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This transcript has not been edited or corrected, but appears as
received from the commercial transcribing service. Accordingly, the FDA
makes no representation to its accuracy

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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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1 implication, the islets in this regulatory

2 setting are being treated as organs.

3 At present, there are 164 islet

4 candidates listed. Now, this I\'m sure is

5 higher. Well, actually this is quite up to

6 date. It\'s interesting that there are 70 in

7 one institution in Canada, which says

8 something about the field at this point.

9 But it\'s also that you don\'t need very many

10 potential recipients of a given blood group

11 and you have enough potential recipients for

12 what donor comes along, because we\'re

13 already starting to see the tip of the

14 iceberg of the difference between supply and

15 demand, I think. As we said, there are a

16 little over 1,000 whole organ pancreas

17 transplants done per year in the U.S. now.

18 How to allocate the islets is

19 going to be undergoing evolution over some

20 years. I\'ll show you that going from a

21 situation in which only whole organ claims

22 get first priority to a mixture is what has

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1 been appealing and what is put out for

2 public comment. There is a concept within

3 the allocation rules, because this country

4 is very heterogenous in many ways, and

5 sometimes the standard rules across the

6 country might be improved in some way or

7 another by some local change or use of a

8 variance for that, so variances could be

9 applied to islet allocation.

10 Probably not terribly relevant for

11 this discussion, but there are variances

12 that are allowed for the purposes and under

13 the settings that are described here. But

14 at any rate, aside from such variances, the

15 candidates for a pancreas, and that will

16 include islets as this comes along at

17 present, are ranked by waiting time, highest

18 priority for whole pancreas. We try to

19 place the whole gland first.

20 If the pancreas cannot be placed

21 nationally, then it will be offered in a

22 similar way, locally, regionally, then

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1 nationally by waiting time, blood group, of

2 course, for clinical islet transplantation,

3 and finally clinical research, if either of

4 those can produce a home for the gland.

5 This is interesting in light of

6 some other stuff you\'ve seen today. But

7 mixing a blend of physiology and sort of

8 logistic fairness, the committee came up

9 with a proposal ‑‑ it\'s interesting,

10 PowerPoint turned a \"less than\" to a pair of

11 scissors. I\'m going to have to think about

12 this for a second.

13 I\'d like to know how to do that

14 intentionally. I\'m sorry I have to

15 remember; I think that\'s a less than. Okay,

16 that\'s a greater than, so this is a less

17 than. Donor age less than 50 years and BMI

18 less than 30 kg/m2. This is sort of the

19 general cutoff for centers using whole

20 pancreas for transplantation.

21 It involves a combination of the

22 issues that are really terribly complicating

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1 in whole organ transplantation and cause so

2 much trouble. It\'s one of the reasons

3 there\'s so much enthusiasm for something

4 different, that is the islets. Also, you

5 want a low BMI, because it is felt that if

6 there\'s a lot of fat deposition in the

7 gland, there is higher likelihood of

8 post‑transplant problems.

9 So in that case, it goes out for

10 whole pancreas with kidney or by itself. Or

11 combined solid organ islet, which has a

12 special case, often, say, a liver‑islet,

13 because it\'s a given patient who needs both

14 and there are some advantages to doing a

15 combined transplant in several settings,

16 it\'s been found. Then further pancreas and

17 then finally islet.

18 The important point is that if

19 those two criteria are not met; that is, if

20 the donor age is beyond the point of time

21 that would be optimal for use for whole

22 gland, or if the pancreas is fatty, it turns

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1 out that there is some enthusiasm that the

2 islet separation works better in this

3 setting. Now, if clearly here, Dr. Shapiro,

4 and Dr. Ricordi and others are clearly not

5 necessarily going to be in favor of this

6 down the road. So I think it will be a

7 tension between whole gland and islet

8 transplant for the moment, and that will be

9 an evolution. I mean, this is something

10 that needs to get sorted out. Changed,

11 removed, whatever.

12 But at any rate, this then goes

13 for first a local pancreas gland if

14 possible, because that\'s a particularly

15 quick and appropriate thing to do, but then

16 islet comes next. So the point is by basing

17 it on these mixture of things, a difference.

18 And this is what is out for public comment

19 and what will be thought about.

20 The OPTN feels strongly that the

21 kind of oversight that it\'s been providing,

22 and the way this is intertwined with its

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1 general mission and contractural purpose, it

2 means that there\'s going to be a problem

3 with non‑member institutions doing islet

4 transplants. Remember, it is a transplant

5 with the need for immunosuppression. Those

6 issues have already been brought up. This

7 is a natural way for the public and the

8 public health interest to best be served, is

9 to have it under this aegis.

10 There\'s also a concern about

11 research allocation resulting then in a

12 pancreas being used for clinical islet

13 transplantation, and that\'s something that

14 clearly the organization wishes to avoid.

15 And I\'m sure the FDA would be in sync

16 because of the process and quality control

17 issues that it would raise.

18 So they must be allocated through

19 the allocation system. Therefore, if a

20 pancreas is initially through that algorithm

21 I showed you allocated for research, but

22 then there\'s a desire to transplant the

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1 islets, let say the islets are separated and

2 they look great by all the criteria being

3 discussed; it has to be reallocated through

4 the OPTN system. At present, that holds

5 because member institutions are also members

6 for other reasons; that is, they have to

7 have a pancreas transplant program as well.

8 OPOs are obviously bound by this, so the

9 pancreas can\'t leave the OPO under other

10 circumstances at any rate.

11 But remember that the pancreas,

12 and by implication the islets, are allocated

13 to a specific patient. The allocation is

14 based on a set of issues, including how well

15 it\'s going to work and how fair the process

16 is. There is a concern about cost and

17 reimbursement with regard to the prohibition

18 against buying and selling organs. That is,

19 the NOTA Section 301, which is now in the

20 Criminal Code and is clearly a legal issue.

21 There are several things that we

22 can see are issues listed here. How to

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1 decide which way to tip the system; I think

2 as islet transplantation matures, that will

3 become a non‑issue if it matures in the way

4 we all hope. Information, program

5 expertise, these are the issues the OPTN is

6 dealing with.

7 So this is me, and I\'d like to

8 continue to be part of this discussion. I

9 think also Laura St. Martin and my bunch and

10 I both feel this is a very important thing

11 for us to continue to work with you about.

12 I should apologize. I have to leave before

13 the end of the morning for another meeting,

14 but you can get a hold of me for future

15 things.

16 Maybe one final sort of thought

17 about the fundamental issue, I think the use

18 of the term \"product\" is appropriate as long

19 as it doesn\'t interfere with the biology

20 that we\'re dealing with. In particular, as

21 this still represents in some ways an organ,

22 and if there is the issue of supply and

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1 demand that I would think might occur,

2 obviously the patients we\'ve seen generally

3 listed so far have been under these very

4 tight protocols, and a large, greatly

5 increased number of patients should be able

6 to benefit from this, then the allocation

7 will become probably as fierce as any of the

8 controversies that are at issue in organ

9 transplantation. And I think the OPTN,

10 under HRSA oversight, is the place for that

11 trouble to occur. So thanks for your

12 attention.

13 DR. RAO: Any questions from the

14 committee?

15 DR. RICORDI: I just have a couple

16 of comments. I was surprised actually to

17 see that it still stands, the fact that it

18 is proposed that islet transplant can be

19 performed only at centers that do pancreas

20 whole organ transplantation. I participated

21 in the initial discussion on this when I was

22 a member of the American Society of

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1 Transplant Surgeon Council. I think there

2 is no rationale at all, and actually would

3 be a major impediment to the progress of

4 islet transplantation, especially if you\'ve

5 seen in other chapter of the proposed rules

6 that even the marginal donors of age

7 above 50 or BMI over 30 have to be first

8 offered to the local whole organ pancreas

9 transplant programs.

10 In a way, that is a way to make

11 sure that you have a direct competition in

12 place whose expertise is not required at all

13 to perform an islet transplant. Because if

14 anything, you need a liver transplant.

15 Surgery on the islet don\'t go in the \-\-\--

16 process vascularized organ, and I think this

17 is really something that, if not horrifies

18 me, make me really think about the whole

19 process and the reason that there is this

20 constant attempt to keep islet

21 transplantation under the shade or underfoot

22 of pancreas transplant would be like to say

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1 that every democratic senator can be elected

2 only in a state where there is a republican

3 governor or vise versa, like as an approach.

4 The other comment is that the fact

5 that 70 patients are on the waiting list in

6 Canada and only 164 are on the waiting list

7 in the United States is related to the fact

8 that in United States, we are all under

9 INDs. So if I have a protocol with FDA that

10 allows me to transplant only 6 patients

11 or 12 patients, I cannot morally accept 200

12 patients on the waiting list when I know I

13 can only treat only 6 of them.

14 So we close recruitments, and this

15 is a limitation. If this procedure would be

16 approved in the United States, I\'m sure that

17 the number of patients on the waiting list

18 will be higher than those on pancreas

19 transplant lists.

20 MR. RAO: Your comments are

21 well‑taken. I\'m sure the FDA\'s taking heed

22 of those issues.

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1 MR. HERING: Dr. Burdick, I would

2 like to thank you for your superb

3 presentation. You really raised all the

4 important issues, including the very recent

5 discussion of the proposed modifications to

6 allocation policies.

7 If I may, I would just like to add

8 a few data to really illustrate the point

9 that we want to make. I think it is

10 important to consider timing of allocation.

11 We discussed yesterday that the single most

12 important factor is determining outcome of

13 islet isolation, and presumably

14 auto‑transplantation, are pancreas

15 procurement and also pancreas preservation.

16 The islet transplant community is

17 therefore very concerned that timing is

18 considered in allocation algorithms, to the

19 point that islet transplant programs are

20 often an opportunity to use what is

21 considered state of art and really maximize

22 utilization of current technology, so that

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1 really, we can maximize the effective use

2 off a very scarce resource.

3 Now if I then look at results, or

4 the pancreas disposition for diseased donors

5 recovered between 2000 and 2002 in the

6 United States, and I have the data here

7 available, there were 18,249 donors. Now,

8 donors with a BMI of 28 or higher, there

9 were some 5,600 donors. BMI 31 and higher,

10 there were 2,072 donors. Now, if I look at

11 this subgroup of donors that are overweight

12 or obese, 77 percent of those pancreases

13 from those donors were not recovered at all.

14 Those are perfectly suitable pancreases for

15 islet transplantation, but are considered

16 less appropriate for pancreas

17 transplantation.

18 I think the data actually support

19 that point. About 10 percent of donor

20 organs from this subgroup of donors were

21 used and recovered for pancreas

22 transplantation.

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1 So I think it is fair to say that

2 there is substantial underutilization of

3 organs from donors that are obese or

4 overweight. Those are perfect donors for

5 islet transplantation, because we have

6 documented over and over again that islet

7 yields are very high, and that we can

8 achieve very acceptable results after

9 transplantation.

10 So for this reason, we like to

11 propose a modification that would consider

12 timing of allocation, but would not limit

13 the use of those organs in the pancreas

14 transplant community. What we consider is

15 that allocation of those organs to a

16 pancreas transplant recipient should be

17 completed by four hours before incision is

18 made, so that if this pancreas is turned

19 down for medical reasons or other reasons by

20 pancreas transplant programs, that the offer

21 can be made to an islet transplant program

22 or to an islet transplant recipient so that

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1 we can really utilize this pancreas.

2 What happens in real life at this

3 point in time is that a lot of time is taken

4 to place this pancreas, and an islet

5 transplant program is very often if not

6 almost always informed about the

7 availability of this pancreas hours after

8 procurement has been completed. So this

9 pancreas can no longer be used.

10 So I think we could optimize

11 allocation, and without compromising the

12 ability of pancreas transplant programs to

13 use this pancreas, and really increasing the

14 availability to islet transplant patients

15 without really modifying the policies too

16 much. So we would like to make this point.

17 And I think the implications for islet

18 transplantation, islet transplant recipients

19 would be profound. But the implications for

20 pancreas transplant recipients would be

21 minimal.

22 DR. BURDICK: Well, thanks. You

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1 know, I\'m sure that I agree with the things

2 you\'re saying. The comment period for the

3 OPTN is closed, but if you haven\'t gotten

4 your message to them and want me to help get

5 that, I certainly would be glad for you to

6 get a hold of me. But I think for the FDA\'s

7 point of view, these issues will continue to

8 be hashed out. It\'s very much an evolution,

9 as I told you. This may very clearly not

10 fly, what has been put out so far; that\'s

11 fine.

12 But if as a product there\'s an

13 issue of ownership and there\'s a

14 possibility, as has happened over the

15 history of transplantation, that individual

16 centers that are fantastic and are doing

17 wonderfully but sort of grab it and start

18 doing things a bit on their own, and then

19 the community finds that they don\'t quite

20 think what\'s happening is fair, there\'s a

21 problem. That\'s why I think that there\'s a

22 place for this oversight.

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1 That will evolve and maybe the

2 islets will turn out to be clearly just a

3 product very different from a organ and this

4 will all evaporate, and that could work just

5 fine, too. I\'m just talking about what the

6 practical sort of societal issues might be.

7 That\'s all.

8 DR. RIEVES: I do have a question.

9 I didn\'t raise my hand though. Dr. Burdick,

10 this is a fascinating area, because as

11 everyone has mentioned, we\'re talking about

12 products. Islet products are unique

13 compared to drugs and biologic therapies in

14 many respects, but yet we have to follow our

15 regulatory standards. I want to be sure I

16 walk away with a clear message as things

17 stand right now. This is not necessarily a

18 request for comments as it directly applies

19 to FDA, because FDA does not generally take

20 cost considerations under review in

21 licensing products. But it has major

22 implications for our sponsors.

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1 If I understand correctly, HRSA

2 regards islets currently as organs.

3 Consequently, currently, the NOTA

4 regulations prohibit the purchase of islet

5 transplants, meaning conceptually, there is

6 not a marketable, in the traditional sense,

7 product, if I\'m understanding correctly.

8 Also somewhat unique to drugs and biologic

9 products, HRSA procedures somewhat regulate

10 or control or influence, if you will, of the

11 distribution of the product, getting at some

12 of the questions comments.

13 Am I correct in this

14 understanding? So our sponsors of islet

15 products have multiple guidances,

16 influences, perhaps regulations that they

17 have to comply with beyond FDA. Meaning

18 that they essentially do not have

19 \"marketable\" products in the same sense that

20 we think of marketable products. Their

21 distribution is somewhat controlled beyond

22 the extent that traditional biologic

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1 products are controlled. Could you comment

2 on that understanding?

3 DR. BURDICK: Two things. That\'s

4 precisely the issue that I\'ve been talking

5 about. You got it. Secondly, I have not

6 been part of the KP committee discussions

7 and the islet cell transplanters\' input and

8 so forth. I don\'t know how mature this is.

9 It may be that a sufficiently persuasive

10 argument against including it in the rubric

11 that I have described is going to be made or

12 has been made.

13 I think my point is that until

14 it\'s clear throughout the country, if you

15 will, that that point has been made and the

16 change is acceptable from the present

17 situation ‑‑ there is plenty of sentiment at

18 present that the islets are not typical

19 product in the way the FDA views a product,

20 and there are people here who can answer

21 more of what they\'re likely to be saying to

22 the OPTN and it\'s a process in evolution.

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1 DR. SALOMON: There\'s a lot of

2 stuff on the table right now, and obviously,

3 you don\'t want to hear me rattle on for 20

4 minutes on it. But I feel strongly about a

5 number of things here. Number one, I

6 strongly support what Bernhard has been

7 saying. Bernhard, Camillo, myself, Richard

8 Nazick sent a detailed proposal to the KP

9 committee in public response. That data

10 that Bernhard was referring to comes from

11 UNOS released data.

12 So at least it\'s the best you guys

13 have given us to go by. It was presented,

14 discussed, and the decision by the KP

15 committee was to disagree and continue to

16 say that still, it\'s still in priority to

17 whole organ programs.

18 The compromise, just to be clear,

19 that Bernhard articulated a few minutes ago

20 is something that\'s come subsequently

21 through discussions, and we\'ll try and go

22 back to the KP committee and get this done.

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1 But your support and your input in this

2 would be very important.

3 The second and the last thing I

4 want to get into is really important. That

5 is, this is exactly what I was talking about

6 yesterday. When I talked about one of the

7 complicating things about this whole field

8 right now is that you\'re in transplantation,

9 and then you\'re into this product and

10 manufacturer part, and then you\'re back into

11 transplantation.

12 A half a dozen different issues

13 that are on the table right now relate to

14 that. Number one, do you need a pancreas

15 program in order to do an islet program? I

16 think that\'s ridiculous. Do you need

17 skilled physicians who know how to take care

18 of transplant patients and use

19 immunosuppression? Absolutely.

20 Second issue, do you need to have

21 pancreas procurement and pancreas for islet

22 governed by the OPTN? I think you do,

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1 because I think right now at least, it\'s

2 really impossible for me to see a system

3 that works equitably when you still have

4 pancreas programs and islet programs that

5 doesn\'t interface seamlessly with the OPTNs.

6 So I totally agree with that point.

7 But lastly, here\'s again the

8 issue. The FDA has said this is a product,

9 we\'re going to deal with it, and the whole

10 field now is under this IND and all the

11 consequences of that. Okay, fine. These

12 guys have worked really hard. The field\'s

13 worked really hard to deal with that, and in

14 a constructive way, I think made tremendous

15 progress. However, the OPTN says no, we\'re

16 organs. The OPTN has to insist that this

17 organ, because if they say that it\'s tissue,

18 then they don\'t regulate it anymore. And I

19 just explained to you why the OPTN cannot

20 allow that.

21 So they\'re at an absolute

22 loggerhead. Then when we go to CMS and say,

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1 well, how much are you charging use to do a

2 whole organ so that we make islets out of

3 it? They go, well it\'s an organ, so you got

4 to pay \$18,000 to \$20,000 for it.

5 DR. RICORDI: Twenty‑seven.

6 DR. SALOMON: How much?

7 DR. RICORDI: 27,000.

8 DR. SALOMON: That\'s what you have

9 to pay in Miami.

10 DR. RICORDI: But that\'s not the

11 same.

12 DR. SALOMON: It\'s less expensive

13 to live in California. But seriously, he\'s

14 right. I\'m giving you a median range. We

15 looked at it and it goes from about \$18,000

16 to \$25,000. It\'s ridiculous, because when

17 we do a whole organ pancreas at San Diego,

18 microprogram would pay \$18,000 or \$20,000

19 for the pancreas. But it\'s a passthrough,

20 through our kidney aquisition fund, through

21 CMS.

22 As long as the OPO is charging us

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1 a reasonable amount of money and they\'re

2 under audit and it\'s all fair and I\'m on the

3 board and we can handle all that, it\'s no

4 problem. But when we want to think about

5 setting up an islet program, it\'s killing

6 us, because we don\'t get any funding for it.

7 What\'s happening is we then have

8 to go and get JDRF and NIH dollars that

9 should be going to support research and

10 advancing science; we have to go beg on our

11 knees to philanthropists who should be

12 moving science forward so we can buy \$18,000

13 organs. I mean, this is nonsense.

14 But when we go to CMS, they go,

15 you know, we don\'t know. It\'s organs. We

16 can\'t really change things. We don\'t have

17 time. We\'ve got lots of other things to

18 worry about.

19 So, I\'m done here, but this

20 obviously has got me going. The issue here

21 is if we want to complete the loop, all the

22 stakeholders have got to get their act

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1 together. I mean, I think the FDA\'s view of

2 this has been positive and appropriate. Not

3 everybody agrees with that, but I think it

4 has been. I think the OPTN absolutely has

5 got a point. I think CMS has got to get on

6 board. There\'s a whole lot of stakeholders

7 waiting for this to get sorted out.

8 MR. RAO: Before you get up, I

9 think this issue may be retreated by several

10 people and make their comments before you

11 respond.

12 DR. MULLIGAN: Actually, this does

13 not exactly involve this. I know how

14 powerfully important your organization is,

15 and it essentially controls the raw

16 materials for this whole activity.

17 In a sense, I would think that it

18 really controls the pace of the whole

19 development of the technology, and that\'s a

20 very, very powerful position to be in. So

21 I\'m curious. Could you tell us something

22 about the decision‑makers here. How are

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1 they picked, what kinds of people they are?

2 Because I would think that it could have a

3 tremendous impact. Very simply, if you have

4 people that like whole pancreases, but don\'t

5 like islets, you\'re going to have a very

6 different point of view and allocation. How

7 democratic is the process? How do they get

8 elected? How long do they sit there? Or

9 how much history is there in this whole

10 thing?

11 DR. RAO: Hold that question.

12 There are several people who requested to

13 ask questions, and I\'m going to ask them if

14 it\'s directly related, to do that right now

15 so that we can have a common response.

16 DR. KURTZBERG: I think that this

17 is an incredibly important issue. I agree

18 with everything that Dan said. I think this

19 goes beyond islet cells, and putting aside

20 the question of how you define something as

21 an organ or a tissue, which is confusing. I

22 think that the FDA needs a new category that

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1 isn\'t licensing, but that allows

2 authorization or sanctioning of a particular

3 therapy so that third‑party reimbursement

4 can go forward, but doesn\'t make it a

5 for‑profit business for selling organs.

6 That category doesn\'t exist right now.

7 But if there was a new kind of

8 designation that said islet cell

9 transplantation or whatever cellular therapy

10 product we\'re talking about, transplantation

11 is sanctioned and is recognized as standard

12 of care, but you don\'t make money on that

13 organ and it\'s not really a license product,

14 that would be a different designation, but

15 it would allow the third‑party pairs in CMS

16 or whoever to say that yes, this is part of

17 patient care and this should be reimbursed.

18 I think that\'s where the FDA has

19 to go with all of these cellular products so

20 that they don\'t become a business for

21 profit, but so that patient care can be

22 reimbursed.

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1 DR. RAO: Dr. Sherwin.

2 DR. SHERWIN: I\'m amazed. I\'ve

3 learned a lot today. This was very helpful,

4 because I had no sense, even though I was

5 present of the American Diabetes

6 Association, what was going on. What really

7 strikes me is that I suspect the people that

8 deal with this issue are the transplant

9 community. When you\'re dealing with

10 diabetes, the people that deal with the

11 patients are the diabetologists, and the

12 endocrinologists.

13 I think we have the best

14 perspective as to how to allocate organs for

15 our patients, and not surgeons who simply

16 treat the patient for a short period of time

17 and don\'t deal with the whole patient. So I

18 was absolutely struck by this situation. I

19 think it\'s a very unique situation.

20 We deal with patients over an

21 extended period of time, and we have to deal

22 with issues that I think are quite complex,

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1 and I think we have probably the best

2 perspective of how to deal with that. So I

3 would ask again, how you make your decisions

4 about who makes these decisions about

5 pancreas versus islet transplants?

6 DR. RAO: Dr. Eggerman. Is this

7 directly related to this whole issue right

8 now?

9 DR. EGGERMAN: Right. Just a

10 quick question in terms of what the basis

11 was of them making the designation of organ

12 versus tissue or cellular therapy; if this

13 was something in terms of established in

14 terms of regulation or was this just a

15 policy or what that was, because that

16 certainly addresses how it might be

17 addressed.

18 DR. RAO: Dr. Harlan, do you have

19 a specific comment to this?

