1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

BIOLOGICAL RESPONSE MODIFIERS ADVISORY COMMITTEE

MEETING #37

Friday, March 19, 2004

8:30 a.m.

Hilton Hotel

Silver Spring, Maryland

PARTICIPANTS

MEMBERS

Mahendra S. Rao, M.D., Chairman

Gail Dapolito, Executive Secretary

Bruce R. Blazar, M.D.

Katherine A. High, M.D.

Jonathan S. Allan, D.V.M

David M. Harlan, M.D.

Joanne Kurtzberg, M.D.

Anastasios A. Tsiatis, Ph.D.

James J. Mule, Ph. D.

Thomas H. Murray, Ph.D.

CONSULTANTS

Jeffrey S. Borer, M.D.

Jeremy N. Ruskin, M.D.

Michael Simons, M.D.

Susanna Cunningham, Ph.D.

Michael D. Schneider, M.D.

INDUSTRY REPRESENTATIVE

John F. Neylan, M.D.

NIH PARTICIPANTS

Richard O. Cannon, M.D.

Stephen M. Rose, Ph.D.

FDA PARTICIPANTS

Jesse L. Goodman, M.D., M.P.H.

Dwaine Rieves, M.D.

Stephen Grant, M.D.

Philip Noguchi, M.D.

Ellen Areman, M.S. SBB (ASCP)

Richard McFarland, Ph.D., M.D.

Mercedes Sarabian, M.S., D.A.B.T.

GUEST SPEAKERS

Stephen E. Epstein, M.D.

Robert J. Lederman, M.D.

Emerson C. Perin, M.D., V.A.C.C.

Silviu Itescu, M.D.

Phillipe Menasche, M.D.

Doris A. Taylor, Ph.D.

C O N T E N T S

Page

Call to Order

Chairman Rao 4

FDA Opening Remarks

Philip Noguchi 8

Open Committee Discussion-Cellular Therapies for

Cardiac Disease

Open Public Hearing 9

FDA Charge to Committee--Introduction of Questions

Stephen Grant, M.D. 37

Committee Discussion of Questions 53

Closing Remarks/Adjourn 270

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

2 Call to Order

3 CHAIRMAN RAO: Welcome to the discussion

4 part of the meeting today. As is usual with all of

5 these meetings, we have to go around and

6 re-introduce the people who are on the committee,

7 and then open it up for public questions

8 subsequently.

9 So I'm going to ask Dr. Neylan to start by

10 introducing himself again, and then we'll just go

11 around the table.

12 DR. NEYLAN: I'm John Neylan. I'm vice

13 president of clinical research and development and

14 Wyeth Research, and I sit on the committee as

15 industry representative.

16 CHAIRMAN RAO: All right.

17 DR. SIMONS: Michael Simons of Dartmouth

18 Medical School. I'm a vascular biologist and also

19 a cardiologist.

20 DR. SCHNEIDER: Michael Schneider, Center

21 for Cardiovascular Development, Baylor College of

22 Medicine. I'm a cardiologist and molecular

23 biologist with an interest in cardiac growth and

24 cardiac progenitor cells.

25 DR. CUNNINGHAM: Susanna Cunningham from

1 the University of Washington School of Nursing in

2 Seattle, and I am the consumer representative,

3 usually with the Cardiovascular-Renal Advisory

4 Committee.

5 DR. BORER: I'm Jeff Borer. I'm a

6 cardiologist from New York. I am chief of the

7 Cardiovascular Pathophysiology Division at Cornell,

8 and the head of the Howard Gillman Institute at

9 Cornell, and chair of the Cardio-Renal Advisory

10 Committee of the FDA.

11 DR. HARLAN: I'm David Harlan. I'm chief

12 of the Islet and Autoimmunity Branch at the NIDDR,

13 within the NIH. My interests are immunotherapies

14 for diabetes and islet transplantation.

15 DR. TSIATIS: I'm Butch Tsiatis. I'm a

16 professor of statistics at North Carolina State

17 University.

18 DR. MULE: Jim Mule, associate center

19 director, H. Lee Moffitt Cancer Center in Tampa. I

20 oversee cell-based therapies for the treatment of

21 cancer.

22 DR. MURRAY: Tom Murray, resident of the

23 Hastings Cents Center; a long interest in ethical

24 issues in medicine and science. I write a lot

25 about genetics and some of these new cellular and

1 gene-based therapies.

2 CHAIRMAN RAO: Dr. Ruskin, we missed

3 you--can you--

4 DR. RUSKIN: Jeremy Ruskin--I'm a

5 cardiologist and electrophysiologist, and I direct

6 the Cardiac Arrhythmia Service at Massachusetts

7 General Hospital.

8 CHAIRMAN RAO: I'm Mahendra Rao. I'm at

9 the National Institute of Aging, and I'm a stem

10 cell biologist.

11 MS. DAPOLITO: Gail Dapolito, Executive

12 Secretary for the Committee. And I'd also like to

13 introduce the Committee Management Specialist,

14 Roseanna, Harvey.

15 Thank you.

16 DR. KURTZBERG: I'm Joanne Kurtzberg. I'm

17 a pediatric hematologist-oncologist, and I run the

18 pediatric bone marrow transplant program at Duke,

19 and the Carolinas Cord-blood Bank, and I have an

20 interest in cord-blood stem cells;

21 transdifferentiation and plasticity.

22 DR. HIGH: My name is Kathy High. I'm a

23 hematologist at the University of Pennsylvania, and

24 my research interests are in gene transfer as a

25 means of treating bleeding disorders.

1 DR. ALLAN: I'm John Allan. I'm a

2 virologist at the Southwest Foundation in San

3 Antonio. My area is non-human primate models for

4 AIDS pathogenesis. I also sit on the HHS

5 Secretary's Advisory Committee on

6 Xenotransplantation.

7 DR. BLAZAR: My name is Bruce Blazar. I'm

8 at the University of Minnesota in the Department of

9 Pediatric Bone Marrow Transplantation. Our lab is

10 focused on the immunobiology of bone marrow

11 transplantation and its complications. In

12 addition, we're using non-hematopoietic cell

13 therapy to treat organ tissue injury after bone

14 marrow transplantation.

15 DR. CANNON: I'm Richard Cannon. I'm

16 clinical director of NHLBI. I'm a clinical

17 cardiologist by training.

18 DR. AREMAN: I'm Ellen Areman. I'm a

19 product reviewer with CBER, Office of Cellular,

20 Tissue and Gene Therapy.

21 DR. McFARLAND: I'm Richard McFarland. I'm

22 a pre-clinical reviewer in the Pharm-Tox Branch in

23 the Office of Cellular, Tissue and Gene Therapy.

