AThis 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                          DAY TWO


















        21                   Gaithersburg, Maryland


        22                  Friday, October 10, 2003




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         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





              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         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






              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         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







              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         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



              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382


         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



        15                      C O N T E N T S


        16     AGENDA SESSION:                            PAGE


        17        Current Status of Clinical Islet           7



                  Allocation of Pancreata for Whole         65

        19        Organ and Islet Transplantation


        20        Ethical Considerations in Allogeneic     115

                  Islet Transplantation


                  Clinical Development of Islet Products   151


                                *  *  *  *  *


              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382


         1                   P R O C E E D I N G S


         2                                             (8:13 a.m.)


         3               DR. SHAPIRO:  Good morning.  On


         4     behalf of Dr. Camillo Ricordi, and


         5     Dr. Bernhard Hering, and myself, and many


         6     other members involved with total islet


         7     transplant activity.  It is a great pleasure


         8     to provide this information today to the FDA


         9     as we consider moving forward with a


        10     possibility of a BLA.


        11               I'd like to emphasize that we come


        12     to you today with a long history of research


        13     and progress in islet transplantation over


        14     now three decades.  With the first


        15     successful islet transplantation and


        16     reversal of diabetes in rodent models by


        17     Dr. Paul Lacy and his colleagues back in the


        18     early 1970s.


        19               The success at the University of


        20     Minnesota with islet auto‑transplants in


        21     the 1970s, and in fact it's worth mentioning


        22     that today there are islet autografts that



              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382


         1     are functional beyond 18 years maintaining


         2     insulin independence with no concerns


         3     regarding the health of those patients


         4     receiving islet autografts ‑‑


         5                    (Power plug pulled)


         6               DR. SHAPIRO:  As I was saying,


         7     the 30 years of research and then the 18


         8     years of success with islet


         9     auto‑transplants, and then the development


        10     of the automated method by Dr. Camillo


        11     Ricordi introduced and published in 1989,


        12     and then the first series of patients


        13     receiving allo transplants using the


        14     automated method in 1990; the success at


        15     Giessen and more recently in Minnesota by


        16     Dr. Bernhard Hering and his group, and also


        17     in Geneva and Milan, with 50 percent insulin


        18     independence rates reported in the


        19     mid‑1990s.


        20               The introduction of the low


        21     antitoxin liberase soclazinaes (?) enzyme;


        22     and then the work from Edmonton, the



              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382


         1     multi‑center trial, and now with subsequent


         2     refinements and techniques and periodicals


         3     including the use of culture and the


         4     two‑layer method for perforlodectorine (?)


         5     transportation and oxygenation of pancreases


         6     during transportation.


         7               So with this recent success that


         8     clearly, and the FDA's aware of this,


         9     there's been an enormous interest and a


        10     large number of new institutions moving


        11     forward with islet transportation.  We are


        12     aware now of at least 75 new centers across


        13     the world trying to develop processes for


        14     islet isolation or clinical transplant


        15     programs.


        16               So if we lay on the map the


        17     current activity in islet transplantation up


        18     to the present time, and we look at the


        19     centers involved with islet transplantation


        20     North America and in Europe now, within the


        21     Edmonton Protocol and beyond the Edmonton


        22     Protocol now, there are over 300 patients



              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382


         1     treated since 1990 with clinical islet alone


         2     transplantation, or with islet after kidney


         3     transplantation, too.


         4               Now what is common between the


         5     three of us and our data at three


         6     institutions and a number of institutions as


         7     well is that we have common protocols.  We


         8     have identical patient selection criteria


         9     for islet‑alone transplants.  We have common


        10     methods for patient evaluation and the


        11     schedule of testing.


        12               We have common methods, as you


        13     heard yesterday, for islet processing using


        14     the Ricordi method across centers.  We have


        15     common methods for maintaining islets in


        16     culture.  We have common methods for


        17     transplant techniques; standard


        18     anti‑coagulation protocols for


        19     peri‑transplant management; standard


        20     post‑transplant screening for complications,


        21     including bleeding and thrombosis.  Standard


        22     post‑transplant monitoring; and standard



              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     definitions of what we regard as being


         2     success and failure with an islet


         3     transplantation.


         4               We have common criteria for


         5     patient selection.  We pick patients for


         6     islet‑alone transplantation who have Type 1


         7     diabetes for more than five years.  Where


         8     there is independent evidence that a patient


         9     is failing despite total compliance with


        10     maximum alternative medical therapy, in


        11     other words, insulin.


        12               The process for patient selection


        13     is typically in layers, with a primary


        14     screen, a secondary screen, two


        15     diabetologists involved independently with


        16     islet programs completing a review prior to


        17     acceptance by an islet program for further


        18     work‑up; and generally, a multi‑disciplinary


        19     team approach for assessments so that a


        20     patient who ends up being listed for islet


        21     transplantation clearly has been through


        22     many separate screenings to get to that




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     point.


         2               Our inclusion criteria for


         3     islet‑alone transplantation generally


         4     include an age between 18 and 65, c‑peptide


         5     negative, capable of understanding risks and


         6     benefits of treatments including evidence of


         7     good compliance.


         8               We only take patients who have


         9     complications of Type 1 diabetes that


        10     include frequent hypoglycemia, metabolic


        11     lability, or very occasionally, evidence of


        12     progressive secondary complications.  We


        13     have a large number of exclusion criteria.


        14     I won't go through these in detail except


        15     just to point out maybe body mass index


        16     greater than 28; insulin requirements


        17     greater than .7 units per kilogram per day;


        18     untreated prolific retinopathy or evidence


        19     where there is inadequate insulin


        20     compliance.  In other words, with a


        21     hemoglobin A1C greater than 12 percent; or


        22     untreated Addison's disease or untreated




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     sialic disease that might confirm the


         2     interpretation of hypoglycemic unawareness.


         3               So how do we select our patients


         4     with hypoglycemia or metabolic lability?


         5     Our patients have to have Type 1 diabetes,


         6     as mentioned, with insulin therapy that's


         7     essentially failed, where patients have


         8     reduced awareness of hypoglycemia, as


         9     defined by an absence of adequate autonomic


        10     symptoms and a plasma glucose level at 58


        11     milligrams per deciliter, indicated by two


        12     or more episodes of hypoglycemia requiring


        13     third‑party assistance within 12 months.


        14               Or patients who have metabolic


        15     instability, characterized by erratic


        16     glucose levels that interfere with daily


        17     activities, and/or requiring two or more


        18     hospital visits for diabetic ketoacidosis


        19     over the proceeding 12 months.


        20               Intensive insulin management is


        21     defined as monitoring glucose values at home


        22     at no less than four times each day, and by




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     the administration by three or more insulin


         2     injections each day.  This has to be


         3     monitored in close cooperation with an


         4     endocrinologist or primary care physician.


         5               More recently, we've tried to


         6     develop more objective criteria for


         7     assessment of both hypoglycemia and


         8     lability.  Dr. Edmond Ryan, a diabetologist


         9     and medical director of our program at


        10     Edmonton has really developed this Ryan


        11     index, which is hypoglycemic score, and a


        12     lability index that replaces the former


        13     scoring system that we used, which was


        14     called the mean aptitude of glycemic


        15     excursion.


