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

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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.

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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

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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

5

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

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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.

7

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.

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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

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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

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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

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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

12

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.

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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

14

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

15

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?

16

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,

17

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.

18

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

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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

20

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

21

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

22

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?

7

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

23

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.

24

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

25

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

26

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:

27

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,

28

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

29

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

30

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

31

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

32

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,

33

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.

34

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.

35

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

36

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

37

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

38

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.

39

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

40

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.

41

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

42

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

43

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

44

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

45

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

46

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

47

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

48

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

49

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

50

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,

51

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,

52

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,

53

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

54

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 are

21 okay.\" And that\'s not something that we need to

22 worry about in terms of the discussion today.

23 Right?

24 So, we know how to make cells\--or some

25 people know how to make cells. And we know that

55

1 each cell is different, so we can broadly divide

2 this and say that: are there specific issues to a

3 particular cell type in a particular disease, or as

4 it\'s applied to the transplanting into the heart,

5 irrespective of the mechanism that you use.

6 And I\'m going to further subdivide this

7 into two broad categories. And I think we should

8 focus on allogenic, because there\'s very little\--we

9 shouldn\'t focus on allogenic, because there\'s very

10 little data on it, and we\'ve not heard any data on

11 whether that\'s going to be the same, except to make

12 a statement that allogenic is different from using

13 autologous cells.

14 And, broadly, I think for cells\--at least

15 in my experience with growing cells in

16 cultures\--there\'s a very big difference between

17 cells which are freshly harvested over a short time

18 period and put back, versus cells which have been

19 grown in culture, have been manipulated in culture.

20 So there will be criteria which will be uniquely

21 different between those two cell types. And we\'d

22 keep those sort of generic points in mind, unless

23 people specifically disagree with any one of those

24 statements.

25 \[Pause.\]

56

1 So\--great. It\'s amazing that we could

2 start with a common basis, then.

3 \[Laughter.\]

4 So let\'s\--

5 DR. MULE: I just have one comment, which

6 relates not necessarily to the use of fresh cells.

7 I think many of us would argue that there are less

8 regulatory hurdles involved with using fresh cells

9 as opposed to using cultured cells\--with the

10 proviso, of course, that with fresh cells it\'s a

11 well-defined population that is being introduced

12 into patients.

13 With cultured cells, what I heard

14 yesterday, I think, is the issue of using fetal

15 calf serum, which raises the point: if we can avoid

16 fetal calf serum, that is a good thing.

17 CHAIRMAN RAO: If you could talk about some

18 of these specifics\--can we just hold that thought

19 for a second. I can come back to that.

20 DR. MULE: Okay.

21 CHAIRMAN RAO: It\'s the second point, also,

22 on some edition-specific\--

23 DR. MULE: It just relates to the product

24 characterization of using in vitro cultured cells.

25 CHAIRMAN RAO: Hold that thought, and we\'ll

57

1 come back to it.

2 Joanne, do you have something on\--

3 DR. KURTZBERG: Yes, I had just one general

4 addition. I mean, I agree with everything you

5 said.

6 I think it would be a sad comment if we

7 came out of here with anything that recommended or

8 facilitated a company making a product as an

9 autologous non-manipulated bone marrow or

10 peripheral blood-derived cell\--much as you would

11 with an organ. And I think that\'s important.

12 CHAIRMAN RAO: So, given that viewpoint-and

13 it\'s clearly going to be a contentious one\--let\'s

14 start at the other end\--and look at cells which

15 have been cultured for a long time period.

16 Does anybody here feel specifically\--like

17 you made the point about serum\--are there specific

18 things that you need to worry about that are unique

19 to cultures which have been in culture for a long

20 time period, and which are going to be transplanted

21 in the heart. And, you know, some of them were

22 raised in issues before. There was this idea of

23 not differentiating, and there was this idea of

24 cells changing, in terms of the different

25 satienability, and only using the third and fourth

58

1 batches. You heard all of that, right?

2 So anybody\--specifically on those

3 comments, on sort of long-term culture?

4 Dr. Schneider?

5 DR. SCHNEIDER: Well, we heard about that

6 from a useful from limited point of view. We heard

7 that part of the efficacy monitoring in the process

8 of manufacturing\--the skeletal myoblasts, and

9 propagating them to a quantity sufficient for human

10 trials\--was to make sure that over time they did

11 not get overgrown by a sub-population that was

12 differentiation-defective. That\'s clearly

13 important.

14 What we did not hear as part of that

15 presentation was that in vivo efficacy also is

16 tested over time, or is tested for consistency

17 between patient subgroups. There are good clinical

18 data now, at least from the trials in Frankfurt,

19 that heart failure patients, or diabetic patients

20 have bone marrow-derived and circulating progenitor

21 cells which are less functional in human grafting

22 than other patients do. And there are some cell

23 culture and in vitro correlates of that. The

24 cell-culture correlates of that are decreased cell

25 mobility and invasiveness. The in vivo correlate

59

1 of that is that if those human cells are put into

2 an immuno-compromised rodent model of hind-limb

3 ischemia, with patient cells that don\'t work, don\'t

4 rescue hind-limb ischemia in a rodent. So there

5 are predictive models, both for clinical

6 heterogeneity, or for potential heterogeneities

7 introduced in the manufacturing process.

8 So I would say that what we heard, in

9 terms of the characterization of culture not

10 introducing a distortion to the potential

11 biological properties of the cells was nicely

12 raised yesterday, but there are other elements to

13 that, including cell heterogeneity over time, and

14 cell function by other measures, that we\'ll need to

15 talk about this morning.

16 CHAIRMAN RAO: So, clearly, one issue is

17 that if you grow cells for some time in culture,

18 you should be testing them at the stage that you

19 would use them, to figure out whether they have the

20 appropriate characteristics and properties that you

21 want to use them for; and that these methodologies

22 exist\--right? You said mobility assays, some other

23 assay.

24 And there was one other sort of issue on

25 this long-term thing\--Dr. Borer, go ahead.

60

1 DR. BORER: I\'d like to\--this is Borer.

2 I\'d like to follow on to what Mike said, because

3 it\'s appropriate to separate out the different

4 categories of the process as these questions have

5 done. But I think it would be unfortunate to

6 completely separate them and forget that they

7 overlap in many important ways.

8 Steve Epstein suggested this in his

9 comment about conditioned medium yesterday, and I

10 want to restate it in another way.

11 We track and we study what we know about.

12 We don\'t track and study what we don\'t know about.

13 And it\'s easy to become fixated on your theory of

14 pathophysiology, or my theory of pathophysiology,

15 and study those things and miss other, or even more

16 important, characteristics and factors.

17 So what we need to do is to combine the

18 characterization of the product with the parameters

19 that we know to look at with some integrator

20 further down the road; that is, injecting these

21 items into animals, or ultimately into people, and

22 look at outcomes. And I don\'t mean just whether

23 the cells survive or not, I mean it\'s important to

24 track meaningful endpoints, even in small studies,

25 so that you can pick up a\'s, so you can pick up

61

1 signals about survival\--if they\'re there.

2 You\'ll never find those in small studies.

3 Therefore, that statement\--that concept\--argues in

4 favor of the FDA\--maybe not in this committee

5 today\--but ultimately defining standards for data

6 collection so that small data sets can be pooled in

7 some way, so that signals can be amplified.

8 Because, ultimately, if we try to define a list of

9 characteristics that ought to be looked at to

10 characterize a product, it will be a lovely list,

11 but it may not be the right list. And the only way

12 we\'re going to know that is by looking at the

13 outcomes.

14 So I would just make that point: that we

15 have to be thinking about data collection

16 strategies to allow us to pool the small data sets

17 into large data sets that allow one to pick up

18 signals that will tells us there\'s something else

19 we should have looked at.

20 CHAIRMAN RAO: I completely agree with you,

21 Dr. Borer, and I think it\'s really important

22 that\--it\'s this general idea of what is required is

23 much more important than any specific list that\'s

24 developed.

25 Doris?

62

1 DR. TAYLOR: Have a question that I don\'t

2 want to see get ignored in this process, which is

3 definition of the cells, and definition of any

4 given product, when a group claims that they\'re

5 injecting\--and the heterogeneity of that product.