24 And my training background is immunopathology and

25 toxicology.

1 DR. RIEVES: Hi, there. My name is Dwaine.

2 I'm a medical officer at the FDA.

3 DR. GRANT: Hi, I'm Steve Grant. I'm a

4 medical office at the FDA. I'm a clinical

5 reviewer, and I'm also a cardiologist.

6 DR. NOGUCHI: Phil Noguchi, acting director

7 of the Office of Cellular, Tissue and Gene

8 Therapies.

9 CHAIRMAN RAO: Thank you, Phil. I'll turn

10 the mike over to you so you can make the opening

11 remarks.

12 FDA Opening Remarks

13 DR. NOGUCHI: Thank you. This will be very

14 short, because we have a lot to accomplish.

15 The first acknowledgment I'd like to do is

16 we neglected yesterday to say that this is Dr.

17 Rao's actual first meeting as the formal chair of

18 the BRMAC committee, and we gave him an easy

19 assignment, which is to make sure we leave on time

20 today.

21 [Laughter.]

22 And to pick up with apologies to Gandhi,

23 yesterday--I think we clearly are in a situation

24 where no one is ignoring this entire field. We did

25 have some laughs yesterday, but it was not laughs

1 about the absurdity of the approach but, really,

2 about all the nuances that we see.

3 There was a quote today in the Washington

4 Post about the success of CNN. And, actually,

5 instead of fighting, I would say we are fulfilling

6 that; and that is the public's business is best

7 done in the public, which this is a very elegant

8 example of. And I'm sure today will be even more

9 of an example. And the goal, of course, is to make

10 sure that when we leave that we do so with a better

11 knowledge of how we can actually win in the end.

12 And, with that, I think Dr. Rao, it will

13 be time for opening the Open Public Hearing.

14 Thank you.

15 CHAIRMAN RAO: We have a couple of people

16 who wanted to make comments. And I want to

17 emphasize right now that if anybody else from the

18 audience needs to make a comment, this is a good

19 time to make it. Sometimes making comments at the

20 time when the committee is deliberating becomes

21 much harder, and it's hard to recognize people,

22 given the time constraints as well.

23 Open Public Hearing

24 CHAIRMAN RAO: The first speaker is going

25 to be Dr. Neal Salomon, and he's going to speak for

1 about five minutes.

2 DR. SALOMON: Good morning. I'm Neal

3 Salomon. I'm a cardiac surgeon, and for the last

4 several years I've worked part-time as an associate

5 medical director for Parexel, a large CRO based in

6 Waltham, Massachusetts. During this time I"ve

7 worked with GenVec, formerly known to us as

8 Diacrin, as both a medical monitor and a consultant

9 in the implementation of their clinical trials,

10 using autologous myoblast transplantation.

11 I would like to very briefly summarize the

12 currently updated results of the three Phase I

13 pilot safety and feasibility studies--as I believe

14 that GenVec currently has the largest clinical

15 experience in the United States.

16 Next slide, please.

17 [Slide.]

18 This is just a brief overview. And all

19 subjects in these studies have received their

20 multiple epicardial injections in the region of

21 maximal transmural myocardial, epicardial scar.

22 The first study was just six patients, all

23 of whom received 300 million myoblasts concurrent

24 with LVAD replacement as a bridge to heart

25 transplantation. I believe that HeartMate was used

1 in all of them.

2 The second concurrently running--run CABG

3 study was a cohort of dose-escalation study; 12

4 patients. All of these patients had EF's less than

5 30 percent, and the injection of myoblasts was done

6 concurrent with their bypass grafting.

7 The third--the most current study--was a

8 cohort of 10 evaluable patients. All of these

9 patients, however, had injection of 300 million

10 myoblasts. However, this group had a much more

11 extensive--and I should say expensive--preoperative

12 evaluation and follow-up using core laboratories

13 standardized protocols for Echo, MRI, PET and

14 multiple, multiple 24-hour Holter examinations.

15 Next slide, please.

16 [Slide.]

17 In slightly more detail, this is the six

18 patients--probably should call it "LVAD" instead of

19 the CHF patients. Three of the patients received

20 heart transplantations. Two died, and one is still

21 awaiting transplant after over two years.

22 Histologic--as part of the informed

23 consent, the explanted hearts were to be made

24 available for histologic evaluation, and that has

25 been completed in five evaluable patients. That

1 was recently published, last year, in JAC. You can

2 see the reference there.

3 We couldn't identify any related SAEs.

4 Next slide, please.

5 [Slide.]

6 This is the dose-escalation study in four

7 separate cohorts. You can see the number of cells

8 was much smaller than was mentioned yesterday in

9 the Paris study. The initial three only got 10

10 million, then 30 million, 100 million, and the

11 final three got the 300 million myoblasts. Seven

12 have completed 24-month follow-up. Five are still

13 within that time period. And, again, we didn't

14 really find any obviously related SAEs in this

15 group.

16 Next slide, please.

17 [Slide.]

18 In the most recent and current study,

19 which has just--I think the last patient is just

20 being enrolled--all these patients received the 300

21 million myoblast cells. There was one early

22 death--an elderly gentleman, bad re-do, bad

23 targets. He died seven days post-op. He was

24 already out of the hospital two days, and a

25 question of primary arrhythmia versus an infarct.

1 And on autopsy, he had fresh thrombus in a

2 right--and a sequential graft going to two branches

3 of the right. We suspect that that fit his

4 clinical pattern and he had a primary MI.

5 And, again, all these patients are getting

6 thoroughly evaluated by serial MRIs, echo, PETs,

7 multiple Holters, by standardized core labs.

8 Next slide, please.

9 [Slide.]

10 And in slightly closer focus--as obviously

11 the AICD, and the arrhythmias is significant issue,

12 both clinically and from a regulatory

13 perspective--let me just tell you a little bit

14 about all these folks.

15 The first--the first patient listed there

16 had an AICD placed prophylactically at week two.

17 He had non-sustained V-tach, and some new kind of

18 chest pain within a week after being discharge.

19 Urgently re-cathed; had significant kinks in his

20 mammary graft; question of flow limitation. Placed

21 on Amyoterone, resolved his arrhythmias, but he had

22 an AICD placed prophylactically anyway.

23 The next two patients are very similar,

24 both at month 10 and month 15. Both patients had

25 AICDs placed, essentially due to progressive heart

1 failure. There was no improvement after

2 the--cardiac function after their grafts. Neither

3 patient ever had VT--and I don't believe any of

4 these three have had a shock.