        16               Just to show you very briefly, the


        17     hypoglycemic score sheet is essentially


        18     filled out by the patient, and we record the


        19     number of episodes and how this interferes


        20     with the patient's activities; whether they


        21     become confused, whether the patient had


        22     developed seizures, whether they have to




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     require outside help to treat.  Essentially


         2     a score is developed from this.


         3               Really just to emphasize here,


         4     here is a population of a control cohort in


         5     Edmonton who have Type 1 diabetes in the


         6     general diabetes clinic.  Here are pre‑islet


         7     transplant patients that have a much higher


         8     hypoglycemia score.  Just to make the point


         9     that islet transplantation is successful,


        10     one year after the islet transplant, you can


        11     see that this hypo score is brought down to


        12     zero.


        13               With regard to assessment to


        14     metabolic lability, it's too early in the


        15     morning for me to fully explain the


        16     mathematical approach to the lability index.


        17     But just to say this does provide robust


        18     data, and again, to illustrate to you how


        19     the lability index demonstrates.  Here again


        20     is our Type 1 diabetes controls.  Here are


        21     our patients before an islet transplant that


        22     have a much higher index of lability




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     compared to the normal Type 1 diabetic


         2     populations.  So these are again a highly


         3     selected subset of patients.  Then after


         4     islet transplantation, the lability index is


         5     corrected down to zero at one year.


         6               How do we define insulin


         7     independence?  I know this was one issue


         8     that was raised in some of the questions


         9     that were passed to us before the meeting.


        10     Essentially, we regard the sustained graft


        11     function with adequate endocrine metabolic


        12     reserve after complete discontinuation of


        13     exogenous insulin, while maintaining a


        14     normal hemoglobin A1C.


        15               There has to be independence from


        16     insulin, and this is defined by adequate


        17     control of glucose when a patient is not


        18     using insulin; where the hemoglobin A1C is


        19     less than 6.5 percent; where the fasting


        20     blood glucose level does not exceed 140


        21     milligrams per deciliter more than three


        22     times a week using the morning fasting




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     glucose level; where the two‑hour


         2     post‑prandial glucose levels using any


         3     post‑meal glucose value does not exceed 180


         4     milligrams per deciliter more than four


         5     times in any one week.


         6               A participant may occasionally


         7     have elevated blood sugars in response to an


         8     intercurrent illness, or when the tacrolimus


         9     level is high, but this period has to be


        10     less than the total of 14 days in order to


        11     calculate this as a patient who is


        12     insulin‑dependent.


        13               To emphasize, in our program at


        14     Edmonton, we've transitioned from research


        15     to being regarded to as clinical standard of


        16     care.  Our non‑research program is funded as


        17     of April 2001 by the same mechanism that


        18     funds hearts, lungs, or livers for


        19     transplantation in Alberta by the government


        20     of Alberta through the Providence‑wide


        21     Services Committee, after a full independent


        22     and critical appraisal committee review of




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     the program data.


         2               So we are regarded as a clinical


         3     standard of care in Edmonton.  This covers


         4     only the non‑research transplants.  We do of


         5     course continue to do research funded by the


         6     Juvenile Diabetes Research Foundation, by


         7     the NIH, and by other organizations, too.


         8               The standards for non‑research


         9     islet processing are currently in evolution


        10     with Health Canada, and we're working


        11     closely with Health Canada, just as the


        12     process is moving forward with the FDA in


        13     the U.S. to try to get similar standards in


        14     place.


        15               The immune protocols are generally


        16     based on sirolimus, low‑dose tacrolimus and


        17     diclisimap (?), but we are willing to vary


        18     this and we can vary this for our


        19     non‑research patients since the


        20     immunosuppression protocol's, just like with


        21     heart, lung, or liver transplant, are


        22     individualized as needed by the patient.




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382


         1     This is not specifically restricted or


         2     mandated by the government.  So we are able


         3     to used approved or off‑label drugs as


         4     appropriate for the management of our


         5     clinical islet patients.


         6               We accept referrals from across


         7     Canada.  You can see, again, just to


         8     emphasize the point that we're very


         9     selective in who we pick for an islet


        10     transplant.  Ten percent of the patients


        11     referred for islet transplant, no more


        12     than 10 percent, end up on the islet


        13     transplant list.  Just to show you the


        14     distribution between the three indications,


        15     hypoglycemia, and hypoglycemic unawareness


        16     forms the bulk of the referrals at 70


        17     percent, lability 25 percent.


        18               So at the University at Alberta


        19     now, we've moved on from the first seven


        20     patients we've transplanted now.  We now


        21     have a consecutive cohort of 58 patients


        22     treated.  This just shows you the follow‑up




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     for these patients; with a median follow‑up


         2     now of 21.5 months.  There are now five


         3     patients beyond four years after transplant.


         4     You can see here the first 15 patients


         5     received fresh islet transplants.  Working


         6     together with Dr. Ricordi and Dr. Hering, we


         7     then switched our program from fresh


         8     transplants to cultured islet transplants.


         9               So you can see we have data on


        10     patients receiving cultured, with a total


        11     of 35 patients, versus 20 patients receiving


        12     fresh transplants.  Most of our patients


        13     require two procedures to provide insulin


        14     independence.  So 24 patients here you can


        15     see had two islet procedures.  There are


        16     five patients that have had a third islet


        17     infusion.


        18               So how can we compare the data


        19     between fresh and cultured clinical islet


        20     preparations?  I know we covered some of


        21     this yesterday, so I'll be brief.  Improved


        22     safety and reduce pac cell (?) volume is one




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     clear advantage of the use of islet culture.


         2     Together with the enhanced opportunity for


         3     completion of product‑released criteria, as


         4     you heard from Dr. Hering yesterday.


         5     Certainly from the patient's perspective,


         6     this increases the practicality of the


         7     procedure.  Not only does it allow islets to


         8     be shipped between centers, but it also


         9     means that the patient does not have to live


        10     in the transplant center while they're


        11     listed.


        12               Data that Dr. Camillo Ricordi and


        13     his group in Miami shared with us is


        14     reporting insulin dependence following


        15     cultured islet transplants, where they have


        16     either been transplanted in Miami or shipped


        17     to the beta group in Houston.  Here, their


        18     survival rate for insulin independence is 80


        19     percent at one year, for a total of 19


        20     patients transplanted.


        21               If we compare our data in Edmonton


        22     with the first 16 patients with the next 35




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     patients treated with cultured islet


         2     preparations, we see no difference in


         3     outcome at one year.  With cultured patients


         4     receiving cultured first islet


         5     transplants, 90 percent of these patients


         6     are insulin‑free at the one‑year time point.


         7     Whereas with the non‑cultured first


         8     transplants, 95 percent of patients are


         9     insulin‑free at the one‑year time point,


        10     with no statistical difference between


        11     these two groups; again indicating that


        12     culture is certainly not detrimental to


        13     outcome.