6 How do you define potency of a given cell

7 population? Is it permissible for it to be less

8 than half of what you\'re delivering? Or does it

9 have to be the majority of what you\'re giving.

10 If you say, \"Okay, we\'re going to give

11 CD34 cells,\" does it have to be a hundred percent

12 CD34? Can it be 50 percent CD34, with a mixture

13 you don\'t know about? And that may change in

14 culture.

15 And so I\'d like to\--

16 CHAIRMAN RAO: So, the important point is

17 that we need a better defined product, and that\'s

18 what is going to be some of the issues that we

19 discuss in this Question 2, as well. Would that be

20 a fair way of stating it?

21 DR. TAYLOR: Yes\--and what\'s an acceptable

22 range.

23 DR. HIGH: I have a question about skeletal

24 myoblast processing. For material derived from

25 humans, is expansion to a set number ever a

63

1 limiting factor, or can every subject, no matter

2 what his age, be expanded to 10

9 cells, and our

3 cell numbers are lot release criteria.

4 CHAIRMAN RAO: Doris, do you want to answer

5 that?

6 DR. TAYLOR: Yes, I\'ll be glad\--Doris

7 Taylor. I\'ll be glad to answer that.

8 There are a limited number of patients

9 from whom you cannot grow cells\--for reasons we

10 don\'t understand. Philippe has published data, and

11 other groups have published data, looking at age.

12 And there doesn\'t seem to be a direct correlation

13 with age and an inability to grow cells.

14 Occasionally we end up with a patient where we

15 can\'t grow the cells and we don\'t know why.

16 They\'re just not there.

17 Now, can you grow 10

9 cells? Generally

18 the question is how long it will take to do that.

19 CHAIRMAN RAO: Go ahead, Joanne.

20 DR. KURTZBERG: I think whenever you work

21 with biologic products there is always an element

22 of unpredictability, and that you can never count

23 on every patient growing the same number of cells,

24 every patient biologically acting the same way.

25 And if you try to design a trial that assumes that,

64

1 you\'ll never finish your trial.

2 So there has to be some understanding that

3 biology is variable.

4 DR. HIGH: But should there be some minimum

5 number that goes into\--on injecting?

6 DR. KURTZBERG: I don\'t\--I think that a lot

7 of these questions are very premature. I just\--we

8 can\'t define the cell type today\--we, you\--anybody.

9 I mean, I think what we have to do is do the

10 studies to get some more data, to have some more

11 general idea of some of this. And maybe the answer

12 will be that\--you know, if a certain kind of cell

13 is beneficial, and you\'ve done a collection from a

14 patient and only collected 80 percent, are you

15 going to deny that patient that 80 percent?

16 Probably not. I don\'t know.

17 CHAIRMAN RAO: Again, I want to

18 emphasize\--and this is maybe just general, for

19 information: this is historically a problem for all

20 cell therapies\--right? And you have to worry about

21 cellular therapy when it\'s a single

22 lot\--right?\--it\'s a one-unit dose that you\'re

23 making, and it\'s from one patient, and you can\'t

24 really do it for each patient. And as you all

25 pointed out, it\'s going to be different from each

65

1 case.

2 And so what Dr. Borer pointed out is that

3 we can\'t come up with a really absolute, specific

4 list\--as you said\--that you can\'t.

5 So what\--how do people do this in any of

6 these systems? And from my limited experience has

7 been that you either say that they\'re the same,

8 because you have some definition of markers, or

9 sets of things that you put together for cells, or

10 you say they\'re the same in terms of some

11 substitute assay in culture.

12 So, for example, if you\'re looking at

13 pancreatic islets, you say they all release this

14 much in terms of the number of cells that you give

15 in terms of insulin release. Or, you know, in

16 Parkinson\'s patients you say, well, this is how

17 much dopamine is released by this particular number

18 of cells, and you say that\'s an equivalency sort of

19 measure.

20 And what, to me, from looking at\--or

21 hearing conversations seems to be that it\'s pretty

22 clear that there\'s going to be that same sort of

23 variability, and that there must be some kind of

24 equivalency measure that must be looked at if you

25 want to collect any kind of data.

66

1 Go ahead.

2 DR. BLAZAR: That was the point I was also

3 going to make is it\'s\--listening to the data

4 yesterday, it looks like multiple cell types may,

5 in fact, be additive or synergistic, so these

6 preparations that are not 100 percent pure may, in

7 fact, have some advantageous\--potentially

8 advantageous aspects to it.

9 So I think if it\'s well characterized, it

10 doesn\'t necessarily have to be 100 percent pure.

11 The dilemma is that if the in vivo readout is the

12 critical final denominator, then the in vitro

13 assays might simply just characterize the product,

14 provide the information to the literature, which is

15 then correlated with the clinical outcomes, and

16 then in retrospect then define, potentially,

17 product limitations.

18 I just don\'t know if you\'d be able to, up

19 front, say that \"this is a desired product,\" so

20 much as \"this is the characterization of that

21 product,\" to the best that we can characterize it,

22 and then try to retrospectively do the clinical

23 outcomes measurement, and then have that define the

24 field of a useful product.

25 CHAIRMAN RAO: Go ahead.

67

1 DR. BORER: This may be a little premature,

2 because I think it will be covered in another

3 question. But the discussion that Dr. High and Dr.

4 Kurtzberg just had I think is important, and I just

5 want to put a bookmark in here.

6 What\'s being raised here is the issue of

7 dose-response. And I would point out\--and you all

8 know this\--that the shelves and the libraries are

9 filled with expired patents of wonderful drugs that

10 were never used, because the dose-response wasn\'t

11 adequately characterized, and the drugs were

12 developed at the wrong dose.

13 Now, I think we\'re\--not with unprocessed

14 bone marrow, but with cultured cells, there is

15 incumbent upon investigators the need to define the

16 dose-response in a broad, and as complete as

17 possible way, because ultimately the application of

18 at least that type of therapy will depend on the

19 adequacy of dose.

20 So I just put that bookmark in. We\'ll be

21 taking about it later.

22 CHAIRMAN RAO: I was actually kind of

23 surprised\--one issue that didn\'t come up with

24 cultured cells was nobody seems to worry about

25 looking at karyotypic stability of cells. And even

68

1 when people talked about this, nobody presented

2 data where they said, well, you know, when we put

3 in 100 million cells, that these cells were

4 all\--you know, we tested an aliquot, or we looked

5 at it.

6 What does the committee feel about

7 karyotypic assessment?

8 DR. BORER: Yes, I must say I had that

9 written down here, but I thought since nobody

10 mentioned it, it was probably silly.

11 The fact is, with multiple passages, I

12 would have thought one would like to know how the

13 error rate increases; that is the replication

14 errors increase, because that\'s going to

15 characterize the population, as well, and one could

16 easily wind up with cells that have all the surface

17 markers that we look for, and the antigenic markers

18 we look for, and, you know, they look like what

19 we\'re interested in, and yet you inject them and

20 you come up with a cell rest in the myocardium that

21 doesn\'t do what you think it should have done.

22 So I would think that it would be very

23 important to assess the karyotype in the final

24 product, as well as in the initial set of cells

25 that you put in.

69

1 CHAIRMAN RAO: Joanne?

2 DR. KURTZBERG: I agree with you, but I

3 have an unrelated point about administration\--and

4 it wasn\'t mentioned yesterday. But there

5 were\--during the talks about the devices, the

6 needle gauge size came up a couple of times, and I

7 heard numbers like 27-gauge, 29-gauge thrown

8 around.

9 And, as a transplanter of hematopoietic

10 cells, we would never put those cells through that

11 small a needle, because they lyse, get crushed, get

12 smashed, break apart. And then you\'re talking

13 about doing it under high pressure, which only

14 increases the probably of cell damage.

15 I understand there are other technical

16 issues related to the heart and getting catheters

17 in there, but I think it\'s really important to talk

18 about that, and at least require some kind of bench

19 testing that would demonstrate that cells can

20 be\--you know, aren\'t damaged when they go through

21 that small a hole under high pressure.