5 And then, the last group, one patient had

6 an AICD week three, who had non-sustained V-tach,

7 also severe LV dysfunction. His pre- and

8 post-operative Holters, however, were not really

9 different, but he had an AICD placed. And the very

10 last one had it, again, placed prophylactically for

11 a position T-wave alternans test, which some

12 cardiologists feel has significant prognostic

13 significance.

14 So my conclusion from evaluating this is

15 that it's really patient-related variables, rather

16 than specific procedure-related variables, and do

17 reflect some expanding indications for the use of

18 AICDs in this problematic patient group, over just

19 the four years that these have been running.

20 And the last slide, please.

21 [Slide.]

22 Thus, the total enrollment is 28 patients

23 over four years. The average follow-up, as you can

24 see, for the CABG patients is a year-and-a-half;

25 for the LVAD patients it's been three months. We

1 could not identify any specific procedure,

2 rejection-related complications; really no

3 definitive SAEs--that one possibility, but probably

4 not.

5 Histologic evidence for cell survival is

6 currently available. And the standardized core lab

7 assessment for all the things mentioned, including

8 Holters, are ongoing. So both I, independently,

9 and GenVec thank you for the opportunity to present

10 this data to the committee and the FDA.

11 Thank you very much.

12 [Applause.]

13 CHAIRMAN RAO: There's just one question

14 for you from the committee, Dr. Salomon.

15 DR. BORER: Borer. I guess when you say

16 the results are pending from the core labs, there

17 really aren't any results yet available. But, let

18 me ask anyway.

19 If I understood properly, one of your

20 studies--I guess it's CABG 002--was a dose-response

21 study--

22 DR. SALOMON: Dose escalation, yes.

23 DR. BORER: Well--escalation, but you had

24 one dose given to four different groups; one dose

25 to each group. That's right?

1 Okay. So you can define a dose-response

2 curve from those data, albeit the numbers are

3 small, you could.

4 Do I understand correctly we don't know if

5 cell survival varied among the doses used in any

6 dose-related way, and we don't know if there was

7 any functional parameter that was altered by the

8 treatment in a dose-related way?

9 And the reason I ask, obviously, is that

10 this is the only study that has, in essence, a

11 control. I mean, it's a dose-response study, which

12 could provide a great deal of information, you

13 know, if the information become available. So

14 that's why I'm asking specifically about that

15 study.

16 The others are, you know, observational

17 studies with millions of confounds. This one has

18 confounds, too. But, you know, in addition to the

19 surgery that everybody had, there was a

20 dose-response design--a parallel group, differing

21 dose design.

22 Can you tell us anything about results in

23 that group? Or they're just not available.

24 DR. SALOMON: You know, this was really

25 confined--with no allusion to efficacy whatsoever,

1 of course, in terms of functional alterations. I

2 haven't addressed that whatsoever. So--

3 DR. BORER: But you made measurements. You

4 have echo, you have PET, you have--

5 DR. SALOMON: Oh, sure.

6 DR. BORER: You have stuff.

7 DR. SALOMON: Sure. Sure.

8 DR. BORER: And I wasn't suggesting you

9 could look at efficacy. I was just asking about

10 functional concomitants of treatment.

11 DR. SALOMON: Right. No--I understand.

12 No--the answer is no obvious correlation;

13 no dose-related correlation. Correct. Too many

14 variables.

15 DR. EPSTEIN: I'd like to ask a

16 question--Steve Epstein. I'd like to ask a

17 question of the FDA.

18 I don't mean to be critical of this study,

19 but in light of what Dr. Manasche said yesterday,

20 if you have concomitant CABG, and you're putting

21 cells in, there is no way you're going to get any

22 information. None.

23 So here are patients who are being exposed

24 to some risk, with the expectation of having no

25 information, because there's a CABG.

1 What is the FDA policy on something like

2 this.

3 CHAIRMAN RAO: Let's leave that question

4 for later, then, Dr. Epstein.

5 Yes?

6 DR. SCHNEIDER: I have a question for you

7 about patient recruitment for the Diagran GenVex

8 study.

9 How many recruiting centers were involved?

10 What was the average number of patients recruited

11 in each? And what was the range in the number of

12 patients recruited by each?

13 DR. SALOMON: By each center?

14 DR. SCHNEIDER: By each center. Because

15 one of the issue in a trial like this is

16 reproducibility, hands-on experience. I'm trying

17 to get a feeling for what the range was in the

18 level of participation and recruitment by the

19 centers.

20 DR. SALOMON: Yes--excellent question.

21 There was a predominance of--I guess I

22 shouldn't say names of centers, so I won't. But

23 there was a predominance in both of the--well,

24 actually, all the trials, with just maybe--we had a

25 total, I believe, in opportunities for eight to 10

1 centers, but virtually 80 percent of the patients

2 came from three to four of the centers.

3 DR. SCHNEIDER: And the other 20 percent

4 came from centers that were doing one or two

5 patients each?

6 DR. SALOMON: Had fewer patients

7 each--correct. Correct.

8 CHAIRMAN RAO: Thank you, Dr. Salomon.

9 DR. CUNNINGHAM: What were the genders of

10 the patients?

11 DR. SALOMON: Only--of all these--of the 28

12 patients, only two female.

13 DR. CUNNINGHAM: Thank you.

14 CHAIRMAN RAO: Thank you.

15 Dr. Reiss?

16 DR. REISS: My name is Russ Reiss. I don't

17 have any slides prepared. I've just been sitting

18 at this meeting for the last day and am somewhat

19 frustrated.

20 I'm a clinical heart surgeon at the

21 University of Utah who--we also have a very active

22 basic science laboratory, and we are also planning

23 to do cardiac trials will cellular therapy.

24 But what I wanted to say--actually, I'm

25 glad that Dr. Salomon did just give a little bit of

1 information from the cardiac surgeon side--and a

2 little bit of rebuttal to Dr. Epstein.

3 I do not believe that just because we can

4 put these in with catheters that that is the actual

5 safest way to do this; and that maybe in the

6 operating room, with the heart under diastolic

7 arrest, completely in a controlled setting that is

8 probably the most controlled, most sterile setting

9 we have from clinicians today is the cardiac

10 operating room. And just some of the quick points

11 I just wanted to let the FDA know, that in response

12 to putting a CABG graft on a heart and saying that

13 you can't tell any difference, I don't agree with

14 that at all. Because we've all revascularized a

15 heart and seen no difference in wall motion,

16 because that area is not graftable, or there's an

17 area there that's thin but not dead. And you may

18 not see anything at all.

19 If you put cells in that area that you did

20 not put a graft on, you can follow that. And we've

21 seen some very nice images--Dr. Lederman yesterday

22 showed beautiful cardiac MRI images with very

23 specific areas of the heart and the walls that can

24 be followed with high definition. We can see what

25 happens to the area that is not revasculizable with

1 a CABG graft.