        14               Our outcome at two years, 79


        15     percent are insulin‑free at two years with


        16     cultured islets.  Four years ‑‑ and these


        17     are fresh islet.  Two of the first three


        18     patients are still insulin‑free at the last


        19     analysis.  Four‑year graft survival by


        20     c‑peptide secretion shows for our entire


        21     series that 88 percent of patients remain


        22     c‑peptide positive at four years.




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1               Data again from the University of


         2     Miami shows that islet after kidney


         3     transplantation can be equally successful.


         4     Here's an example of three patients


         5     receiving islets after kidney transplants,


         6     all three of whom are completely


         7     insulin‑free with the complete absence of


         8     hypoglycemia.


         9               So if we pool our data at the


        10     three sites, Miami, Minneapolis, and


        11     Edmonton, for cultured islets, we now have a


        12     cumulative total of 75 patients treated.


        13     Ninety‑nine percent of these patients


        14     demonstrate primary islet graft function.


        15               One‑year C‑peptide secretion is


        16     evident in 96 percent of patients.  One‑year


        17     insulin independence rates are evident in 85


        18     percent of these patients.  These outcomes


        19     clearly match the current success rate of


        20     the pancreas alone transplantation across


        21     the U.S.


        22               Complications including main




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     portal vein thrombosis have not been seen in


         2     this series of patients.  There is no main


         3     portal vein thrombosis.  We have seen the


         4     left portal vein branched on, but only at


         5     our site in Edmonton, not in Miami or


         6     Minnesota in three cases.  So the risk


         7     overall is at 4 percent.  There have been no


         8     deaths, no cancers, no lymphomas, no CMV, no


         9     EBV infections to date.


        10               Again, showing the collaboration


        11     between the three centers, we routinely now


        12     use the transplant bag rather than the


        13     syringe for islet delivery, to make sure


        14     that we have uniformed product that is not


        15     exposed to additional risks in the radiology


        16     department.  We can show you sustained


        17     evidence of graft function over time, really


        18     evidenced by normalization of hemoglobin


        19     A1C.


        20               This shows our cohort of islet


        21     transplant patients at one, two and three


        22     years data showing normalization of




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     hemoglobin A1C less than 6.1 percent.  If we


         2     compare this to consecutive patients


         3     undergoing pancreas transplantation at our


         4     own institution, we see virtually identical


         5     hemoglobin A1C function out to three years.


         6               If we compare the hemoglobin A1C


         7     in our non‑cultured versus cultured islet


         8     preparations, again we see no difference in


         9     outcome, with normalization of hemoglobin


        10     A1C in both transplant groups.


        11               We see evidence of sustained


        12     C‑peptide secretion over time.  So these


        13     patients are generally not losing C‑peptide


        14     secretion.  If you look here, these are the


        15     fasting C‑peptide levels.  These are the


        16     stimulated C‑peptide levels.  Again, showing


        17     stable data shown here across three years of


        18     follow‑up.


        19               We're currently in the process of


        20     working with Miami and Minnesota to complete


        21     prospective quality of live and cost utility


        22     studies.  These are in evolution of the




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     present time.  Just to show you one example,


         2     the hypoglycemia fear score is significantly


         3     reduced after islet transplantation and


         4     remains stable over time.


         5               Complications after islet


         6     transplantation can occur despite this being


         7     a minimally invasive procedure.  Here's a


         8     list of complications encountered at our own


         9     site the University of Alberta.  We've had


        10     an unusually high incidence of liver bleeds,


        11     at 14 percent.  This has been entirely due


        12     to the fact that we were giving a loading


        13     dose of aspirin just before the patient


        14     received their percutaneous procedure, to


        15     try to improve islet engraftment.


        16               Since we've recognized this


        17     complication, the use of aspirin has been


        18     withdrawn from our protocols.  Other


        19     complications that occur commonly include


        20     mouth ulceration, in 87 percent of patients;


        21     dyslipidemia, in 44 percent of patients that


        22     respond to statin therapy; transient rises




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     in liver function tests.  And we do see


         2     changes on the MRI scan, with steatosis in


         3     the liver in about 23 percent of patients.


         4     Again, no deaths, no cancer, no lymphomas,


         5     no CMV.


         6               I mentioned the bleeds that have


         7     occurred after transplant.  Here's a patient


         8     having a laparoscopy for a bleed that


         9     occurred at the site of puncture in the


        10     liver.  This is a preventable complication.


        11     We believe this is the technique developed


        12     at the University of Miami where a


        13     collagen‑thrombin plug is placed in the


        14     catheter tract.


        15               The University of Miami has had no


        16     further bleeding using that approach.  In


        17     Edmonton we've been developing a Nd:YAG


        18     Laser for a very similar approach really to


        19     ablate the liver.  This is in a large animal


        20     model, but we've been using this in patients


        21     to seal the catheter tract.


        22               At the University of Minnesota,




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     also, in a consecutive series of 20


         2     consecutive patients there, not a single


         3     bleed when the combination of coils and


         4     gelfoam are used to mechanically and


         5     physically ablate the catheter tract.  So


         6     this is a preventable complication, in our


         7     opinion.


         8               Data from the International


         9     Multicenter Trial of the Edmonton Protocol,


        10     I'm showing you data that has been presented


        11     and has been in the public forum since May


        12     of this year, when this data was presented


        13     at the American Society of Transplantation


        14     meeting, ATC meeting.  The objectives of the


        15     ITN trial was to replicate the Edmonton


        16     Protocol at multiple sites; provide a base


        17     of qualified islet centers for future ITN


        18     tolerance trails; and really to define the


        19     challenges of applying one common protocol


        20     for patient selection, islet preparation,


        21     and immunosuppression across multiple


        22     centers.




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1               Also with the ITN to potentially


         2     explore mechanisms of islet acceptance and


         3     rejection in collaboration with the


         4     tolerance assay subgroup.


         5               A total of nine sites moved


         6     forward with this trial.  This is three


         7     sites in Europe and the five sites in North


         8     America.  We look at the success, it


         9     certainly has been variable by site, but


        10     what we can say very clearly from this data


        11     is the Edmonton Protocol has been


        12     successfully replicated by a number of


        13     sites.  Not by everybody.


        14               But this really illustrates the


        15     challenges involved with preparation of


        16     islets and with the clinical care of


        17     patients.  Now this data shown here with


        18     four sites not delivering insulin


        19     dependence; again, I would emphasize this is


        20     data reported in May 2003.  This data has


        21     not been subsequently updated, and there's


        22     no question this data has improved since




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     then.  But subsequent analyses are pending.


         2     I'd also draw your attention to a letter in


         3     correspondence in today's issue of "The


         4     Lancet," and I'll just read it to you.


         5               "As co‑principal investigators of


         6     the ITN Multicenter trial, we wish to


         7     clarify the importance of the preliminary


         8     analysis.  A 90 percent insulin‑free rate


         9     was noted in three centers with longstanding


        10     expertise in islet preparation and in


        11     clinical use of immunosuppression, not only


        12     at the Edmonton site where the protocol


        13     originated.