22 CHAIRMAN RAO: Dr. Murray?

23 DR. MURRAY: If we\'re going to worry about

24 dose response\--that\'s if we need a numerator and a

25 denominator\--right?\--the denominator\'s going to be

70

1 response. We\'re not talking about that right now,

2 we\'re talking about the numerator, which\--what do

3 we count as being part of the dose? Is it how many

4 hundreds of millions of cells? Is it how many

5 millions of myoblasts in a set-up preparation? Is

6 it how millions of cells with the normal karyotype

7 of a particular cell type?

8 I feel very uncomfortable with the

9 tremendous uncertainty of what it is we think we\'re

10 looking at, and what subsets of that\--the

11 collections of cells we\'re looking at, etcetera.

12 Some clarity on that I think would be helpful.

13 CHAIRMAN RAO: Doris?

14 DR. TAYLOR: Specifically, with regard to

15 myoblasts, I think one of the issues is the assays

16 you design for your cells. And with myoblasts\--I

17 can\'t say that we\'ve looked at the karyotype of our

18 cells over time. What I can say is that we\'ve

19 looked at the ability of our cells to fuse and

20 terminally differentiate and form myotubes; and

21 that that\'s used as a potency measurement of these

22 cells.

23 And I think that is the kind of assay that

24 makes a lot of sense in this particular setting,

25 because once they\'re terminally differentiated,

71

1 they\'re not going to continue to divide in the

2 myocardium.

3 I will say that\--I didn\'t present these

4 data yesterday, but we have preclinical data over a

5 number of years showing that if we purify the cells

6 to too great a degree of homogeneity they are less

7 effective than if there is a mixture of cells

8 present. And that doesn\'t surprise me, given the

9 mitogens that, I think, are delivered by the

10 fibroblasts and other cells that are there.

11 CHAIRMAN RAO: Dr. Borer, did you have a

12 comment?

13 DR. BLAZAR: Yes. I think the issue of

14 passage numbers and serum requirements is really

15 critical, and as these studies go forward, even

16 with characterizations, if the products look the

17 same at three passages, and you\'re using them at

18 five or six passages, the cells may well

19 differentiate in a way that can\'t be well monitored

20 in vitro.

21 And I don\'t know necessarily that there\'s

22 an optimal passage number, but I think as the

23 studies report their results, it will be very

24 important to discuss those two issues which may

25 affect in vivo survival and differentiation, as

72

1 well as karyotype stability.

2 CHAIRMAN RAO: That\'s a really important

3 point, and maybe I can try and summarize what I

4 felt was the sense of just this specific point:

5 that when you keep cells in long-term culture, it\'s

6 really critical to look at passage number. And

7 that\'s more an absolute rather than just saying,

8 \"Well, you know, I used passage eight and it has

9 the same apparent phenotype as an early passage,\"

10 but that you really want to keep track of the

11 passage number. And you can\'t just automatically

12 assume one will be the other.

13 DR. BLAZAR: I think even added to that is

14 cell density. We know that cell density is a

15 critical influencer of differentiation potential,

16 and minor changes in cell density can have

17 significant abilities, not only to look at the

18 growth rate, but can differentiate cells in ways

19 that may be picked up in later passages because of

20 the cell contact and growth-factor issues

21 that\--where one population influences another.

22 So I think, again, as we go forward, as

23 much information in the reports as possible, to try

24 to look at these effects, and if they are going to

25 vary in even individual patients, so that there can

73

1 be a net body of information in the literature, it

2 would be helpful retrospectively in evaluating the

3 outcomes.

4 CHAIRMAN RAO: It\'s a good time to sort of

5 consider also what you raised as an issue of the

6 growth-factors in serum, and cytokines, which

7 should be used in the manufacturing process

8 perhaps. And if you have a specific comment\--

9 AUDIENCE: Actually, it was back on the

10 unmanipulated cells\--I just wanted to make a

11 comment on those.

12 CHAIRMAN RAO: We\'re going to come back.

13 Hold it and see if you need to make that comment at

14 that time.

15 Go ahead.

16 DR. SCHNEIDER: Michael Schneider.

17 I wanted to state that with respect to

18 heterogeneity, skeletal muscle-derived cells over

19 time in culture, in addition to the issue that

20 Doris mentioned about the variable percentage of

21 fibroblasts, there are two other specific

22 populations to be vigilant about in the skeletal

23 muscle preparations.

24 One of them is the so-called side

25 population, or SP cells, which are very small in

74

1 number, but\--as many members of this panel know\--in

2 bone marrow account for much, if not all, of the

3 long-term self-renewal potential. And so it would

4 be important to know whether the manipulation of

5 the skeletal muscle cells in culture over time

6 might be depleting that from the starting

7 population; or, alternatively, enriching for that

8 relative to the starting population.

9 There also has been described in rodents,

10 by several labs, a SCA positive population, similar

11 to the progenitor cells that we see in adult rodent

12 hearts. SCA-1 is an allelic variant in rodents

13 that doesn\'t have a precise equivalent in humans.

14 But as Dr. Itescu alluded to yesterday, markers

15 such as STOW-1, indicative of the pericyte might

16 well be good indicators of the SCA-1 equivalent in

17 the skeletal muscle preparations.

18 And so my point is that, in terms of the

19 drift in time over culture, it\'s important to know

20 in a consistent and reliable way what is happening

21 to these other sub-populations that may be

22 contributing to the in vivo efficacy.

23 CHAIRMAN RAO: So that\'s really\--it seems

24 to be a really quite important point, is that since

25 we don\'t know what is the\--and it\'s the point you

75

1 made, as well\--is that we may not know the

2 effective cell, and we need to know both about the

3 concentration of the effective cell, in terms of

4 whatever you think its mechanism is, as well as the

5 other cells that are going to present in the media,

6 because we may or may not know how useful or how

7 bad they may be\-- whatever may be the case.

8 DR. SCHNEIDER: It\'s not that these would

9 be necessarily contributing to the skeletal muscle

10 formation in large number, but they may be

11 producing cytokines, growth factors, acting on the

12 other injecting cells or, as several speakers

13 alluded to yesterday, having some other kind of

14 favorable effect on the host.

15 DR. MULE: If it\'s true that 90 percent of

16 the injected cells are dying, it\'s hard for me to

17 imagine, first of all, how one can do an

18 appropriate dose-response. And secondly, we may

19 spend an enormous amount of time trying to

20 understand the makeup of the culture before it goes

21 into a patient. But not having an understanding of

22 whether certain subsets of cells within that

23 heterogeneous population are dying off in

24 vivo\--with a 90 percent overall die-off, it\'s a

25 struggle to understand\--and it gets back to Dr.

76

1 Borer\'s concern about having appropriate endpoints

2 in the trial that will allow you to get some

3 biologic information about the cells that not only

4 go in, but those that survive.

5 DR. MURRAY: This is Tom Murray.

6 My friend Carol Greider was once trying to

7 teach me about Belgian beers. And the lesson

8 didn\'t particularly take. But apparently\--they go

9 through multiple fermentations, and they utterly

10 change their character, depending upon whether it\'s

11 the first, second, third, fourth\--I don\'t know how

12 many times they do it.

13 And I heard yesterday\--and maybe a little

14 bit even today\--the possibility that in different

15 passages the cells\' properties change. And it

16 seems to me there are just\--crudely, three

17 possibilities. One is it doesn\'t matter how many

18 passages, at least up to a certain limit, but the

19 cells are the same all the way through. And that

20 does not seem to be the case. I don\'t hear anybody

21 saying that that\'s the case.

22 The second possibility is: they change,

23 but in a continuous fashion. That is, whatever

24 changes there are, they simply\--they\'re additive,

25 so the changes in each passage, they become more

77

1 extreme.

2 A third is\--and this is what I thought I

3 heard yesterday\--was that, in fact, they change in

4 interesting ways, such that three and five may be

5 more alike than four. I may have the specific

6 numbers wrong.

7 It would be very helpful for the FDA, I

8 think, to ascertain what the best scientific

9 evidence is as to which of those three models is

10 the correct one, and then that will have

11 implications for whatever you decide.

12 CHAIRMAN RAO: So\--I want to get back to

13 the point that Dr. Murray made, and that is that

14 all of this assessment that one considers, you need

15 to consider not just at the time that you\'ve got

16 the cells into a wire, but really have to have some

17 assessment of what that means when you get them

18 into the heart. Is that the emphasis that you\'ve

19 been making?