2 And I would say that all the concerns that

3 have been raised with catheters--we heard yesterday

4 that the catheter was very safe, and nothing ever

5 happens in the cath lab. We'll that's not true.

6 Cardiac surgeons repair valves, we repair aortas.

7 That thin transverses the groin, the aortic arch.

8 There's all kinds of misadventures that happen with

9 catheters that cardiac surgeons have to fix.

10 So I would just say to the FDA that, you

11 know, it's going to be done with a catheter one

12 day. It's already being done outside this country.

13 I think that is going to be eventually how the

14 majority of cellular therapy is going to be

15 delivered. But, as far as safety, some of these

16 trials probably should be also considered in the

17 cardiac setting, in the operating room, where much

18 of the pre-clinical data has been done with direct

19 injection, under arrested heart.

20 And the last thing, about safety: all our

21 patients also go to the ICU, and they're under the

22 most monitoring on a daily basis that you can have.

23 And we can also apply what other types of safety

24 monitoring the FDA would like to see us do. But

25 often the catheter patients do not get the same

1 level of post-operative monitoring.

2 So, just a plug for the cardiac surgery

3 side, since it seems that we're a little bit

4 under-represented.

5 CHAIRMAN RAO: Thank you, Dr. Reiss.

6 Dr. O'Callaghan?

8 DR. O'CALLAGHAN: My name is Michael

9 O'Callaghan, and I"m the vice president of

10 pre-clinical biology at Genzyme. I'm responsible

11 for many of the pre-clinical studies that are to

12 look after safety and efficacy for the cell

13 products and many other products at Genzyme.

14 I'd like to thank the FDA for, first,

15 allowing us to speak and, secondly, for putting on

16 this two-day series of seminars, because I think

17 it's critical to the way we move forward.

18 I would remind people of this document

19 called "Innovation and Stagnation," which is a

20 document that just recently came out from the FDA.

21 And if you look at the graph which is on Figure 2,

22 you will see that in 1993, there were 17 BLAs

23 submitted to the FDA, and progressively over the

24 next 10 years to 2003, there was virtually a

25 straight line downward plunge to 14 last year. If

1 you continue that, that's 5 BLA losses per year.

2 So by 2007, there won't be any.

3 So, I think what we're talking about

4 today--and some of the things that we're talking

5 about today--is how do we get to a better process

6 or procedure or strategy that will allow industry

7 and the FDA to come to a more transparent, perhaps,

8 and faster or more efficient approach to this.

9 If you think about some of the issues that

10 have been discussed and the complexity of what

11 we're dealing with, you may recall from much of

12 yesterday's conversation that many of the

13 procedures that we are using to deliver cells--in

14 fact all of them--invoke some sort of pathology of

15 themselves. So if you think about the emboli that

16 were produced in the intra-coronary delivery, or

17 you think about needle tracks or catheter delivery

18 systems that ago through the wall or travel through

19 the heart, there is a primary pathology created by

20 that.

21 On top of that, there is the pathology

22 that is behind the infarct itself; whether it's a

23 recent infarct or an old infarct, which complicates

24 interpretation, and complicates the safety and

25 efficacy issues we're trying to deal with.

1 A third variable, of course, is the cell

2 death that we all heard about, obviously invokes

3 some sort of pathology. And, on top of that, we

4 have our understanding of the pathological, or

5 physiological processes that we have in great

6 abundance in the literature, and that's our sort of

7 background in trying to understand how to provide

8 studies that answer the safety questions or the

9 efficacy questions.

10 And then on top of this background, we're

11 attempting--with the few surviving cells that are

12 there, and presumably the ones that are going t o

13 give benefit to the patient--out of that morass,

14 try to find out whether there is a safety issue, or

15 efficacy, on top of many of the other things, like

16 CABG.

17 So, how does that translate to dealing

18 with the regulatory authorities in trying to

19 demonstrate that there is safety and that there is

20 efficacy? The difficulty, of course, is that

21 background. I think the other difficulty is

22 outlined, in part, in this document: and that is

23 that the process as it is at the moment is an

24 iterative one, where it's almost like a five-year

25 poker game, where each one is holding the cards

1 against their own chest and only giving out the

2 card that matters. And that goes on for several

3 years, and as you play your card, or pick up a new

4 card to try and strengthen your hand, you end up

5 spending a lot of money in the process and, in the

6 end, many of these products shown on this graph die

7 very slowly.

8 So my plea at the moment, or to this body,

9 is that we need to think about how we are going to

10 make the process more transparent so that quicker

11 decisions can be made. And I think it has to be

12 translated at two levels: one is at the level of

13 policy and strategy--how the FDA is going to

14 interact with industry. And, secondly, what was

15 pointed out yesterday by Dr. Noguchi and McFarland,

16 how to translate that down to the individual case,

17 where the sponsor and the FDA are having to work

18 out, between them, on that one individual case, how

19 to get to a satisfactory solution as quickly as

20 possible.

21 Thank you.

22 CHAIRMAN RAO: Thank you, Dr. O'Callaghan.

23 I think the FDA shares the frustration--and all the

24 stem-cell biologists also, in how can one translate

25 some of these things into an appropriate

1 methodology that can be used.

2 I'm going to ask Dr. Noguchi to maybe say

3 a couple of words on what a BLA is so that people

4 who may not be familiar with it are aware of what a

5 BLA application is.

6 DR. NOGUCHI: Okay. Yes--BLA stands for

7 "Biologics License Application." It's given under

8 the authority of a section of the Public Health

9 Service Act that we call "Section 351," and it is

10 in a parallel situation to the Food, Drug and

11 Cosmetic Act. The main distinction, from the legal

12 point of view, is that if you have an approved

13 NDA--new drug application--you don't need a

14 simultaneous BLA, and vice versa.

15 The basic requirements for a license

16 application is that you have a product--let's give

17 a hypothetical example of a cellular product for

18 future cardiac repair--that can be made in a manner

19 that is consistent; that is, for many biologics, we

20 do not need to have an ultimately precise

21 definition and specification for a pure entity,

22 however we want you to be able to make it the same,

23 time after time after time, within certain limits.

24 If we go back to the original law--1902

25 law--the legislative history is basically states:

1 what we want is something that's safe relative to

2 the indication; that's pure as possible; and that

3 is potent, so that the practicing physician, in his

4 or her capacity, will have some confidence that

5 when this product is given that their patient will

6 have some expectation of therapy; that is, they'll

7 be better after than before.