20 DR. HARLAN: I do, and I wish to

21 support the comment that islets being

22 subservient to pancreas is problematic. I

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1 wish to support the comment from

2 Dr. Kurtzberg that thinking of a new way to

3 reimburse for this product is a very, I

4 think, fruitful avenue of investigation.

5 The specific point I wish to make is on I

6 think your penultimate slide, Dr. Burdick,

7 it said pancreas transplantation is now a

8 proven therapy. In this city, where the

9 famous quote is \"depends on what the

10 definition of \'is\' is\" was said, I would say

11 it depends on what your definition of

12 \"proof\" is.

13 We have an analysis that\'s been

14 discussed in professional circles that looks

15 at an end point of patient survival; looking

16 at patients listed for pancreas transplant,

17 those who get it, and those who don\'t. We

18 find that you\'re more likely to survive, if

19 you\'re listed for a pancreas transplant, so

20 you fill all the criteria that we\'ve heard

21 about, and you don\'t get the transplant over

22 a four‑year time interval, so long as kidney

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1 function is normal. So I\'m an equal

2 opportunity conservative observer of all

3 therapies.

4 I\'m fairly conservative in my

5 views of islet transplant, but I\'m equally

6 conservative in my views of pancreas

7 transplant. I think we have to at least

8 keep open the question of just how proven a

9 therapy it is, and echoing what Dr. Sherwin

10 said.

11 DR. RAO: Dr. Burdick, you now

12 have heard several comments directly related

13 to this.

14 DR. RICORDI: Can I make one last

15 one, very short? It\'s just that there is

16 currently no representation from active

17 islet transplant program on the

18 kidney‑pancreas committee when you refer

19 that this could have been discussed in that

20 occasion.

21 Also to express how my concern,

22 and I\'m sorry if I lose my traditional

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1 diplomacy at times, is that to give a very

2 defined example. We received an offer

3 for 51‑year old pancreas; with this rule has

4 to be offered before to whole organ pancreas

5 programs, and we arrived to the limit where

6 the pancreas surgeon was not doing the

7 procurement. He decides well, I decide when

8 I have visual confirmation tomorrow morning

9 when I get that if I use it, or if it can be

10 offered to islet.

11 That was clearly a wasted organ.

12 So this is just an example of how hundreds

13 of organs that could be valuable, not just

14 for transplantation but also for research

15 purposes. There is tons of diabetes

16 research depending on islets that are

17 distributed for research that are equally

18 important.

19 My anger or concern is that I want

20 to make every pancreas count, either for

21 clinical pancreas, clinical islet, or

22 research. But we can not accept as a

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1 community that hundreds of pancreases are

2 wasted because of lack of timing in the

3 location and these kind of lobbying battles.

4 DR. BURDICK: Thank you. The

5 biggest single block to this moving ahead

6 right now is not the board of directors,

7 it\'s not anybody\'s fault. It\'s just that

8 the field is very early and you have the

9 mass in terms of intellectual and

10 experiential activity here in the room

11 before you, and it\'s something that needs to

12 have more of an impact on the country than

13 it has.

14 Maybe I could go to Dr. Ricordi

15 first. I\'m not quite sure why there isn\'t

16 somebody who is in islet transplantation on

17 the KP committee, but it\'s certainly

18 something that HRSA will look into, I

19 promise. But it\'s not a surprise, because

20 this is happening fast and it\'s new.

21 I know from the work that you\'ve

22 been doing for many years that it doesn\'t

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1 seem like it\'s happening fast, but it has

2 not gotten out in the way that you\'ve

3 presented it.

4 Let me just go through a few other

5 things. I think that there are now data

6 that both whole organ transplantation and

7 islet transplantation do make a difference.

8 Exactly how much difference and how to

9 select patients and so forth are big issues.

10 There are so many problems in both of these

11 areas still at this point that it\'s hard to

12 deny Dr. Harlan\'s skepticism, and I agree

13 with that.

14 However, I think we should

15 consider them both proven therapies, with

16 the caveat that I said that if islets can be

17 made to work even nearly as well as whole

18 organ, and it looks like they\'re going to

19 be, they\'re far better as a therapeutic

20 approach.

21 Now, Dr. Salomon, we\'re going to

22 continue discussions. I pretty much agree

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1 with what he had to say. I actually

2 described yesterday somewhat about the board

3 of directors. Tell me if I have only a

4 minute left or something, because there are

5 a lot questions. I\'ll try to go through

6 this quickly.

7 For the last 20 years, there\'s

8 been a process that has been overseen

9 closely, with some friction and sparks, but

10 often things going very, very smoothly

11 between the government and the private

12 contractor. It is not a bunch of transplant

13 surgeons. It has about 50 percent

14 transplant professionals on the 40‑ or 50‑

15 member board of directors. The others

16 are ‑‑

17 DR. RAO: Is there anybody from

18 the diabetology or endocrinology?

19 DR. BURDICK: Well, let me address

20 that. The way the policies occur is through

21 a series of committees. KP has been talked

22 about this: Liver, intestine, there\'s

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1 cardiac. The cardiologists have a great

2 deal of input in the deliberations and the

3 issues that come to the thoracic transplant

4 committee. Diabetologists, nephrologists,

5 and others for the kidney‑pancreas.

6 Hepatologists for liver transplantation, and

7 in fact, the president of the board this

8 year is a hepatologist from the Mayo Clinic.

9 And I should say that this

10 represents 50 percent of the representation.

11 The others are ethicists. Dr. Childress can

12 tell you he\'s served in these committees:

13 patients, community representatives. The

14 community people now are there for three

15 years because of having a chance to sort of

16 get used to a lot of the technical things.

17 The other people are voted through

18 the regions in the country to be on

19 committees, and then as members of the

20 board, and they\'re there for two years. So

21 that\'s the structure.

22 There\'s a lot of care to the sort

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1 of heterogenous representation that I think

2 everybody would want. It\'s a very

3 responsible group that takes this very

4 seriously. I\'m not aware of sustained

5 attacks by anybody who\'s come in close

6 contact with this who would say it\'s not

7 working very well.

8 You asked about terminology.

9 \"Organ\" is actually in Stedman\'s Medical

10 Dictionary, \"a somewhat independent body

11 part that performs a special function.\" I

12 think there\'s nothing more intelligent I can

13 say than that. I\'ve talked about

14 Dr. Harlan\'s and Dr. Ricordi\'s.

15 DR. RAO: Can I ask Phil to

16 respond in particular also to what Joanne

17 Kurtzberg said.

18 DR. NOGUCHI: Yes, thank you.

19 Dr. Burdick, if I don\'t get a chance to

20 thank you before you leave today, we really

21 appreciate your presence and your courage

22 and being able to actually address all these

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1 issues.

2 Just parenthetically, I would just

3 have to say that what Dr. Burdick has gone

4 through here is typically what FDA goes

5 through on a continual basis, but very often

6 we\'re not even allowed to speak in return.

7 We have a lot of sympathy for all the points

8 being addressed here.

9 One of the things that I think

10 that this really does illustrate, and it is

11 a major reason why the BRMAC has been

12 constituted and will continue to be expanded

13 in its unique role in cell tissue and gene

14 therapy, is in fact that we are seeing an

15 intersection where many different interests

16 are coming together, where in fact, as those

17 of us who have had some interaction with

18 HRSA and with the UNOS system, as FDA has

19 always known about itself and UNOS knows

20 about itself, and HRSA knows about itself,

21 good‑minded people think about the same way.

22 We have different laws and regulations and

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1 restraints, but we by in large usually do

2 come out ultimately to similar types of

3 conclusions.

4 I wanted to address the issue of

5 product, because I\'ve been thinking about

6 that. There clearly is a whole industry

7 called blood banking, which is non‑profit,

8 which is not sold. You cannot buy blood,

9 but you pay for the services. It\'s a system

10 that has its own flaws. In a non‑profit

11 situation, no matter what happens, expenses

12 rise, and then how do you actually maintain

13 the quality? That\'s clearly a major, major

14 issue.

15 But we do have precedence where

16 with the concept of a product, nobody owns

17 blood, but it\'s given freely, and it\'s

18 distributed not freely, but with somewhat

19 minimal costs, and yet the impact on public

20 health is tremendous as well as some of the

21 unfortunate events that happen.

22 We do have actual experience in

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1 FDA in terms of reimbursement. There\'s a

2 whole class of products called medical

3 devices in which actually much of it is

4 reimbursed during the investigational stage.

5 That is not to say that we can automatically

6 extend this across all FDA‑regulated

7 products. However, I think there are those

8 of us within and without the agency who

9 would really like to explore that a little

10 bit further.

11 Some things, such as these which

12 cross from transplantation into cellular

13 products, ultimately gene therapy and other

14 things as well, clearly some form of

15 societal commitment to the actual process of

16 investigation is warranted, and how we get

17 there, again, is not a singular agency kind

18 of approach, but is dependent on all of us

19 here, and others who aren\'t here as well.

20 Just to say in terms of the issue

21 of multiple oversight or overlapping

22 oversight, Dan Salomon knows this well, as

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1 do others on the committee, when we talk

2 about gene therapy, we have additional

3 intersections with the National Institutes

4 of Health which have had very interesting

5 and sometimes stormy discussions, but again

6 at the end of the day, we do come out with

7 very similar approaches and opinions about

8 what has to be done.

9 So I think that is a clear message

10 for us at FDA to open and extend even more

11 our interactions with HRSA and with the

12 transplant community in general. I have

13 been at some of those UNOS meeting where in

14 fact the community participants have

15 ironically done what many of us at FDA would

16 like for many things is, well, why can\'t you

17 tell us what the outcomes are at each

18 individual centers so that we the patients

19 can judge better for ourselves where we

20 would like to go? There\'s been very

21 interesting discussions as to back and forth

22 about that.

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1 I think I\'ll just try to end here

2 to just say that this particular discussion

3 that we\'ve had, although I didn\'t quite

4 expect it would necessarily generate this

5 interaction, clearly, it has touched

6 everyone\'s passion for trying to make sure

7 that the right thing gets done.

8 If we have organs that aren\'t even

9 harvested but could literally save people\'s

10 lives, that\'s an issue that needs to be

11 worked on. This is not an FDA‑alone issue.

12 It\'s not a HRSA‑alone issue. Clearly, it is

13 all our issues, especially as Dr. Kurtzberg

14 keeps pointing out, where is the rest of

15 society to really commit to making these

16 things happen? This will cost money. This

17 will cost funding. This will cost

18 dedication and effort. It will cost making

19 new rules and regulations. None of which is

20 going to be easy given all the increased

21 responsibilities that we have.

22 But I think this is perhaps a good

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1 time for us to say this conversation will be

2 continued. I regret we can\'t continue too

3 much of it more here. But I think it is a

4 good segue right into Dr. Childress\'s next

5 discussion, which I think really gets back

6 at the whole heart of what we\'re talking

7 about: Is this an FDA‑regulated product.

8 No, this is a resource and this is one of

9 many resources that are now being developed

10 that needs to be delivered. It\'s our duty

11 here to help us get to that point.

12 I hope I\'ve at least answered a

13 couple questions and maybe pointed this to

14 some of the discussion for the rest of the

15 morning.

16 DR. KURTZBERG: I really

17 appreciate that response, but I have a

18 question. What process will take this

19 forward? I don\'t understand quite how to do

20 it. Does the government need new

21 legislation? Do these agencies have to come

22 together with CMS or whatever? How would

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1 that happen?

2 DR. SALOMON: I personally have

3 been talking to different people that

4 represent the different groups, FDA, JDRF,

5 NIH, NCRR, the Islet Consortium Group that I

6 participate in. The only thing that makes

7 sense to me is for some sort of

8 stakeholders\' meeting that brings together

9 the endocrinology community, the transplant

10 community, patient community, basically all

11 those who have a stake in this area, and

12 just reasonably sort through what are very

13 clear barriers.

14 As I\'ve tried to say, each of the

15 different pieces is okay by themselves and

16 internally consistent with the missions of

17 these groups. It\'s just that when you take

18 them altogether, you suddenly realize some

19 of the contradictions that are here. We

20 just need to get everyone together and say

21 here are a bunch of patients with a bad

22 disease, let\'s work it out.

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1 DR. KURTZBERG: It\'s more than

2 just this disease and these patients. It\'s

3 a policy that has to be established.

4 DR. RAO: I really wanted to

5 emphasize that, that it\'s really a policy,

6 which we might have to visit the same issue

7 many, many times depending on whether you

8 use stem cells or any other tissue. We look

9 at Parkinson\'s Disease, anything, and this

10 might be the sort of \-\-\-- so it would be

11 very worthwhile working out a good policy of

12 how people can talk together.

13 On that note, I\'ll ask

14 Dr. Childress for the next issue.

15 DR. CHILDRESS: Well, I think it\'s

16 a pleasure to be here. Let me start a

17 little different way than I planned to.

18 Aristotle once said that ethics and politics

19 have to be treated together. He did a book

20 on ethics and he did a book on politics, and

21 they were seen as basically part of the same

22 work.

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1 I think you heard a discussion

2 this morning that suggests how indeed ethics

3 is often imbedded in a larger discussion

4 about politics, by which I mean issues of

5 control.

6 We are seeing different frameworks

7 within government. We\'re also hearing a

8 discussion of different professional roles

9 and responsibilities in this regard. So my

10 thoughts about ethics today will put the

11 ethical considerations in the context of

12 this discussion rather than being an

13 abstract formulation.

14 I will step back from some of the

15 immediate discussions, offer up some general

16 points, and then come back in and illustrate

17 with some of the discussion we\'ve had today

18 and has gone on elsewhere.

19 Let me also say a word about

20 conflicts of interest. I was a vice chair

21 of the federal task force on organ

22 transplantation, which formulated the

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1 guidelines that ultimately became part of

2 the OPTN and the structure for the OPTN. I

3 served on the board of directors at UNOS in

4 the early years, and then subsequently on

5 the ethics committee.

6 But I have not been on the ethics

7 committee for the last, I don\'t know, three

8 or four years. I\'ve not been part of this

9 discussion at UNOS, and I\'ve only actually

10 followed it at some distance. So maybe

11 that\'s an appropriate type of background for

12 beginning this presentation.

13 Let me also note that we are, as

14 the discussion has indicated, in an

15 evolutionary situation. An evolutionary

16 situation in terms of the field of science;

17 does it work here in terms of the medicine

18 related to this arena in terms of isolation

19 of islet cells, et cetera.

20 But we\'re also in a evolution I

21 think in our conceptual frameworks. I think

22 we\'ve heard a bit of discussion about that

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1 today because of not only the competing, but

2 overlapping governmental frameworks, we also

3 have some contested and potentially

4 conflicting conceptual frameworks. In

5 particular, how we think about exactly what

6 it is we\'re dealing with.

7 So with that in mind, let me offer

8 a few comments about ethical analysis. I

9 think much of what we do in ethical analysis

10 does involve looking at general moral

11 considerations. Principle like benefitting

12 patients, not harming them; maximizing

13 welfare; what we call utility; respecting

14 autonomy; acting justly, et cetera.

15 Much of what goes on in ethical

16 analysis is trying to make these very broad

17 concepts more specific, because they are too

18 broad to give us very much guidance. So

19 when we talk about what does utility mean in

20 the context of medicine, in the context of

21 organ transplantation, then we have to make

22 it much more specific or assimilate for

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1 justice. These principle may come into some

2 conflict, or there at least may be tension,

3 so we at times have to try to balance them.

4 A lot of what I\'ve experienced in

5 the context of debates in UNOS about

6 allocation had to do with balancing

7 principle, trying to find some way to hold

8 onto all of them in the context of

9 developing allocation policies. Of course

10 central in this discussion are the

11 principles of justice and utility.

12 But this is not the only way we

13 engage in ethical analysis. Much of the

14 discussion that has gone on here quite

15 appropriately has basically appealed to

16 moral precedence or analogies. We have

17 settled, and it may not be all that settled,

18 moral judgments about certain kinds of

19 cases, and they provide relevant analogies

20 and we\'ll move into a new area or a rapidly

21 developing area.

22 For example, much of the

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1 discussion has preceded my reference to

2 policies toward and judgments about organ

3 transplants and what light they shed on a

4 discussion of islet transplantation. We\'ve

5 talked about various kinds of analogies.

6 Obviously, with solid organ transplantation,

7 bone marrow transplantation, blood products.

8 There\'s one we haven\'t really spent much

9 time talking about and might be useful, and

10 that\'s to think about the products that come

11 from bone and skin.

12 That\'s an area under the tissue

13 part that FDA, I believe, regulates in terms

14 of safety, but there are other

15 considerations that clearly arise there.

16 Of course, the interaction of

17 science and ethics is critical to this. I

18 think some of the arguments about islet

19 transplantation, about allocation, or about

20 donors, reflect if not scientifically based,

21 at least developing science, where things

22 may not be fully settled yet. Although

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1 clearly from what we\'ve heard from the three

2 major centers, a lot is settled, or really

3 strong evidence about a lot of directions.

4 Now, to think just a little bit

5 about justice and utility, two concepts I

6 suggested are very important in thinking

7 about. In particular, allocation, but more

8 broadly than that justice, giving each

9 person his or her due, what is due that

10 person. Again, since Aristotle, there\'s

11 been a recognition that treating people

12 justly at a very minimum on the formal

13 levels means treating equals equally and

14 similar cases in a similar way.

15 But obviously, there\'s a big

16 problem with that. As someone said of Vince

17 Lombardi, the late coach of the Redskins and

18 the Packers, he treated all of his players

19 equally, like dirt. You can have a form of

20 equality, but what\'s really critical are

21 what are the relevant similarities and how

22 should we respond to those similarities.

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1 Well, the material criteria of justice are

2 basically efforts to specify relevant

3 similarities and differences. When we\'re

4 thinking about patient selection, is need

5 the critical thing? Is the probability of

6 success critical? Is ability to pay

7 relevant, et cetera?

8 Now, utility basically means

9 maximizing welfare, and we\'re not here

10 talking about social utility, though that

11 might be part of the background. We\'re

12 really concentrating I think on medical

13 utility and trying to maximize the welfare

14 persons suffering from particular diseases.

15 But if we\'re trying to specify

16 medical utility, trying to give it some

17 concrete meaning, what would be most

18 important, again thinking about again

19 maximizing the welfare patient suffering

20 from a particular disease? Well, need

21 obviously is one consideration. Probability

22 of success is another.

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1 Now, there are difficulties

2 obviously in defining and assigning weights

3 to these criteria, whether we\'re talking

4 about research or the experimental phase, or

5 in actually established therapy. In

6 particular when we\'re talking about success,

7 we\'ve already heard a lot of discussion

8 about what should count as success, and

9 clearly there are degrees in relation to

10 islet transplantation.

11 We may set the standard in certain

12 way for a clinical trial and actually in a

13 different place for therapy, what would

14 count as effective therapy. So there are

15 difficulties, again, in defining and

16 assigning weights to these, but also,

17 there\'s a possible tension between them in

18 that urgency of need, at least in several

19 contexts of organ transplantation, may

20 reduce the probability of success. And how

21 one addresses both of those in relation to

22 each other then becomes a critical matter in

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1 trying to maximize welfare among patients

2 suffering from a particular disease.

3 It\'s already come up in our

4 discussion. There are issues of justice and

5 medical utility and allocation. One has to

6 do with established therapy versus

7 experimental therapy, as we\'re trying to

8 allocate, say, a pancreata which should have

9 priority, how do we go about setting the

10 standards of allocation. Also, we\'ve had

11 attention already to the question of the

12 number of organs per recipient, with islet

13 transplant recipients requiring sometimes

14 two, sometimes three organs in contrast to

15 one pancreas in the context of pancreatic

16 transplantation.

17 Now, this has been debated in

18 different ways in the organ allocation.

19 Clearly even in the UNOS criteria for

20 thinking about islet transplantation, if you

21 saw the priorities that were set, you did

22 have some combined organ transplants, and

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1 then there have been situations with some

2 recipients in the U.S. receiving as many as

3 four or five organs that could have been

4 assigned individually to other recipients.

5 So there is an important question

6 here about medical utility and justice,

7 about how many organs in fact one has a

8 right to. How far do the claims go? In

9 terms of medical utility, of maximizing

10 welfare among patients suffering from

11 diseases. You can see also that you might

12 maximize the welfare by spreading these

13 organs out, getting more people. But you

14 can see how that debate goes than in trying

15 to think through particular policies.

16 Now, time waiting has been

17 recognized as a non‑medical criterion of

18 justice that is different from medical

19 utility. It\'s often been used as a

20 tie‑breaker. It\'s received a certain weight

21 in organ transplantation policies in UNOS.

22 Again, often to break a tie.

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1 There are other issues of justice

2 and medical utility. Debates in particular

3 about other criteria. This is more broadly

4 in terms of organ transplantation. Some of

5 these do play a role in the context that

6 we\'re talking about. I mean, is it

7 appropriate to set an age limit? It may be

8 appropriate to do that in the context, for

9 example, of a clinic trial. When is it

10 appropriate to do that in the context of

11 therapy?

12 I might just say another word

13 about age. Sometimes that can enter into

14 the discussion of sort of as a social

15 utility consideration. I think we have to

16 be very cautious about that. But sometimes

17 it may enter in as an appropriate medical

18 indicator, as a surrogate for some other

19 things, but probably would then need to be

20 examined more carefully.

21 Ability to pay has come up as a

22 considerations in our discussions so far.

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1 Clearly the context in the U.S. is different

2 from the one in Canada. Even when we talk

3 about being eligible for third‑party

4 reimbursement, we still have to recognize

5 again the 45 million who are uninsured at

6 any one time in the United States, and in

7 any given year, the 20‑plus million who pass

8 through that group of 45 million.

9 The UNOS proposals, Jim Burdick

10 has nicely discussed already. So I\'ll just

11 simply touch on a couple points in relation

12 to them. There was here a recognition of a

13 need for a more uniformed system because of

14 the large number of variances that have been

15 granted by two OPOs for groups trying to

16 address islet transplantation.

17 The proposed big change has

18 already been discussed, and I won\'t go

19 through that. Jim discussed this and other

20 matters quite well. I\'ll would just note a

21 couple of other points.

22 After admission, the waiting list

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1 for islet transplants. Priority would be

2 set by waiting time alone in the proposal.

3 So there\'s elimination of HLA matching.

4 Elimination of statuses, non‑urgent and

5 urgent. I think this has been a problem

6 throughout organ transplantation, and where

7 much of, if there were concerns about

8 justice in the United States related to

9 access to organ transplants, actually much

10 of the concern arises to the level of the

11 admission to the waiting list. That\'s where

12 there\'s a lot more discretion.

13 Once the person\'s on the waiting

14 list, then the criteria that have been laid

15 out, defended publicly and developed with

16 public input, obviously with expertise being

17 primary, then those criteria have been in

18 operation. But the admission to waiting

19 lists has been a much more controversial

20 matter. And I would just note, and Jim may

21 want to speak to this ‑‑ he\'s already left

22 so he can\'t speak to it ‑‑ that I didn\'t see

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1 as much in the proposals addressing this.

2 The ownership question, the

3 question of property has been an important

4 part of our discussion. It\'s traditional

5 among legal philosophers to think about

6 property as having to do with a bundle of

7 rights of ownership. Some I\'ve seen list as

8 many as 20 or 25 different aspects of

9 ownership. They include right to use, to

10 exclude others from using, to transfer by

11 gift, transfer by sale, and so forth. But

12 there are many situations where we set

13 limits as a society on the exercise of

14 property rights or what will count as a

15 property right.