20 So if you\'re going to have deaths, then

21 you need to know that you\'re going to have 90

22 percent die each time, because that\'s going to

23 significantly change your dose, if you do something

24 with it. Is that a fair\--

25 DR. TAYLOR: I think one of the issues that

78

1 you need to think about in considering that is that

2 the geometry of the injections, and the number of

3 injections is really going to probably change the

4 number of cells that die. If you inject a giant

5 bolus of cells, it doesn\'t take a rocket scientist

6 to figure out the fact that more are likely to die

7 than if you inject 10 smaller populations

8 throughout the scar, based on the nutrients they

9 receive.

10 So I think you have to factor into trial

11 design the injection patterns for these cells as

12 well.

13 CHAIRMAN RAO: Dr. Borer?

14 DR. BORER: I thought that the issue I\'m

15 about to raise really would be subsumed under the

16 preclinical studies area, but I looked at the

17 question, and it\'s really not only.

18 And that is\--and that follows from some

19 points Dr. Itescu raised yesterday which broadly

20 involve drug-biologic interaction. These products

21 will be given to patients who have\--who will have

22 multiple drugs in their bodies at the time the

23 products are given. And I don\'t think we know\--I

24 mean, I don\'t know the research in the field, but I

25 didn\'t hear much about it yesterday\--I don\'t think

79

1 we know how the drugs that routinely are given to

2 patients who have the target diseases affect the

3 growth and development of the cell products.

4 And I think this needs to be

5 characterized. I don\'t know what we\'ll learn, but

6 one could just, for example, learn that maybe you

7 have to stop beta blockers for a few weeks in

8 people with heart failure who are being given

9 cells, because the cells won\'t grow properly\--or

10 optimally.

11 And I think that characterization has to

12 begin before one gets to the in vivo experimental

13 model studies, that it really does require some

14 benchwork to look at the effect of drugs on the

15 cell population.

16 So, again, just to bookmark\--but we

17 haven\'t talked about drug-biologic interactions,

18 and I think that\'s an important area that we need

19 to consider throughout these discussions.

20 CHAIRMAN RAO: Bruce?

21 DR. BLAZAR: I wanted to come back to the

22 cell death rate. I think one possibility is, of

23 course, mechanical, and the cells don\'t survive

24 when they\'ve been removed from an in vitro culture,

25 and they\'re undergoing cytokine withdrawal,

80

1 etcetera. Another possibility is that they\'re just

2 not receiving the proper inductive signals in vivo.

3 If it was the latter case, then a

4 dose-response curve would actually help, because

5 it\'s still going to be the same fraction of cells

6 that is not receiving the appropriate inductive

7 signals. And I think there is ample data in

8 animals, with a variety of cell types, to say that

9 if there is not a stimulus for proliferation the

10 cells will either sit there or they will undergo

11 cytokine withdrawal, or other apoptotic cell death

12 pathways.

13 So I think despite the death rate, it\'s

14 critical to evaluate the dose response because we

15 do not know, as you remove these cells from the in

16 vitro environment, what proportion of cells would

17 survive in any location, given under any

18 conditions. And while it\'s important to evaluate

19 the cell death rate, I believe that several of

20 these may relate to just inappropriate environment

21 to be induced to proliferate the way that they are

22 in vitro.

23 DR. MULE: I agree with you, Bruce.

24 My concern is that it will not allow you

25 to achieve the highest dose

81

1 response\--conceivably\--limited by practicality, for

2 instance. I mean, if you go up to 10

10 cells, and

3 you\'re losing 90 percent of those cells,

4 realistically, how many cells can you generate over

5 a given period of time, given the injections that

6 are needed. Those type of issues\--

7 DR. BLAZAR: We don\'t know how many is

8 necessary\--what fraction of surviving cells is

9 necessary for a clinical benefit.

10 If you look at bone marrow infusions, most

11 of those cells die. The vast majority of them are

12 terminally differentiated myeloid cells, and, you

13 know, we\'re injecting products where the cell

14 survival rate is extraordinarily low. And, again,

15 I think it\'s the inductive signals that are

16 required.

17 Once it is known how best to manufacture

18 cells to receive the appropriate inductive signals

19 and to put them in the appropriate inductive

20 environment, then we\'ll realize more of the

21 clinical benefit. But even for now, I think, that

22 as the dose response curves are done, since we

23 don\'t know the fraction of cells surviving

24 necessary for clinical benefit, those studies just

25 have to be done and looked at the data

82

1 retrospectively.

2 CHAIRMAN RAO: Dr. Allan?

3 DR. ALLAN: The comment I\'d like to make is

4 when I read Question 1 what I see is safety. And

5 most of the discussion here seems to be on

6 efficacy; what\'s the right formulation in order to

7 get the right response, or dose response. And to

8 me, what I see the question is is mostly safety.

9 And so therefore it\'s like the preparations, that

10 if it\'s 80 percent fibroblasts maybe you don\'t want

11 to give it, but if it\'s, you know, 80 percent

12 myoblasts, then\--what are the safety

13 considerations? And so for a lot of this, it\'s

14 really\--because we\'re going to be stuck on Question

15 1 for the rest of the morning if we keep

16 introducing efficacy into the discussion.

17 And I would say we just want to stick to

18 safety.

19 CHAIRMAN RAO: Yes\--I, in fact, would even

20 say that we want to stick to manufacturing right

21 now\--you know. So\--meaning, at the product. So

22 all we\'re looking at is that can we define a

23 product in light of what it will be, with some

24 reasonable criteria, in terms of\--

25 DR. ITESCU: Yes, and I think that was

83

1 really my point to Dr. Borer. Whilst I agree that

2 there are many scientifically valid questions to be

3 asked, I think the cell product that\'s being

4 defined by whatever is being addressed needs to be

5 viewed no differently than a pharmaceutical

6 composition. And I think that\'s really the job of

7 the FDA, to ask questions about, obviously, safety,

8 but also dose-response questions, about efficacy,

9 about production, manufacturing\--scientifically

10 valid questions then follow on from that.

11 But the definition of the product is the

12 key, I think. And that can be based on surface

13 phenotype or function.

14 CHAIRMAN RAO: Go ahead.

15 DR. WENTWORTH: Yes, my name is Bruce

16 Wentworth from Genzyme Corporation. I just want to

17 make a small observation.

18 There\'s been a number of suggestions of

19 tests and assays that might be performed on cells.

20 Some of those are, in fact, done in the normal and

21 routine monitoring of cells in production. Every

22 production facility will set limits on the number

23 of passages that are used. I would point out that

24 it is actually population doubling is perhaps the

25 more relevant figure, rather than passage number;

84

1 and the conditions under which cells are passaged.

2 However, in cell therapy, really, it can

3 never be quite like pharmaceuticals. Cells are

4 inherently variable. There\'s no way around that.

5 And I would ask you, in a moment of quiet

6 reflection, to look at the back of your hand. You

7 will see warts, cells that are dark, skin that\'s

8 light, hair, no hair\--it\'s all the product of

9 karotynocites. Every one of them works. All of

10 them are different.

11 You can make a useful product from that

12 that actually saves the lives of burn patients. So

13 if we spend a great deal of time analyzing the

14 karyotypic difference, which is inherent to the

15 back of your hand, we\'ll get nowhere and you\'ll

16 have no new product.

17 Thank you.

18 CHAIRMAN RAO: Dr. Borer, and then Dr.

19 Harlan.

20 DR. BORER: Just a philosophical point. As

21 Dr. Allan points out, we\'re talking primarily here

22 about preserving safety, but first of all, there

23 are dose responses for safety endpoints as well as

24 for efficacy endpoints. And so you have to know

25 these things. And, in addition, I think it\'s very

85

1 artificial to talk about \"safety,\" and not consider

2 other effects\--other effects of the product\--that

3 might contribute to clinical effectiveness because,

4 at the end of the day, the issue isn\'t absolute

5 safety, it\'s safety that\'s acceptable for the

6 intended use.

7 So, one really has to keep the equation in

8 mind always between effectiveness and toxicity. So

9 I think it\'s reasonable to characterize the product

10 in all these ways, even though it sounds like

11 \"effectiveness,\" in fact the safety

12 characterization and the efficacy characterization

13 are really different ways of looking at exactly the

14 same characteristics.

