         2     AGENDA SESSION:                            PAGE



               Session 1:


                  Conflict of Interests Meeting             11

         5        Statement


         6        FDA Introduction                          16


         7        Federal Oversight of Allogenic            37

                  Islet Transplantation


                  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

                  and Virology


                  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


        22     Bioethics.













         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













         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













         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


        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













         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













         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













         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













         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


        19     importance.


        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


         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













         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


        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













         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













         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


         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













         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


         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













         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


        20     today.


        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


        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













         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


        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













         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.













         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


        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













         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


         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,













         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


        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













         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.













         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













         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.













         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


         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













         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


        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













         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,













         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













         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.













         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













         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


        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













         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













         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


        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,













         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













         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.













         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.













         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













         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


        22     CBER.













         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


         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













         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


         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













         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


        22     operations.













         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


        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













         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


         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













         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


        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













         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













         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













         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













         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













         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,













         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













         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













         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













         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


        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













         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


        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













         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


         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













         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