16 For example, it\'s my automobile,

17 but I can\'t go out and set it on fire in the

18 parking lot. There are certain things

19 society won\'t let me do. I can\'t destroy it

20 that way. In the U.S., we have, in the

21 National Organ Transplant Act, banned

22 transfer by sales. That came in in the

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1 mid‑1980s. Arguably, it was not illegal in

2 most states following the Uniform Anatomical

3 Gift Act to sell organs until the mid‑1980s,

4 when the National Organ Transplant Act was

5 passed.

6 Who owns donated organs? In cases

7 of directed donation, obviously, this is

8 being directed to a particular individual,

9 then the procurement and transplant team

10 exercise a trusteeship over those organs for

11 that particular individual unless the

12 original donor gives a different direction.

13 But most of the cadaveric or deceased organs

14 are now undirected donation.

15 The task force on organ

16 transplantation, as Jim Burdick mentioned

17 yesterday, offered a philosophical view that

18 we should think about donated organs, where

19 there hasn\'t been directed donation, as

20 belonging to the community. The

21 professionals involved in procurement and

22 transplantation are trustees or stewards of

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1 those donated organs for the public welfare.

2 Doing this for the public welfare

3 then brings into play both medical utility

4 and also justice. The criteria used for

5 allocating the organs should be set with

6 expert, but also public participation. The

7 criteria should be developed in public. So

8 the comments that have been offered now on

9 the most recent proposals have been public

10 comments and have included not only expert

11 opinion, but, broadly, public responses.

12 Now, I would just note that UNOS

13 in its proposal for allocation is also

14 offering perhaps an optimistic view that it

15 can expand the donor pool. We\'ve already

16 talked a bit about expanding in moving to

17 over 50 years old and a body mass index

18 over 30 in an effort to reduce the wastage

19 of pancreata.

20 As you\'ve already heard data about

21 how few are obtained even if the

22 individuals, in donating organs, did not

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1 exclude those, they\'re not obtained with the

2 frequency that should be the case. Then

3 there\'s also an interest in, and some

4 supposition about, possibly increasing

5 donation. Now, this has been a problem in

6 the United States, and this is probably in

7 much of the world, and that is how we can

8 increase the organs. Especially now as we

9 move into areas like islet transplantation;

10 we not only have the needs that are already

11 being unmet for organs, but also we need

12 more organs.

13 There are several different ways

14 that have been implemented or proposed for

15 obtaining organs. Express donation is the

16 one we use in the United States by the

17 individual while alive through a donor card,

18 or documented gift, or by the next of kin

19 after the individual\'s death.

20 We do have presumed donation for

21 corneas in at least a dozen states when the

22 bodies are under the auspices of the medical

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1 examiner\'s offices. These have been held to

2 be Constitutional by the Supreme Courts in

3 Georgia and Florida, and the U.S. Supreme

4 Court let them stand as well without an

5 explicit hearing. It\'s not clear whether

6 those really are presumed donations; that is

7 whether the silence really means that the

8 individuals were willing to have their

9 organs used for others, or whether the

10 individuals were silent because they didn\'t

11 know they had the option. In which case, it

12 may not be presumed donation but more like

13 routine salvaging, with the possibility of

14 opting out if you are aware that you have

15 that option.

16 Of course, Jim Burdick said we may

17 have to come back to the issue of sales and

18 purchases, which obviously many people

19 proposed as a way to deal with this

20 shortage, but as a way that been excluded in

21 the United States.

22 In conclusion, let me just note

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1 that I think that as we continue to reflect

2 on these areas, we have to think through the

3 broad general principles that are relevant

4 for our efforts here. In particular

5 thinking about allocation, I\'ve focused on

6 medical utility and on justice.

7 I think that there are also the

8 precedents, and part of what we\'re trying to

9 do in this discussion is see what will

10 really count as a precedent for our

11 reflection here. And that\'s in part

12 complicated by virtue of the governmental

13 and professional roles involved. But it\'s

14 also complicated because actually, the way

15 we approach a particular area like organ

16 transplantation, and then how islet

17 transplantation came in, we do transfer

18 concepts and we bring new activities under

19 those concepts, and this is one where I

20 think it is appropriate to have a good broad

21 debate about how best we can understand

22 what\'s going on.

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1 There\'s still developments in

2 science that are occurring that will

3 obviously will have an impact on the

4 relevant ethical judgments.

5 In terms of the competing

6 concepts, I would just note, and Phil nicely

7 focused, on some of the issues in blood.

8 Selling blood is still legal, but we don\'t

9 use it as a practice. But even when it was

10 used as a practice, it\'s interesting that

11 there was an effort to keep it from being

12 viewed as a product in a strict sense.

13 So a court opinion addressed the

14 issue of how we should think about liability

15 where the blood ends up being bad. The

16 court held that this is not a matter of

17 product liability, but rather the provision

18 of blood is a service. We do have

19 inconsistences in the way we go about

20 approaching things, and I think that what

21 we\'re trying to do, as has already been

22 suggested, is find a way that we can

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1 adequately address the critical and

2 important patient needs here. And I would

3 emphasize those under medical utility and

4 justice, in a way that address the kinds of

5 constraints and limits as well as directions

6 that are provided by our governmental and

7 professional roles and responsibilities.

8 Thank you very much.

9 DR. RAO: Thank you,

10 Dr. Childress.

11 DR. MEYERS: I think the longer I

12 hang around the government, the more insane

13 I get. The FDA is funded not by a health

14 subcommittee in Congress, but by the

15 Agriculture Committee, because 100 years

16 ago, when it started, it regulated food,

17 because many people were getting sick from

18 food.

19 So 100 years later, you still have

20 to talk to the Agriculture Appropriations

21 Committee about funding for the FDA. Now,

22 it turns out that an egg in a shell is

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1 regulated by the Department of Agriculture,

2 but as soon as you crack the egg open, the

3 FDA regulates it. That\'s insanity.

4 The same thing is basically

5 happening here, because the FDA wants to

6 regulate the islet, but it can\'t regulate

7 the whole pancreas. It doesn\'t make any

8 sense to me.

9 If these people behind me were

10 developing a drug for diabetes, the FDA

11 would say you have to study it on 2,000

12 to 3,000 people. You could not even bring

13 it to the FDA for approval without a huge

14 clinical trial. Yet we\'re talking here

15 about a maximum of 300 people in the world

16 who\'ve undergone this procedure. So I\'m

17 wondering if you think it\'s ethical to say

18 well, this is a new very interesting

19 technology, and therefore, we can bend the

20 rules or make a new set of rules for this

21 technology; allow something through with

22 such a small amount of clinical data.

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1 DR. CHILDRESS: I\'m clearly going

2 to turn that question over to someone else.

3 But I would just say that as I understand

4 it, our task here is not to bend those

5 rules, but actually to do one very specific

6 small things. I\'ll ask Phil to respond to

7 that.

8 DR. RAO: I\'ll ask you to hold

9 for ‑‑

10 DR. CHILDRESS: Okay.

11 DR. KURTZBERG: I had a different

12 question. You alluded to the fact in

13 allocation that ability to pay was

14 important, and that there are 45 million

15 uninsured Americans. But this goes beyond

16 that, because many of the insured Americans

17 will not have this procedure approved by

18 their insurance company because it is

19 \"experimental.\" So that\'s a much bigger

20 issue in the transplantation and cellular

21 therapies field.

22 MR. CHILDRESS: I quite agree.

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1 But my point is that when we\'re thinking

2 about issues of justice, fairness, and

3 equity in allocation, we need to keep in

4 mind that sort of all these circles, and who

5 gets in and who gets out. I quite agree

6 with the point you\'re making here though.

7 DR. NOGUCHI: To respond to

8 Abbey\'s concern here, in no way do I think

9 that we\'re asking, nor would we ever be

10 asking, for bending of the rules, because

11 the rules have based on well over 100 years

12 of conflict throughout this nation and

13 people have died because of them, and have

14 led to the implementation of these rules.

15 What we are saying is that in the

16 very broadest sense, the Food, Drug and

17 Cosmetic Act gives us authority to regulate

18 articles intended to affect the structure

19 and function of a body, its amelioration,

20 prevention, et cetera, disease, for a

21 specified indication. I think that is the

22 key; that there are many components to this.

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1 We can approve that which works for a very

2 specific thing or we can improve things for

3 broader indication.

4 In the case of vaccination, we

5 approve it to prevent disease in literally

6 every child that goes to school in this

7 country. Those are all part of the same

8 rules. We do not bend the rules for any of

9 them. But we are very specific in requiring

10 that when something is approved by the FDA,

11 that it works in the intended indication,

12 that it can be made in a good fashion, such

13 that the practicing physician can take heed

14 and say I expect that this will do the

15 intended effect.

16 We all know that each effective

17 therapy also has adverse events. But I

18 don\'t see that we are in any way bending any

19 rules. We are exploring the edges of our

20 authority. We are asking the questions of

21 does this make sense, or does this not make

22 sense. Dr. Childress has illustrated to us

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1 very broad basic ethical concepts which are

2 inherit in everything that we discussed.

3 But I assure you, Abbey, we are not going to

4 be bending rules.

5 DR. RAO: Did you have a comment?

6 DR. HARLAN: Yes. I\'d like to

7 comment on one bullet of one slide that said

8 part of the ethical consideration is

9 comparing existing therapies with

10 experimental therapies. That\'s the point

11 that for Type 1 diabetes over the last 20

12 years, and perhaps Dr. Sherwin would

13 comment, the prognosis for this disease has

14 clinically, significantly, statistically

15 significantly, and quite dramatically

16 improved.

17 So that as we consider

18 less‑established therapies in the ethics of

19 this, we have to consider the fact that this

20 is not a disease like x‑links (?) skid, or

21 liver failure, or heart failure. As bad as

22 it is, and I will with God as my witness say

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1 there\'s nobody in this room that wants the

2 cure of the disease more than I do, but it

3 is a disease that is imminently treatable

4 with a excellent long‑term prognosis now

5 much better than it was even 20 years ago.

6 That\'s statistically documented.

7 DR. CHILDRESS: We do have

8 justification for going forth with clinical

9 trials. I assume you\'re not disputing that.

10 It may be important to have options open to

11 people who may find if there is something

12 that could be successful, that could in

13 terms of their quality of live, et cetera,

14 make a difference.

15 DR. RICORDI: Yes. As good as

16 these treatments are, there are still

17 over 1,000 people dying everyday from

18 diabetes, and the subgroups that we are

19 addressing are clearly the higher risk. So

20 I think that is an established point.

21 By my comment was that I think

22 there is a common misconception that when

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1 you use more than one donor for islet

2 transplant, you\'re wasting precious organs

3 that could have cured individual patients

4 through organ transplantation. Because in

5 fact, this is done with organs that are

6 discarded that are suboptimal.

7 This is an argument that is

8 advanced by pancreas transplant surgeons

9 generally that is becoming common sense a

10 way to \-\-\-- islets is for organs, or two or

11 three, or one and half. When instead the

12 retransplant rate in pancreas

13 transplantation reaches 25 percent; that is

14 done with perfectly good first choice, first

15 pick organs. So I think that is one thing

16 to consider.

17 DR. CHILDRESS: Can I respond? I

18 very much agree with that. Certainly the

19 UNOS criteria that are being proposed are an

20 effort basically to do that, and one could

21 debate then whether specific criteria

22 actually do exactly what they\'re after,

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1 because in the U.S., we obviously have

2 complications of the local, regional,

3 national, and a lot of other things play

4 into this. But certainly the way the

5 criteria have developed, they are really an

6 effort to deal with and to incorporate now

7 organs that would not have been otherwise

8 used, and to make them primary in the

9 allocation process.

10 DR. RICORDI: A proposal that I

11 advanced in discussions with Salomon and

12 others is that you can establish some kind

13 of equal distribution in a small subgroup of

14 donors that are not generally used for

15 pancreas for the first pancreas. But then

16 if you need a supplemental dose to take care

17 of the last six units of insulin, you can

18 use an organ that wouldn\'t be used for organ

19 transplant. That would be much more

20 acceptable, I believe.

21 DR. CHILDRESS: Right, right.

22 DR. SALOMON: I think that has to

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1 amplified. I mean, the data you\'ve heard

2 today shows that conservatively, 70 percent

3 of pancreas organs every year today are not

4 being used. So the premise that there is a

5 large number of pancreata that would not be

6 used for anyone that could be used for

7 supplemental transplants is perfectly borne

8 out by the data. So really what we are

9 talking about is competing fairly for the

10 good pancreata for the first transplant.

11 DR. CHILDRESS: I would just note

12 on that, that that figure goes up depending

13 on the age group, too. The age group of the

14 potential donor. It\'s about 62 percent

15 overall not obtained, and then as you move

16 in the age group, it goes higher.

17 DR. SALOMON: Just to reiterate

18 what Bernhard told you, if you take the BMI

19 of 28 or greater, the statistics are that

20 less than 10 percent of those are taken.

21 That means 90 percent are not used. If you

22 go to 30 or greater, it\'s 97 percent are not

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1 taken.

2 DR. RICORDI: Moreover, if you

3 count the pancreases or the number of

4 recipients that can be done under INDs, for

5 islet transplantations, your counting is

6 between 6 and 12, or maybe 20. So this is

7 out of the 6,000 possible donors. It\'s much

8 more ethically difficult to accept that if

9 you have these few patients on which you can

10 test in your therapy, you impose them to

11 perform that with suboptimal or bad

12 pancreases. That is what you are trying to

13 address.

14 DR. MULLIGAN: Yes, from an

15 ethical point, this issue of allocating

16 pancreases for either organ transplantation

17 versus islet cells, is there a case that

18 this composition as a group that makes

19 decisions ought to be looked at in more

20 detail? I mean, you made some comments

21 about the sense that the community owns

22 these things. Seems to me these are

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1 critically important decisions.

2 DR. CHILDRESS: This I think picks

3 up a point that was made earlier. I have

4 not looked at the current composition of

5 UNOS. You did hear a few comments from Jim

6 Burdick, UNOS\'s board of directors. But

7 then there are also the committees. The

8 committees play a very, very important role.

9 And you don\'t have to member of the board of

10 directors to be on the committees. So there

11 are different layers of development.

12 Given the size of the board of

13 directors, often a very carefully

14 thought‑out subcommittee report to a

15 committee, and then the committee report to

16 the board of directors will be adopted if it

17 seems to be plausible. So there are the

18 different levels of participation. I\'ve not

19 looked at the board composition or the

20 committee composition for our purposes today

21 to be able to make some judgment.

22 But I think the point that\'s been

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1 made and I think Jim Burdick heard it as

2 well, to go back and look into this and make

3 sure ‑‑ and the reason you want to make sure

4 that you have representation is you want to

5 make sure that all the relevant concerns get

6 identified and adequately addressed.

7 DR. O\'FALLON: I presume it\'s true

8 for all organ transplant situations that we

9 recognize that there aren\'t enough organs

10 for the patients that require the organs.

11 Clearly, the group that you have

12 participated in for these years must have

13 had some very serious ethical discussions

14 regarding this matter. I realize you

15 presented some of these points, but how do

16 we move forward? This seems like to me at

17 times almost an impossible ethical dilemma

18 to address.

19 DR. CHILDRESS: You\'re approaching

20 it on the procurement side, the shortage

21 scarcity generally. UNOS is under contract;

22 the organ procurement and transplantation

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1 network. Much of the discussion we\'ve had

2 focuses on the allocation issues, because

3 that\'s clearly a set of issues that will

4 arise when you have situation of scarcity.

5 But then you\'re quite right, and I just

6 mentioned a couple of points in passing that

7 if you can increase the available supply,

8 then obviously we need to take steps to do

9 so.

10 Interestingly, the proposals over

11 the last 15 years, ranging from required

12 requests to routine referral, to this, that,

13 or the other, have actually only modestly

14 increased the supply of cadaveric or

15 deceased organs. We in the United States

16 have moved much more rapidly toward the use

17 of living donors. Now we have more living

18 donors than we have cadaveric donors; that

19 is acts of donation. Clearly you get from

20 the cadaver many more organs.

21 I have just listed some of the

22 options in terms of structures or modes of

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1 transfer. I guess the big question is, I

2 think we\'re at the point of keeping

3 expressed donation as the model for the

4 foreseeable future. It\'s very difficult to

5 find effective ways to increase that. Now,

6 if we\'re talking about organs for brain‑dead

7 donors, we only have about 12,000 to 13,000

8 of those each year in the United States.

9 So from one standpoint, we may not

10 be doing that badly, getting about half of

11 those. From another standpoint, 50 percent

12 lost to the possibility of benefitting

13 others is a serious problem.

14 DR. RAO: I think there were

15 several issues raised. It\'s something which

16 is sort of awkward in the sense that it\'s

17 something which is not directly under the

18 control of the FDA even if it was regulated.

19 This is this whole process of allocation.

20 But I want to make sure that we

21 get the issues and allocation clear, in my

22 head at least. There\'s an issue of a level

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1 playing field in the sense of how pancreata

2 are allocated. Whether the process of islet

3 transplantation or isolation should be done

4 in a center which also does whole pancreas

5 transplantation; whether one should extend

6 the isolation process so that we can also

7 harvest pancreata or encourage in some

8 fashion harvesting pancreata thick tissue

9 from people with a higher BMI, which would

10 not normally be considered optimal for

11 pancreatic transplantation.

12 And a whole issue in addition is

13 how does one conform to certain sets of

14 standards in terms of getting reimbursement,

15 working with the OPTN as tissue so that

16 there is an appropriate mechanism for being

17 able to perform the whole process in a

18 reasonable way. Did that in some sense

19 capture most issues that have been raised in

20 this discussion?

21 DR. RIEVES: Thanks for your

22 patience this morning. We have not had a

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1 break, so it does take a great deal of

2 patience to go through this. My name is

3 Dwaine Rieves. I\'m going to somewhat shift

4 the gears. We\'ve had a very interesting

5 discussion that\'s touched on the complexity

6 of oversight, of cellular products.

7 We\'ve touched on policy issues.

8 We\'ve recognized a number of problems that

9 our sponsors and the governmental agencies

10 are going to have to deal with. What we\'re

11 hoping to do though from here on out in our

12 discussion is talk about the clinical

13 science regardless of the policy, regardless

14 of many other issues, the clinical science

15 is proceeding, and is going to continue

16 proceeding.

17 What we want to be confident of is

18 that our sponsors, our investigators, who

19 are conducting this clinical science are

20 performing their science in a manner that

21 FDA, if need be, can verify the results and

22 can interpret the data. So from here on

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1 out, we hope to obtain some feedback about

2 the realities, the tangibles, with respect

3 to clinical testing of islet products.

4 This talk\'s going to brief, and

5 perhaps it\'s old news to many people here in

6 this room, but I think it\'s important that

7 we understand where FDA is coming from and

8 the principle that we apply to evaluating

9 clinical data. In my talk, I\'m first going

10 to talk about the purpose, go over the

11 regulatory background, and briefly touch on

12 the questions.

13 The purpose of our discussion as I

14 had mentioned is to obtain insight,

15 perceptions, thoughts. We want you to put

16 on your thinking cap. Perhaps give us

17 recommendations with respect to two aspects:

18 Clinical study design issues. If a sponsor

19 comes to us with what the sponsor is

20 proposing is \"a pivotal study or a

21 definitive study, a phase three study,\" we

22 need to be able to give them some feedback.

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1 We\'re looking to the committee to

2 express opinions on certain aspects of

3 clinical study design, such as endpoints,

4 such as the type of design control, that

5 sort of thing.

6 As you\'ve noted, there have been

7 clinical data collected. The purpose of our

8 discussion this afternoon is not actually to

9 evaluate that clinical data. That clinical

10 data was presented largely as to provide an

11 overview, an example of what\'s being

12 collected in the field. But the clinical

13 data are being collected, and FDA will

14 probably have to evaluate that data. So

15 your feedback that we get today will be very

16 useful in interpreting those clinical data.

17 The bottom line with respect to

18 licensure. FDA examines two major items.

19 The first is those clinical data must be

20 sufficient for the agency, the advisors, the

21 many people who provide input into the

22 licensure decision, to assess the

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1 risk/benefit of the product.

2 Secondly, and perhaps just as

3 importantly for our sponsors to remember in

4 the clinical development of their product,

5 those clinical studies must be designed and

6 conducted in a manner such that the sponsor

7 and the agency can work together to describe

8 the use of that product in a label, such

9 that we\'re able to tell the practitioner

10 what types of immunosuppressants, for

11 example; the other concomitant medications,

12 such that that claim has a reasonable

13 likelihood of being reproduced if the

14 practitioner actually uses that product in a

15 manner similar to its use in the pre‑market

16 clinical studies.

17 Everything I\'m saying is coming

18 from a guidance document, or multiple

19 guidance documents actually. If you go to

20 the FDA website, www.fda.gov/cber in

21 particular in the reading room, and look for

22 guidance documents, you\'ll find multiple.

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1 Here, I\'m citing two of perhaps

2 the most important guidance documents with

3 respect to clinical data gathering with

4 prospects of obtaining licensure.

5 The first one is the guidance

6 called, \"Guidance for Industry: Providing

7 Clinical Evidence of Effectiveness for Human

8 Drugs and Biological Products.\" That\'s

9 important, because as you heard yesterday,

10 at the current time, islet products are

11 regulated both as biologic products and also

12 as human drugs. Consequently, the Public

13 Health Service Act applies to it; the Food,

14 Drug and Cosmetic Act applies to these

15 products.

16 The second guidance is, \"Guidance

17 for Industry: Choice of Control Group and

18 Related Issues in Clinical Trials.\" The

19 last bullet on this slide highlights another

20 guidance document that\'s actually relatively

21 new, and is very useful for sponsors who

22 want to obtain \"binding\" feedback from the

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1 agency.

2 This guidance document provides a

3 description of the process whereby a sponsor

4 can submit a clinical protocol to the agency

5 and the agency is under a timeline, 45 days,

6 to provide the sponsor feedback with respect

7 to whether that protocol for that study will

8 be sufficient to provide substantial

9 evidence of efficacy for the product. Those

10 comments, if the FDA determines that that

11 study is acceptable, are binding upon the

12 agency.

13 So two major aspects to clinical

14 development are products, from an FDA

15 regulatory standpoint, risk/benefit analysis

16 and the ability to write a label.

17 The next several slides concern

18 the risk/benefit assessment. A dichotomous

19 concern here. One is obviously safety, but

20 I put substantial evidence of effectiveness

21 at the top of the list, because that\'s

22 usually the greatest challenge for our

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1 sponsors in developing their products,

2 because obviously, a placebo is usually

3 safe. The challenge comes in in proving

4 that a product is not a placebo, it actually

5 does something. So it\'s providing this

6 \"substantial evidence of effectiveness\" that

7 is so important. This terms comes directly

8 from the Food, Drug and Cosmetic Act. It\'s

9 a very carefully chosen choice of words, as

10 we\'ll see.

11 The Act, as well as our

12 regulations, say that this substantial

13 evidence of effectiveness must come from

14 \"adequate and well‑controlled

15 investigations.\" Now, the risk aspect of

16 this, the safety aspect, the clinical data

17 that go into safety determinations, comes

18 not only from adequate and well‑controlled

19 investigations, but it actually comes from

20 the totality of the clinical database. It

21 comes from the exploratory investigations

22 leading up to what is commonly called the

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1 pivotal clinical studies, or what we call

2 adequate and well‑controlled investigations.