15 CHAIRMAN RAO: And I\'m going to try and ask

16 everyone that let\'s try and focus on this first two

17 sets of questions, which is: we\'ve got cells\--some

18 kind of cell\--and right now we\'\'ve only focused on

19 the cells that you\'ve got in long-term passage, and

20 that we\'ve got some specific issues that we might

21 want to consider when they\'re there, and one of the

22 issues was that passage number is important, and

23 the second issue was that you really should look at

24 karyotypic stability as well, and that you should

25 have some readout on what that composition of the

86

1 cell type is, and that none of these can be done

2 just in culture. You really need to do them after

3 you\'ve implanted the cell in some fashion so that

4 you have some readout of what you\'re actually

5 delivering in terms of a product.

6 And Joanne made the really important

7 point, I felt, was that what that means is that you

8 have to include in this whole process is how you\'re

9 going to deliver\--right? That gauge of the needle

10 that you deliver through; the method of delivery is

11 going to be as important in that whole process as

12 anything else, because 27-gauge for somebody is

13 going to lyse their cell type, and if you use a

14 30-gauge, it\'s certainly going to give you based,

15 and maybe that will be effective, but the mechanism

16 will be different, you know.

17 And so those points seem to be pretty

18 clear from what needs to be done. And I thought

19 that another point that came up was that when you

20 think about composition you\'re not just thinking

21 about the effective composition of the cells, but

22 you\'re really thinking about the total composition

23 of a cell, because heterogeneity may be important

24 in its function, but also what the other cells are

25 doing may be equally important in what they might

87

1 not do\--right?\--or what they might worsen.

2 And we need to have that information. And

3 the points you made about collecting that data is

4 really critical in terms of having that sort of

5 data in terms of defining a product.

6 So let\'s see if we can add to that,

7 specifically in terms of these cells, because I\'d

8 like to try and extend this to also the non-passage

9 cells as well and see if there\'s anything, really,

10 that\'s specifically different in those as well.

11 DR. KURTZBERG: Well, I think you can learn

12 lessons from cell therapy that\'s already in

13 progress. And there are some simple things that

14 are always done, like viability, sterility\--and

15 those\--especially for the long-term passage cells,

16 there has to be a protocol for determining

17 sterility that doesn\'t involve setting up a culture

18 the day you deliver the cells, because that\'s not

19 going to be useful information.

20 I think in most settings you would

21 characterize the population by phenotype or

22 whatever other method you have, and maybe the

23 potency assay would be a colony-forming assay, or a

24 cytokine-production assay, or whatever. But

25 whatever is decided would be done on all products.

88

1 I think, also\--

2 CHAIRMAN RAO: Joanne, let me add just one

3 point what you made\--just make sure that I\'ve got

4 that appropriate.

5 Whatever surrogate assay you use has to

6 match, or you have to have some data that it\'s a

7 representative assay for what function you\'re going

8 to use. Is that\--

9 DR. KURTZBERG: To the best of your

10 ability.

11 CHAIRMAN RAO: To the best of your ability.

12 DR. KURTZBERG: I mean, again, what Bruce

13 said is that it may just characterize the cell,

14 rather than directly correlate with your efficacy.

15 But it\'s the best you can do at the time.

16 And then, finally\--and this may have more

17 relevance in the future\--but there will be other

18 contaminating cells in some of these populations,

19 like t-cells, or macrophages. And while it may or

20 may not have relevance, I think that at least

21 knowing what immune-mediating kinds of cells are

22 there could be important, and they should be

23 characterized as well.

24 CHAIRMAN RAO: Dr. Simons.

25 DR. SIMONS: I would like to raise the

89

1 issue that the effects observed in all of the

2 studies may have nothing to do with the cells that

3 have been actually injected\--at least with the live

4 cells\--and it\'s the dead cells that are having this

5 effect.

6 With 90 percent of the cells dying, I find

7 it hard to believe that whatever is left is really

8 responsible for most of the biological effects

9 observed. And that could be different in a setting

10 of an acute myocardial ischemia, versus the setting

11 of sort of chronic CHF patients. But I think, in

12 talking about what this material is, it is

13 important to consider that it could be t he dying

14 cells, or the dead cells, that are the active sort

15 of ingredients here, which I think sets a very

16 different set of issues than if the active material

17 is what\'s going to be left of the dividing cells.

18 And I would like to hear what people think

19 about that.

20 CHAIRMAN RAO: I thought before we go into

21 discussion\--comments from some of the other people.

22 DR. HARLAN: I think you were making this

23 point, Dr. Rao, but I believe that we don\'t know if

24 any of these surrogate characterization tests that

25 we wish to do are true North. I think we need a

90

1 \"true-North\" assay. For bone marrow

2 transplantation we\'ve had a lethally irradiated

3 mouse, where we can test the various assays to see

4 where they\'re predicative of anything.

5 What I heard yesterday is that we don\'t

6 necessarily have a true-North assay in the clinic,

7 or even in animal models, to say that this cell

8 population is doing what want it to do. And

9 without that, all of the characterization is

10 difficult to judge.

11 CHAIRMAN RAO: A really important point,

12 and let\'s keep that in mind. And I think it\'s good

13 that you brought it on the table.

14 Go ahead.

15 DR. SCHNEIDER: I would disagree with Dr.

16 Harlan\'s point because I think that the true North

17 is there. We don\'t know why the true North is

18 working.

19 The true North would be to inject the

20 human cells proposed for use in human patients into

21 an immuno-compromised rodent and show efficacy, as

22 Dr. Itescu did. That could be done most directly

23 by intra-cardiac injections or, as a surrogate for

24 their angiogenic capacity in vivo, as rescue of

25 hind-limb ischemia. And I think both of those are

91

1 perfectly appropriate assays to test for the

2 angiogenic potential, or the myogenic potential of

3 the proposed populations.

4 What I wanted to comment on, prompted by

5 Bruce Wentworth\'s remarks, is to point out that the

6 FDA, I think, has to anticipate some very different

7 kinds of protocols in terms of manufacturing coming

8 down the pike. Some of those will be large, very

9 centralized studies using GMP facilities such as

10 what we heard about from Genzyme, and as Dr. Rao

11 alluded to\--other companies with large, long-term

12 experience in cell production of many kinds.

13 What I as an academic investigator see as

14 one of the potential risks to the field is the

15 illusion among academic investigators that cell

16 therapy is easy, because of the proliferation of

17 clinical trials that have been reported with high

18 visibility. And as trials move or propose to move

19 from a single, highly experienced center into half

20 a dozen, or a dozen, or two dozen centers with

21 variable degrees of experience, both in cell

22 production and in cell administration, that\'s, in

23 my mind, one of the principal issues for defining

24 the criteria in terms of purity of cells and in

25 vitro surrogates, and even in vivo surrogates

92

1 before a given trial be given a green light.

2 CHAIRMAN RAO: Can I expand on that

3 statement before we get the comments.

4 I think what you\'ve said is somehow also

5 representative of what Dr. Grant started with, in

6 terms of the frustration for the FDA; or, how can

7 you really use data from one trial or the other to

8 pool it when you have large numbers of small

9 samples?

10 And I think what\'s coming through here is

11 that you can\'t pool that data unless you really

12 have very clear-cut description of what you really

13 have put in\--right?\--in terms of the quality of the

14 cells, or the number, or\--you know, the markers

15 that they exist, or some clear-cut surrogate

16 marker. You know, it may be\--as you pointed

17 out\--that it has to be done in an animal model, or

18 it has to be done\--but unless you have a common set

19 of readouts which are all consistent, you won\'t be

20 able to pull the data across many of the clinical

21 trials, and you won\'t be able to extrapolate from

22 one trial to the other.

23 And I think that was true, even when Dr.

24 Menasche, when he presented the data that they had

25 shown that, you know, when\--even if you take

93

1 skeletal muscle and you look at different labs, if

2 they do it slightly differently, you get different

3 results. And so you really have to be very

4 critical, in terms of how you can compare and not

5 compare and it won\'t be okay.

6 DR. SCHNEIDER: It\'s the second of those

7 aspects that I was trying to emphasize; the risk of

8 extreme variability, even with a single trial,

9 between different production sites.