        14               The average rate of insulin


        15     independence among the remaining six


        16     clinical sites was 23 percent, including one


        17     site with an interim success rate of 67


        18     percent.  Thus, the Edmonton Protocol has


        19     been replicated successfully at other


        20     clinical sites, and in some cases with a


        21     high degree of success.  Although this data


        22     is preliminary, we view this result as a




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     positive one, which confirms the great


         2     benefits to patients of islet


         3     transplantation and provides additional


         4     justification for continued investigation of


         5     islet transplantation as a treatment for


         6     brittle forms of Type 1 diabetes."


         7               Finally, I draw your attention to


         8     data emerging from the University of


         9     Minnesota, with truly a remarkable series of


        10     now 20 patients treated with successful


        11     single donor islet transplants for Type 1


        12     diabetes.  Dr. Hering may address this


        13     further in discussion.  But essentially, in


        14     order to achieve single donor islet


        15     transplant success, there were seven


        16     strategies implemented, including excluding


        17     pancreas organs from donor organs aged 50 or


        18     higher; limited ischemic injury of islets by


        19     processing within eight hours, sometimes


        20     quite a bit less than that time, to optimize


        21     islet function; avoiding islet toxic


        22     reagents during the islet processing, using




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     culture of islets as we've mentioned to


         2     allow pre‑transplant initiation of


         3     immunosuppression; providing potent


         4     prophylactic anticoagulation and aggressive


         5     insulin therapy prior to transplant; and


         6     increasing the immunosuppressive and


         7     anti‑inflammatory potency of the induction


         8     of immunosuppression while avoiding


         9     calcineural (?) inhibitors in maintenance of


        10     immunosuppression.


        11               This shows the remarkable success


        12     of these patients undergoing this form of


        13     transplant.  Here's a patient with a single


        14     donor islet transplant at the University of


        15     Minnesota with totally normal oral glucose


        16     tolerance test and perfect glycemic control


        17     across one year of follow‑up.


        18               Thank you for your attention.


        19               DR. RAO:  Thank you, Dr. Shapiro.


        20     Any questions for Dr. Shapiro?


        21               DR. RIEVES:  Hi there.  My name is


        22     Dwaine Rieves.  Could you very briefly




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     provide a perception, share some of your


         2     thinking regarding some of the clinical


         3     benefit in your studies, in your procedures,


         4     beyond perhaps the avoidance of exogenous


         5     insulin?  You've touched on improvement in a


         6     fear index, and I suspect that you also have


         7     thoughts about other clinical outcomes that


         8     these patients may have achieved.  Can you


         9     comment on that?


        10               DR. SHAPIRO:  Certainly.  I would


        11     say that most patients who come to us for an


        12     islet transplant, their aim isn't to attain


        13     insulin independence.  It may be the


        14     program's aims, but it's certainly not many


        15     of the patient's aim, sort of suffering from


        16     severe hypoglycemia.  Most patients have no


        17     problem staying on a small amount of insulin


        18     if needed in order to rid themselves of the


        19     day‑to‑day difficulties and challenges of


        20     recurrent hypoglycemias.


        21               I would emphasize to you that


        22     these patients are at quite high risk when




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     they face recurrent hypoglycemias.  For


         2     example, at our three sites, there have been


         3     in fact three deaths in patients that were


         4     listed for islet transplant from


         5     hypoglycemia.  I mentioned to you, we


         6     haven't had any deaths after an islet


         7     transplant.  So clearly these patients are


         8     at added risk because of their recurrent


         9     hypoglycemias.


        10               In other words, in our sense, even


        11     with just one islet transplant, as long as


        12     the patient's maintained c‑peptide


        13     secretion, their risk of hypoglycemia is


        14     completed obviated, so they have very much


        15     more stable glucose control, and in fact


        16     rapid correction of hemoglobin A1C even


        17     though they're requiring at that point small


        18     doses of insulin.  So from the patient's


        19     perspective, there clearly is a benefit from


        20     that.


        21               If you're asking about what are


        22     the longer‑term benefits of a successful




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     islet transplant in terms of secondary


         2     complications, I think that is a harder one


         3     to answer right now.  We currently use the


         4     surrogate endpoint of correction of the


         5     hemoglobin A1C; we would expect that if


         6     patients maintain a hemoglobin A1C within a


         7     normal range over time, they will enviably


         8     have reduced progression and maybe reversal


         9     of some of the secondary complications in


        10     exactly the same way as that's been shown


        11     with successful whole pancreas


        12     transplantation.


        13               But we don't have long‑term data


        14     really to prove that at the present time.


        15     That will emerge, but I suspect just like in


        16     pancreas transplantation, it may take 10 or


        17     maybe 15 years to really prove that point.


        18               DR. EGGERMAN:  Yes, Tom Eggerman,


        19     NIDDK.  I noticed you had an incidence or


        20     prevalence of steatosis of like 22 percent.


        21     I'm wondering if all that changed over time


        22     in terms of severity as well as prevalence.




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1               DR. SHAPIRO:  So this is a finding


         2     that is recognized on ultrasound with


         3     heterogeneity of the liver, and it's


         4     recognized when we screen all of our


         5     patients by MRI scan over time;


         6     approximately 22 percent of patients have


         7     changes on MRI scan compatible with mild


         8     steatosis.  Occasionally, it can be more


         9     than mild.


        10               The patients have a normal liver


        11     function test however, and we see this as


        12     being a direct physiological impact of high


        13     dose local insulin secretion in the liver.


        14     It's an interesting physiological


        15     observation, but we don't think it has any


        16     clinical concern beyond that.


        17               The reason we say that is that


        18     islet autotransplant patients also have


        19     these changes.  I mentioned to you that


        20     there are patients now out beyond 18 years


        21     after an islet autotransplant with these


        22     kinds of changes too that have not led to




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     any clinical difficulties.


         2               So it's an observation.  I can


         3     tell you too that we have a patient that


         4     lost c‑peptide secretion over time who had


         5     changes of the steatosis.  When she lost her


         6     c‑peptide secretion, she completely resolved


         7     the steatosis.  So we think this is related


         8     to high local insulin and it's a reversible


         9     phenomenon.


        10               DR. EGGERMAN:  But is there a


        11     steady increase over time, or is it ‑‑


        12               DR. SHAPIRO:  No, it seems to


        13     remain stable.


        14               DR. EGGERMAN:  In terms of


        15     prevalence as well as severity?


        16               DR. SHAPIRO:  Well,


        17     cross‑sectional data is really unavailable


        18     to us now.  Longitudinal studies are in


        19     progress.  I don't think we have the


        20     evidence so far to say it's getting worse


        21     over time.  It may be getting better.


        22               DR. RAO:  I noticed you showed




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     this correspondence letter where there was


         2     difference between the success rate at the


         3     three centers versus the other multicenter


         4     trial runs.  Is there any speculation why


         5     there was that difference?


         6               DR. SHAPIRO:  Again, I would


         7     emphasize that the data presented is


         8     extremely preliminary.  It has changed and


         9     evolved over time.  I think it really


        10     illustrates the fact that new islet


        11     transplant centers are moving forward.


        12     There's a considerable learning curve in the


        13     manufacturer of islets that we all know and


        14     recognize.