3 The next few slides explore the

4 substantial evidence of effectiveness.

5 Expectation. What defines substantial

6 evidence of effectiveness? It\'s an

7 interesting choice of words. \"Substantial.\"

8 I guess whoever wrote that law could have

9 chosen \"reasonable,\" for example. They

10 could have chosen \"any evidence.\" They

11 could have chosen \"some,\" but they didn\'t.

12 They choose \"substantial.\"

13 So to address that question of

14 what substantial means, the FDA constructed

15 the substantial evidence of effectiveness

16 document. At the core of that document is

17 the take‑home message that efficacy or

18 effectiveness is determined from independent

19 clinical studies; meaning that a clinical

20 benefit is reproduced in an adequate and

21 well‑controlled study.

22 You noticed I\'ve underlined the

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1 \"s\" here. It\'s a plural. Independent

2 substantiation of findings, meaning more

3 than one adequate and well‑controlled

4 investigation assessing the efficacy of the

5 product. However, if you go to that

6 guidance document, and this is very

7 important for perhaps some of the potential

8 indications that could be constructed from

9 the use of islet products, as well as for

10 many other unusual rare diseases, there are

11 exceptions.

12 The guidance document goes into

13 much greater detail than what I\'m touching

14 on here. I\'m only hitting the highlights.

15 The guidance document provides a very

16 notable exception. When a single study may

17 be regarded as providing substantial

18 evidence of effectiveness. I\'m going to

19 highlight what that guidance document cites

20 as one example. There are other examples.

21 But the guidance document says a single

22 study maybe considered sufficient when that

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1 study shows a clinically meaningful affect

2 on mortality, irreversible morbidity or

3 prevention of a disease with a potentially

4 serious outcome, and when confirmation of

5 that outcome in a second study is

6 impossible. The implication being that it\'s

7 ethically impossible to conduct an

8 additional clinical study.

9 The guidance document provides

10 what are called characteristics of a single

11 study. The example from the guidance

12 document is large multicenter studies, large

13 sample size, multiple centers involved in

14 the clinical study; the single study shows

15 consistent findings in subgroups of the

16 overall population database; there are

17 consistent findings in multiple endpoints,

18 secondary, tertiary type endpoints; the

19 efficacy outcomes are statistically very

20 persuasive. The document notes that none of

21 these \"characteristics\" are determinative.

22 For example, having simply a large

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1 sample size doesn\'t tacitly mean that that

2 study will be sufficient. The document

3 emphasizes that the determiner is somewhat

4 more subjective, that the results from that

5 clinical studying in the proposed clinical

6 indication are strongly persuasive.

7 With respect to substantial

8 evidence of effectiveness, that information

9 must come from adequate and well‑controlled

10 studies. So the next few slides look at the

11 definitions of \"adequate and

12 well‑controlled.\" Here, I\'ve highlighted

13 what our regulations denote as the major

14 characteristics of \"an adequate\" clinical

15 study. I group it into three p\'s, for

16 example.

17 The first p refers to the product.

18 Somewhat we touched on the importance of

19 this yesterday. For these adequate and

20 well‑controlled investigations, the product

21 must be manufactured at a point such that

22 the data are interpretable, meaning that

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1 product is almost the same product that will

2 be distributed post‑licensure.

3 The study agent needs to be

4 standardized for identity, strength,

5 quality, purity and dosage form; language

6 that\'s applicable to drugs interpreted as

7 safety, purity, potency. The other \"p\"

8 applies to the protocol, the prospective

9 nature of the clinical studies.

10 The adequate clinical study needs

11 an acceptable study design in which the

12 protocol sufficiently describes the dose,

13 the evaluations, the endpoint, analyses.

14 There are multiple other components of an

15 acceptable clinical protocol.

16 Finally, how the clinical study\'s

17 actually conducted. The performance of the

18 clinical study, such that the clinical study

19 needs to be performed in a manner consistent

20 with good clinical practice such that the

21 data are verifiable. When it comes time for

22 licensure, FDA can send out inspectors if

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1 need to be to look at the source documents,

2 the hospital records; can look at the case

3 report forms; can check the case report

4 tabulations and the statements that are

5 actually submitted to the agency. And that

6 we can cross‑check all that information to

7 make sure there are not transcription errors

8 for example, the wrong numbers plugged into

9 the data set. It\'s a very important aspect

10 of our job.

11 The other component of the

12 adequate and well‑controlled phrase there.

13 The \"well‑controlled.\" What does that mean?

14 Why is it needed to be controlled? It\'s

15 required in order to discriminate outcomes

16 caused by the study agent from outcomes due

17 to other factors. As you can imagine, the

18 natural progression of the disease, the

19 observer, the patient expectation, the

20 inherent biases we bring to new products,

21 and the impact of concomitant therapies.

22 Within control groups, hopefully

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1 we can separate out these various items that

2 may influence the outcome.

3 What are the types of control?

4 They can be broadly grouped into two major

5 categories: Concurrent controls and

6 non‑concurrent controls. Within the subset

7 of concurrent controls, the controls may be

8 obviously a placebo control; they can be

9 active control, comparison of the

10 experimental agent to another agent. For

11 example, a new thrombolytic compared to an

12 old thrombolytic.

13 The control could be a different

14 dose. It could be a multiple‑arms study in

15 which the primary outcome measure is an

16 attempt to examine a dose response effect.

17 A high dose compared to a low dose. That

18 sort of thing. Or a clinical study can use

19 a concurrent control where there is no

20 treatment, where the control arm is a group

21 of subjects who receive standard care; they

22 don\'t actually receive an

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1 indication‑specific comparator treatment.

2 An approach that\'s commonly done in cancer

3 clinical studies.

4 Finally, the bullets at the bottom

5 of this slide notice that FDA does consider

6 non‑concurrent clinical controls. In

7 general, that refers to historical or

8 external controls. As you can imagine,

9 there\'s strengths and weaknesses to both

10 types of controls.

11 This slide attempts to come to a

12 conclusion on balance with respect to these

13 strengths and weaknesses. As noted in our

14 guidance document on controls, we come away

15 with the conclusion that there are

16 substantial strengths to concurrent

17 controls, and there are substantial

18 weaknesses to historical controls.

19 The strength of concurrent

20 controls is that there is a minimization of

21 bias. In one way of thinking, in any

22 clinical study, there\'s always some bias.

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1 There\'s bias inherent in the eligibility

2 criteria with respect to how a product may

3 ultimately be used. The beauty of

4 concurrent controls is that we are able to

5 hopefully control that bias, primarily

6 through the ability to conduct randomization

7 as well as blinding.

8 With historical controls, it\'s

9 largely impossible to control bias. There\'s

10 an inherent selection factor in the choice

11 of those control subjects. Consequently, as

12 noted in our document, the use of historical

13 controls is generally recommended only when

14 there is thought to be a profound treatment

15 effect and the course of the disease being

16 examined is highly predictable. Such as the

17 data are highly persuasive.

18 Then the other aspect of licensure

19 considerations ties into an acceptable

20 safety. We certainly cannot ignore the

21 safety considerations, even though they

22 perhaps maybe a little bit easier to obtain

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1 in terms of clinical trial design. But

2 major considerations in reviewing a clinical

3 safety database ties into consideration of

4 the subject characteristics. For example,

5 if our sponsors use a laundry list of

6 eligibility criteria such that there are

7 definitive clinical studies are only

8 performed among a very, very select subset

9 of the potential population who may desire

10 to receive this product, is it appropriate

11 in the label to generalize those findings

12 from that very small subset to a larger

13 subset, or should we try to attempt to

14 construct a package insert, a label, that to

15 a certain extent reiterates the eligibility

16 criteria? We prefer not to do that.

17 We prefer that our sponsors take

18 into consideration the potential

19 generalizability of their data in the design

20 of their clinical study.

21 What about the number of subjects

22 and the extent of exposure in these

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1 subjects? Should the sample size be small?

2 Certainly on common diseases, we anticipate

3 seeing small sample size databases.

4 Questions with respect to the extent of

5 exposure. For chronic diseases, the

6 question of how long and how great a

7 exposure to the experimental agent should be

8 obtained is always on the table. That\'s one

9 of the issues we hope to address this

10 afternoon.

11 Diabetes is a chronic illness. Is

12 it reasonable to license a product where we

13 have clinical data from one year? Do we

14 need two years before we can sufficiently

15 even address the question of a risk/benefit

16 of assessment. The duration of follow‑up

17 sufficient for a chronic disease.

18 In licensure consideration, as I

19 noted, two big aspects: The ability to

20 assess the risk/benefit, and are the

21 clinical data sufficient for us to write a

22 label.

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1 With respect to the labeling

2 aspects, the label, the package insert

3 should contain, \"a summary of scientific

4 information needed for safe and effective

5 use of the product.\" That generally applies

6 to clinical data. Occasionally, animal data

7 are included in the package insert,

8 especially with respect to reproductive

9 toxicity, the other carcinogenicity‑type

10 issues.

11 Aspects of the label. The major

12 aspects are noted here. There are subsets

13 within these aspects. The label

14 considerations. The sponsor should generate

15 clinical pharmacology data. There is a need

16 for pharmacokinetics, the description of

17 pharmacodynamics of the products. There is

18 a need for a clinical studies sections. For

19 islet products, this may be especially

20 important, because that clinical study

21 section would describe the types of

22 immunosuppressives that were used, the

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1 dosages, that sort of thing. Information

2 that the practitioner will need to have

3 access to to use the product sufficiently.

4 Of course, the label needs to

5 state the indication and usage, which is

6 sort of at the heart of FDA regulation. The

7 ability to authorize a sponsor to make a

8 claim about their product. The label will

9 contain contraindications, describing those

10 situations where the product should not be

11 used. Of course, warnings, precautions,

12 adverse reactions, overdosage of use.

13 Finally, a description of the dose, the

14 cellular dose, and the administration

15 directions.

16 Getting back to the core aspect of

17 the label, meaning the indication, the

18 claim, which conceptually may be one of the

19 benefits of licensure is that there is an

20 imprimatur to make a claim about a product.

21 All indications shall be supported by

22 substantial evidence of effectiveness based

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1 on adequate and well‑controlled studies. A

2 lifting here from the regulations.

3 So the purpose of our discussion

4 this afternoon is not so much to talk about

5 deficiencies in the policies of how these

6 products are regulated. I think those

7 questions are pretty obvious to everyone in

8 this room.

9 What we\'re hoping to do is to get

10 insight from the panel members, thoughts,

11 perceptions, recommendations even, such that

12 we can go back to our sponsors, give them

13 feedback and try to advance the field to

14 help FDA help interpret the data our

15 sponsors are generating, as well as to help

16 FDA to try to steer our sponsors into

17 collecting the data such that we can resolve

18 this issues of licensure.

19 As we noted, there\'s no assessment

20 of the presented data. The questions are

21 briefly summarized here. The very first

22 question that we\'re going to ask the group

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1 to discuss, to comment upon, deals with

2 endpoints for these definitive clinical

3 studies. Is insulin independence ‑‑ meaning

4 simply the avoidance of exogenous insulin,

5 for example, is that a sufficient primary

6 endpoint on which to make a claim of

7 efficacy, for example? Or is the avoidance

8 of life‑threatening hypoglycemia? There are

9 many potential indications, endpoints that

10 could be examined here. We need feedback on

11 those issues.

12 Other clinical development

13 concerns are noted in question number two.

14 It deals with the requisite length of

15 follow‑up. Is there a certain period of

16 time that FDA really should have follow‑up

17 even before we make that assessment of a

18 risk/benefit. Meaning at least one year,

19 for example. At least two years. Give us

20 your thoughts, perceptions on the duration

21 of follow‑up.

22 The use of historical controls.

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1 It\'s going to be a pretty obvious question.

2 Is it applicable? Is it reasonable to use

3 historical controls in this setting? Do you

4 envision claims indications that, by their

5 very nature ‑‑ for example, fear indicies,

6 that sort of claim ‑‑ could that be based on

7 historical control, or would we need a

8 concurrent control? We need feedback on

9 these types of concerns.

10 Then of course, we want your

11 thoughts on the generalizability of data and

12 how the data could be used in a package

13 insert, for example, where it looks as if

14 our sponsors may study a very small subset

15 of people with Type 1 diabetes. So your

16 thought perceptions are greatly appreciated

17 in that respect. I think that\'s my last

18 slide. That\'s it. Thank you for your

19 attention.

20 There are lots of questions here

21 and FDA certainly cannot answer them all.

22 But we hopefully can address some of the

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1 questions related to clinical development of

2 islet products. Thanks.

3 DR. RAO: We had no requests for

4 any comment from the public. Is there

5 anybody who\'d like to make a comment? In

6 that case, I propose we adjourn for lunch

7 and then take up the discussion of the

8 questions after that.

9 (Whereupon, at 11:02 a.m., a

10 luncheon recess was taken.)

11 \* \* \* \* \*

12

13

14

15

16

17

18

19

20

21

22

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1 A F T E R N O O N S E S S I O N

2 (12:10 p.m.)

3 DR. RAO: We\'ll begin the final

4 part of this meeting. This will be the time

5 to see if we can address some of the issues

6 specifically regarding the clinical data

7 part of the issues that FDA raised.

8 In terms of starting the

9 discussion, what I\'m going to try and do is

10 ask Dr. Sherwin to make a couple of comments

11 on issues, and just following up on diabetes

12 and what kind of lead‑outs he feels one

13 needs in cases of patients who have had some

14 kind of transplant. Maybe we\'ll use that as

15 a starting point to look at things.

16 DR. SHERWIN: Well, these are

17 unprepared remarks. Just to begin, there

18 are two types of diabetes. One\'s an

19 autoimmune disease that destroys the beta

20 cells. There\'s another kind of diabetes

21 that affects the majority of people that is

22 due to beta cell failure in the face of

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1 insulin resistance.

2 We\'re really talking about

3 treatment of the former, where there\'s

4 specific beta cell loss. But the

5 complications of diabetes are not that

6 different, at least the long‑term

7 complications, which take many years to

8 develop. They involve the small vessels

9 that principally involve ‑‑ from a clinical

10 perspective, although they involve all the

11 vessels in the body, the retina, and kidney,

12 and consequently, one can ultimately see

13 blindness in about 30 percent of patients,

14 ultimately legal blindness.

15 About 30 percent of people develop

16 kidney failure with Type 1 diabetes, and

17 neuropathic complications occur. All these

18 complications tend to develop over an

19 extended period of time. Most

20 complications, the retinal and renal

21 complications, really start to occur after

22 the first decade and really are into the

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1 second decade. Consequently, the slow

2 development of those kinds of complications

3 mean long‑term studies. So that\'s a

4 difficult thing to deal with.

5 The other complication that leads

6 to death in most people with diabetes is

7 actually cardiovascular disease. That\'s

8 even true for patients with Type 1 diabetes

9 as well as Type 2. There\'s a much higher

10 rate of heart attack and stroke. And

11 clearly, women are disproportionally

12 affected because they lose their protection,

13 as a woman, from cardiovascular disease. Of

14 course, that also develops very gradually,

15 and making assessments of impact on that is

16 not an easy thing and requires long‑term

17 studies such as the DCCT.

18 There are then these short‑term

19 complications. The major one that one deals

20 with in this setting of islet

21 transplantation today is the problem of

22 hypoglycemia in patients with Type 1

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1 diabetes. I should point out that there are

2 more patients with Type 2 diabetes who are

3 on insulin than Type 1. Nevertheless, the

4 complication of severe hypoglycemia is much

5 more common in Type 1 patients. The reason

6 for that is that those patients are not

7 insulin‑resistant, number one, or generally

8 not. Number two, they develop

9 counter‑regulatory defects that increase

10 their susceptibility.

11 So as soon as a patient with

12 Type 1 loses their beta cell function, their

13 alpha cell function is lost as well.

14 Consequently, they have no glucagon response

15 to hypoglycemia, and that\'s a very

16 consistent finding in patients that do not

17 have beta cell function.

18 The other thing that happens to

19 these patients is, as they become more

20 susceptible to hypoglycemia and as we try to

21 treat them more aggressively today, they

22 develop loss of their other key

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1 counter‑regulatory hormone, epinephrine.

2 This adrenal medullary defect is

3 due to hypoglycemia itself, and perhaps due

4 to the disease itself, which people haven\'t

5 emphasized as much, but there is a loss of

6 adrenal medullary function that combines

7 with the lose of glucagon and the inability

8 of the beta cell to regulate itself and

9 reduce its own insulin secretion, so

10 hypoglycemia becomes a problem.

11 Now, the major reason we encounter

12 this is because our methods of delivery of

13 insulin are unphysiologic, as I\'m sure you

14 well know. So that we try in good practice

15 to simulate physiology as best we can by

16 delivering insulin subcutaneously. And

17 there are a number of different systems that

18 have evolved to try to deliver insulin

19 physiologically, and the problem we face

20 clinically is that we don\'t have a feedback

21 control system, so we rely on the patient\'s

22 compliance with frequent monitoring of

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1 glucose, but it\'s impossible to get as many

2 readings as one would like to function to

3 like a beta cell.

4 A beta cell has its own sensor and

5 can continually adjust its secretory rate,

6 something we cannot do by insulin delivery.

7 Consequently, even though we deliver insulin

8 more physiologically and more effectively,

9 we often don\'t overcome the problem of

10 hypoglycemia. This has been the major

11 impediment to our ability to effectively

12 treat diabetes.

13 We do know that treatment matters.

14 Clearly, the DCCT study, which was a

15 beautiful study that was conducted by NIH,

16 clearly demonstrated benefits in terms of

17 the classical complications of diabetes. I

18 think the UKPDS data and the EDICTS

19 follow‑up studies from the DCCT provide

20 soft, but some evidence I think that

21 cardiovascular disease can be improved by

22 controlling glucose.

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1 The other thing that is

2 interesting from the EDICTS study was that

3 in those patients that were aggressively

4 treated for the 6‑1/2 years, once they got

5 off that kind of regimen where they weren\'t

6 followed as closely and their glucose levels

7 rose to the levels seen in the control

8 group, the benefits seemed to persist for an

9 extended period of time.

10 So there was some memory effect or

11 some benefit, even from that intervention

12 over a six‑ or seven‑year period, which

13 seemed to lead to some benefit.

14 So from a clinical perspective,

15 most patients can be treated effectively I

16 think with the regimens we have today.

17 Between insulin pumps, and long‑acting and

18 short‑acting insulins that have been

19 recombinant insulins. I think the majority

20 of patients do reasonably well. I think we

21 can have a significant impact on their care.

22 Now whether an islet transplant

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1 would be a more effective way of treating

2 these complications is up for grabs I think

3 at this point. I\'m not sure.

4 Theoretically, I think the control is

5 better, but what the downside is in terms of

6 the drugs that are used with the islet graft

7 are really up in the air. So from the

8 standpoint of long‑term complications, I

9 don\'t think we know which approach would be

10 a better approach in the long run.

11 Really, that will require a

12 long‑term clinical trial, head‑to‑head

13 perhaps, to really look at this issue if

14 islet transplantation really became

15 available to a large group of people. I

16 think what we\'re talking about today,

17 however, is a specific problem; namely,

18 severe hypoglycemia, hypoglycemia

19 unawareness.

20 That problem is in many cases

21 hyatragenic (?) and probably could be dealt

22 with by seeing specialists who are perhaps

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1 expert in this area. Some of these patients

2 probably would benefit from more

3 physiological insulin delivery systems, and

4 perhaps a lot of their serious problems ‑‑

5 they\'d still have hypoglycemia, but the

6 serious problems might be diminished by

7 better medical care.

8 There are some patients who even

9 in the best care don\'t do well. It is, from

10 a psychological perspective, knowing

11 patients who suffer from that problem, it

12 has a tremendous impact on their ability to

13 function normally. Or for children, surely,

14 for parents to deal with the problems. So I

15 think there are a subgroup of patients that

16 theoretically could benefit from this.

17 I think that looking at whether

18 you could actually document and clearly

19 demonstrate superiority of this approach, I

20 believe it could occur. It could occur in a

21 relatively short time from the perspective

22 of hypoglycemia. Then the problem is if the

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1 primary indication is hypoglycemia, how long

2 would you need to look at this to really

3 resolve that question? It wouldn\'t take as

4 long as the chronic complications,

5 obviously, because these are acute events.

6 The problem is detecting them and

7 really documenting that indeed you\'re

8 dealing with hypoglycemia, because many

9 patients experience symptoms which they

10 attribute to hypoglycemia and may even feel

11 better after eating, but that doesn\'t always

12 mean that they have hypoglycemia.

13 Then there are a lot of patients

14 who are unaware of hypoglycemia. And I

15 should point out that these events that do

16 occur frequently in these patients, the

17 long‑term consequences of that over one\'s

18 lifetime are not clearly established. It\'s

19 clear that for young children who have

20 hypoglycemia, I think, before the age of

21 five or six, and I have pediatricians here

22 to back me up one way or another ‑‑ clearly

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1 there in the developing brain, episodes of

2 hypoglycemia are serious, and will have an

3 impact on long‑term function cognitively.

4 As far as adults, it\'s not clear.

5 The studies from the DCCT over a period

6 of 6‑1/2 years didn\'t show any differences

7 between those people who had severe

8 hypoglycemia and those that did not. But

9 these were young people, young adults, and

10 we have no idea when they reach middle age,

11 and now they will with our therapies, how

12 they will function; whether they\'ll be

13 premature, senescence, things like that, we

14 have no clue about.

15 So I think the story about what

16 the impact in adults of hypoglycemia is a

17 question that remains unanswered. So the

18 problem then becomes if this clinical trial

19 is going to deal with hypoglycemia, it\'s a

20 new ballgame. It\'s difficult, because A1C

21 is not enough. A1C is very important,

22 because if you\'re not achieving hopefully a

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1 normal A1C, for example, if you\'re given an

2 islet transplant and you don\'t normalize

3 A1C, you\'ll reduce hypoglycemia because you

4 have a higher glucose. A1C becomes a

5 problem. It\'s a very important one from the

6 standpoint of long‑term benefit, clearly,

7 for patients. But if the indication becomes

8 hypoglycemia, it becomes not the whole story

9 by any means.

10 Then the question is how does one

11 define hypoglycemia. How do you design a

12 clinical trial that will adequately

13 determine it? If you have high‑risk

14 patients, you need to do a power analysis

15 obviously, and I haven\'t even begun to do

16 that in my head. But I suspect that if you

17 had patients that had two events at least

18 per year, that it wouldn\'t take too long to

19 sort out, because it\'ll be a striking

20 difference in the incidence. So that would

21 be one criteria that one could use.

22 There are criteria that people

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1 have developed for hypoglycemia; going to

2 the emergency room, needing IV glucose,

3 needing glucagon, et cetera; hopefully with

4 a documented glucose as well.

5 DR. SALOMON: Can I just ask you a

6 question as long as you\'re on that line.

7 It\'s not two episodes a year, it\'s two

8 episodes a month more typically in these

9 patients, isn\'t it?

10 DR. SHERWIN: Well, severe

11 hypoglycemia that requires help, emergency

12 room?