10 CHAIRMAN RAO: Go ahead\--you\'ve been

11 waiting for a long time, and then Dr. Itescu.

12 DR. GRANT: Thank you. Stephan Grant from

13 Viacel.

14 My question relates to the testing of the

15 finished products. Do you think\--would the

16 committee support a position saying that in vitro

17 or in vivo differentiation studies would not be

18 part of the final specification of the finished

19 products, because certainly, I think, if we just

20 transfer what we are doing with the small-molecule

21 drugs, or even with recombinant proteins, we are

22 normally not testing, for example, the receptor

23 binding or a biological assay for potency or for

24 efficacy for the batch release.

25 So the question is basically: would the

94

1 committee support a position saying, well,

2 differentiation assays, in vitro, in vivo, are good

3 for profiling of the product, but not mandatory for

4 the release of the finished goods?

5 CHAIRMAN RAO: I\'m going to try and take

6 the liberty of answering for the committee, and if

7 people disagree\--

8 I think that that\'s not\--the sense from

9 the committee that I got was that, you know, it\'s

10 really important. It\'s important that you know.

11 And from what Dr. Murray has said, and what other

12 people said, that you really need to have some

13 potency equivalent\--right?\--that has to be\--

14 DR. GRANT: May I just add a comment?

15 I was not\--I\'m not saying that we don\'t

16 need such assays to be performed, but the question

17 is if we have to test batches of finished products,

18 batches to be released for clinical trials, or

19 later for the market? The question is whether a

20 differentiation assay should be part of every

21 batch-release specification?

22 CHAIRMAN RAO: I don\'t want to be too

23 specific, so we\'ll leave that topic on the table

24 right now.

25 Go ahead, Dr. Itescu, and then\--

95

1 DR. ITESCU: I just wanted to add to what

2 Dr. Schneider said. I agree with him

3 entirely\--that I think that we do have good

4 immunosuppressive models\--small models\--where you

5 can test whatever human cell type you want. And I

6 think that could easily be a surrogate outcome for

7 potency for any given product that you\'re

8 interested in.

9 I think, in addition to that, we would be

10 able to put together some sort of consensus on what

11 constitutes cardiac improvement. We really barely

12 touched on that, really, yesterday, but I think, as

13 a group, you\'d find some sort of consensus about,

14 maybe, systolic improvement. And I think if you

15 had those two combinations, in terms of

16 differentiation in vivo plus functional

17 improvement, you\'ve got potency.

18 CHAIRMAN RAO: Dr. Cannon, and Dr.

19 Kurtzberg.

20 DR. CANNON: I wanted to follow up on Dr.

21 Kurtzberg\'s comment about immuno-reactive cells.

22 I think it\'s also important for us to

23 consider how the cells are obtained. I think there

24 is interest in cytokine mobilization of cells, and

25 certainly the experience in giving GCSF by our

96

1 transplanter colleagues has been very favorable.

2 They really haven\'t seen much in the way of

3 complications\--a few.

4 But it may be very different in our

5 patient populations that we want to treat. And the

6 point I want to make is I think it will be

7 important for us to characterize these cells as to

8 whether they contain activated immuno-competent

9 cells that might destabilize plaque.

10 CHAIRMAN RAO: Hold the thought, I\'m going

11 to try and summarize that and just make sure that

12 I\'ve captured it, if it turns out I haven\'t.

13 DR. KURTZBERG: I\'d just like to propose\--I

14 think you need a cardiac therapy study group. I

15 think the people who are interested need to come

16 together, build a consensus, decide on how you\'re

17 going to monitor your products and characterize

18 your products; decide on what your endpoints are

19 going to be for your clinical trials.

20 Because you have several products, and

21 several endpoints, and several diseases\--and

22 there\'s models to do this in cancer therapy, in

23 transplant therapy. And I think that\'s what has to

24 happen now in order to pull this all together.

25 CHAIRMAN RAO: Can I try and extend\--if you

97

1 have a comment, is it specific to this?

2 DR. TAYLOR: It is\--it\'s specific to

3 actually two things: one, to Dr. Schneider\'s

4 comment about different groups coming forward.

5 One of the things that frightens me most

6 about he field\--and that I hope the FDA is going to

7 be the regulatory body on\--is the number of phone

8 calls I get from physicians saying, \"I can take

9 cells out of the bone marrow,\" or \"I can grow cells

10 in a dish.\" \"I can do a study, and here\'s the

11 study I\'m going to do.\" And it concerns\--with no

12 experience, necessarily, preclinically, in terms of

13 understanding the vagaries of cell therapy, or the

14 vagaries of growing cells, or measuring cells.

15 And so I really am concerned about that.

16 In terms of pulling together a cardiac

17 study group, one of the commitments that I and a

18 couple of other people in the field have made is to

19 get all the thought leaders, in terms of academic

20 investigators who are doing this work

21 internationally, together to try to come to a

22 consensus this year about what endpoints we need to

23 be measuring, preclinically and clinically.

24 DR. RIEVES: Dr. Rao, we appreciate all the

25 comments. They\'re very useful.

98

1 But in your summary, could you also

2 incorporate the perspective of overall product

3 development? Characterization, for example, is

4 usually regarded as a continuum. As you\'ve heard,

5 we need some details in early clinical development,

6 but our regulations, our acting procedures, allow a

7 great deal of flexibility, such that flexibility

8 for initiating a Phase I clinical study may be

9 considerable with respect to manufacturing,

10 compared to the flexibility that might be

11 reasonable prior to initiating a Phase III study.

12 So, in your summary and discussion could

13 you also incorporate the stages of product

14 development? And specifically, we\'re interested in

15 early stages.

16 CHAIRMAN RAO: Before we get to that, can I

17 try and also\--in the interest of time\--try and

18 extrapolate from all this discussion?

19 You know, we looked at long-term passage

20 cells, and I want to say that many of these issues

21 apply, but to a lesser extent if you\'ve directly

22 harvested the cells. And you can\'t extrapolate

23 from one cell type to the other if the mode of

24 selection is different.

25 And as has been already pointed out from

99

1 the data that\'s available, that if you mobilize

2 bone marrow cells it\'s not that one mononuclear

3 cell population is the same as another mononuclear

4 population, because we don\'t know the mechanism of

5 action, and we don\'t know the cell type. So that

6 each cell type used in cardiac therapy, in some

7 sense, irrespective of whether operatively you call

8 it the same, is different because you have to

9 define that particular product in terms of how it

10 was isolated, and from what patient population it

11 was done. So even though it\'s a one-shot dose, you

12 can only compare it with a single one-shot dose

13 from another patient where it was made and

14 harvested much the same way.

15 So many of the issues that we raised here

16 for passage cells apply to these cells in a generic

17 way, but there will be specific concerns which are

18 specific to each of those modalities.

19 Does that seem like a fair statement?

20 DR. HARLAN: If it\'s true\--and one thing\--I

21 agree with what you said, but one thing that was

22 stated, and if it\'s true I think it\'s a great

23 outcome of this session, is that if the community

24 agrees that injecting the cell of interest, or the

25 cell gamish of interest into immuno-compromised

100

1 mice with an infarcted or dysfunctional myocardium,

2 and the endpoint is an improvement in systolic

3 function\--if the community agrees that that\'s

4 true-North and a good bio-assay, then that\'s a

5 wonderful outcome of this session to use as a

6 surrogate gold standard.

7 If it doesn\'t\--

8 CHAIRMAN RAO: Dr. Harlan, we\'re going to

9 come back to models, and so I really want to\--

10 DR. HARLAN: Okay.

11 CHAIRMAN RAO: \--try and keep that\--

12 DR. HARLAN: But it if doesn\'t, then I

13 endorse what Dr. Kurtzberg said about a working

14 group to try to come up with\--

15 CHAIRMAN RAO: Yes. Specifically to

16 manufacturing.

17 DR. HARLAN: Specifically to

18 manufacturing\--and to Dr. Rieves\' comment\--a number

19 of benchmarks were discussed, including some

20 potentially onerous ones\--were they to be applied

21 to every patient\'s cells. And, in fact, some of

22 the assays that I was suggesting, such as testing

23 for in vivo efficacy in hind-limb ischemia clearly

24 could not be applied in a workable timeframe to

25 testing an individual patient\'s cells prior to

101

1 giving those cells back to the same patient.

