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       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@

         2

         3

         4               FOOD AND DRUG ADMINISTRATION

         5        CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

         6

         7

         8

         9               BIOLOGICAL RESPONSE MODIFIERS

        10                 ADVISORY COMMITTEE (BRMAC)

        11                         Meeting 36

        12                          DAY TWO

 

        13

 

        14

 

        15

 

        16

 

        17

 

        18

 

        19

 

        20

 

        21                   Gaithersburg, Maryland

 

        22                  Friday, October 10, 2003

 

 

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                                                             2

         1     PARTICIPANTS:

 

         2        BRMAC MEMBERS:

 

         3           MAHENDRA S. RAO, Acting Chair

                     National Institute on Aging

         4

                     JONATHAN S. ALLAM

         5           Southwest Foundation for Biomedical Research

 

         6           BRUCE R. BLAZAR

                     University of Minnesota

         7

                     DAVID M. HARLAN

         8           National Institute of Diabetes and Digestive

                     and Kidney Disease

         9

                     KATHERINE A. HIGH

        10           University of Pennsylvania

 

        11           JOANNE KURTZBERG

                     Duke University Medical Center

        12

                     ALISON F. LAWTON

        13           Genzyme Corporation

 

        14           RICHARD C. MULLIGAN

                     Harvard Medical School

        15

                     ANASTASIOS A. TSIATIS

        16           North Carolina State University

 

        17           ALICE J. WOLFSON

                     Wolfson & Schlichtmann

        18

                  TEMPORARY VOTING MEMBERS:

        19

                     JAMES F. CHILDRESS

        20           University of Virginia

 

        21           LYNNE L. LEVITSKY

                     Harvard Medical School

        22

 

 

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                                                             3

         1     PARTICIPANTS (CONT'D):

 

         2        TEMPORARY VOTING MEMBERS (CONT'D):

 

         3           ABBEY S. MEYERS

                     National Organization for Rare Disorders

         4

                     CAROLE B. MILLER

         5           St. Agnes Healthcare

 

         6           W. MICHAEL O'FALLON

                     Mayo Clinic

         7

                     DANIEL R. SALOMON

         8           The Scripps Research Institute

 

         9           ROBERT S. SHERWIN

                     Yale University School of Medicine

        10

                     JANET H. SILVERSTEIN

        11           University of Florida College of Medicine

 

        12        CONSULTANTS:

 

        13           JOHN J. O'NEIL JR.

                     LifeScan, Inc.

        14

                     CAMILLO RICORDI

        15           University of Miami School of Medicine

 

        16        GUESTS/GUEST SPEAKERS:

 

        17           BERNARD J. HERING

                     University of Minnesota

        18

                     JAMES SHAPIRO

        19           University of Alberta

 

        20           THOMAS L. EGGERMAN

                     National Institute of Diabetes and Digestive

        21           and Kidney Diseases

 

        22

 

 

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                                                             4

         1     PARTICIPANTS (CONT'D):

 

         2        GUESTS/GUEST SPEAKERS (CONT'D):

 

         3           JAMES BURDICK

                     Health Resources and

         4           Services Administration

 

         5           FRANCISCA AGBANYO

                     Health Canada

         6

                  FOOD & DRUG ADMINISTRATION (FDA) PARTICIPANTS:

         7

                     JESSE L. GOODMAN

         8           Center for Biologics Evaluation

                     and Research

         9

                     KATHRYN CARBONE

        10           Center for Biologics Evaluation

                     and Research

        11

                     RAJ PURI

        12           Center for Biologics Evaluation

                     and Research

        13

                     CAROLYN WILSON

        14           Center for Biologics Evaluation

                     and Research

        15

                     ANDREW BYRNES

        16           Center for Biologics Evaluation

                     and Research

        17

                     NANCY MARKOWITZ

        18           Center for Biologics Evaluation

                     and Research

        19

                     STEVEN BAUER

        20           Center for Biologics Evaluation

                     and Research

        21

 

        22

 

 

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                                                             5