8 So I think--that's sort of more of a

9 philosophical thing, but the end game is really: if

10 you have something that we know works, and can

11 be--works in a manner that it can be convincing,

12 which is usually based on planned clinical

13 trials--occasionally we may have historical data

14 that can be used in terms of an approval. But,

15 clearly, for experimental products such this--we

16 heard yesterday, eloquently--that without a placebo

17 how do you know that this is actually working,

18 since all the non-controlled trials say they all

19 work.

20 So if it's effective in a reproducible

21 way, and you can make the product the same again

22 and again and again, so that, again, the practicing

23 physician gets a vial of cells, says, "Okay, I know

24 this is pretty potent. This is the dating period.

25 I can give it. Or, if it's past the dating period,

1 maybe I'll give a little bit more." It's to give

2 the physician the maximum flexibility in

3 prescription, as well as to validate and provide

4 that assurance that the product actually works and

5 can be made consistently. That's what the BLA is

6 all about.

7 It can be done by a major pharmaceutical

8 company. It has actually been done, in a few cases,

9 by universities and by state public health

10 entities. So it's a very flexible approach. It

11 can go all the way from the very largest

12 multi-center, multi-national, hundreds of thousand

13 patient trials down to even those with about five

14 to 10.

15 So it's a flexible mechanism. But, again,

16 the end game is: does it work? If it does, we'll

17 approve it.

18 CHAIRMAN RAO: Thank you.

19 I think a couple of people have questions

20 for you, sir.

21 DR. MURRAY: Phil, what's your response to

22 Dr. O'Callaghan's claim that we've gone from having

23 rather a large number of these BLA applications in

24 a year, to a declining trend? Is that--if that's

25 the data--I have no reason to doubt the data, but

1 the interpretation of it was what is not clear to

2 me.

3 DR. NOGUCHI: Yes, myself not having all

4 the primary data at hand--but it is--like anything

5 else, it depends on what is put into the

6 publication. We do, for example, license blood

7 banks, and those, literally, will be coming in at a

8 much higher rate. We do not necessarily count

9 those as new molecular entities.

10 It is true, but it's not just for

11 biologics applications, but also for molecular

12 entities--for drug molecular entities--that in a

13 very real sense there has been a tremendous set of

14 developments and follow-through of things that are

15 known. And we have entered, somewhat

16 asynchronously, a time where there a lot of things

17 that have been solved, in a somewhat prosaic way.

18 All the easier diseases really have been done, and

19 now we're dealing with the ones that are very hard.

20 Cancer, as an entity, sounds like it's not just

21 one, it's a very hard disease in order to make

22 progress above and beyond extension of live for

23 several months, or--and so forth.

24 So a lot of what we're seeing is: what's

25 known has been done for those diseases for which we

1 know how to treat. But what we are now seeing is

2 all the rest of them here: cardiovascular disease,

3 congestive heart failure. We saw how the cascade

4 is just a very long one, and we're trying to

5 intervene at perhaps a point where it's a little

6 bit hard to reverse years of damage. Likely it can

7 be done, but how we get there is very dependent, to

8 a great degree, on what the science and knowledge

9 of disease is.

10 So, I think what we are seeing is that we

11 are seeing fewer applications in the whole drugs

12 and biologics arena. And part of that is that our

13 scientific knowledge, on the one hand, for making

14 products is expanding rapidly, but our

15 understanding of the--quote--"simplicity" of

16 disease is proving to be--well, it may be very

17 simple, but, boy, that's pretty darn hard compared

18 to what we already know.

19 There are no easy solutions to any of

20 these diseases that we see right at the moment.

21 And that's part of the lag we're seeing.

22 Dr. McClellan's emphasis on the

23 critical-path initiative is really to try to help

24 everyone to come back and focus as to what are

25 those things that will make a difference, and then

1 what are those things that are simply going to be

2 increments and improvements that may only give us a

3 little bit of extension of life, a little bit

4 longer acting drug, but may not be actually

5 altering the fundamental disease.

6 CHAIRMAN RAO: Joanne?

7 DR. KURTZBERG: I have a question that goes

8 back to the cardiac transplantation issue at

9 hand--or the cellular therapy issue at hand.

10 In the current proposed tissue regs,

11 minimally manipulated or non-manipulated products

12 are not really candidates for BLA or licenses. So,

13 for example, if you take bone marrow from a sibling

14 and you transplant it directly into the patient,

15 there's no license involved with doing that.

16 And some of the therapies that both are

17 being done now and are being proposed involve what

18 we've done with bone marrow for years; taking it

19 and putting it somewhere else--in this case,

20 usually autologous, or mobilized blood, or even

21 CD34 AC133-- selected products for which there

22 already are devices that are either under IND or

23 licensed.

24 So how would the FDA--you know, so this

25 therapy crosses a bridge between using things that

1 we use already, but just putting them in a

2 different place; and then, also, modifying

3 those--some things, ex vivo, with culturing and

4 other technology.

5 You could interpret the regs as they are

6 proposed as saying the minimally manipulated

7 product doesn't need a license or a BLA, and only

8 the ex vivo manipulated or culture, transfected,

9 etcetera and so forth products do.

10 What's the FDA's view of that.

11 DR. NOGUCHI: Well, we really did not have

12 this meeting to try to focus on the question of

13 whether we need this approach versus that approach.

14 However, I'll just quickly say a couple of things.

15 First, the tissue regulations are still in

16 the process of being finalized. However, the

17 point--one part of the regulations does say that if

18 you use something that would otherwise be

19 considered to be not manipulated beyond its normal

20 biological characteristics, if it's used in a

21 manner that inherently does not seem that it

22 logically follows--which is what happens in this

23 case--we've already heard yesterday, and we see

24 throughout the past year, in terms of the active

25 literature, if bone marrow cells of whatever never,

1 however purified, are put into the heart by means

2 of devices, or by direct injection, or by surgical

3 procedures, that, in fact, either you get

4 regeneration of heart, you get vascularization, you

5 get transdifferentiation--none of which have been

6 proven by any means, in any clinical trial, let

7 alone in any animal studies that have been done--we

8 term that a "non-homologous use," because it has

9 not been shown, and the current science does not

10 show that any of those possibilities are actually,

11 in fact, what happens.

12 And so, for that reason, we are saying

13 these are highly experimental procedures they're

14 using in addition to the product itself, which is

15 experimental. We're using products--other products

16 such as catheters in an experimental way--and, all

17 put together, clearly merit the justification and

18 the overview of FDA regulation at the IND level.

19 DR. KURTZBERG: I'm not questioning that.

20 But--

21 CHAIRMAN RAO: I'm going to cut this here,

22 because this is not part of the whole mandate for

23 the committee. And these questions--this whole

24 idea of--I just wanted people to know about the

25 BLA.

1 DR. KURTZBERG: But it is important.

2 Because if it works, do you then have to go have a

3 BLA, or a license to use bone marrow for this, when

4 you wouldn't have a license to use bone marrow for

5 the other indication therapy.