2 So, in part of our recommendations to the

3 FDA, some of the benchmarks that we were alluding

4 to are benchmarks for the overall consistency and

5 quality of a production facility, rather an

6 benchmarks to be assayed on every lot of cells,

7 given to every patient.

8 CHAIRMAN RAO: So, to go back to what you\'d

9 said, then\--so is it true, for the sense\--for early

10 studies, as Dwaine pointed out, that when you\'re

11 looking at Phase III trials, and you\'re looking at

12 a company, and you\'re releasing a product where you

13 have a long history, there\'s a different set of

14 requirements. But when you\'re doing this early,

15 you want to have a definite cell type which you can

16 then take reasonably to a Phase III trial if you

17 were going to do it. What would be sort of a

18 minimal criteria that people would consider as

19 important in terms of how you look at product

20 development?

21 And, to me, it still seems\--and, again, I

22 would have the committee weigh in on this, is that

23 we still need a minimal definition of what\'s in

24 that cell type. And we clearly still need how it

25 was isolated\--as, clearly, distinction, because

102

1 that\'s a different cell type. And we need to know

2 the passage number and the karyotypic stability of

3 the cells when they\'ve been grown in culture, and

4 that\'s irrespective of whether you\'re doing it

5 early or late, because otherwise you won\'t be able

6 to compare.

7 And you need a lot of the data and

8 information so that if you have any of the small

9 trials, that you can actually see if you can truly

10 extrapolate\--like you pointed out\--from one trial

11 to the other, so that you have that. And that in

12 the readout you need some sort of potency-type

13 assay where you can say\--which is a maybe generic

14 substitute, and it may be the best that one can

15 have, given the limitations in the field on what

16 can be there. And maybe for myoblasts it can

17 diffuse and form myoblasts because that\'s the

18 mechanism of action, and that\'s what you use each

19 time; and that for the overall generic product that

20 you have\--so let\'s say it\'s myoblasts from

21 different patients\--you should have some kind of

22 biomarkers and assays that have been defined in a

23 more rigorous fashion.

24 Is that\--

25 DR. SCHNEIDER: May I play the Devil\'s

103

1 advocate for a moment with respect to karyotyping?

2 I\'m curious how one would use the data

3 from karyotyping if an abnormality were to be found

4 after three or four weeks of what I consider to be

5 relatively short-term culture, if there were no

6 objective evidence for tumor formation in animals

7 following six to 12 months of follow-up in

8 preclinical data? I mean, are you using

9 karyotyping as a surrogate endpoint for tumor

10 formation even in the absence of data that tumors

11 would occur?

12 CHAIRMAN RAO: Hold that thought, and I

13 think maybe Bruce is going to take about what we

14 missed in saying this is the dose.

15 DR. BLAZAR: No, I wanted to follow up on

16 your point as well. I think part of the issue as

17 you go to define the products is if you\'re going to

18 call something a skeletal myoblast, it has to have

19 certain proportion of cells\--which I haven\'t heard

20 what that is\--that are defined as skeletal

21 myoblasts. It should have some limitations as to

22 what the other cells are.

23 For karyotyping\--which I think is

24 important\--we need to know whether there are

25 unstable karyotypes, even if retrospectively to go

104

1 back and say \"this culture was a different culture

2 than another culture,\" regardless as to the

3 tumorgenic risk.

4 And for the assays, I think if you\'re

5 going to use in vivo assays as readouts, then they

6 have to be able to reproduced from lab to lab with

7 some sort of standardized ability to say that this

8 cell has a certain potency. With islets, that can

9 be shown; that many different labs can come up with

10 the same sort of readouts.

11 But the difficulty for me in listening to

12 this discussion as outside the field is I\'m still

13 walking away with saying I don\'t know what kind of

14 product definitions are going to be required, other

15 than recording the data. What is a reasonable

16 composition of matter? And are there potency

17 assays that are exportable and evaluable in

18 multiple different laboratories for assessing some

19 level of potency that can be reported in the

20 literature to correlate with clinical outcomes?

21 DR. KURTZBERG: I agree with that, and I

22 also don\'t think a panel of non-experts should be

23 the people deciding the potency assay. I think

24 that people who are experts in the field ought to

25 decide that and come back and say this is what we

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1 think is the best we can offer.

2 CHAIRMAN RAO: Dr. Epstein?

3 DR. EPSTEIN: Dr. Rao, I think you

4 summarized the issues brilliantly. I\'d just like

5 to make two points.

6 I think a consensus panel of experts would

7 be critical to define in vitro and in vivo assays.

8 I think it\'s critically important to make certain

9 we understand that myogenesis is different from

10 angiogenesis, so that you have two consensus

11 panels.

12 But then I would suggest\--because the

13 point just raised is excellent\--not everybody has

14 the ability\--not every laboratory, not every

15 facility has the ability to do a reliable in vivo

16 assay. And I would suggest that the FDA consider

17 the possibility\--perhaps in collaboration with

18 NIH\--of developing a core laboratory so that

19 products can be sent to that core laboratory and

20 tested in an absolutely uniform way.

21 And Michael made a very important point.

22 The in vivo assay is not going to really be helpful

23 in the acute situation. But we can retrospectively

24 analyze the results, and try to correlate an in

25 vivo assay with a beneficial effect or a

106

1 non-beneficial effect. But I think for some of

2 these assays, they\'re rather sophisticated. You do

3 have to have experience with it, and I would

4 think\--and I don\'t know if it\'s financially

5 feasible\--but that development of a core laboratory

6 where specimens can be sent would be a very

7 important part and role for FDA to play in

8 characterizing what we\'re giving these patients.

9 CHAIRMAN RAO: Dr. Mule, did you have a

10 comment?

11 DR. MULE: I just wanted to get back to Dr.

12 Rieves\' point about the stages of product

13 development as it relates to the complexity or the

14 outgrowth of trials associated with cell-based

15 therapies. And there is a history here from other

16 cell-based therapies, not necessary, of course, in

17 treatment of heart disease.

18 But the point, again, is that if one is

19 running a Phase I trial and it\'s limited to a

20 single institution, it\'s inconceivable to me that

21 that individual should be held responsible for a

22 transportable assay that other sites not affiliated

23 with the single-site study should be given the

24 stamp of approval, for instance. I think that

25 comes later.

107

1 I think for these limited Phase I studies

2 that are single institution, to me it would almost

3 be a barrier to require that investigator to have a

4 robust enough assay that\'s transportable. That\'s

5 my point.

6 CHAIRMAN RAO: I want to ask the FDA: do

7 you feel that you\'ve heard enough about Question 1

8 and Question 2, in terms of a generic picture on

9 these things, or just left too open in your mind in

10 terms of what can be done?

11 Go ahead.

12 DR. AREMAN: Well, I just wanted to make

13 one point that\--people have been discussing potency

14 assays. And we really do not require that there be

15 a potency assay in place when you start doing a

16 Phase I or a pilot study. You should be

17 considering what you might use as a potency assay

18 when you get to your Phase III trial. But that

19 definitely is not\--should not be a barrier to

20 initiating a Phase I trial.

21 CHAIRMAN RAO: Yes, I think all the

22 committee members, in one sense, were trying to say

23 that if you have to take these cells and

24 extrapolate them, you have to know some measure of

25 what they\'re doing, and so you need that. You

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1 don\'t necessarily have a direct dose-response or

2 potency that you need, but you need to be able to

3 say that when I take this lot, and I want to put

4 them in, because I think that this is the

5 mechanism, that these cells do fuse and form

6 myotubes and at passage four, this is what they do.

7 Or, you know, in passage one, this is what they do.

8 And so it\'s just one more characterization

9 assay on what it\'s going to do, and that this lot

10 has that kind of phenotype. When you have cells,

11 you have to define them in some fashion as a

12 phenotype, and we can\'t just do it with markers.

13 DR. ITESCU: I would just like to\--the

14 conclusion that was just drawn about a barrier;

15 that increasing the data required to move into

16 Phase I being a barrier to a single center

17 initiating a trial being a bad thing. I think, in

18 fact, it\'s exactly the opposite from my

19 perspective: it\'s a good thing.