13 DR. SALOMON: You didn\'t add the

14 emergency room thing in there. I don\'t know

15 enough to say that they end up in the

16 emergency room. But patients I had ‑‑

17 DR. SHERWIN: I thought the

18 criteria is ‑‑

19 DR. SALOMON: Who have been on

20 that close to the line had at least one to

21 two episodes a month.

22 DR. SHERWIN: Oh, sure they have

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1 more than that.

2 DR. SALOMON: At least one of

3 those episodes a month, they end up with the

4 paramedics in their bedrooms, but I don\'t

5 about whether they actually end up in the

6 ER.

7 DR. SHERWIN: I don\'t know. Maybe

8 I\'m wrong. I thought your criteria was at

9 least two events a year.

10 DR. HERING: I think this is

11 correct. This is two events a year. I

12 think I wanted to emphasize one point.

13 Patients make a serious effort and measure

14 glucose levels every two hours, including

15 during the night, in order to avoid

16 hypoglycemia. So I think really the

17 lifestyle is clearly affected. I think that

18 is how they can avoid more episodes of

19 severe hypoglycemia.

20 I think you have to understand

21 this as well and take this into

22 consideration. That is why I think

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1 documenting absence of symptom perception,

2 neurogenic symptom perception, I think that

3 is one way of looking at this. Or in the

4 setting of a clinical trial, I would ask a

5 question whether there is an epinephrine

6 response to developing hypoglycemia. If

7 this response is lost in addition to the

8 glucagon response, which is lost in 100

9 percent of all people with 1 diabetes

10 within 5 or 10 years, this will help

11 identify this subgroup that let us

12 basically ‑‑ not in a position to develop

13 any symptoms, any warning symptoms anymore.

14 That would define this, and whether they

15 have episodes of severe hypoglycemia

16 requiring assistance or not should not

17 really be the only criterion that is of

18 importance.

19 DR. SHERWIN: Well, I think you\'re

20 right in part. You could set up criteria of

21 epinephrine response that was less than 20

22 percent or 10 percent of normal. But most

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1 people that we treat with insulin pumps have

2 suppressed epinephrine responses. They have

3 no glucagon and still, they don\'t end up in

4 emergency rooms. They do okay. I mean,

5 they don\'t do perfectly. They may do better

6 with a transplant. I accept that. But

7 that\'s another issue.

8 Getting back to the point. One

9 possibility is to clearly document

10 hypoglycemia and severe as the easiest way

11 to do it. The other is to think about, in a

12 trial which I never heard of doing really

13 for FDA would be using sensors as a way of

14 really picking up. Even though there are

15 deficiencies in all these glucose sensing

16 devices, although they\'re approved, they\'re

17 not perfect. You\'ll false‑positives,

18 false‑negatives. But if you have a good

19 comparator, you should be able to

20 distinguish easily between the two, I think.

21 That might be very helpful as well

22 in terms of trying to sort out what\'s going

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1 on. I\'ll stop. I took too long.

2 DR. RAO: Let me try and see if

3 I\'ve summarized some of the points that

4 you\'ve made and trying to keep a little bit

5 more general in terms of the issues. The

6 issue at least I thought I was trying to

7 address in this case was, you\'ve decided on

8 some criteria, you\'ve selected a set of

9 patients, and you\'ve decided that you\'re

10 going to use islets for transplant.

11 DR. SHERWIN: Yes.

12 DR. RAO: Now we\'re going to

13 follow these patients after they\'ve been

14 transplanted over a certain time period. We

15 want to ask ourselves, well, they were

16 diabetics before, so there\'s a certain set

17 of tests that we were going to follow

18 routinely that\'s sort of standard of care

19 that you would do. Those would be things

20 that you might have to follow.

21 As you rightly pointed out, there

22 are very specific tests that you need to

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1 consider, and perhaps one of the things that

2 was not considered was looking at

3 cardiovascular abnormalities that might

4 occur in a long‑term patient.

5 Over and above what would be

6 standard, perhaps there would additional

7 specific tests that one would want to

8 consider in any person who\'s had islet

9 transplant. One obvious thing that came to

10 mind in my mind was how do you monitor the

11 immune suppressed state? Should one be

12 monitoring that because that\'s an important

13 criteria in terms of success versus failure?

14 Should that be a criteria that the

15 committee might feel that makes sense or is

16 important? Is the measure for hypoglycemia

17 that is recommended here as a measure that

18 was a readout, should there be a glucose

19 tolerance test each time? Or is it that you

20 need to look at epinephrine or glucagon?

21 What is the sense in the community

22 as to what would be a reasonable way to

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1 measure that there has been, and how long

2 should one follow it up on, or frequency in

3 some sense?

4 DR. SHERWIN: Well, if you want to

5 look at recovery of counter‑regulation, the

6 best way to do that is to standardize the

7 stimulus, because it becomes a little

8 harder. But that can\'t be done in many

9 places, so that creates a potential problem,

10 I suspect.

11 The key point to me is your

12 primary indication has to be hypoglycemia

13 for this kind of a study. So those are

14 secondary issues. The secondary issue is do

15 you restore epinephrine response? The best

16 way to do that would be to what we call a

17 hypoglycemic clamp for maybe an hour, and

18 lower glucose to a specific level. So you

19 standardize the stimulus before and

20 sequentially, and look at the epinephrine

21 response.

22 You\'re not going to restore the

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1 glucagon response, but hopefully you could

2 restore the epinephrine response. It

3 wouldn\'t take very long to show that. You

4 could probably do it in a month and know

5 whether you\'ve made significant progress.

6 Surely by three months, I would suspect

7 you\'d be able to know pretty well what\'s

8 going on in terms of that, from the

9 perceptive of an islet graft.

10 DR. RAO: Do you have a comment on

11 that?

12 DR. HARLAN: I do. I agree

13 largely with what Dr. Sherwin said, as far

14 as inclusion criteria and an immediate who

15 should be studied. But I think we have to

16 keep in mind that it\'s not just insulin and

17 hypoglycemia, but all these patients need

18 treatment with immunosuppressive therapies

19 which have significant toxicity and problems

20 associated with them. So I really think

21 that the endpoint should be quality of life

22 measures and complication measures on an

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1 intention to treat basis. Because it\'s a

2 very complex equation to integrate all those

3 various things.

4 DR. RAO: Is there a standard

5 quality of life measure that the community

6 agrees on? For example, there was this fear

7 index was something that was followed up.

8 Is that a reasonable measure, since as was

9 pointed out earlier, hypoglycemic response

10 is the criteria we\'re using to select

11 patients, for example?

12 DR. HARLAN: I believe it\'s

13 insufficient, because it doesn\'t take into

14 account what can be fairly significant

15 toxicity associated with current

16 immunosuppresives. But it points out how

17 difficult this study would be, because as

18 Dr. Ricordi has pointed out and Dr. Hering,

19 there is no standard of care

20 immunosuppression. This is a constantly

21 evolving business. So we start out

22 comparing two things at the beginning. At

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1 the end of the study, the things that you\'re

2 comparing are irrelevant. It makes it

3 difficult.

4 DR. RAO: Dr. Viner.

5 DR. VINER: I think Dr. Sherwin

6 raised another interesting point, and that

7 was the entry criteria for these patients

8 and the use of other improved metabolic

9 approaches, or more physiological

10 approaches, including insulin pumps. I\'m

11 wondering if the data that we have to date

12 approaches or addresses that issue.

13 In particular, how much better are

14 these patients doing in terms of their

15 hypoglycemia controls compared to those

16 patients that would be put on an insulin

17 pump? And should there be some kind of

18 randomized trial that includes those two

19 different approaches?

20 DR. RAO: Hold your thought until

21 we get a response on that.

22 DR. LEVITSKY: I think that to

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1 look at quality of life without a randomized

2 trial becomes impossible. I mean, you just

3 can\'t do that. You can look at objective

4 measures like episodes of hypoglycemia, if

5 you can document them, or hemoglobin A1C, or

6 glucose excursion.

7 But once you are dealing with

8 something where the Hawthorne Effect becomes

9 very important, you can not look at that.

10 These people all want their quality of life

11 to improve and will improve even if their

12 renal disease is developing. So you can\'t

13 use those measures in this unless you do a

14 controlled trial.

15 DR. RAO: One should not consider

16 a generalized quality of life measure,

17 because it won\'t have good predictive value

18 as a follow‑up. But specific measurement

19 quantifiable measures would.

20 DR. LEVITSKY: I\'m not sure you

21 could use any without a controlled trial. I

22 would have to talk to someone who did those

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1 sorts of things for a living. But my

2 experience with them is that they are very

3 subtle and hard to interpret and you have to

4 have a controlled group. You can\'t just

5 input a change and then look at what the

6 person says about the change.

7 DR. RAO: Dr. O\'Fallon.

8 DR. O\'FALLON: Well, certainly,

9 the conversation which I thought was

10 restricted to what kinds of measurements we

11 would be interested in has gone pretty far

12 afield. We need to do a randomized clinical

13 trial. Whether we use quality of life

14 measurements or not is kind of beside the

15 point. Certainly there\'s a lot of research

16 going on in the quality of life arena right

17 now. I don\'t know if any that is specific

18 to people with diabetes, but I can imagine

19 that it wouldn\'t be hard to work on some of

20 them.

21 DR. SILVERSTEIN: There are. They

22 use the DCCT, too.

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1 DR. O\'FALLON: I just said I don\'t

2 know. So if there are existing scales,

3 maybe they could be modified to take into

4 account some of the things that are going to

5 have to be hoped for as our endpoints in a

6 study of this point. But we certainly need

7 to decide on what those endpoints are and

8 what kind of measurements we\'re going to

9 look at before we start deciding about

10 whether a randomized clinical trial is even

11 a possibility here.

12 DR. SILVERSTEIN: This is also

13 just addressing quality of life. We\'ve done

14 studies on quality of life in children.

15 There are some validated standardized

16 questionnaires, and I don\'t think we need to

17 decide on which ones to use at this

18 particular time. But we did use the

19 children as their own controls. I

20 understand what Dr. Levitsky is saying about

21 wanting to have improved quality of life,

22 but there are some objective things. Days

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1 of work missed, you know, things like that

2 that affect day‑to‑day functioning that can

3 be assessed, I think.

4 DR. RAO: I think the FDA is going

5 to try and remind us that we want to really

6 discuss the specific outcomes measures as

7 listed here in terms of follow‑up. Go

8 ahead.

9 MR. DAPOLITO: Actually, that\'s

10 exactly right. To try to keep this a little

11 bit focused here, we\'re talking about

12 endpoints. There were several items within

13 Dr. Sherwin\'s comments that were very

14 useful. One point I want to be sure I have

15 clarity on, if I understand correctly, the

16 clinical meaningfulness of asymptomatic

17 hypoglycemia in adults is unclear. That\'s a

18 very important regulatory status there. Did

19 I understand that correctly?

20 DR. SHERWIN: In terms of

21 cognition. In terms of risk, there is a

22 greater risk. Because what happens is that

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1 patients for example may have a glucose

2 of 50 and be functioning and seem fine and

3 not recognize as anything as going on. But

4 a small change all of a sudden can throw

5 them from functioning into totally

6 non‑functioning. It\'s sort of like in a

7 healthy individual without diabetes, they

8 have a lot of room as they begin to drop to

9 develop symptoms and other cues that allow

10 them to take protective action quickly;

11 whereas, these patients, the window becomes

12 so narrow between function and falling

13 apart, that there is a risk form that

14 perceptive.

15 So the risk of unawareness is

16 severe hypoglycemia, and then perhaps an

17 auto accident or something like that. In

18 terms of whether these changes in glucose

19 that are lower than normal that they\'re

20 unaware of, is that impacting on how they\'re

21 going to function when they\'re 55

22 cognitively, that\'s what I was saying that

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1 we don\'t know about.

2 DR. RAO: Did you want to

3 continue?

4 DR. SHERWIN: No, no.

5 DR. RAO: Dr. Shapiro, did you

6 have something to add?

7 DR. SHAPIRO: No, I was only going

8 to comment very briefly on the quality of

9 life instruments currently being used in

10 islet transplantation. Dr. Jeffrey Johnson

11 from our health economics unit has a panel

12 of six different tests, including

13 immunosuppressive quality of life scores;

14 health utility index; cost utility indices;

15 that are being tested in fact across the

16 board at the collaborative islet transplant

17 registry, across the ten centers network

18 trial and at their own site. That data is

19 being generated currently.

20 DR. RAO: Go ahead.

21 MR. DAPOLITO: Hi, again to talk

22 about the asymptomatic hypoglycemia in adult

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1 issue. For example, if we came to you say a

2 year or so from now with a couple of pivotal

3 studies that show the sponsor profoundly

4 impacts the outcome of asymptomatic

5 hypoglycemia as detected by sensors; there\'s

6 no clinical correlate whatsoever in these

7 data. It\'s asymptomatic hypoglycemia. How

8 would you view those data?

9 DR. SHERWIN: Tough. I would say

10 it\'s not good, because my intuition tells me

11 that. That\'s why I emphasized before

12 events. Because clearly events are events,

13 they\'re serious. During the course of the

14 DCCT, in the intensively treated patients

15 who were optimally treated, the best

16 possible care, the rate of severe

17 hypoglycemia that required help from someone

18 or emergency room visits went up threefold.

19 So in the best of circumstances, as we

20 improve the treatment, we had a threefold

21 increase in these serious events.

22 So it indicates we have better

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1 treatments, we can lower glucose, we can

2 have an impact on the chronic complications.

3 There is a subgroup of people, maybe

4 overemphasized in number; I suspect that may

5 be true. But there are clearly are a

6 subgroup of people who really are in

7 trouble.

8 MR. DAPOLITO: Again, may I

9 follow‑up on that? I find myself wondering

10 are we talking about a surrogate? Any

11 outcome that doesn\'t have a clinical

12 manifestation might be viewed as a surrogate

13 for a clinical outcome. Meaning, the

14 patient knows no difference here. If we

15 have this data and we come to you, the

16 question will be is this a surrogate?

17 Again, making this determination has

18 regulatory implications. I want to be sure

19 we have clear understanding of your

20 thinking.

21 DR. SHERWIN: My thinking would be

22 that if I saw that, I would think that the

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1 therapy that didn\'t create that was a

2 superior therapy. That\'s my judgment.

3 That\'s clinical medicine. It\'s a judgment

4 call on that. I\'m not sure that all the

5 facts are in. I know that those people will

6 have a higher likelihood of having some

7 serious event at some point. It might be in

8 a car somewhere. They\'ll be at risk. Their

9 risk will go up. That\'s for sure. So I

10 would say it\'s not a good thing.

11 If you didn\'t see it in one

12 therapy and you did see it in the other, you

13 would say it\'s more efficacious. But then

14 you have to balance of course what David was

15 saying is obviously the risk. We\'re just

16 focusing on efficacy right now. There are

17 obviously potential risks.

18 So I don\'t know how to judge the

19 whole story, but if I am just focused on

20 that one question, is a lower glucose bad,

21 below normal, I would say yes, because I

22 think the risks are higher as a result. But

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1 then it\'s not as bad as if you have events.

2 Because events mean a lot more, and

3 therefore, I can accept more toxicity, more

4 risk from the other side. That\'s the way I

5 look at it.

6 DR. RAO: So if one is measuring

7 events already, is there any specific

8 additional monitoring that\'s in your mind

9 absolutely critical, for example, or in

10 anybody\'s mind, absolutely critical?

11 DR. SHERWIN: I think you want to

12 get a better picture. These are secondary.

13 I think the primary, in my own view, would

14 be the events. The other issues are looking

15 at continuous monitoring; getting a sense of

16 how much subtle hypoglycemia; whether you\'re

17 losing your epinephrine response; what\'s the

18 effect on cognition in general. All these

19 other issues become parts of secondary

20 endpoints that you\'d like to think about

21 when you\'re addressing risk of hypoglycemia.

22 I\'ve said enough.

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1 DR. RAO: Let\'s look at the first

2 question in a little bit.

3 DR. HERING: I would like to make

4 the following comment. I think a defined

5 use could be restoration of u‑glycemia,

6 which is difficult if not impossible to

7 achieve in a small subgroup of patients.

8 Dr. Sherwin quoted the DCCT study that the

9 risk of hypoglycemia increased three‑ to

10 fourfold. We have to understand that those

11 patients with a history of hypoglycemia were

12 excluded from participation in this study.

13 So the true risk is possibly

14 higher than just a three‑ to fourfold

15 increase in severe hypoglycemia. So I think

16 there\'s a group of patients that cannot

17 experience the benefit of u‑glycemia,

18 because hypoglycemia is the single most

19 limiting factor in terms of delivering

20 intensive insulin therapy. So those

21 patients have no really opportunity to have

22 u‑glycemia restored unless transplantation

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1 is performed. This is a small subgroup.

2 I think if you now want to monitor

3 outcomes, I think the incidences of

4 hypoglycemia can be monitored. I think I

5 would not necessarily only look at severe

6 hypoglycemia, which is a life‑threatening

7 event every single time it occurs, I think

8 one could measure the episodes of events

9 with glucose levels below 54 or 50 mg/dL

10 without any associated warning symptoms.

11 I think one could do this over a

12 period of time, for example, using a

13 continuous glucose monitoring system over a

14 three‑day period every month and see what is

15 the incidence of hypoglycemia that is not

16 noticed by patients. Because very single

17 hypoglycemia, whether you have symptoms or

18 not that are relatively severe will continue

19 to change the threshold to the point that

20 your risk of severe hypoglycemia increases.

21 Hypoglycemia begets hypoglycemia. I think

22 it\'s a vicious cycle.

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1 The second outcome measure should

2 be the hypoglycemia fear survey, because

3 this is another instrument that has been

4 used already. This had turned out to be the

5 most responsive quality of life, if you

6 wish, instrument. It was used in islet

7 transplant patients, and I think this would

8 indicate whether quality of life is improved

9 in this group of patients as based on the

10 hypoglycemia fear survey instrument.

11 DR. RAO: I want to try and go

12 back to the first question and look at what

13 is considered a good outcome. So you\'ve

14 transplanted cells, and you heard that one

15 criteria that\'s been used is to look at

16 insulin independence at a period of one

17 year. Is that a good measure or is too

18 rigorous? Should reduction in insulin usage

19 be a criteria, or should it always be this

20 criteria? Should it be for four years?

21 Should it be for one year? Should it be for

22 ten years? Is there a consensus, opinion,

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1 suggestions?

2 DR. LEVITSKY: I think that

3 insulin independence should be the gold

4 standard; insulin independence without

5 hypoglycemia. The problem is that you can\'t

6 have insulin independence in an individual

7 who\'s hypoglycemic over time. But I would I

8 guess at this point caution against the use

9 the presently available commercial devices

10 to continuously measure blood sugar over

11 three, because they keep redoing their

12 computer algorithms to deal with normal

13 blood sugars.

14 If many normals use them right

15 now, they end up finding out they\'re

16 hypoglycemic a good deal of the night.

17 They\'re actually not. It\'s a problem with

18 the computer algorithms. So I think that it

19 could really upset the data that you were

20 trying to collect if you use the present

21 equipment.

22 DR. RAO: Dr. Harlan.

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1 DR. HARLAN: The question I\'d like

2 to raise in regards to using insulin

3 independence, on the one hand, it appears

4 like a very clear endpoint, and it is. But

5 the question I wish to raise about it is

6 that, as Dr. Shapiro presented the data

7 today, that was defined as not having a

8 fasting blood sugar above 140 more

9 than three days a week, or not having

10 a two‑hour post‑prandial above 180 I

11 think three times a week.

12 But those are not normal blood

13 sugars. We don\'t know if that level of

14 glycemia control is going to yield the

15 long‑term safety that we are looking for.

16 It looks black and white, but it\'s not black

17 and white. I would much happier if it was

18 insulin independence with normal glycemia,

19 using currently defined criteria.

20 DR. SHERWIN: I think that was a

21 very fair statement, by the way. I forgot

22 to comment on that yesterday.

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1 DR. SILVERSTEIN: I think that

2 insulin independence is a gold standard.

3 But I would also accept basically a

4 honeymoon definition, where people would now

5 have the ability to maintain normal glycemia

6 with low doses of insulin as being a

7 success. The only time when you can really

8 manage diabetes easily is during the

9 honeymoon when they have still some

10 endogenous insulin. Even if they require

11 some exogenous.

12 MR. DAPOLITO: Could we get some

13 feedback also on, again, the insulin

14 independence as an endpoint. Correct me in

15 my thinking if I\'m misunderstanding.

16 There\'s an understanding that the

17 achievement of u‑glycemia is a good thing

18 based on certain data that suggests it\'s a

19 good thing in people who are not taking

20 immunosuppressives.

21 Are we comfortable generalizing

22 the data from people who are not receiving

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1 immunosuppressives, such that u‑glycemia,

2 conceptually a surrogate, we are very

3 confident that u‑glycemia in this secondary

4 group of patients is the same as u‑glycemia

5 in the patients who are not receiving

6 immunosuppressives.

7 Because when we say insulin

8 independence is the gold standard, perhaps

9 it\'s the gold standard among the average

10 somewhat complicated diabetic patient. But

11 does that implication carry over to a

12 patient population that now is receiving

13 multiple concomitant medications that may

14 impact their long‑term outcomes above and

15 beyond simply the glycemic control?

16 DR. EGGERMAN: I just wanted to

17 expand a little bit on what was said there.

18 Insulin independence is still a surrogate

19 until proven otherwise, particularly in this

20 patient population. If you could have

21 definitive clinical outcome that can be

22 utilized as an endpoint, I think there\'s

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1 significant strength in that in that you

2 will achieve something that is more

3 definitive and wait for the experts to

4 answer Dwaine\'s questions.

5 But I think that when you have to

6 choose between surrogates versus definitive

7 clinical endpoints, there\'s a real strength

8 in the clinical endpoints until you get

9 enough data to know if those surrogates are

10 actually translating into clinical benefit.

11 DR. RAO: Before you respond, let

12 me make sure I get this clear. One would

13 suggest that in addition to insulin

14 independence, quality of life measures would

15 be very important because they would be more

16 direct clinical endpoints. There\'s no other

17 surrogate substitute for insulin

18 independence.

19 DR. EGGERMAN: Right. To evaluate

20 it, you have to look at all the clinical

21 possible outcomes that occur using that

22 surrogate endpoint, and that would take a

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1 significant amount of time to determine.

2 Certainly previous trials have required

3 many, many patients to ascertain that over a

4 long period of time.

5 DR. RAO: Dr. Shapiro.

6 DR. SHAPIRO: I was just going to

7 comment further on whether our goals should

8 be restoration of complete, perfect glucose

9 control or not. That would be a wonderful

10 goal if we could achieve it. But

11 realistically, we\'re taking patients who are

12 on intensive insulin therapy or optimal

13 insulin therapy, who have unacceptable

14 glucose control to a point where these

15 patients are now off insulin and have

16 acceptable glucose control, and more

17 importantly, have normal hemoglobin A1C. I

18 think that\'s a realistic practical goal for

19 us to achieve right now.

20 There is data from the University

21 of Milan that shows quite clearly now, in a

22 large cohort of islet transplant patients,

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1 approximately 50 patients that have been

2 followed for 10 years with ongoing c‑peptide

3 secretion that have islet and kidney

4 transplants. In those patients that have

5 ongoing islet function, their mortality

6 rates and their survival and their kidney

7 grafts have improved.