        15               Despite tremendous support


        16     provided, with the three of us traveling to


        17     each institution to train as institutions


        18     moving to the three sites to learn the


        19     techniques, not every center has been able


        20     to deliver good islets.  That's one factor.


        21               I think the second factor is that


        22     basic management of clinical




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     immunosuppression in some cases has led to


         2     rejection when patients were not maintained


         3     in perfect target range of tacrolimus or


         4     sirolimus after transplants.  In other


         5     words, some patients lost islet function as


         6     a direct result of rejection.


         7               DR. RAO:  Maybe to expand on that


         8     question just a little bit.  You had


         9     measures of potency that were talked about


        10     in terms of the manufacturer of the product.


        11     In some sense, those should have been


        12     predictive of what the islets would do at


        13     different centers if there's an appropriate


        14     SB.  Was there any sort of correlation when


        15     you said that there was a learning curve and


        16     despite the fact that there was huge


        17     training, the difference was completely


        18     learned?


        19               DR. SHAPIRO:  Well, I would


        20     comment that on the first look of that data


        21     didn't show any obvious factor or any


        22     evidence from the potency assays, but again,




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     that was very preliminary data.  We have a


         2     lot more data accrued since the initial


         3     analysis.  I think in subsequence analysis


         4     maybe something will emerge in terms of


         5     evidence of impacted potency or islet mass


         6     in terms of correlation with clinical


         7     outcome.  That data is pending currently.


         8               DR. SHERWIN:  Jim, you haven't


         9     shown data looking at actual insulin


        10     secretion in these people.  I just wonder


        11     how normal is the actual secretion of


        12     insulin, beginning by the glucose levels


        13     first.


        14               DR. SHAPIRO:  Of course.  We have


        15     accrued a fair amount of metabolic data with


        16     Dr. Ryan in our group and Dr. Pati (?)


        17     looking at insulin and oral glucose


        18     tolerance, intravenous glucose tolerance,


        19     and response to arginine (?) challenge.


        20     What I can tell you from our own site data


        21     is that most patients have impaired glucose


        22     tolerance.  Some patients have normal




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     glucose tolerance.  If a patient can


         2     maintain insulin independence with a normal


         3     hemoglobin A1C, but have an impaired glucose


         4     tolerance, and that really is a reflection


         5     of the fact that still some of our patients


         6     have a marginal islet implant mass that's


         7     sufficient to allow them to discontinue


         8     insulin.  So insulin secretion is not


         9     normalized in most patients.


        10               I think Dr. Hering might want to


        11     comment though, because I think his data,


        12     where virtually all have been able to


        13     achieve a normal oral glucose tolerance I


        14     think speaks to the point that probably in


        15     his data, these patients have much more


        16     endocrine reserve.


        17               DR. HERING:  This is again very


        18     preliminary.  But just to indicate the fact


        19     that you can achieve fairly good metabolic


        20     control after islet transplantation.  In a


        21     very small group of recipients that were


        22     monitored for one year, at one year




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     post‑transplant, 80 percent of patients


         2     showed a normal oral glucose tolerance test


         3     with two‑hour glucose levels below 140, and


         4     actually being between 90 and 120 in most


         5     patients.  I think this may be due to


         6     careful selection of donor organs and


         7     patient selection, but just to illustrate


         8     that this can be achieved.


         9               DR. SHERWIN:  The people that have


        10     impaired glucose tolerance, are they more


        11     likely to require insulin subsequently or is


        12     that a marker in any way?


        13               DR. HERING:  Not necessarily.  No,


        14     not necessarily.


        15               DR. RAO:  I just remind all the


        16     members and the committee to shut off their


        17     speakerphones.


        18               DR. HIGH:  I just wanted to ask,


        19     in terms of risk/benefit in this sort of


        20     procedure:  If somebody rejects their


        21     transplant if they stop taking their


        22     immunosuppressive regimen, are they




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     essentially left exactly as they were before


         2     the transplant?  So in other words, there's


         3     no downside risk to rejecting it; they're


         4     just the way they were before they started.


         5               DR. SHAPIRO:  Thank you for that


         6     question.  From a practical sense, patients


         7     that completely lose graft function and


         8     become c‑peptide negative are usually back


         9     at square one.  So if they had severe


        10     hypoglycemias beforehand, they lose complete


        11     graft function, they're back where they were


        12     and they're no worse.


        13               The only theoretical risk to the


        14     patient is if they were to become sensitized


        15     with a high panel reactive (?) antibody, so


        16     if they were to progress to develop kidney


        17     failure and need a kidney transplant, it


        18     might in theory be difficult to match them.


        19               If we look at the data in practice


        20     however, there's one patient of ours that


        21     lost c‑peptide function that had a high peak


        22     PRA at 67 percent after the islet




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     transplant.  This is resolved down to 2


         2     percent currently.  So overall, I would say


         3     the risk of sensitization, provided this


         4     careful management and careful weaning and


         5     withdrawal of immunosuppression, the risk of


         6     the sensitization is not high.


         7               DR. LEVITSKY:  Given that many of


         8     these patients seem to be on the edge


         9     metabolically in terms of their glucose


        10     tolerance, do you give them any sort of


        11     special nutritional counseling?  What is the


        12     nutritional regimen that you like to keep


        13     them on?


        14               DR. SHAPIRO:  Well, it depends on


        15     what the metabolic control of the patient is


        16     like.  If patients have a normal oral


        17     glucose tolerance test, they can usually


        18     tolerate a normal diet and have no problems


        19     whatsoever.  If patients have impaired


        20     glucose tolerance and elevated blood sugar


        21     levels, we do have a dietician involved with


        22     the program who would maintain the patient




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     on a diabetic diet.  Beyond that, there


         2     would be no major restrictions.


         3               DR. RAO:  Dr. Silverstein, did you


         4     have ‑‑


         5               DR. SILVERSTEIN:  I did have a


         6     question about compliance.  Have you had a


         7     problem with noncompliance in any of our


         8     patients?  If so, are there any predictors


         9     that you could note for noncompliance with


        10     their regimen post‑transplant?


        11               DR. SHAPIRO:  Maybe Dr. Ricordi


        12     would want to comment on that, too.  We have


        13     had one patient that really had very severe


        14     hypoglycemias before his transplant, was


        15     clearly quite difficult to assess.  We


        16     anticipated there would be potential


        17     problems afterwards.  This patient was


        18     therefore not included in a research trial,


        19     but was in a more clinical standard of care


        20     protocol.


        21               That patient continues to take his


        22     immunosuppression, but has not really




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     complied with close post‑transplant


         2     monitoring.  I think these patients really


         3     are very similar to other transplant


         4     patients.  What we do to try to avoid these


         5     kinds of challenges is have a detailed


         6     psychological and psychosocial evaluation of


         7     our patients before transplants so that we


         8     can try to anticipate some of those


         9     challenges afterwards.


        10               DR. RICORDI:  We had one case in


        11     which we just had to stop immunosuppression


        12     because the patient was not tolerating the


        13     drugs, so that we raised in discussion


        14     whether we should test immunosuppression


        15     regimen before islet transplant to identify


        16     people that don't.