         1     PARTICIPANTS (CONT'D):

 

         2        FDA PARTICIPANTS (CONT'D):

 

         3           AMY ROSENBERG

                     Center for Drug Evaluation

         4           and Research (CDER)

 

         5           EMILY SHACTER

                     Center for Drug Evaluation

         6           and Research

 

         7           GAIL DAPOLITO

                     Executive Secretary

         8           Center for Biologics Evaluation

                     and Research

         9

                     ROSANNA L. HARVEY

        10           Committee Management Specialist

                     Center for Biologics Evaluation

        11           and Research

 

        12        BRMAC #36 FDA PLANNING COMMITTEE MEMBERS:

 

        13           PHILIP NOGUCHI

                     Center for Biologics Evaluation

        14           and Research

 

        15           CYNTHIA RASK

                     Center for Biologics Evaluation

        16           and Research

 

        17           DARIN WEBER

                     Center for Biologics Evaluation

        18           and Research

 

        19           DWAINE RIEVES

                     Center for Biologics Evaluation

        20           and Research

 

        21           KEITH M. WONNACOTT

                     Center for Biologics Evaluation

        22           and Research

 

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                                                            6

         1     PARTICIPANTS (CONT'D):

 

         2        BRMAC #36 FDA PLANNING COMMITTEE MEMBERS

                  (CONT'D):

         3

                     NICHOLAS I. OBIRI

         4           Center for Biologics Evaluation

                     and Research

         5

                     RICHARD McFARLAND

         6

                     STEPHEN GRANT

         7

                     SUSAN LEIBENHAUT

         8

                     JOHN ELTERMANN JR.

         9

                     JOHN FINKBOHNER

        10

                     SARAH KIM

        11

                     SUSAN ELLENBERG

        12

                     GHANSYAM GUPTA

        13

                     ROBERT MISBIN

        14

 

        15                      C O N T E N T S

 

        16     AGENDA SESSION:                            PAGE

 

        17        Current Status of Clinical Islet           7

                  Transplantation

        18

                  Allocation of Pancreata for Whole         65

        19        Organ and Islet Transplantation

 

        20        Ethical Considerations in Allogeneic     115

                  Islet Transplantation

        21

                  Clinical Development of Islet Products   151

        22

                                *  *  *  *  *

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                                                             7

         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

 

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                                                             8

         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

 

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                                                             9

         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

 

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                                                             10

         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

 

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                                                             11

         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

 

 

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                                                             12

         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

 

 

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                                                             13

         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

 

 

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                                                             14

         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

 

 

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                                                             15

         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

 

 

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                                                             16

         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

 

 

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                                                             17

         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

 

 

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                                                             18

         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.

 

 

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                                                             19

         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

 

 

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                                                             20

         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

 

 

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         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

 

 

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         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.

 

 

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         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

 

 

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         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

 

 

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         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

 

 

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         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

 

 

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         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,

 

 

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         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.

 

 

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         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

 

 

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         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

 

 

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         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

 

 

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         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

 

 

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         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

 

 

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         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

 

 

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         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.

 

 

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         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

 

 

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         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

 

 

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         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

 

 

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         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,

 

 

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         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

 

 

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                                                             41

         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

 

 

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         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

 

 

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         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

 

 

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         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

 

 

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                                                             45

         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

 

 

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         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

 

 

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                                                             47

         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

 

 

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         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

 

 

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         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

 

 

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         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,

 

 

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         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

 

 

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         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

 

 

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         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

 

 

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                                                             54

         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

 

 

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                                                             55

         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

 

 

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         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

 

 

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                                                             57

         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

 

 

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         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

 

 

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                                                             59

         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

 

 

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                                                             60

         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

 

 

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                                                             61

         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

 

 

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         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

 

 

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                                                             63

         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.

 

 

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                                                             64

         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

 

 

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         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

 

 

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                                                             66

         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.

 

 

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                                                             67

         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

 

 

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                                                             68

         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

 

 

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                                                             69

         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.

 

 

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                                                             70

         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

 

 

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