8 DR. RAO: Dr. Salomon.

9 DR. SALOMON: A little bit of this

10 reminds me of Sam Dash during the Watergate

11 hearings when we kept referring to the fact

12 that he was just a little lawyer from the

13 backwoods area.

14 SPEAKER: It was Sam Ervin.

15 DR. SALOMON: It was Sam Ervin.

16 Anyway, I\'m corrected. The feeling is the

17 same here. I feel like I\'m just the little

18 general practitioner from Southern

19 California. Number one, you have a patient,

20 I have these patients, who are ending up

21 with the paramedics in their bedrooms a

22 couple times a year, if not a couple times a

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1 month. Then a year later, they haven\'t had

2 a single episode. We\'re like going well,

3 now we need to be more objective and maybe

4 they need to go ‑‑ I think Dr. Sherwin was

5 very patient. Put them in a GCRC metabolic

6 unit and do a glucose clamp and measure

7 their epinephrine and glucagons. I mean, am

8 I missing something here?

9 I think the patients would say

10 thank you very much. Then there\'s the whole

11 lot of very serious issues that I think we

12 could discuss about what was the trade‑off

13 on the immunosuppression, and then we need

14 to wait 5 or 10 years and do a couple

15 thousand patients and look at whether their

16 retinopathy and the progression of their

17 renal disease changed. I\'m all for that.

18 If you guys were regulating kidney

19 transplantation that way, then you\'d put us

20 out of business. I\'ve got thousands of

21 patients who bless me every time they come

22 to the clinic about the wonderful lives they

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1 have now with a creatinine clearance

2 of 40 mL per minute. Everyone here who

3 hopefully doesn\'t have renal disease has got

4 a clearance of 100 mLs per minute. But now

5 we\'re having this conversation about how,

6 well, maybe we need totally normal glucose

7 control. Again, show me a diabetic who\'s

8 not sticking themselves with a needle and

9 tell me they are going to be upset a year

10 later.

11 I don\'t know why we\'re making

12 something relatively simple so complicated

13 under the rubric of an objective outcome

14 principal.

15 SPEAKER: I\'m Krista Nuratha (?)

16 from the NIH, and I\'m just a little

17 practitioner in that sense, and you make my

18 comment almost superfluous, because I think

19 it\'s a question of how closely do we look.

20 If we just look at blood sugars during the

21 day measured by these transplanted patients,

22 we see nice blood sugars. If look closer,

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1 we all agree that we do not see a normal

2 first phase insulin release after a

3 challenge. We do not see normal immediate

4 post‑prandial blood sugars. We see all

5 kinds of abnormalities, but that may not be

6 the goal.

7 The goal may be that the patient

8 has now very nice blood sugars during the

9 day overall and you don\'t necessarily need

10 to look at the fine points. But there\'s

11 just one danger in that we think that maybe

12 the definition of insulin independence may

13 lead some people who care for these patients

14 to not institute a little bit of insulin

15 therapy that they would just require to

16 normalize or improve their blood sugars,

17 because the outcome is insulin independence.

18 So if now our very successful

19 patients are on a little bit of insulin,

20 they don\'t count as full successes anymore.

21 That shouldn\'t be the case. That\'s why I

22 like very much your comparison to the

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1 honeymoon phase. These are successful

2 patients. They are easily managed, no

3 hypoglycemia, little bit of insulin. That\'s

4 success.

5 But we need to look at the other

6 side, and therefore create something that is

7 a global picture. If somebody needs to

8 build in a toilet in the car because they

9 have more or less normal blood sugars, but

10 have to go to the bathroom 15 times a day

11 for a prolonged period of time, that

12 minimizes again the success.

13 So in the end, you need something

14 that puts several criteria, and therefore,

15 probably something like quality of life that

16 would take that into account would very much

17 help to kind of give us some objective

18 outcomes measures. So it must be a puzzle.

19 I agree fully that the closer we look, the

20 more abnormalities we find, and that may not

21 be the best way to judge islet

22 transplantation outcome.

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1 DR. RAO: Please identify

2 yourself.

3 SPEAKER: I\'m Kim Ritter. (?) I\'m

4 a patient at NIH. I had transplant

5 almost 2‑1/2 years ago. As the doctor over

6 there mentioned, I was one of those patients

7 that had the lows at least twice a week.

8 Okay, I didn\'t go to the paramedics, or I

9 didn\'t go the hospital because I refused,

10 because they take away your insurance and

11 all sorts of other reasons. But you can\'t

12 believe the difference this makes.

13 I have a life. I don\'t have to

14 have a babysitter when my husband goes away.

15 I can watch my children. My three‑year‑old,

16 as she was at the time years ago, learned

17 how to feed me raisins because she couldn\'t

18 open the refrigerator yet. I\'m not on

19 insulin right now and I may be on low dose

20 shortly, but my sugars this morning

21 were 114. There\'s nothing you can say to

22 replace the difference in not having a low.

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1 I could function very normally at a 40 blood

2 sugar. If I wasn\'t paying extremely good

3 attention and I didn\'t check my sugars, you

4 know, 5 to 10 times a day, I wouldn\'t catch

5 the 40 to the 30 or the 20, where I passed

6 out and had no recollection of anything.

7 It\'s a difference that you can\'t judge.

8 The islet transplant; yes, there

9 are problems with the rejection drugs. I

10 can\'t deny that. I\'ve had the nausea. I\'ve

11 had mouth sores. I\'ve had a lot of the

12 complications, but they\'re nothing compared

13 to the lows. You have a life. You can\'t

14 cross that. It\'s a big difference.

15 DR. RAO: I guess this really

16 re‑emphasizes the point that quality of life

17 scores of some fashion are important in

18 terms of considering follow‑up and those

19 issues that are there. Go ahead.

20 SPEAKER: Hello, I\'m Ellen Birdie

21 again. I would just like to summarize

22 exactly what you had to say and the way that

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1 both Kim and I feel. Throughout the past 28

2 months since my transplant, people have

3 often asked me, how do you feel? How do you

4 feel now that you don\'t have diabetes, now

5 that you\'ve had an islet transplant?

6 I always say, you know, I think

7 it\'s much more effective to show you rather

8 than to just tell you. My shirt says \"kiss

9 my islets.\" These are pictures of islets on

10 my shirt.

11 DR. RAO: Thank you. I\'m going to

12 try and summarize this a little bit, because

13 there are several other things we\'ll also

14 discuss as well, and then Dr. Ricordi, if

15 you feel you need to make a comment on that,

16 then we\'ll go with that.

17 DR. RICORDI: Very briefly, to

18 emphasize the fact that insulin independence

19 has been in a way imposed on the islet field

20 by pancreas transplant results, because we

21 have to compare our results with those of

22 pancreas transplants. But the data that

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1 Shapiro is referring of the Milan trial

2 following up patients for 10 years,

3 successful islet transplant versus an

4 unsuccessful with a kidney transplant, with

5 difference of patient survival or death

6 from 90 percent survival to 45 patient

7 survival at 10 years.

8 These were in all patients that

9 require insulin, small doses. So this is to

10 re‑emphasize that I wouldn\'t underestimate

11 whether it is better to give like six units

12 of insulin of single injection with an islet

13 transplant, single dose, versus trying to

14 achieve this complete insulin independence

15 to continue to measure our results with

16 pancreas transplantation.

17 But there is clearly a metabolic

18 effect and a beneficial effect if you

19 normalize hemoglobin A1C, even if you have

20 to take a single injection a day of insulin.

21 DR. RAO: Go ahead.

22 MR. DAPOLITO: I just want to try

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1 to be clear on what I may be hearing. It

2 sounds of if a number of folks have opinions

3 that the primary endpoint should be

4 something with tangible clinical benefit;

5 something that patients know, experience, if

6 I understand correctly, as opposed to a

7 primary endpoint which may be a hypothetical

8 endpoint.

9 Meaning, for example, u‑glycemia,

10 in the absence of any symptomatic correlate.

11 Is that the correct perception? Because I

12 don\'t want to walk away thinking ‑‑

13 DR. RAO: I was going to ‑‑

14 DR. SALOMON: You were on it, but

15 keep going. U‑glycemia without an insulin

16 injection is really tangible for a diabetic.

17 MR. DAPOLITO: Okay.

18 DR. RAO: Is that to say it\'s not

19 a substitute.

20 DR. SALOMON: If they have to be

21 on total perineal nutrition to get it, that

22 doesn\'t work for me.

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1 MR. DAPOLITO: But we don\'t

2 need ‑‑

3 DR. SALOMON: I\'m just saying

4 there\'s a way to do this. We can be

5 practical.

6 MR. DAPOLITO: I want to be sure.

7 The avoidance of exogenous insulin with

8 u‑glycemia will be viewed as a sufficient

9 primary implant. Thoughts?

10 DR. SILVERSTEIN: You can use some

11 insulin.

12 SPEAKER: How are you going to

13 define u‑glycemia?

14 DR. SILVERSTEIN: Yes, I think

15 that they can have some insulin, and the

16 question is ‑‑

17 SPEAKER: Dr. Silverstein, use

18 your microphone please.

19 DR. SILVERSTEIN: I\'m sorry. I

20 think that you need to allow these patients

21 to have some insulin injection and still be

22 considered a success. The real question

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1 then is how do you define u‑glycemia?

2 Hemoglobin A1C less than 6.5 percent with

3 low glycemic excursion seems reasonable to

4 me. I don\'t know how ‑‑

5 DR. RAO: I think we are repeating

6 ourselves to some extent, and so what I am

7 going to try and do is exercise some

8 executive authority here and try and

9 summarize and then see if there was any

10 really dramatic way I\'ve missed a summary or

11 if I\'ve left out something.

12 So what seems to me pretty clear

13 from the conversation here has been that you

14 need to follow‑up and you need to follow

15 them up quite a long period of time, given

16 that these are diabetics who would have

17 lifetime follow‑up in some fashion. There\'s

18 a standard follow‑up that people have used

19 for diabetics, and that seems to be a

20 reasonable way to follow them up.

21 There are certain specialized

22 things that you need to worry about in

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1 patients who\'ve got islet transplants, and

2 part of that seems to be to worry about the

3 immune suppressive regimen that\'s been

4 there, and to use as an outcome measure that

5 you need both outcome measures which is

6 quantifiable in some sense achieving insulin

7 independence, which is loosely defined in

8 that you don\'t have to a normal glycemic or

9 u‑glycemic curve in response to a glucose

10 challenge; and that one can use surrogate

11 measures such as glucosylated hemoglobin and

12 serum c‑peptide as measures of what your

13 glycemic state is.

14 But in addition to this, quality

15 of life measures are going to be quite

16 important as part of the endpoint in terms

17 of looking at any of these cases. Is there

18 any additional really specific test that

19 seems to have been missed, or a huge gap in

20 terms of what one would consider follow‑up

21 which is not there?

22 DR. SALOMON: Yes, I think the

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1 other one that came up in Dr. Shapiro\'s

2 discussions, and I think the

3 endocrinologists have done a good job with

4 things like MAGE, which is the mean aptitude

5 of glucose excursion; James had come up with

6 an alternative, which I think if he could

7 justify that, would be fine for a clinical

8 trial.

9 I defer to my endocrinology

10 colleagues if they want a different test.

11 But they have some objective tests that are

12 useful in further defining what\'s going on.

13 DR. SHERWIN: Obviously, the other

14 thing that you\'re going need to look at,

15 even though we assume everything will be

16 alright, is microobrevenarious (?). You may

17 even want retinal photographs. One of the

18 things that we observe when we put people on

19 insulin pumps was an acute deterioration in

20 their retinopathy, and then it went away,

21 and then things improved.

22 The assumption would be that you

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1 might see a similar phenomenon here or you

2 might not. But I do think that\'s relevant.

3 Whether one should look at ‑‑ if

4 you\'re really going to do a trial, I mean,

5 it depends on the magnitude and the money

6 and so on ‑‑ is to think about some of the

7 markers of cardiovascular disease, you know,

8 see reaction to protein, things like this.

9 Just to keep a feeling for what these

10 regimens might be doing from that

11 perspective, islet six, et cetera.

12 So I\'d think about the

13 complications, but my focus still is on the

14 primary promise; this not a big subgroup of

15 people, but there are real subgroup of

16 people that I think therapy can have big

17 impact, and we have to prove it to the

18 world. I think that\'s one of the issues.

19 You want to do a good study, I

20 think, that really tells you unequivocally

21 that this approach is superior to the best

22 medical approach that we can come with.

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1 That won\'t take too long.

2 DR. RAO: Brief?

3 DR. HARLAN: It will be brief. I

4 has sensing maybe a developing groundswell

5 that it shouldn\'t be insulin independence,

6 but it should be u‑glycemia which is the

7 goal, rather than insulin independence. I

8 say it for two reasons. One is, it\'s not

9 proved. I accept your point that we don\'t

10 know that glycemia is as important to the

11 immunosuppressed patient as it is in others,

12 although the great preponderance of data is

13 that anytime it\'s been looked, at it\'s

14 glycemia, glycemia, glycemia, that regulates

15 endpoint.

16 So I think from a practical

17 standpoint, since we really are interested

18 in patient long‑term outcome, if we can

19 achieve that easily ‑‑ and I agree with

20 Dr. Ricordi perfectly, and I think patients

21 would agree with it ‑‑ if you can give them

22 an islet transplant and a single shot of

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1 insulin a day and they\'ve got normal blood

2 sugars, that\'s a fantastic success and

3 shouldn\'t be defined as anything less than

4 that.

5 Then the practical issue is that

6 we want these islets to survive as long as

7 possible once we transplant them. There\'s

8 also considerable, not proof, but

9 considerable data that high blood sugars in

10 and of itself decreases the survival of

11 those islets. So if we choose anything less

12 than normal glycemia, it\'s bad for two

13 reasons, I think. One, bad for the patient,

14 and two, bad for the islets.

15 I was sensing that people were

16 starting to agree on this. I\'d rather it be

17 u‑glycemia than insulin independence.

18 DR. RAO: Point taken. Does the

19 FDA feel that we\'ve covered this question

20 adequately?

21 MR. DAPOLITO: I think it\'s good

22 to get clarity. If I understand correctly,

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1 on 1A, the take‑home message is that the

2 avoidance or the minimal use of insulin with

3 u‑glycemia is a reasonable primary endpoint

4 per se. There likely will be symptomatic

5 correlates with that type of endpoint, but

6 the interpretability of that endpoint is not

7 contingent upon symptomatic correlates;

8 meaning, that endpoint of avoidance or

9 minimal use of insulin with u‑glycemia in

10 and of itself is a clinically meaningful

11 endpoint. Is that correct?

12 DR. SILVERSTEIN: Could I ask a

13 question? We\'re talking a lot about

14 hypoglycemia, but one of the indications for

15 islet transplants was also metabolic

16 instability, with I believe two or more

17 episodes of DKA in a year. We haven\'t

18 addressed that at all. But I think that

19 that is a reasonable inclusion criteria,

20 assuming that the person has been compliant

21 and has received optimal insulin therapy

22 before hand.

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1 To that end, I would think that we

2 should use not only episodes of

3 hypoglycemia, but number of episodes of DKA

4 as an endpoint to be monitored.

5 DR. RAO: What\'s there as part of

6 the monitoring and the readout and what has

7 been followed. But it\'s an important point.

8 Something to keep in mind.

9 I\'d like to go on and try and get

10 some discussion. We can come back to it if

11 we have time, if there\'s any burning

12 question left. But let\'s consider the

13 section question as well. I\'m going to read

14 this out, because I want and try and make

15 sure that we get this all clear to people,

16 including myself.

17 It says \"regarding the overall

18 clinical development program for responses

19 allogenic islets, please discuss the

20 importance and the meaningfulness of the

21 following types of clinical data with

22 respect to the ability to form a

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1 risk/benefit assessment of the product.\"

2 I read this to mean that you use

3 this, and you now want to predict what is

4 the risk of using this, and in some set of

5 tests or in some sort of criteria, what is

6 the benefit? For me, this was a little bit

7 hard, because from all the data that we

8 heard, even though it\'s preliminary, there

9 didn\'t seem to be any risk.

10 I know I\'m stating this too

11 boldly, mainly for effect, but that is true,

12 right? There was no adverse response to

13 report. There were no deaths. There\'s no

14 infection criteria to report.

15 DR. LEVITSKY: The risk of

16 immunosuppression with renal disease though

17 is still ‑‑

18 DR. RAO: Yes. Exactly.

19 DR. SHAPIRO: Just to clarify. We

20 didn\'t say there was no risk. We said that

21 that was acceptable, and that there were no

22 deaths or life‑threatening events. It\'s not

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1 the same as saying this is risk‑free.

2 DR. RAO: It certainly helped

3 start the conversation, didn\'t it? Go

4 ahead, Dr. Silverstein.

5 DR. SILVERSTEIN: One of the

6 issues we don\'t really know is what the

7 long‑term affects, or even how long the

8 lipid elevations will remain after you begin

9 therapy. I want to just agree with

10 Dr. Sherwin that I believe that some measure

11 of cardiovascular outcome should be

12 included. Somebody mentioned that they were

13 already doing some intimal chorodid (?)

14 thickening studies. That\'s a hard one to

15 reproduce. Maybe even brachial artery or

16 radial artery tonometry might be easier and

17 more reproducible, but something like that

18 might be of use.

19 DR. RAO: Do you have a comment?

20 SPEAKER: One of the major risks

21 for me ever present is infection. Not that

22 I get more infections, but if I get an

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1 infection, it is major in a minute. It just

2 blows up. So that is a constant risk on

3 immunosuppressives.

4 DR. HARLAN: I just want to

5 mention some of the risks that we have seen

6 in our six patients. We\'ve seen anemia in

7 five of the six; thrombelsidapenia in four

8 of the six; neutropenia requiring GCFS

9 treatment in two; peripheral edema; profound

10 fatigue in a couple. Renal insufficiency in

11 one requiring discontinuation of the agents.

12 Severe diarrhea in a couple. Mouth ulcers

13 in the five of the six. Arthralgias,

14 fatigue. Two of patients have been here to

15 tell you it\'s a great thing. But it is a ‑‑

16 DR. RAO: We should say whether

17 these are short‑term ‑‑ early versus late.

18 DR. HARLAN: They can be late.

19 One of our patients who was

20 insulin‑independent for 19 months developed

21 a Rapamyacin‑induced numimytis, which is a

22 known complication of the agent that didn\'t

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1 respond to decreasing the doses, and

2 eventually for her, she said it\'s been

3 wonderful being off insulin for 18 months,

4 but I\'ve had enough.

5 So there are problems associated

6 with it. I feel like I\'m frequently the one

7 saying the downside of this, but you\'ve

8 already heard from two of our patients that

9 have experienced the miracle of it, too.

10 It\'s not free. That\'s for sure.

11 DR. HERING: I think it is

12 important to emphasize that, like it was

13 said before, that islet transplants should

14 be done in centers that have expertise with

15 the management of immunosuppression. You

16 may want to point out how many patients have

17 you immunosuppressed before you enrolled

18 your first patient into this one clinical

19 trial.

20 I think this is perhaps part of

21 the equation, and I want to make this point

22 because this is an expertise that is

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1 required, and it is not to say that if you

2 have this expertise, you can prevent

3 complications, but it will clearly add to

4 the safety of the patient care if this

5 expertise is available.

6 DR. RAO: Maybe I can ask you this

7 question. Since immune suppression is

8 life‑long, it means the follow‑up in terms

9 of the risk that one has to worry about is

10 life‑long in case of this patient? Is that

11 what would the consensus perhaps in terms of

12 the complications associated with immune

13 suppression?

14 DR. HERING: I agree completely.

15 We have no understanding of the risk of

16 immunosuppressive protocols that we use at

17 this point in time. Immunosuppressive

18 therapy has undergone major changes. We

19 assume and believe, that the risk/benefit

20 profile has improved, but I agree with you.

21 The long‑term implications are completely

22 unknown, have not been studied. That is why

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1 it is more than reasonable to follow

2 patients long‑terms.

3 DR. RAO: Dr. Sherwin.

4 DR. SHERWIN: I may be wrong,

5 because it\'s not my area. But my impression

6 is that there\'s accelerated arthrosclerosis

7 in patients who received transplants in

8 general, not this kind. So from my

9 perspective, that\'s my big fear. And I

10 don\'t know why that is. I don\'t know if

11 anybody has any ‑‑

12 DR. SALOMON: I think it\'s correct

13 what Dr. Sherwin says. If you look at

14 liver, kidney, and heart transplants ‑‑

15 hearts maybe not quite fair because there\'s

16 more going on there ‑‑ but if you look at

17 liver and kidney transplants, pancreas

18 transplants, there\'s certainly an increased

19 incidence of ischemic cardiovascular and

20 peripheral cardiovascular disease.

21 The mechanisms are something that

22 we\'re intensively aware of right now in the

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1 transplant field. Because to be honest with

2 you, as our success is now routinely getting

3 out at 10, 12, 15 years, the focus in the

4 field has appropriately turned to the fact

5 that the major cause of a kidney transplant

6 failing, after chronic rejection, is

7 basically the patient dying of an ischemic

8 cardiac event with a functioning kidney.

9 That\'s been a real wake‑up call over the

10 last 5 or 10 years in our field.

11 Issues. Hypertension\'s been

12 extremely poorly controlled. We probably

13 have not been anywhere near aggressive

14 enough in lifestyle changes, dietary

15 changes, exercise, and functionality. We\'re

16 experiencing the transplant population in

17 intense microcosms of what\'s happening in

18 the whole society in general. Because of

19 the other risk factors present in this

20 group, it\'s amplified manyfold in the

21 transplant population.

22 So without going on a lot further

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1 than that, I think that\'s an area that is

2 part of transplantation and

3 immunosuppression. It\'s absolutely a part

4 of this discussion today. It\'s something

5 that we need to do better, and we\'re trying

6 really hard at it.

7 DR. HARLAN: Yes, in response to

8 Dr. Hering\'s question, I\'ll start with a

9 general response and then a specific one.

10 The general one is, as I alluded earlier

11 today to this recent paper in The New

12 England Journal that looked at the incidents

13 of renal insufficiency in the transplant

14 population. It\'s a significant proportion,

15 anywhere from 7 to 21 percent of patients

16 that get a non‑kidney transplant that end up

17 with renal insufficiency.

18 We know that the number one

19 predictor of mortality of patients with

20 diabetes is if they develop kidney

21 insufficiency. Number one.

22 Number two is we have an analysis

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1 that looks nationwide in this country

2 from 1995 to the present date to what the

3 impact on survival is of a patient that gets

4 a pancreas graft if they\'ve got normal

5 kidney function, and it\'s not good.

6 Those patients do less well than

7 similar patients that don\'t get the

8 transplant. If you look at the one endpoint

9 that everybody in this room would agree

10 upon, and that\'s whether the patient is

11 alive or dead; that most of that mortality

12 does occur in the immediate post‑transplant

13 period, but the risk of death never gets

14 better in the transplant group. That\'s

15 cause for concern. I think that\'s due to

16 the immunosuppressive protocol.

17 Then the last point is that it\'s

18 true that I never had much experience with

19 immunosuppressive therapy before we

20 transplanted our six patients, but we\'re a

21 member of a team that has three experienced

22 transplant surgeons, and all of our

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1 immunosuppressive dose adjustments were made

2 with advice and consent from them, and that

3 our transplant unit success at the NIH has

4 been 100 percent graft survival at one year.

5 So I think that our experience is really not

6 different than what anybody else sees.