6 CHAIRMAN RAO: And that's certainly an

7 important issue, but I don't think we want to

8 address it in this committee because it's not part

9 of our mandate for the question.

10 [Pause.]

11 Are there any additional comments from the

12 audience? Anyone?

13 Go ahead. Just make sure you identify

14 yourself, and if you have any financial--

15 DR. GRANT: My name is Stephan Grant. I'm

16 working with Viacel in Boston, and I'm running the

17 European branch of Viacel--a small company named,

18 Curion.

19 I would like to make a comment to the

20 issue of immunosuppression in animal studies.

21 There has been a position by Dr. Itescu yesterday

22 saying, well, it doesn't make sense to use

23 immuno-compromised animals treated with cyclosporin

24 or rapomycin, or whatever, in order to do our

25 studies.

1 I would like to challenge that position a

2 little bit, because I think we also heard that stem

3 cells are quite heterogeneous, and we see the

4 problem that how can we make sure that an animal

5 stem cell preparation is really very homologous to

6 the human stem cell preparation, which may carry

7 the same name but could be different, in terms of

8 the cell composition or other factors. And we

9 don't have the tools in our hands to discriminate,

10 or to decide whether the animal stem cells are

11 really the same--have the same quality, the same

12 properties, the same purities as the human product.

13 So we had made a conscious decision to

14 work with immunosuppressed animals,

15 immuno-compromised porcine--pigs, treated with

16 cyclosporin, and tested our stem cells, human stem

17 cells in that setting, with good results so far.

18 And I think taking that strategy, we are

19 on the safe side with respect to testing our

20 products in terms of efficacy and safety, because

21 we don't have to make this transition or

22 translation of the animal that, say, the animal

23 data generated with animal stem cells then into the

24 human setting.

25 And somehow, I--I mean, I think it's fine

1 if the authorities accept the, let's say known

2 xenograft, or xenograft-avoiding strategy, but it

3 would be--I think it would be a pity if we would

4 now have a dogma that studies with

5 immuno-suppressed animals would make sense in this

6 context.

7 CHAIRMAN RAO: Thank you.

8 DR. ITESCU: I accept that point. That's a

9 valid point.

10 The point that I was making simply is if

11 you're going to use immuno-suppression in an animal

12 model with human cells, you've got to take into

13 account the potential effects of the drugs on the

14 cells you're studying. And as long as you've got

15 appropriate controls, as long as you've taken that

16 into account, it's reasonable to look at those sort

17 of models.

18 CHAIRMAN RAO: We're going to move on.

19 Briefly? Is this relevant.

20 AUDIENCE MEMBER: I'm very sorry to

21 re-comment, but Dr. Epstein's query didn't really

22 get a response--at least from me.

23 And the other issue is the clinical trial

24 design, with human subject protection. And these

25 pilot studies weren't designed--efficacy as a

1 stand-alone procedure, because clearly you have to

2 get safety and feasibility first.

3 So, it's really difficult to do cell

4 implantation studies, I think, as a stand-alone

5 procedure, and they had to be done concomitantly

6 with bypass grafting. I think that was really the

7 rational; not to prove efficacy.

8 Thank you.

9 CHAIRMAN RAO: Thank you.

10 I'm going to ask the FDA to pose the

11 questions.

12 Dr. Grant?

13 FDA Charge to Committee

14 DR. GRANT: Hi--I'm Steve Grant. I'm one

15 of the clinical reviewers here at FDA. I'm also a

16 cardiologist.

17 I wanted to start out today by thanking

18 the members of the committee and the invited

19 speaker--as well as the speakers who were kind

20 enough to join us during the open public

21 hearing--for coming here and sharing their time.

22 We know they all have very busy and very productive

23 professional lives, and we thank you for joining us

24 today to discuss these very important issues.

25 I'm going to briefly review why we've

1 asked you to come here yesterday and today. And

2 I'll then review the questions that we've asked you

3 to discuss.

4 Next slide, please.

5 [Slide.]

6 We have asked you to discuss certain

7 safety concerns that need to be addressed to

8 initiate human trials of cellular therapies for

9 cardiovascular diseases. These concerns are part

10 of our mission to promote and protect public

11 health. We are, however, also responsible for

12 facilitating the development of safe and effective

13 therapies--and I've put up here an addition that

14 was made to the FDA Mission Statement in August

15 2003.

16 This revision explicitly states that "the

17 FDA is responsible for advancing the public health

18 by helping to speed innovations that make medicines

19 and foods more effective, safer and more

20 affordable."

21 Although this was made explicit in the

22 2003 revision, facilitating the development of safe

23 and effective therapies does promote the public

24 health, so I would argue that this was always

25 implicit in our mission statement.

1 We have convened the committee to solicit

2 advice about certain issues that have delayed the

3 development of potential therapies for

4 cardiovascular disease.

5 Next slide, please.

6 [Slide.]

7 Here's one of the clinical challenges that

8 exists in cardiology--I think you've heard about it

9 from several speakers yesterday. There's--very

10 simply stated--there's over a million people in the

11 United States who acute myocardial infarction every

12 year.

13 For those of us who have a bit of gray

14 hair, they can remember when taking care of MIs

15 consisted essentially of putting people to bed.

16 The mortality rate for MI has been declining fairly

17 rapidly. It's gone down 30 percent over the last

18 two decades. And this has been due, at least in

19 large part, to the advent of reperfusion therapy;

20 both thrombolysis and percutaneous coronary

21 intervention. However, these therapies are not

22 entirely effective. Most patients who will suffer

23 acute myocardial infarction will be left with a

24 variable amount of left ventricular dysfunction.

25 Because increasing numbers of these

1 patients are surviving, there are many, many more

2 patients each year that have diminished cardiac

3 reserve. It fact, congestive heart failure is the

4 only cardiovascular diagnosis whose absolute

5 incidence is increasing year by year. And it's

6 partially due to the aging of the population, but

7 it's also, in large part, due to this phenomenon.

8 And therefore we are very interested in

9 facilitating cellular therapies because they may

10 benefit these growing numbers of patients with

11 congestive heart failure.

12 Now, I don't want to suggest that this is

13 the only indication for which I think these

14 products might be used, or that even for sure, that

15 this is an appropriate indication. Conceptually,

16 there are many, many other types of cardiac disease

17 that could be benefitted by cellular therapy.

18 Next slide, please.

19 [Slide.]

20 I'm going to talk a bit about the

21 regulatory requirements. Before a new product is

22 administered to humans, FDA is required to conduct

23 an independent and detailed assessment of the risk

24 to human subjects. The regulations provide the

25 mechanism by which we conduct this assessment.