        17               Because it's very individual, the


        18     response.  Some patients tolerate it very


        19     well and others have problems.  Some adapt


        20     and some just don't cope.  But I wanted to


        21     comment on the fact on what is normal islet


        22     function of islets transplanted in a liver




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     and the immunosuppression, because this is


         2     very important.


         3               You cannot compare it with normal


         4     islet function in a non‑diabetic subject,


         5     because even in organ transplant recipients


         6     who are not diabetic who undergo maintenance


         7     immunosuppression with calcineural


         8     inhibitors, like in some of these protocols,


         9     you clearly have impaired insulin secretion.


        10               This is because of the


        11     diabeticogenic affect of some of these


        12     immunosuppressive drugs.  As the


        13     immunosuppressive protocols will improve


        14     with new agents, you will see less of this


        15     chronic deleterious affect on islet


        16     function.  There are results from


        17     Dr. Hering, who has new protocols that point


        18     in this direction.  We also have preclinical


        19     data in nonhuman primates showing that if


        20     you avoid the diabetic immunosuppression,


        21     the islet function to a liver is identical


        22     to that of a native pancreas, and that




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     actually improve over time for the first


         2     year post‑transplant.


         3               So those are very important


         4     indications that I think even if islets in


         5     the liver is a different physiologic


         6     setting, so you that we may expect some


         7     little differences in glucose metabolism or


         8     insulin secretion; that the problem of


         9     chronic toxicity will be most likely


        10     resolved with the use of less toxic


        11     immunosuppressive drugs.


        12               MS. BIRDIE:  Hello.  I would like


        13     to introduce myself.  My name is Ellen


        14     Birdie.  I have received "the product."  I


        15     received the product at NIH with Dr. Dave


        16     Harlan in June of 2001.  I would like to


        17     make a comment and address the issue of the


        18     fear of hypoglycemia.  Dr. Shapiro mentioned


        19     that they had a graph to try and measure


        20     what the effect of that is.


        21               I would be off the graph, because


        22     that fear is an overriding fear that




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     permeates your whole life.  You never know


         2     when you may pass out and be on the


         3     crumbling edge of the hypoglycemic cliff


         4     with no warning at all.  Before transplant,


         5     this often happened to me while I was


         6     driving the car.  Often on 495, in the


         7     middle of the road, or on back roads, where


         8     I would just stop the car and pass out.  One


         9     time, I passed out for three hours.


        10               So that fear is hard to measure


        11     what effect that has on your whole life and


        12     your whole life of everyone else around you;


        13     your friends, your relatives, who are


        14     consistently monitoring you all the time to


        15     make sure that you are okay.


        16               So I would just like to stress the


        17     importance of not having that fear anymore.


        18     I don't know how you could even begin to


        19     measure that.  Thank you.


        20               DR. RAO:  Dr. Eggerman.


        21               DR. EGGERMAN:  Yes, I was


        22     wondering if there was any differences




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     between those patients that are


         2     insulin‑independent and those that remained


         3     significantly c‑peptide positive but require


         4     some insulin in terms of the degree of


         5     hypoglycemia unawareness.


         6               MR. SHAPIRO:  As I mentioned,


         7     patients that have either partial graft


         8     function or complete graft function, neither


         9     patient is faced with episodes of


        10     hypoglycemia.  If you're asking me of


        11     response of an islet transplant to correct


        12     hypoglycemic unawareness, I think that's a


        13     different question.


        14               We do have data, and we've


        15     published this data in patients who we've


        16     taken controls and patients with Type 1


        17     diabetes, we've taken the normal population,


        18     and looked at the stepped hypoglycemic


        19     clamp.  What we've shown is that even though


        20     patients are clearly not facing evidence of


        21     hypoglycemia at all, in an artificial


        22     situation with a stepped hypoglycemic clamp,




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     patients do not have complete restoration of


         2     hypoglycemic responsiveness or glycogen


         3     responsiveness, or epinephrine


         4     responsiveness after islet transplantation.


         5               So it would appear that even


         6     though the alphacell function isn't


         7     physiological, I should say, in islet


         8     transplant patients when the islets are in


         9     the liver, the clinical impact of a


        10     partially successful islet transplant, where


        11     there is dynamic insulin response in


        12     accordance to glucose levels, these patients


        13     are not facing hypoglycemic reactions.


        14               DR. SHERWIN:  James, though I


        15     wouldn't be quite as cavalier as that, in


        16     the sense that patients probably remain


        17     unaware or at least their counter‑regulatory


        18     systems are still not quite normal, even,


        19     surprisingly, after the treatment.  So they


        20     may have mild changes, not enough to be


        21     clinically important, that we can tell.


        22               But they may actually have lower




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     glucose at certain times of the day, after a


         2     large carbohydrate meal, for example, and


         3     would be unaware of that.  Whether that is


         4     of any consequence clinically is something


         5     else.  I don't know, but it's possible.


         6     Until you have a good sensor and do


         7     continuous monitoring in the outpatient


         8     setting.


         9               DR. SHAPIRO:  Thank you for that


        10     point.  We accept that.


        11               DR. HERING:  If I could comment, I


        12     think there's good technology as we you


        13     know.  A continuous glucose monitoring


        14     system which will ‑‑


        15               DR. RAO:  You lost your mic.


        16               DR. HERING:  Which should clearly


        17     allow better evaluation of glucose control


        18     in hypoglycemic episodes.  But I wanted to


        19     emphasize also that islet transplants can


        20     restore epinephrine secretion in response to


        21     hypoglycemia and can restore normal symptom


        22     perception.  We have documented this and




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     published this in transplantation many years


         2     ago, and it may not be a consistent finding


         3     in every single person.


         4               But this study in which we


         5     compared patients undergoing a stepped


         6     hypoglycemic clamp test before and after


         7     islet transplantation clearly documented the


         8     possibility that this can be restored to


         9     normal.


        10               DR. RAO:  Tom.


        11               DR. HARLAN:  In a recent New


        12     England Journal article looking at the


        13     incidence of renal insufficiency in


        14     non‑kidney transplant recipients, they


        15     reported, depending on the organ


        16     transplanted, an incidence of anywhere


        17     from 7 to 21 percent of nuance at renal


        18     insufficiency.  I wonder if you could


        19     comment on the incidence of that


        20     complication in the islet transplant


        21     population.


        22               MR. SHAPIRO:  Of 58 patients, we




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     have two patients that have evidence of


         2     elevated creatinine.  Did not require


         3     dialysis, but clearly have progressed with


         4     their renal insufficiency, with significant


         5     underlying diabetic changes, with impaired


         6     creatinine clearance prior to their


         7     acceptance to the program.


         8               The means and the rest of the


         9     group of patients really have unchanged


        10     creatinines over time.  The one measurement


        11     that we are concerned about is the degree of


        12     proteinuria in patients.  Occasionally we do


        13     see accelerated proteinuria in patients that


        14     have microbminuria (?) when referred for


        15     islet transplantation.


        16               I can think of one patient in


        17     particular that had secretion of .2 grams


        18     for 24 hours prior to transplant.  This rose


        19     to 2 grams for 24 hours.  Went on to


        20     tacrolimus and sirolimus immunosuppression.