7 DR. ALLAM: Clarification on two

8 points, actually. One is, if you had 50

9 percent of your islet cell patients over a

10 long period of time develop renal

11 insufficiency, would that preclude you doing

12 islet cell transplants, even if you had

13 like, say, 25 to 50 percent of the patients

14 who needed a kidney transplant in 20 years,

15 would that preclude the islet cell

16 transplant?

17 The other issue I wanted to

18 address too is, you make it sound like you

19 don\'t have any adverse events. So he was

20 saying he has anemia, thrombelsidapenia in

21 some of his patients. Do you not see that

22 at all in your patients?

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1 DR. SHAPIRO: I did outline in my

2 presentation, and for the sake of time, I

3 didn\'t have a chance to go through every

4 single line item and report complications.

5 I highlighted the major points. The

6 bleeding risk in 14 percent of patients.

7 Anemia we\'ve seen in about 10 to 15 percent

8 of patients. Mouth ulcerations about 85

9 percent of patients. An acute transient

10 event that resolves over time.

11 Patients requiring statin therapy

12 in 44 percent of patients. Peripheral edema

13 in about 10 percent of patients. The MRI

14 changes in the liver that I mentioned to

15 you, with steatosis in about 22 percent of

16 patients. Left side ‑‑

17 DR. ALLAM: Wouldn\'t consider

18 those a risk, though.

19 DR. SHAPIRO: Say again.

20 DR. ALLAM: Those would not be

21 strictly considered a risk. They\'d just be

22 construed ‑‑

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1 DR. SHAPIRO: You\'re asking about

2 adverse events. These are a summary of

3 adverse events that are reasonably

4 frequently encountered in islet transplanted

5 patients. They may not be life‑threatening,

6 but they\'re adverse events. So I certainly

7 wouldn\'t want you to go away with the

8 impression that there are no adverse events

9 in an islet patient.

10 DR. HERING: Yes, I think we

11 clearly see complications like this was

12 presented here. But I think you have to see

13 the big picture. We also understand that

14 patients have not completely nominal

15 function if you use very sophisticated

16 tests.

17 But I think you have to really

18 balance the risk and the benefits, and if I

19 listen to patients like today, I see there

20 could be substantial benefit. And you have

21 to balance this. I think this is what will

22 be important and needs to be studied.

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1 I think many years ago, in a major

2 pancreas transplant program as part of a

3 quality of life study, patients were asked

4 what is more difficult or more challenging

5 for you, to manage diabetes or to manage

6 immunosuppression? 95 percent of the

7 patients said managing diabetes is more

8 difficult.

9 Then patients who lost their

10 pancreas transplant function and had

11 undergone major surgery were asked, would

12 you recommend this treatment to your best

13 friend or to your family member? The vast

14 majority said yes, I would recommend this

15 treatment to my very best friend, even

16 though I rejected or lost my transplant.

17 I think we have to keep this in

18 context. We are all aware of the problems

19 of immmunosuppression. That is why all our

20 research, experimental and clinical, is on

21 immunosuppression and on improving

22 immunosuppression. We are clearly aware,

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1 but we also see benefits that are associated

2 with the treatment that is delivered. We

3 understand this needs to be studied and

4 documented.

5 DR. ALLAM: The hypothetical. If

6 islet cell patients at 10 years down the

7 line require a kidney transplant, let\'s

8 say 25 percent of them, you\'re considering

9 doing islet cell transplants and you\'re a

10 kidney transplanter, would you advise your

11 patients ‑‑ I mean, how would you deal with

12 this?

13 DR. SALOMON: Well, the problem

14 with judging the incidence of kidney failure

15 in a diabetic population is the starting

16 setpoint of how much damage has been done to

17 the kidney before you do the islet

18 transplant. The way things are going right

19 now, a lot of these patients, really all of

20 those patients, have had diabetes for a long

21 time.

22 The mean time of onset of kidney

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1 disease after the initial diagnosis of

2 diabetes is 17 years. It occurs in about 30

3 percent of diabetic patients. Most of these

4 patients who are getting islet transplants

5 right now are 17, 20 years plus

6 post‑transplant. Because of the populations

7 that we\'re looking at. You know, people

8 who\'ve had years of difficult to control

9 diabetes, or years of these hypoglycemic

10 events. There may be exceptions. Do you

11 know, Bernhard or James, what the mean age

12 onset after ‑‑

13 DR. RAO: Yes, 26 years.

14 DR. SALOMON: So just as a reality

15 check to what I\'m telling you. At that

16 point, if you had a kidney biopsy on every

17 one of these patients ‑‑ and that\'s not a

18 crazy concept by the way ‑‑ you would find

19 in essentially 30 percent of them

20 significant changes already. So once you

21 had a calcineurin inhibitor regimen into it

22 and then you follow it out 10 years, it\'s

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1 just a question of how many of those

2 patients without the calcineurin inhibitors

3 would have ended up with renal disease, and

4 that has to be figured in. That\'s not such

5 an easy one to answer.

6 But the fact is, I think, I agree

7 with what Bernhard said as well. This is a

8 moving target, and that immunosuppression is

9 consistently now changing. We\'ve been given

10 this whole bunch of really potent new drugs

11 over the last five years. We\'re really now

12 getting much better at using them. The idea

13 of using calcineurin‑free immunosuppression

14 is something that I think is going to become

15 a reality in many programs over the next

16 five years.

17 I was telling at lunch, we have an

18 experience now that just got finished two

19 years out, 60 patients, 30 on a calcineurin

20 inhibitor regimen and 30 without kidney

21 transplants: Their mean creatinines are 1.8

22 m/dL in the calcineurin group and 1.0

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1 milligrams, I mean totally normal, in the

2 Rapamyacin group at two years.

3 These are things that can be

4 accomplished, so I think that\'s kind of

5 putting it into context, if you will.

6 DR. HERING: I think the opposite

7 is also true. Clearly, I agree with you

8 that you see problems, and 10 to 25 percent

9 may have required a kidney transplant, while

10 very high dose calcineurin inhibitor therapy

11 was used. Some patients seem to have a

12 genetic predisposition, even in the context

13 of low dose of therapy.

14 But there is another documented

15 subgroup of patients who showed, based on

16 kidney biopsy, evidence of diabetic

17 nephropathy of the time of pancreas

18 transplantation. Patients were biopsied 5

19 and 10 years later ‑‑ and this was published

20 in 1998 in The New England Journal of

21 Medicine. All diabetes‑related changes

22 basically had resolved.

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1 So I think you see both pictures.

2 I think that\'s why you need to select your

3 recipients very carefully and try to

4 minimize risks.

5 DR. SHERWIN: I think that\'s a ‑‑

6 DR. SALOMON: That\'s a really good

7 point. I just wanted to say that in my

8 discussion, that was omitted, and I\'m glad

9 Bernhard brought it up, and that is true. I

10 think the appropriate response here is that

11 this a good discussion now of risk and

12 benefit, and this is what has to constitute

13 the informed consent for these patients.

14 DR. SHERWIN: But I would bet that

15 renal disease would probably be better as a

16 result of this therapy, on balance. That

17 would be my guess. The only one that I

18 worry about is the cardiovascular side, to

19 be honest.

20 DR. RAO: So let\'s try and see

21 from what we\'ve heard in terms of risk. The

22 sense seems to me from listening to everyone

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1 is that the predominant risk is the immune

2 suppressive therapy that the patients

3 undergo. It\'s a moving target, but you

4 really have to monitor, just like you would

5 in any immune‑suppressed patient. The

6 things that you worry about are the kidney,

7 the liver, the heart, and those will need to

8 be monitored.

9 Before we move on to the other

10 sort of aspects or subheadings in this

11 section, is there any other additional risk

12 from islets specifically that one needs to

13 monitor or one thinks may be important in

14 terms of looking at this?

15 DR. RICORDI: Yes. To me, the

16 major risk in this procedure is an

17 inexperienced team performing it. I think

18 there will be direct proportionality of the

19 severity and the number of side effects, the

20 rate of failure. And I\'m not pointing out

21 any one specific one problem. But it is

22 very dangerous to generalize, if you have an

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1 experience with a few patients; if you see

2 very high incidents of complication or side

3 effects, then you should critically

4 reevaluate what they\'re doing, compare the

5 results with those of others and prepare to

6 move to the next step.

7 In pancreas transplantation, which

8 is not regulated by FDA, a center that I

9 will not name had decided to enter into the

10 field, and they had three out of their first

11 four patients died following pancreas‑alone

12 transplantation. The suggestion to that

13 group was to stop. There was no FDA

14 imposing.

15 That is something that comes from

16 your community, the hospital. So it is

17 really something that shouldn\'t be

18 underestimated. In the case of islets,

19 maybe less dramatically, but that is a risk

20 there should be considered. So the issue\'s

21 not can be done, because it has been shown

22 that it can be done. It is not should be

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1 done, because I think has been demonstrated

2 that it should be done. The real issue is

3 who should do it at this stage.

4 DR. LEVITSKY: Dr. Ricordi, you

5 just gave me the opening I was waiting for.

6 We were sitting at lunch today talking about

7 the fact that none of us had asked a very

8 important question, which is that we were

9 shown 10 centers in the larger study and 3

10 of them did superbly and some of the others

11 didn\'t so well at all. We never found out

12 whether it was an islet problem or some

13 other problem. Are there data on the

14 quality of the islets at the different

15 centers?

16 DR. SHAPIRO: That question was

17 asked. There is some data on the quality of

18 the islets. There\'s also some data on the

19 immunosuppressive levels in the patients

20 that were maintained or weren\'t maintained.

21 In four of six cases, in fact, where there

22 was early rejection events.

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1 So I think cumulatively, there is

2 data to suggest reason for graft failure at

3 those sites was islet‑related in some cases,

4 graft‑related in others,

5 immunosuppressive‑related in others.

6 Ongoing analysis is going to outline that in

7 a little bit more detail.

8 DR. RAO: I think it\'s not really

9 relevant to the kind of question we\'re

10 trying to answer right now. So I\'ll wait on

11 that.

12 DR. O\'NEILL: One of the risks

13 that haven\'t really been discussed but were

14 presented by Dr. Shapiro were the risks

15 involved with the transplant procedure

16 itself, with bleeds, thrombosis, and

17 bleeding. I think that\'s something

18 certainly the panel should discuss.

19 DR. EGGERMAN: One other issue

20 that was discussed yesterday I didn\'t hear

21 you mention were related to the possible

22 sensitization if you have multiple donors

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1 that are supplying islets for an islet

2 recipient, for subsequent transplantation.

3 DR. RAO: Dr. Sherwin, do you have

4 anything to add?

5 DR. SHERWIN: The islets are put

6 in the liver. So one issue, even though the

7 data so far don\'t support it, is steatosis,

8 possibility of nash, (?) even though it

9 seems unlikely. The other question I would

10 have is when islets are put in the liver

11 does the insulin escape the liver? Is there

12 peripheral hyperensonemia (?) as a result or

13 not? If that has implications perhaps in

14 terms of cardiovascular disease.

15 DR. SHAPIRO: Maybe I can answer

16 the issue first about the concern about

17 nonalcoholic steathohepatitis, and is this

18 going to be a risk in the 22 percent of

19 patients we\'ve identified that have

20 steatosis on MRI. I don\'t think we have

21 long‑term data in our patients today.

22 I think we as a group regard the

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1 MRI findings as being benign and expected in

2 islet patients, which in our feeling is that

3 these are unlikely to have long‑term

4 sequelae. The reason in addition to that

5 that we feel this way is that islet

6 autografted patients have similar findings,

7 and some of those patients are followed up

8 beyond 18 years and do not have nash. So

9 our feeling is that that is unlikely.

10 Your second question: Is insulin

11 spilled from the islets into the systemic

12 circulation, whether or not it\'s embolized

13 to the liver and re‑vascularizes through the

14 pancreatic arterial system. The answer is

15 probably yes. Exactly how much insulin then

16 follows through the portal circulation and

17 is how much is delivered systemically, I

18 don\'t think we know for sure.

19 I think very detailed clamp

20 studies and hepatic vein instant output

21 monitoring might be required to define that

22 in more detail. I\'m not personally aware of

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1 data that really defines that today.

2 DR. RAO: I want and try and move

3 on to the next few questions as well,

4 because those are really quite important in

5 terms of issues for what happens with any

6 kind of study.

7 DR. SALOMON: Mahendra, do you

8 want to answer one last question here? That

9 is, do we mean it should be three years,

10 five years?

11 DR. RAO: I tried to get a summary

12 on that, and it seemed that the biggest

13 complication was immune suppression, and for

14 that you\'d have to have long‑term, but that

15 there was no pre‑submission data that you

16 could collect because the data was

17 short‑term for almost all the patients that

18 were there.

19 DR. SALOMON: Certainly for

20 immunosuppressive side effects, two to three

21 years would be good for a large number of

22 them. Not all of them of course, but almost

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1 all the serious infectious complications

2 occur in the first year. Most often, things

3 like PTLD occur in the first, though I don\'t

4 think that\'s really a big risk here

5 actually. Hypertension, cardiovascular,

6 risk factor increases.

7 So the only thing that would

8 really require more than two years follow‑up

9 to answer those questions would be actual

10 measurements in changes in, let\'s say, I

11 like the idea of the retinal pictures and

12 measurements of vascular function; several

13 were mentioned. That would take 5 to 10

14 years probably.

15 MS. HARVEY: Can I just make a

16 comment on that? I know it\'s not easy, but

17 I come back to what is it that the FDA is

18 going to be giving approval on for the BLA

19 that we\'re talking about? This a very

20 important aspect for the patients, the

21 overall risk/benefit. But should we really

22 be studying the long‑term implications of

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1 the immunosuppressant therapy as part of the

2 approval of the islet cells and their

3 effectiveness? I don\'t know the answer, but

4 I just raise it as a question around.

5 Should we really be looking at the

6 immunosuppression piece of that or not?

7 DR. SALOMON: Just so my comments

8 are clear, I was responding to a factual

9 question. You know, how long do you have to

10 follow it? That\'s the answer, as best I can

11 say, based on my experience. I wasn\'t

12 trying to imply that you\'d hold up a BLA

13 approval for 5 to 10 years while you finish

14 this, no.

15 DR. RAO: Go ahead.

16 DR. DAPOLITO: Just a comment, and

17 again getting to what Dr. Lawton was talking

18 about. It gets back to the choice of the

19 benefit outcome, the primary endpoint in

20 these studies. It sounds as if what I\'m

21 hearing is that the panelist is comfortable

22 accepting clinical data that from the basis

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1 from a risk/benefit analysis that does not

2 include long‑term follow‑up data, such that

3 the committee, depending on how persuasive

4 the benefit is, would accept the risk that

5 there is a potentially substantial mortality

6 disadvantage in the long‑term associated

7 with the product, if I\'m understanding

8 correctly. Am I wrong?

9 MS. MEYERS: It sounds to me like

10 it\'s not the product, it\'s the

11 immunosuppressive agents that are used.

12 That\'s were the risk is.

13 MR. DAPOLITO: Again, it gets back

14 to that we don\'t operate in a vacuum. As

15 with all concomitant therapies, you look at

16 the entire package.

17 DR. RAO: Let\'s move on to the

18 next aspect, because I think it will

19 illustrate some of these things more and it

20 will help.

21 DR. RICORDI: Can you just keep in

22 mind also that we do also islet after kidney

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1 in patients that are already taking

2 immunosuppression, in which we don\'t think

3 they interfere with the selection. In that

4 case, there is no added risk of the islet

5 procedure. So we\'d like to if possible

6 suggest that we keep separate, and what is

7 the risk associated to the product, and it\'s

8 a figure set to the risk of

9 immunosuppression that is in constant

10 evolution, hopefully in the right direction.

11 DR. RAO: Yes, I think here, all

12 we\'re trying to look at was what are the

13 kinds of monitoring things in terms of

14 assessing risk and benefits. To me, this

15 was really an important question and I think

16 it\'s something to really consider,

17 historically controlled clinical data. How

18 does one compare, and how specifically the

19 appropriateness of the use of historical

20 controls in the whole development, and

21 whether data from studies that have no

22 concurrent controls would be sufficient to

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1 provide substantial evidence of

2 effectiveness of the product.

3 Spots of this issue were raised

4 where people said, well, should we be

5 implanting insulin pumps in any kind of

6 study, or you know, is that the concurrent

7 control? Or can we can just look at the

8 historical controls since the endpoints are

9 so clear‑cut in terms of looking at insulin

10 independence. We know what happens with the

11 patients in terms of if they are labile and

12 that subgroup has clear predicable outcome,

13 can we use historically controls.

14 Maybe just some sense from people,

15 in a yes and no fashion, so that we can then

16 have a discussion on it.

17 DR. SILVERSTEIN: Could I just

18 bring up one that you haven\'t mentioned,

19 which is having the patient serve as his or

20 her own control. We could actually, in this

21 scenario, fulfill Cox Postulates, because

22 you have them before, you have them during,

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1 and in a certain proportion of them, they\'ll

2 fail and go back to the way they were

3 before.

4 DR. RAO: That\'s an important

5 point.

6 DR. HERING: Yes, I would like to

7 echo this point. I think that the point

8 that needs to be made in this context is

9 that islet transplants are considered

10 predominately if not exclusively in patients

11 in whom other treatment options have

12 consistently failed to ameliorate the

13 situation.

14 So you cannot possibly compare to

15 insulin pump treatment. That is why it

16 might be difficult to randomize patients,

17 because the control arm has failed to

18 deliver.

19 DR. RAO: These are really

20 important points. I\'d like to bring up

21 peoples\' opinions on them. Dr. Salomon.

22 DR. SALOMON: Yes, I was just

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1 going to say I agree completely that a

2 randomization protocol would be hard to

3 follow, with these hypoglycemic unawareness

4 patients, for example. I think you would

5 have ethical problems, but I defer to my

6 colleague, Jim Childress, for that.

7 But in contrast, there is a group

8 that was mentioned by Camillo that I

9 personally favor, and that is the

10 islet/kidney combination, because there,

11 we\'re going to immunosuppress them for the

12 kidney transplant anyway. In those

13 patients, actually, you could number one,

14 have a control group, because there\'s plenty

15 of patients who are going to get kidney

16 transplants that could be compared in the

17 same center with similar immunosuppressive

18 regimens.

19 But I would say, just to finish,

20 that historical controls, to say that we

21 support those I think would contradict

22 everything we\'ve been saying. Because I

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1 can\'t tell you five minutes ago that, you

2 know, we\'re evolving our experience and our

3 skills using these immunosuppressive drugs

4 and then tell you right now that I think

5 historical controls are fine.

6 DR. RAO: There was an important

7 idea here, right, and we heard a little bit

8 more about, is that the patient has already

9 failed therapy. You follow them, so you

10 have pre‑ and then you have post‑, and then

11 you have a follow‑up which is mandated, and

12 could a patient in that sense serve as their

13 own control so that you wouldn\'t really need

14 to ‑‑ or would that be sufficient in

15 peoples\' minds?

16 DR. O\'FALLON: Well, I\'m going to

17 have to say no.

18 DR. SHERWIN: No. No, yeah.

19 Yeah. First of all, historical controls I

20 would not accept. Number two, what Janet

21 described as a reasonable approach, it

22 depends on how definitive you want the

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1 answer. I\'m a little concerned about the

2 history before patients going in. I mean,

3 the problem you face is that the level of

4 care that\'s delivered to the patient has a

5 lot to do with the outcome. Ideally, what

6 you\'d like to do is compare head‑to‑head in

7 some way; either note change in therapy in a

8 group of patients that were defined.

9 I mean, the problem is defining

10 the population to start with, and then in

11 that population demonstrate a difference

12 Ideally, you would like to compare it in

13 part to the best therapy available, and

14 ideally, you\'d like to compare it with pump

15 therapy and show it\'s better, and that would

16 be a very useful piece of information, and

17 it would really put islet transplantation on

18 a map definitively, and it wouldn\'t have the

19 diabetologists arguing that we have a better

20 therapy.

21 On the other hand, I think it

22 depends on finances, a lot of other issues.

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1 I think if you have good historical data

2 before and after, it\'s reasonable. It\'s not

3 the best. The best is head‑to‑head, do it

4 like a regular clinical trial just like you

5 would do a drug.

6 DR. RAO: Go ahead.

7 DR. LEVITSKY: I agree with that.

8 I would just add one thing, which is, you

9 could have in your control group a crossover

10 option if they met certain stopping rules.

11 Like they had x‑many life threatening

12 hypoglycemic events.

13 DR. SHERWIN: Absolutely.

14 DR. LEVITSKY: So that you could

15 keep everybody safe, and it could be a

16 6‑month or a 12‑month time frame so that you

17 weren\'t ‑‑

18 DR. SHERWIN: Yes. I would

19 totally agree with that. I mean, in fact,

20 that would be one way of inducing people to

21 be randomized, is they would have the

22 option, depending on the data, to be first

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1 in line.

2 MS. HARVEY: One of the issues

3 with all of this discussion, as always the

4 case with controls, is the ethical issues

5 for the patients, with the treatment versus

6 the standard of care, which we\'ve heard is

7 not good enough at the moment.

8 The one issue I wanted to raise

9 is, from the discussions from around this

10 source material, it seems like over the last

11 couple of days everything we\'ve heard is

12 there\'s not enough pancreases to go to the

13 patients available. So why would we not use

14 the excess patients who are getting standard

15 of care without the islet transplantation as

16 a control group?

17 DR. O\'FALLON: That was exactly

18 what I was going to say. We\'ve been told

19 there\'s a waiting list. All you\'d probably

20 have to do is set up a monitoring system so

21 that you were following the people on the

22 waiting list to the same extent that you

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1 were following the people that were getting

2 the transplant. That\'s not perfect, but ‑‑

3 DR. SALOMON: No. The problem

4 with waiting lists; if we talk about a year

5 follow‑up maybe, you\'re pushing it on the

6 waiting list, but that\'s possible. But you

7 really are asking for three‑ to five‑year

8 follow‑up eventually, then your design\'s

9 flawed from the very beginning, because

10 nobody\'s going to be on your waiting list

11 for five years. There\'s too much going on

12 in that patient to ‑‑

13 DR. SHERWIN: Right. If your

14 indication is severe hypoglycemia, if that\'s

15 the defined beginning group that you\'re

16 looking at, then you don\'t need that. I

17 think if you focus in on that complication,

18 we\'re talking about no more than two and

19 maybe one year.

20 DR. SALOMON: But the problem is,

21 I remind you how it would look then. So we

22 start the trial together, and five years go

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1 by. We get up at a major meeting event of

2 endocrinologists and conclude that it\'s

3 fantastic, based on the fact that the

4 patients were really different over a

5 six‑month period compared our patients in

6 five. Then someone like Abbey says but the

7 immunosuppression was a major risk factor,

8 and you immunosuppressed all your patients

9 for five years. Where\'s your control group

10 for that?

11 DR. ALLAM: Those are two

12 different questions. So you\'re really

13 asking for two different control groups.

14 You\'re asking for a control group on risk

15 and a control group on efficacy; right?

16 DR. RAO: Dr. Shapiro?

17 DR. SHAPIRO: Just a point of

18 clarification. Are you asking or suggesting

19 for a randomized comparison of patients on

20 pump therapy versus an islet transplant? Or

21 are you proposing, as we\'ve doing so far,

22 taking on patients that have failed on pump

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1 therapy and giving them an islet transplant?