1 They provide the framework wherein we can answer

2 this question--which is never trivial, I don't

3 think, for any trial, but most certainly is not

4 trivial for novel therapies such as these--and that

5 is: how do we balance individual subject safety

6 against the potential public health benefits of new

7 therapy?

8 The risks are borne by the few, and the

9 benefits go to the many. And our society has

10 designed a mechanism, and provide a framework, and

11 charged us to make this assessment. And the

12 regulations are how we do that.

13 This risk assessment must be

14 sufficiently--must include sufficiently detailed

15 information regarding the following: product

16 characterization and safety testing. And I think

17 it's fairly obvious--safety testing, that we

18 wouldn't transmit, for example, infectious agents

19 in a product.

20 Product characterization--as Dr. Noguchi

21 has already discussed--is a bit more difficult for

22 cellular therapies than it is for a drug. A drug,

23 you know the--you can characterize the reagents

24 that go into it. You know and understand precisely

25 the manufacturing processes. You can chemically

1 characterize what comes out. You understand--you

2 manufacture the pill.

3 We talk about manufacturing with cellular

4 therapies as well, although even to my ear it still

5 always sounds a little strange to talk about

6 "manufacturing." I mean, we're really--it's a

7 process that we use to produce these cells, and

8 that process, in some ways, is the way we

9 characterize them. But, still, there are certain

10 concerns that we have to be able to characterize

11 that end product in some way that's

12 meaningful--because you can't run a clinical trial

13 if you don't understand what you're giving to the

14 patients. I think it's kind of self-evident that

15 if you don't understand, or don't have a way of

16 characterizing what you've done, you don't have a

17 trial you have a case series of a group of people

18 who are given something you don't understand.

19 You have to provide supportive

20 pre-clinical or clinical data. You have to provide

21 data that allows us to independently assess the

22 risk to the subjects as best as can be done. I

23 mean, we've heard already about the difficulties of

24 finding appropriate pre-clinical models. That

25 doesn't--because they're difficult doesn't excuse

1 you from not having any.

2 And you need to be able to identify a safe

3 starting dose. And then you need to have a

4 monitoring plan that suggests that you're going to

5 be able to detect the adverse events in a timely

6 fashion, so that any subject that suffers those

7 adverse events can be identified and treated

8 quickly, and so that subsequent subjects will not

9 be exposed to the same adverse events.

10 Next slide, please.

11 [Slide.]

12 And with that as the background, I want to

13 go through the common issues that have delayed

14 initiation of clinical trials in this area--and

15 I've probably seen most of the submissions to the

16 FDA, And these are the four things that we have

17 identified as being problems.

18 One: the cellular product that is

19 administered--or the cellular product that's

20 proposed for the clinical trial is different from

21 that that's used in pre-clinical studies. You

22 know, we--some people, I think, would advocate--we

23 certainly heard yesterday people who would say once

24 you've seen one bone-marrow mononuclear cell you

25 may have seen them all. But there may be

1 differences within these preparations.

2 Secondly: insufficiently detailed safety

3 data--and particularly, we will sometimes get, as a

4 safety data base, just published reports. It's

5 very difficult to get, from a publication, the kind

6 of detail. We have to be able to do an independent

7 analysis and, generally, publications will not

8 include a detailed protocol, which will include all

9 the protocol-specified assessments, and it won't

10 include either the case report forms for a clinical

11 study, the line item of raw data for a pre-clinical

12 or non-clinical study.

13 Three: limited information about the

14 compatibility of the cellular product and the

15 delivery device.

16 Four: an inadequate plan for monitoring of

17 subjects during and after product administration.

18 And I think you'll see that the questions

19 that we've asked you, with the exception of the

20 seventh, which is just a bit different--but the

21 first six clearly all are derived from these

22 issues. We'd like to get advice about these issues

23 so that we can help understand how to resolve

24 these, and so the investigator community can help

25 understand, so that we can get submissions that

1 will go forward.

2 Next slide, please.

3 [Slide.]

4 So the advice that we seek from you are

5 general comments and recommendations about certain

6 manufacturing issues, certain preclinical testing

7 issues, and about pilot clinical design, with

8 respect to certain issues that need to be addressed

9 to permit safe initiation of clinical

10 development--which we are quite anxious to see

11 happen.

12 Next slide, please.

13 [Slide.]

14 Question 1--well, these first two

15 questions are going to relate to safety in

16 characterization of the cellular product.

17 Question 1: we know that because the

18 specific cells, mechanism of action and cell-device

19 interactions are still in very early stages of

20 investigation, the appropriate and adequate safety

21 testing and characterization have not yet been

22 defined, and may conceptually vary, based on the

23 cell source and type of manipulation.

24 We would like you to discuss the intrinsic

25 safety concerns for cellular products for the

1 treatment of cardiovascular diseases, and the

2 testing that should be performed to ensure

3 administration of a safe product. Among the

4 factors that you might consider are tissue source,

5 manufacturing process, formulation, storage, route

6 and site of administration.

7 In your printed version, in the briefing

8 document, these came out as "a, b, c, d." We by no

9 means think that you have to discuss each of those

10 as a separate subpoint, but consider them, instead,

11 in your discussion of the overall question. And I

12 would caution the committee to try to remember that

13 we're talking here about treatments of cardiac

14 diseases. The larger field of cell therapy is

15 quite a broad one, and we would like to stay to the

16 specifics of cardiac therapy today.

17 Question 2--

18 Next slide, please.

19 [Slide.]

20 --these products are all heterogeneous, in

21 terms of cell types contained and, in some of them,

22 the biomarkers also are different on different cell

23 types; the degree of heterogeneity present in

24 administered cellular products may be an important

25 variable in characterization or in determining

1 their safety or efficacy.

2 Therefore, please comment on the elements

3 of product identity and characterization necessary

4 to generate meaningful data about safety and

5 efficacy. And, conceptually, we think that these

6 may include comments about specific

7 biomarkers--that would be most particularly with

8 the bone marrow-derived products--and the types and

9 percentages of cell types that would apply to both

10 the products derived from muscle biopsies, as well

11 as those derived from bone marrow or from

12 peripheral blood.

13 And there may be other parameters that you

14 would identify as being important. And we would

15 ask for your comments.

16 Next slide, please.

17 [Slide.]

18 Question No. 3--the next couple of

19 questions, 3 and 4, concern the kinds of

20 pre-clinical data needed to assess safety, and

21 identify a safe starting dose prior to initiating

22 human clinical trials.

23 Various--we've already had part of a

24 discussion of this. Various animal models have

25 been proposed to support the safety of cellular

1 products used in the treatment of cardiac disease.