        21     This patient in fact was taken off sirolimus


        22     and given higher dose tacrolimus, and in




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     fact the proteinuria result is back down to


         2     baseline presently.


         3               DR. HERING:  If I could comment.


         4     I think both patients showed not long


         5     proteinuria before islet transplantation but


         6     also had evidence of impaired kidney


         7     function, as measured by impaired creatinine


         8     clearance.  So I think patients had advanced


         9     kidney disease.  Those patients should


        10     probably be excluded from participation as


        11     long as calcineural inhibitors are used in


        12     protocols.


        13               DR. SHAPIRO:  Dr. Hering, you're


        14     absolutely right.  The protocols in fact


        15     have been modified since our earlier


        16     experience with that.  So we now exclude


        17     patients that have microbminuria or who have


        18     evidence of significantly impaired


        19     creatinine clearance.


        20               DR. RICORDI:  I think this is a


        21     very important point that Dr. Hering raised,


        22     because it is important to distinguish what




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     are side effects or complications related to


         2     the islet transplant, or what could be a


         3     result of the particular kind of


         4     immunosuppressive agents used.  In the case


         5     of the calcineural inhibitor and who can


         6     benefit from that, you have to exclude


         7     patients who already have progressing kidney


         8     disease.


         9               But it's not to say that in the


        10     future, when you have other normal


        11     flotoxic (?) agents in the battery of


        12     agents, these patients will become


        13     candidates, because actually one of the


        14     objectives of islet transplantation will be


        15     to prevent progression of neuropathy and


        16     intervene early in the course of the disease


        17     before you need a kidney transplant.


        18               DR. O'FALLON:  In your map, you


        19     showed patients being referred to you from


        20     all over Canada.  If I remember the correct


        21     number, you said about 10 percent of them


        22     pass through your screening process.  What




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     proportion of them were ultimately


         2     transplanted, and for those who weren't


         3     transplanted, what were the reasons why they


         4     weren't transplanted?


         5               DR. SHAPIRO:  That's the dynamic


         6     snapshot of our data, so I think it


         7     was 1,200 patients who had undergone


         8     primarily screening, and 10 percent of


         9     patients, as you correctly identified, were


        10     listed for an islet transplant.  At the


        11     present time, we have approximately 70


        12     patients on our islet transplant, waiting


        13     list, actively awaiting islet transplants


        14     from across Canada.


        15               Currently, I would say the


        16     patients that we turn away for islet


        17     transplant have applied for primary screen


        18     but maybe have been found to have c‑peptide,


        19     or have Type 2 diabetes, or have


        20     insufficient cardiac reserve, or have


        21     inadequate renal reserve.  Patients with


        22     inadequate renal reserve, we don't always




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     turn down.  In fact, we tell them, just like


         2     Dr. Ricordi mentioned, that there are new


         3     protocols and development and we will keep


         4     their names on file and contact them again


         5     when we have protocols active that


         6     calcineural inhibitor are free.


         7               I don't have an up‑to‑date


         8     breakdown for you as to exactly what


         9     patients were turned away for what reasons.


        10     That could be analyzed for you.


        11               MR. RAO:  There are no more


        12     questions.  Thank you, Dr. Shapiro.  We'll


        13     go to the next speaker.  I'd like to take a


        14     moment and have the new members of the


        15     committee introduce themselves, starting


        16     with Dr. Silverstein.


        17               DR. SILVERSTEIN:  Hi, I'm Janet


        18     Silverstein, a pediatric endocrinologist


        19     from the University of Florida.


        20               DR. RAO:  Dr. Rieves.


        21               DR. RIEVES:  Hi.  My name is


        22     Dwaine Rieves.  I'm chief of the clinical




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     branch with the FDA's cell and gene therapy


         2     group.


         3               DR. VINER:  I'm Dr. Norm Viner.


         4     I'm the clinical trial application unit head


         5     at Health Canada, BGTDU, which is the


         6     equivalent to CBER.


         7               DR. RAO:  Our next speaker is


         8     Dr. Jim Burdick.  He already spoke


         9     yesterday.  He's from HRSA, and he's going


        10     to speak a little bit more on the allocation


        11     of pancreata for whole organs and islet


        12     transplantation.  We have the mandatory I


        13     guess PowerPoint break.  Were there any


        14     other questions for any of our speakers?


        15               I had one question for any of the


        16     three centers.  Do you ever consider looking


        17     at immune‑typing the cells themselves when


        18     you harvest them, or try and match it with


        19     patients in any fashion?


        20               DR. SHAPIRO:  Generally, we list


        21     our patients by blood group only.  We do not


        22     actually match.  We actually type, and




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     occasionally, we'll do a prospective


         2     cross‑match.  Certainly one benefit of


         3     culture, as opposed to fresh transplant, it


         4     does provide an opportunity to do a


         5     prospective cross‑match.  We do have some


         6     patients now listed that have been


         7     sensitized by previous pregnancies or blood


         8     transfusion.  Those patients do get a


         9     prospective for cross‑match and we try to


        10     actually match to avoid similar antigens.


        11               DR. RAO:  I noticed that in


        12     several of your cases, you have to do more


        13     than one transplant.  Do you find an


        14     increased problem when you do the second or


        15     is the success rate pretty much the same?


        16               DR. SHAPIRO:  It's virtually the


        17     same.  So after one transplant, the


        18     patient's insulin requirements will


        19     typically fall by about 50 to 60 percent.


        20     The second islet transplant will typically


        21     bring that down to zero.  We don't see


        22     evidence of sensitization between the first




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     or second transplant.  We don't see issues


         2     or challenges generally in patients


         3     receiving a second transfusion.


         4               DR. RAO:  Any antibody monitoring


         5     that you look at?


         6               DR. SHAPIRO:  We do look at


         7     antibodies.  We do flow screens.  We do


         8     auto‑antibody screens for gas 65, ICA 512,


         9     and MIAA.  We do that before transplant and


        10     at different time points after transplant to


        11     see, if the outpatients have evidence of


        12     deteriorating graft functions, to see if


        13     there's evidence of suggestion that these


        14     patients might have recurrent auto‑immunity.


        15               DR. BURDICK:  Since we're spending


        16     a minute here about the auto‑immunity issue,


        17     because I think that as far as I know, that


        18     hasn't been addressed, and of course that is


        19     of concern.  But the clinical observation


        20     that liver transplantation or things


        21     involving the liver somehow are often able


        22     to mute the immune response.  Now that's




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     semi‑soft science in general, but it's


         2     certainly an important clinical conviction.


         3     I wonder if it's possible that you're having


         4     an effect on auto‑immunity that would be


         5     good by the fact that they're sitting in the


         6     liver.  Is there any way to look at that, or


         7     have you thought about that at all?


         8               DR. SHAPIRO:  Thank you, James.


         9     It's a nice concept that when we deliver


        10     islets or antigen intraportly, that it might


        11     lead to clinical tolerance to auto ----


        12     antigens.  But I agree with you that the


        13     science surrounding that is soft.  I would


        14     say far more important in fact is the fact


        15     we have these patients on potent


        16     immunosuppression, and for example, the


        17     combination of low dose tacrolimus and


        18     sirolimus, we tested in the NOD auto‑immune


        19     mouse model and found it to be extremely


        20     effective as long as the medications are


        21     maintained in preventing recurrence of


        22     auto‑immunity or primary auto‑immune




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     destruction of islets in that model.