2 DR. SHERWIN: I have to think

3 about that. It depends on how they failed,

4 why they ‑‑ I mean, I don\'t 100 percent

5 know. Assuming that they failed and then

6 you could document a lead‑in period well

7 enough, perhaps that would be a reasonable

8 approach. I mean, I won\'t argue that. I

9 just worry when I hear that they couldn\'t be

10 managed, and therefore, they need this

11 therapy. I\'d like to define a group that

12 has a serious problem, randomize them to one

13 therapy that I think is the best, compare it

14 to the other and show a difference. I\'d

15 like them all starting out at the same part.

16 That\'s the best way to do it.

17 DR. RAO: So can we make a

18 statement here then? I mean, it seems to me

19 a very clear‑cut, absolute consensus here

20 was that historical controls are not

21 adequate, and that seems very clear. There

22 was some idea that one needed a comparison,

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1 and it\'s not clear what that comparison is

2 and we\'re not really making an absolute

3 suggestion on a comparison. But clearly

4 there has to be some kind of comparison, and

5 it should be on a reasonable time point.

6 Since the criteria for inclusion

7 is hypoglycemia in this case as having, you

8 know, uncontrollable hypoglycemic episodes,

9 then perhaps you could have a short‑term

10 read‑out in terms of looking at that in any

11 kind of comparison, which would be done.

12 There would have to be of course discussions

13 on what kind and whether it could be

14 particularly accurate, and whether there

15 would be crossover issues, et cetera. But

16 that would be something that would be ‑‑

17 would that ‑‑

18 DR. SALOMON: I\'d say the clear

19 point that I think Dr. Allam made was there

20 could be efficacy controls and side effect

21 controls, and that we should deal with those

22 separately. The other point I think, just

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1 to add what you just said, is that depending

2 on the trial design, the controls could be

3 different. As I said, a control for the

4 kidney/islets is really rather reasonable to

5 ask for since there are going to be many

6 patients getting kidney transplants that

7 with diabetes that won\'t get islets in the

8 same center, or certainly in an adjacent

9 center with an equivalent immunosuppressive

10 protocol. So that would be a much easier

11 group. So I think you\'ll adjust your

12 controls and the application to the trial

13 design.

14 DR. RAO: I think that seems like

15 a pretty fair consensus. Since we have some

16 time, there are two important questions.

17 I\'m not sure we\'re going to get to all of

18 this here, but it\'s the third part of the

19 question. There are two parts. I\'m going

20 to try and see if we can slide through the

21 last part and see whether we can get some

22 kind of general consensus.

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1 \"Additionally, please discuss

2 those baseline characteristics that you

3 regard as important for a sponsor to

4 consider in the clinical development of the

5 product.\" To me, this seems like inclusion

6 criteria, how do you decide what kind of

7 patients you\'re going to include. We heard

8 presented here that there was a very

9 clear‑cut and narrow definition of patients

10 that were going to be considered in this

11 case, and these were these severely

12 hypoglycemic, who\'ve had more than two

13 episodes of hypoglycemia and had tried

14 conventional therapy and failed it in some

15 definite criteria.

16 Is there specific inclusion or

17 exclusion criteria, based on what you\'ve

18 heard so far in terms of age, extent, or

19 nature of diabetic complications, which are

20 absolute exclusionary or inclusionary, or

21 things that have not been considered that

22 one would want to?

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1 DR. SHERWIN: I don\'t know. To

2 try to resolve that one question, I would

3 think people with other complications,

4 cardiovascular disease, for example. If

5 someone had angina, I would be a little

6 concerned about enrolling them in a trial

7 like this. It would be mainly I think the

8 severity of complications. I don\'t have

9 enough experience compared to the ‑‑

10 DR. RAO: What about pre‑existing

11 kidney failure or something? Is that ‑‑

12 DR. SHERWIN: You know, kidney

13 disease in and of itself can alter the rate

14 of hypoglycemia. So if you had a control

15 group, you\'d have to standardize it. If I

16 had my way, I would avoid that, but I don\'t.

17 Personally, as a scientist, I\'d like to keep

18 it as clean as I could. But the surgeons

19 might have a totally different perspective,

20 and they have more experience in this area.

21 DR. VINER: I wonder if there

22 might be some way of including the

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1 population of patients where immunotherapy

2 might be considered a benefit as opposed to

3 a risk. That group of patients may be

4 patients like rheumatoid arthritics that

5 also have diabetes, where there\'s a

6 coexistence of autoimmune disorder, and they

7 have therapeutic benefits from the ongoing

8 immunotherapy. I wonder if there\'s been a

9 selection of patients so far to date, and if

10 that\'s been considered.

11 DR. LEVITSKY: In order to obtain

12 a group that you want to study that will

13 have an immediately accessible endpoint, you

14 need a very small, well‑defined group of

15 patients who have ‑‑ in this case, we\'ve

16 selected very severe hypoglycemia as the

17 endpoint. If we were also to look for

18 people with severe hypoglycemia and

19 rheumatoid arthritis, we would have to cast

20 a rather wide net. I don\'t think you could

21 do that. I think that won\'t be ‑‑

22 DR. RAO: Go ahead, Dr. Harlan.

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1 DR. HARLAN: We are approaching

2 this question along this line exactly. I

3 have a couple provisoes, and I promised

4 James Shapiro I\'d make a statement that I

5 want to make after I make this specific

6 comment that will get to this.

7 But the general comment is that

8 testing immunosuppressives in a population

9 that absolutely needs them, to us, is a

10 patient with Type 1 diabetes and kidney

11 failure that needs a kidney transplant. The

12 way you randomize it is that some of the

13 patients get islets and some of them don\'t.

14 They all get immunosuppressed. They all

15 benefit from the kidney transplant. No

16 question. That\'s well‑established in the

17 literature.

18 They all need immunosuppression,

19 and now you can ask the specific question,

20 do the islets make a difference.

21 DR. SHERWIN: David, is the

22 immunosuppression identical?

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1 DR. HARLAN: Yes, we have that ‑‑

2 DR. SHERWIN: Do we know the

3 outcomes per renal disease?

4 DR. HARLAN: Yes.

5 DR. SHERWIN: Okay.

6 DR. HARLAN: I think that\'s a nice

7 small study; getting enough patients to do

8 is tough. And that addresses one point. I

9 know I\'ve been saying a lot of, cautionary,

10 is the way I\'d word them. Other people

11 would say negative statements about islet

12 transplant.

13 But I absolutely, as evidenced by

14 these two people sitting here, believe in

15 this as a field that needs to be

16 investigated and perfected. We are going to

17 proceed with this. I hope my cautionary

18 comments haven\'t been viewed as too

19 negative.

20 The other statement I\'ll make is

21 that when I say things here, I have to say

22 it, especially because I\'m wearing the

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1 uniform today, I want it to be known that

2 I\'m speaking with an investigator with a

3 passion for this cause, just like many

4 people in this room, but I\'m not professing

5 or any official NIDDK or NIH policy.

6 The third point I wish to make is,

7 I wish these three people and anybody else

8 doing research in this field all the credit

9 in the world for getting a field that all

10 the experts predicted would never be here

11 for 20 years to this point. I hope my

12 negative or cautionary comments haven\'t been

13 viewed other than being very laudatory and

14 respectful for all that they\'ve done.

15 DR. LEVITSKY: You selected an

16 excellent population for study, but from the

17 point of view of immunosuppression, what are

18 you going to use as your endpoints for

19 success in terms of the diabetes component?

20 DR. HARLAN: Maybe I can just

21 discuss this with you privately.

22 DR. RAO: To me, it seems then

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1 that it\'s clear the way the selection of

2 baseline characteristics is nearly defined

3 by very narrow specific population that has

4 been laid out in a reasonable way, and that

5 that\'s reasonable and that there shouldn\'t

6 be any additional specific criteria.

7 It didn\'t seem that ‑‑ even apart

8 for the obvious, right? In terms of obvious

9 complications ‑‑ that for immunosuppression

10 which would be a no‑no or something else

11 that would there, and there\'s no way to make

12 it broader or more inclusionary, given the

13 waiting list and the shortage of material

14 and what\'s existing, so that the criteria as

15 laid out seems to be reasonable in my

16 opinion.

17 I want to try and spend a little

18 of time here, because this is, I think,

19 going to be contentions and a little bit

20 difficult to be able to say this with any

21 definiteness. Let\'s say that you have a

22 small trial or you have a small study, and

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1 you have two arms and it\'s well‑controlled,

2 and you use hypoglycemic episodes as a

3 clinical outcome that you can measure.

4 Can you generalize from this to

5 then say well, you know, here\'s this case.

6 Here, we have islets, they secrete insulin.

7 We know that you can correct an insulin lack

8 by this. Can we generalize it to treatment

9 of other diabetics who need insulin? Again,

10 I\'m making it broader than perhaps one would

11 want, but it\'s a useful way to start

12 thinking of this and say, can we generalize

13 from this? If not, would adding additional

14 parameters to study allow us to generalize

15 from such a study?

16 DR. SHERWIN: Well, I don\'t think

17 you can generalize from the short, small

18 trial. You can maybe generalize with

19 respect to this specific question you

20 address if the study is done well.

21 DR. RAO: Safety.

22 DR. SHERWIN: But the key

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1 question, you know, in terms of looking at

2 the big picture will be safety for all

3 people with diabetes. Most people with

4 diabetes can be treated reasonably well, and

5 we can reduce their complication rate

6 significantly with the current standard of

7 care. But it\'s not perfect.

8 So then you have to say well, one

9 is not perfect and there are problems. What

10 are the problems on the other side to assess

11 risk/benefit ratio? The decision about how

12 far you can expand the group really requires

13 long‑term trials and information that will

14 require five, maybe even seven years to sort

15 out.

16 But I do think that if you show

17 benefitting the most severe patients with

18 hypoglycemia, that the net will expand a

19 little bit beyond that very narrow group,

20 because a lot of people have lots of

21 problems, maybe not quite as bad. And you

22 would begin to increase your net a little

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1 bit. But I don\'t think you\'d want to say

2 that you\'re ready for prime time for all

3 people with diabetes. I think we would need

4 to have more information. That\'s going to

5 take more time, I think.

6 DR. RAO: Dr. Levitsky, do you ‑‑

7 DR. LEVITSKY: No.

8 DR. RICORDI: I just hope that

9 this discussion is not going towards an

10 indication that we should do another five

11 years of randomized trials. This is an

12 important issue. These studies may be done

13 and hopefully should be done. I\'m not sure

14 who would pay for such a large trial. But

15 in pancreas transplantation, for example, or

16 even in kidney transplantation, you have

17 procedures that have never been evaluated

18 prospectively; the kidney versus dialysis,

19 or kidney/pancreas transplantation versus

20 kidney alone.

21 Now there are insurance

22 reimbursable, and so that it would be like a

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1 death sentence to impose to the islet field

2 that you have to show it through randomized

3 trials in the next five years before you can

4 support immunosuppression for the patient

5 that may benefit now. Even if in a reduced

6 cohort.

7 DR. SALOMON: I think that as I

8 said yesterday, when were talking about the

9 product, the same kind of concept is

10 applicable here. It\'s the biology of

11 diabetes in this case, just as yesterday it

12 was the biology that defined the

13 functionality of an islet prep.

14 So in this case, my thinking is

15 that if we look at the data that we have now

16 and maybe refine it over the next few months

17 to fill in the some of the gaps that have

18 come out of these very good discussions

19 today, and demonstrate that the biology of

20 these diabetic patients is really

21 significantly and positively impacted upon

22 by successful islet transplant, that to me

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1 ought to carry a lot of weight.

2 We should be careful. Even though

3 I agree with the concept, if someone asked

4 me the same question you asked Dr. Sherwin,

5 you know, could you generalize from this one

6 little group? His answer is correct.

7 You\'ve got to be careful. I mean, you know,

8 the other group is a diabetic patient with

9 kidney failure.

10 So I totally agree with his

11 comment. At the same time, I certainly

12 would be very careful not to go the other

13 direction, and that is to ignore the

14 tremendous impact on restoring the biology

15 of glucose homeostasis in a diabetic patient

16 for 20, 25 years, who suffered with it, and

17 narrow down things and put another five‑year

18 barrier in front of this field. That would

19 be a real shame.

20 DR. RAO: I think that was very

21 clear from Dr. Sherwin\'s comments.

22 DR. SHERWIN: And that\'s surely

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1 not what I would want to do.

2 DR. SALOMON: I totally agree.

3 This was not directed to you.

4 DR. SHERWIN: It\'s somewhere in

5 between. We want to expand but not

6 indiscriminately.

7 DR. RAO: I think at this point in

8 time, it\'s not say this is a moot point, but

9 the tissue is not available to expand. I

10 think the immunosuppressive treatment is not

11 safe enough to expand. It seems to me it\'s

12 almost a very appropriate setting. So you

13 have a treatment that is available because

14 of donor tissue where it would only

15 deliver 1,000 or 2,000 times a year.

16 There is a patient group that may

17 not be much larger at this point in time

18 that are really in need of treatment that is

19 different from the most sophisticated

20 insulin delivery systems. So I think it

21 kind of is almost a perfect match.

22 DR. O\'FALLON: That just saves us

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1 from having to make a difficult decision,

2 because the fact of the matter is we\'ve

3 defined or we expect to see defined a very

4 small group. If it\'s expanded more than

5 just that little bit that you\'re talking

6 about, we might get into the situation where

7 the therapy is no more effective than what

8 is actually going on now without the

9 transplant.

10 We certainly don\'t have enough

11 tissue and enough pancreata to do this. It

12 certainly seems that a very carefully and

13 well‑designed study in this small

14 population\'s going to terribly important,

15 and they should collect as much information

16 as they possibly can about the biology of

17 what\'s going on.

18 DR. SALOMON: I just want to make

19 sure that the transcript\'s clear, at least

20 from my contribution to it. 30 percent of

21 patients with endstage renal disease in the

22 United States have Type 1 diabetes. That

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1 number\'s shifting around a little bit, which

2 is only because the Type 2 diabetics now are

3 contributing more, so they\'re knocking out

4 some of our Type 1s. Let\'s say 25 percent

5 are Type 1 diabetics. From my point of view

6 at least, you don\'t want to do anything to

7 prevent those patients who are getting

8 kidney transplants and fully

9 immunosuppressed with state‑of‑the‑art

10 immunosuppression; you don\'t want to do

11 anything to create now another barrier that

12 would prevent them from getting an islet

13 transplant.

14 DR. RAO: Would you like to make a

15 comment?

16 MR. DAPOLITO: Dr. Rao, so

17 often ‑‑ the Lead Advisory Committee\'s a

18 little unclear of the message. I want to be

19 sure on something that Dr. Ricordi actually

20 commented on. It goes back about to the

21 discussion about five minutes ago regarding

22 historical controls.

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1 Now, I scratched these notes, and

2 this is what I was hoping to get feedback

3 on. I probably misinterpreted this, but I

4 want clarity. If I understand correctly,

5 the consensus is that historically

6 controlled clinical data present major

7 challenges with respect to data

8 interpretability and are probably

9 insufficient with respect to definitively

10 accessing risk and benefit; meaning

11 conceptually, if a sponsor comes to us with

12 what they regard as efficacy data, but those

13 are not randomized control clinical data, in

14 general, our bias should be that those type

15 data present problems.

16 Could you enlighten me if I\'m

17 misinterpreting?

18 DR. RAO: I don\'t think that that

19 was what was the implication of that

20 statement. Not completely. That isn\'t the

21 way I understood it.

22 DR. O\'FALLON: I think we have to

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1 worry about the interpretation of the word

2 \"historical.\"

3 MR. RAO: Yes.

4 DR. O\'FALLON: \"Historical\" means

5 something that already took place before the

6 study that we\'re talking about. We all

7 talked about several different kinds of

8 concurrent activities that would fall short

9 of the purest textbook definition of a

10 randomized control trial, but at least we

11 were all encouraging each other to expect

12 that there was a possibility that this

13 concurred information could be used.

14 If you used the word \"historical\"

15 correctly as things that took place back in

16 time somewhere, then that\'s what we said.

17 We don\'t want to use that, but it has to be

18 randomized goals.

19 DR. SALOMON: But there was

20 another principle that was in your slides.

21 That was this word \"persuasive.\" I really

22 like that. I think that the first onus is

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1 that whatever the sponsor presents to you is

2 persuasive. On the front page of the USA

3 Today that I managed to glance at as I

4 walked out my hotel room was that a new

5 cancer drug was having significant effects

6 in breast cancer.

7 My response as I was walking out

8 to the door was excellent. That\'s a super

9 good way ‑‑ you know, much better than the

10 headlines in California recently, by the

11 way. My response there is nobody\'s going to

12 hold up the use of that drug for the next

13 five years while they determine the

14 long‑term risks of using it.

15 So I think that \"persuasive\" is

16 the word you have to remember. I mean, as

17 far as I\'m concerned, if you cure diabetes

18 in terms of the biology; if you restore

19 u‑glycemia to a group of patients who\'ve had

20 diabetes for 25 years, that\'s persuasive,

21 and I think you need to put that first, and

22 then everything else comes after that.

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1 DR. RAO: That\'s what I was trying

2 to say when I said not precisely, that no

3 historic controls could be used. Go ahead.

4 SPEAKER: I hope we\'re not totally

5 rejecting historical controls. I think

6 there are certain historic controls that I

7 think everybody would accept. And one

8 doesn\'t want to give the message that you

9 would not accept it.

10 For instance, if a year after

11 transplant, a patient who started out with

12 Type 1 diabetes is now c‑peptide positive, I

13 think we would all accept based on

14 historical controls that that did not happen

15 by chance, that was a result of the

16 treatment, right? We would all accept that,

17 I think.

18 Similarly, we know a lot of

19 information from the DCCT trial, which is

20 also historical controls. We know roughly

21 that if you have a certain hemoglobin A1C

22 level, you will roughly have a certain

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1 incidence of severe hypoglycemia.

2 Now let\'s say after a transplant,

3 the patient has a hemoglobin A1C of 5 and no

4 severe hypoglycemia, I think we would

5 accept, based on historical controls, that

6 that didn\'t happen randomly, that that was a

7 result of the treatment, even though without

8 a controlled comparison.

9 So we then ask well, what if

10 Dr. Ricordi comes up with 100 consecutive

11 patients who start out with a hemoglobin A1C

12 of 10 and are poorly controlled; they\'re in

13 the hospital all the time; and then a year

14 later, they\'re c‑peptide positive; they have

15 a hemoglobin A1C of 5; and they have no

16 hypoglycemia, would we really say well, we

17 need controls; we can\'t approve that.

18 I think we have to be careful

19 about the comparisons of renal failure in

20 renal transplants versus dialysis. I mean,

21 there\'s certain things that I think we

22 should accept and not be, you know, overly

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1 rigorous at this stage and really cut off

2 what may be a very important field.

3 DR. SALOMON: Bob, I think that

4 the point there gets back to a principle we

5 articulated earlier, and that is that there

6 can be controls of efficacy, in which case

7 you made a nice argument for historical

8 controls in that particular experimental

9 design for efficacy would be very useful.

10 Yet those same controls would not be useful

11 for risk.

12 DR. ALLAM: Maybe I\'m off‑base

13 here, but I guess the way I\'m looking at it

14 is if you want to allow these types of these

15 clinical procedures to go forward, yes.

16 Historical data would probably be okay in

17 some cases. Now, if you\'re talking about a

18 BLA, I don\'t have that familiarity with

19 licensing a biological product. But it may

20 raise the bar in terms of what kind of

21 controls you need. Because that ‑‑

22 MR. DAPOLITO: We do consider

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1 historical controls in some cases as

2 sufficient. Again, it gets back to the

3 persuasiveness of the data and how the

4 control data set is established.

5 DR. RAO: Kathy.

6 DR. HIGH: Just to add to that

7 point, I think for example the recombinant

8 proteins that are used to treat hemophilia,

9 patients were allowed to, in a run‑in

10 period, essentially be their own controls

11 for the licensing, for example, recombinant

12 factor nine.

13 DR. SILVERSTEIN: I would think

14 that if part of the protocol was to put

15 these patients on the state‑of‑the‑art, best

16 therapy, for instance, the pump, and then

17 compare how they do on transplant versus the

18 pump, that would take care of Bob\'s problems

19 with having the patient as their own

20 control.

21 DR. SHERWIN: I think that\'s a

22 reasonable approach. I mean, it\'s not the

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1 perfect, but it is good enough given what I

2 expect to be the outcome. My guess is it\'s

3 going to be a very obvious effect. Based on

4 that assumption, I would say using the

5 patient as their own control probably will

6 be adequate.

7 If it wasn\'t for that feeling,

8 then I would argue strongly the other way.

9 But I think that using historical controls

10 always raises issues in the scientific

11 community. This is such a controversial

12 therapy still that I just feel that having

13 solid data in the long run will be good for

14 these guys. I would like to see the field

15 move forward.

16 I don\'t think that doing a trial

17 where people then can raise all sorts of

18 issues will be in the best interest of their

19 efforts.

20 DR. RAO: Dr. Ricordi.

21 DR. RICORDI: I just wanted to

22 echo that I\'m perfectly in agreement with

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1 what you mentioned regarding that there are

2 some historical controls and other

3 historical controls. Of course, if you will

4 compare with insulin therapy at the

5 beginning of the \'30s to now would

6 inappropriate.

7 But we have spent

8 collectively \$280 million taxpayer money to

9 do the DCCT trial and would be a pity for

10 you to now say well, this cannot be used any

11 longer to judge what the benefit ‑‑ even in

12 the risk in development of complications,

13 because there are now algorithms that have

14 been developed based on that huge trial that

15 can point out how the risk decreased for a

16 varying degree percent point of hemoglobin

17 A1C that you can decrease and you can deduct

18 like cost of treatment, quality of life,

19 risk of progression of complication. There

20 is huge volume of data coming out from these

21 very expensive and extensive trials.

22 DR. RAO: I mean, I think

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1 Dr. Salomon really summarizes when he said

2 persuasive evidence. If you have two arms

3 of a trial, one can\'t be a historical set of

4 controls if you have two arms of a trial.

5 But certainly, you know, when you\'re

6 comparing or you\'ve looked at failed

7 patients and then you\'re following them and

8 you look at recovery, then that\'s certainly

9 not the same as saying it\'s a historical

10 control. And that was not what the

11 intention was when the committee pointed

12 this out in terms of looking at historical

13 controls.

14 If that\'s true, then we really

15 have surprisingly come to some sort of

16 consensus in a lot of this. I\'m going to

17 try and see if I can summarize question

18 three and see whether we have to reopen it

19 as well. It\'s a small number of patients

20 which are a pretty defined population. In

21 that small number of patients, whichever,

22 pretty defined population, we don\'t think

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1 that you can really generalize to a large

2 extent to the rest of the diabetic

3 population.

4 Maybe a small extent based on the

5 fact that there are other hypoglycemic

6 patients or that people who have kidney and

7 pancreas islet transplants, maybe you can

8 generalize to hypoglycemic patients, but not

9 broader than that. There aren\'t any

10 specific tests that one could add to try and

11 generalize it.

12 Thank you everyone for your time.

13 I declare the meeting closed.

14 (Whereupon, at approximately

15 2:16 p.m., the MEETING was

16 adjourned.)

17 \* \* \* \* \*

18

19

20

21

22

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