2 These include studies of both small and large

3 species; studies utilizing either immune-competent

4 or immuno-compromised animals.

5 Each model has some advantages and

6 limitations, which have been reviewed by the

7 speakers and previously discussed. For instance,

8 human cellular products can be tested in

9 genetically immuno-compromised rodents, but these

10 animals provide limited clinical monitoring of

11 cardiac function, and cannot be used to assess the

12 safety of devices. Large animals allow for more

13 extensive monitoring of cardiac function and the

14 use of the same delivery device intended for

15 clinical use.

16 Please discuss the merits and limitations

17 of various large and small animal species for

18 providing pharmacologic, physiologic and

19 toxicologic support for cellular products used in

20 the treatment of cardiac disease, and please

21 consider the following: the intended human clinical

22 cellular product; the delivery system that's

23 proposed in the clinical trial; and extrapolation

24 of study results from animals to humans.

25 Question No. 4: Please discuss the merits

1 of animal models of ischemic disease with respect

2 to ability to generate proof of concept data, and

3 generate toxicologic data of relevance to the

4 clinical disease. And, conceptually, animal models

5 of ischemic disease could include normal

6 animals--or no ischemic disease--as Dr. Vouye

7 presented a very interesting study with essentially

8 normal dogs.

9 The models--again, the models of ischemia

10 that are available are many; cryoablation,

11 ligation, ligation-reperfusion, ameroids.

12 Question No. 5, please

13 [Slide.]

14 The next question concerns the types of

15 evacuations needed to assess the compatibility of

16 the cellular product with the delivery device.

17 Please discuss evaluation of potential interactions

18 between cellular products and cardiac catheters;

19 adverse effects of catheters on the viability and

20 functionality of a specific cellular product;

21 factors other than cell concentration and simple

22 viscosity that might contribute to clogging or

23 other adverse events; injection of cells into

24 system circulation, the pericardial space, thoracic

25 space via needle catheter; effects of depth or

1 spread of injection into they myocardium on either

2 the safety or, potentially, the efficacy.

3 Question No. 6--these last two questions

4 are about two design elements of early-phase

5 clinical trials. The theoretical risk of these

6 products include the generation of non-cardiac

7 tissues, abnormal cardiac tissue and/or local

8 inflammation. These outcomes potentially could

9 lead to myocardial dysfunction, arrhythmias, or

10 conduction abnormalities.

11 Also, these products are administered

12 because some of the cells contained are

13 self-renewing and possess developmental plasticity;

14 that is, they can differentiate into cells not

15 found in the tissue from which they were obtained.

16 Since uncontrolled cellular proliferation may

17 result in tumor genesis, these products could

18 theoretically result in subjects' developing

19 neoplasia.

20 So, please discuss the appropriate

21 frequency and duration of follow-up. In addition

22 to any other events, please consider the following

23 potential adverse pathological and clinical events

24 in your discussion items: scar formation, left

25 ventricular dysfunction, ventricular arrhythmias,

1 and neoplasia.

2 Next question, please.

3 [Slide.]

4 Some adverse--this is the question that's

5 not--that is a little bit different than the

6 previous six, but I think it's important to

7 discuss. Some adverse events potentially due to

8 administration of these products, such as

9 ventricular arrhythmia, worsening left ventricular

10 contractility and death may be identical to events

11 that occur during the natural history of the

12 underlying disease. The subjects in these

13 trials--in many of these trials--have been quite

14 sick. So a high proportion may suffer one or more

15 of these adverse events.

16 Consequently, adverse events related to

17 the cellular product or its administration might

18 not be discernible without concomitant controls.

19 However, invasive procedures are frequently

20 utilized to deliver these cellular products.

21 Please discuss the pros and cons of using

22 control groups in these early clinical studies,

23 including any need for randomization or masking.

24 Within your discussion, please also comment on the

25 use of placebos in these studies; for example,

1 transendocardial injection of saline into the

2 heart.

3 I would like to make a couple of points

4 that aren't on my slide--one specifically about

5 this. I want to make absolutely crystal clear that

6 there is no--nothing in the regulations that

7 prevent the use of controls in Phase I studies, and

8 there have been many Phase I studies that did have

9 controls. So there is no regulatory prohibition of

10 this, nor is there any unstated policy of the

11 agency that we don't allow controls in Phase I.

12 I've heard that stated many places. I just want to

13 make that absolutely clear.

14 Secondly, I would--these questions, any

15 one of them, would allow for several hours, I

16 think, of very useful and intelligent discussion.

17 To get through them is going to be a challenge. I

18 would encourage the committee to remember that

19 these are issues that need to be dealt with so that

20 we can resolve certain safety issues to allow

21 initiation of early-phase clinical trials. I would

22 discourage you--the discussion yesterday was quite

23 interesting, but I would discourage you from

24 discussion of issues that are dealt with in

25 later-phase clinical trial: appropriate end-points,

1 eventual populations for therapy. These are things

2 about which we haven't presented any data.

3 And I will note that--as you will note in

4 the agenda--that FDA is always asked the questions,

5 after all the FDA speakers, we never leave any time

6 for us to be asked question--for good reason.

7 [Laughter.]

8 Committee Discussion of Questions

9 CHAIRMAN RAO: Thank you, Dr. Grant.

10 So, I guess now we come to the hard part.

11 Many questions, very little time. And we're going

12 to try and get through all of them so that we give

13 the last few questions also fair discussion.

14 I'm going to try and see if we can try and

15 focus the discussion a little bit, and focus on the

16 manufacturing question, and try and get that

17 addressed before the break.

18 So I'm going to make some blanket

19 statements and ask the committee to see whether

20 they agree or disagree with them, and then sort of

21 go from there.

22 The first statement I'm going to make is

23 that: a cell is a cell is a cell is not true. Even

24 though in the heart you can put them in and they

25 all seem to have the same effect, it's still not

1 true, in terms of how they have an effect and what

2 you need to do in terms of the numbers that you put

3 in and so on. So cells have to be treated

4 differently.

5 That's one statement.

6 The second statement I'm going to make is

7 that it seems the FDA and pharmaceutical companies

8 know about how to manufacture cells to some extent.

9 That's generic in terms of cells. I mean, Genzyme

10 presented data on what their GMP facilities look

11 like. They aren't the only company--and I'm sure

12 there will be many other companies who will be

13 willing to tell us how they are much better at

14 doing it.

15 [Laughter.]

16 So it does seem to me that the general

17 issues about cells, in terms of, you know, "Well,

18 we have to look at viral testing, and we have to

19 look at micoplasma, and we have to see that, you

20 know, when we look at cells that the supplies