         2               So I think the dominant force is


         3     in fact the presence of immunosuppression,


         4     rather than the fact that the islets are


         5     delivered at an intraportal site to the


         6     liver.


         7               DR. SHERWIN:  James, you commented


         8     on the fact that you had to use statins in a


         9     number of patients.  Just curious about the


        10     degree of change in the lipid profile.  And


        11     have you looked carefully at the size of LDL


        12     and things that might give you a sense of


        13     atherosclerotic risk in these patients.


        14               DR. SHAPIRO:  Dr. Eddie Ryan I


        15     think could comment on that far better than


        16     I could.  We certainly have done detailed


        17     studies in terms of lipid profiles, and


        18     we've done serial screens for carotid


        19     intimal thickness to see if there's evidence


        20     of progression or reversal of


        21     atherosclerosis in the carotid vessels.


        22     Those studies are underway presently.




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1               Dr. Hering, do you have any


         2     comment?


         3               DR. SHERWIN:  How much does the


         4     LDL go up?


         5               DR. SHAPIRO:  Predominate changes


         6     been in cholesterol, and we followed the


         7     diabetes target guidelines for initiation of


         8     therapy.  When we initiate statin therapy,


         9     it reverses to normal in the vast majority


        10     of cases.


        11               DR. SHERWIN:  This is seen with


        12     other types of transplants, am I right?


        13               DR. SHAPIRO:  It is.  Go ahead,


        14     Dr. Harlan.


        15               DR. HARLAN:  I just have a couple


        16     comments on questions that were raised.  One


        17     is, two of our patients elected to


        18     discontinue immunosuppression.  One because


        19     of progressive renal insufficiency, despite


        20     no proteinuria prior to transplant, and


        21     despite normal creatinine clearance prior to


        22     transplant; another because of




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     Rapamyacin‑induced numimytis (?).  So we


         2     have seen the elevated creatinine despite


         3     normal kidney function as far as we could


         4     measure prior to transplant.  In both of the


         5     cases that elected to discontinue


         6     immunosuppression, we saw sensitization


         7     that's persisted.  So it's ‑‑


         8               DR. RAO:  Define "sensitization."


         9               DR. SHAPIRO:  Sensitization means


        10     that the recipient has learned to recognize


        11     donor tissue.  So that if those patients


        12     needed a transplant down the road, it could


        13     be more difficult to find a suitable donor


        14     for them.  So what we always, in obtaining


        15     informed consent, inform people that if it


        16     fails, they may not be just back at


        17     baseline, that it could be more difficult if


        18     they needed a transplant down the road.


        19               DR. RAO:  Thank you.


        20               DR. BURDICK:  Good morning, again.


        21     I'd like to start by just noting that


        22     there's been back and forth about exactly




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     what the material is that we're talking


         2     about and what it's going to be called.


         3     Whether it's a product, clearly has been


         4     established, it is.  I'd just like to


         5     emphasize that I think the important thing


         6     is we're all on the same page.  We want a


         7     treatment which will involve this entity


         8     that's been declared a product.


         9               But we want something that's


        10     effective and it's safe.  It's clearly going


        11     to be dominantly, I think, a public process,


        12     with very definitely the appropriate federal


        13     oversight.  So we don't want to let any


        14     particular name get in the way of that


        15     desire.


        16               Today, what I want to talk about


        17     is what is happening with the marvelous new


        18     promise that is as yet a promise, but it's


        19     coming closer, in terms of the actual


        20     treatment process which is being done


        21     through the OPTN that our division oversees


        22     in HRSA.




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1               Just to review, this is under the


         2     NOTA, the Organ Transplant Network,


         3     specified through the National Organ


         4     Transplant Act, and also through the Social


         5     Security Act.  An important point that we


         6     need to come back to is the prohibition


         7     against purchase or sale of transplantable


         8     organs.  The main arm in this in terms of


         9     the community is the voluntary process that


        10     the OPTN has underway with also the


        11     potential for CMS intervention for certified


        12     centers if centers do not participate


        13     appropriately.


        14               This is what the makeup of the


        15     transplant field in this country is at


        16     present.  You can see historically of


        17     course, kidney is the big one.  But there


        18     are many centers doing a small number of


        19     pancreas transplants, and 37 declared


        20     pancreas islet cell programs.  This has


        21     changed.  You've seen a more recent slide.


        22     There is no membership process of islet




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     programs at present in the OPTN.


         2               But the OPTN clearly, and


         3     therefore the community, clearly feels that


         4     this falls under the realm of the other


         5     things that are being done with organ


         6     transplantation.


         7               The KP committee that has members


         8     on it and which is very sensitive to issues


         9     in whole organ and islet cell transplant has


        10     this process underway.  In fact, recently


        11     issued for public comment their policies


        12     that are proposed, and those responses are


        13     now being viewed, and the board will meet


        14     again in November to think about this more.


        15               Let me just stop for just a second


        16     and mention that part of the OPTN process is


        17     that in order to list patients on the


        18     deceased donor list, and therefore receive


        19     organs, a program has a series of criteria


        20     they must be in compliance with, including


        21     membership, including professional staff


        22     that have had appropriate training and




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     background, and many other process things


         2     about the program.


         3               Then the member must be conformed


         4     to policy of the OPTN.  Finally, the


         5     institution's data are reviewed and members


         6     that fall out, that are not doing


         7     sufficiently well by the criteria


         8     established by the OPTN membership


         9     committee, are reviewed and process is taken


        10     as necessary if it's felt there are poor


        11     results that the OPTN wishes to provide


        12     penalties against.


        13               This is very a effective process


        14     in maintaining a situation in which organ


        15     transplants are used optimally in the


        16     country.


        17               So this is the process that is


        18     envisioned for islets as well.  So the rules


        19     would be that the hospital doing the islet


        20     transplant must be in a center approved for


        21     whole pancreas transplants.  As with


        22     everything else, data must be provided.




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382







         1     Remember, these data are national, complete,


         2     and reviewed twice a year.  So what is


         3     available to the community, and as an aside,


         4     to the FDA, is not a surrogate of some sort


         5     or another that is processed or other things


         6     for outcomes, but the outcomes.  It's the


         7     country's outcomes.


         8               What happens to the islets?  How


         9     they are going to be able to handle the


        10     actual implantation or the transplantation


        11     and the other issues that have been raised


        12     all must be clear.  All patients must be


        13     listed on the computer waiting list,


        14     centralized waiting list, with allocation


        15     rules that we'll talk about in a minute.


        16               OPTN members, and I'll stress that


        17     OPTN members, in order to participate in the


        18     process, that includes all organ procurement


        19     organizations and all transplanting


        20     programs, shall not provide organs to


        21     non‑member transplant centers.  Now, those


        22     issues are included here because by




              (202) 638‑2400     1‑800‑522‑2382    (703) 684‑2382