20 I think we want to raise the barrier to

21 the level where you understand as much as you can

22 about the biology of the product, about the potency

23 of the product and about the safety of the product.

24 I think we want to raise the barrier to prevent the

25 conclusions that we\'re coming to that every cell

109

1 type works, that many small trials have been

2 initiated. We can\'t conclude anything at this

3 point in time because not enough product

4 understanding has occurred.

5 And I think to increase the barrier is a

6 good thing, not a bad thing.

7 CHAIRMAN RAO: I think the FDA always likes

8 to hear that\--

9 \[Laughter.\]

10 \--people are asking for regulations.

11 DR. MURRAY: I mean, I view this through

12 the prism of how we treat the human subjects in

13 these trials. And if\--to the extent that we can

14 actually draw meaningful data from the trial, we

15 just have a better justification for involving

16 human subjects. And even in these Phase I trials.

17 To the extent that we have total

18 non-standardization, and, you know, we\'re letting a

19 thousand flowers bloom, I understand some might

20 favor that, but I think, at minimum, we want to be

21 able to have comparability, or at least to know the

22 bases for comparability from trial to trial. And

23 that\'s simply one way of showing respect for human

24 subjects.

25 Now how do you do that? It\'s not simple.

110

1 I mean, I will return to this when we get to the

2 clinical\--discussion of the clinical issues. But

3 that would be a reason I would advocate, you know,

4 any sort of cooperation, standardization, etcetera,

5 that we can ascertain at this time would be

6 desirable from that perspective.

7 CHAIRMAN RAO: I\'m going to ask Dr. Grant

8 and Dr. Rieves\--do you feel that you\'ve got a sense

9 of what the community feels, basically, on the

10 whole manufacturing process and early stages?

11 DR. RIEVES: The information\'s been very

12 useful. If we understand correctly\--with my

13 confederates here\--the feedback that we are getting

14 is largely consistent with what we have been trying

15 to apply to cellular product development\--not only

16 in the cardiac field but in other fields in

17 general. Your comments are very useful.

18 If we are understanding correctly, you are

19 not objecting to some flexibility in early product

20 characterization. You\'re encouraging exploration,

21 but that has to be tempered by the need for

22 attempts at the most consistency as possible, such

23 that the data are interpretable. And, basically,

24 we\'re not hearing objections to the procedures that

25 we\'ve been using in cellular product development,

111

1 in terms of manufacturing information.

2 CHAIRMAN RAO: I think one important point

3 that came through, I think, as a caveat, at least

4 to me, was that one can\'t simply consider a product

5 at the level of \"you\'ve got it in a vial,\" because

6 that really doesn\'t define it in any fashion. And

7 so there has to be some information on what happens

8 when you put it into any model that you do. And if

9 there\'s going to be death, we need to know that

10 that\'s consistent, because if you have too little

11 death or too much, that will be a problem. If

12 you\'ve selected for some sub-population that grows,

13 that\'s going to be a problem.

14 So that\'s going to be\--and that the mode

15 at which you deliver it can\'t be extrapolated. So

16 you can\'t say, \"Well, you know, today I used a

17 27-gauge needle, and that was how we defined this

18 product in the manufacturing that you\'re going to

19 use.\" It\'s got to be at least factored in in terms

20 of what has to be done when you\'re comparing

21 anything, or when you look at the sense.

22 But, other than that, you look at what\'s

23 the best that can be done.

24 But, to me, it seemed that those were two

25 additional things that people don\'t normally

112

1 consider in drug release maybe. But that needs to

2 be factored in to the cells. At least that was my

3 sense.

4 DR. SCHNEIDER: To paraphrase Dr. Murray:

5 let a dozen flowers bloom.

6 \[Laughter.\]

7 I think that for many of us, the hazard,

8 as I\'ve said, is the impression created by the high

9 visibility trials that this is easy; that this can

10 be done by any cardiologist or cardiac surgeon with

11 access to a blood bank. And that\'s adamantly to be

12 discouraged.

13 CHAIRMAN RAO: Go ahead, Dr. Noguchi.

14 DR. NOGUCHI: Yes\--I think this has been an

15 excellent discussion, and we appreciate the rigor

16 with which the committee and all the participants

17 here want to move the field forward.

18 I will point out that, to a large extent,

19 this is not FDA\'s field. It is our job to look and

20 to evaluate independently what comes in. If,

21 indeed, you\'re talking about a dozen flowers, if we

22 get 4,000 applications I can guarantee you my staff

23 will review every single one of those applications.

24 We would prefer\--

25 \[Laughter.\]

113

1 \--that we get some selectivity, but that

2 is not our judgment. That is not our duty, and

3 that is not our responsibility. The responsibility

4 is clearly that of the community that is trying to

5 develop these products. That is clearly

6 determining what may be true North or North by

7 Northwest, or even maybe giving you the first step

8 on the journey. It\'s not for FDA to tell you, it\'s

9 for you all, together, to come to consensus to

10 develop the scientific knowledge to consider the

11 subjects absolutely as the center of all your

12 discussions, and bring that, not just to us, but to

13 the public so that we can have a reasonable

14 discourse about it.

15 So I think, really, we\'ve heard\--for the

16 manufacturing, we\'ve heard a lot of very good

17 suggestions. We\'ve heard a lot of preliminary

18 discussions. The refinement of this we will help.

19 But it\'s up to all of you to provide the data so

20 that we can make the evaluation.

21 CHAIRMAN RAO: So, as Joanne pointed out,

22 somebody has to help formulate a committee of, you

23 know, cardiologists to look at that.

24 DR. TAYLOR: Dr.\--

25 CHAIRMAN RAO: Is it a big comment?

114

1 Because you\'re keeping everybody from a break now.

2 \[Laughter.\]

3 DR. TAYLOR: Dr. Rao, there is one issue

4 that I didn\'t hear at all, and that\'s vehicle. And

5 I think vehicle is an important issue that we can\'t

6 ignore here: what the cells are injected in.

7 CHAIRMAN RAO: Yes\--I think that\'s an

8 important point, and I sort of\--people raise this

9 issue, and it was raised before in terms of whether

10 serum is good or bad, and whether there\'s a

11 serum-shock effect, depending on how much is there.

12 Dr. Epstein, for example, pointed that out. And

13 that excipients, just like in any drug, are also an

14 important component that has to be fully defined in

15 terms of doing this. And I think that\'s going to

16 be important to do when you look at comparing

17 anything, or look at when you\'re delivering cells.

18 And you\'re absolutely right; it\'s even the

19 glucose, and the PBS that you put in when you

20 deliver cells, it\'s going to be important. And I

21 think that\'s an important thing that the committee

22 would suggest to the FDA as well, is that when you

23 define that product, that that information should

24 also be collected.

25 DR. SCHNEIDER: Very quick response to Dr.

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1 Noguchi\'s suggestion about a process for consensus

2 development.

3 Betsy Knable and NHLBI have planned for

4 this coming September what promises to be the most

5 authoritative collection of investigators on the

6 subject of cardiac cell repair. And it might be

7 useful to communicate with them that, as one

8 potential long-term outcome of that meeting, that

9 process of consensus committees be engendered.

10 CHAIRMAN RAO: So we\'ll take a 10-minute

11 break, and attack some of the next questions.

12 \[Off the record.\]

13 CHAIRMAN RAO: Back on the record.

14 It\'s time to get back to work, I guess.

15 \[Pause.\]

16 So this is going to be a little bit

17 easier, though not doubt as contentious, I guess.

18 And the only reason I think it\'s going to be a

19 little bit easier to consider this issue is that

20 we\'ve discussed aspects of this already. And I\'m

21 going to try again to see if we can summarize a

22 little bit of what people have already talked

23 about.

24 So there seems to be some consensus in the

25 field that if you\'re looking at physiology and

116

1 overall global function, and you\'re looking at

2 certain of the tests which are non-invasive, it

3 seems that you are quite critical in terms of

4 needing some large animal models.

5 However there are some disadvantages to

6 large animal models, and there are alternatives in

7 terms of small animal models which may be useful

8 because they have certain specific advantages.

9 And one contentious issue seemed to be

10 that even though we have some advantages with small

11 animal models, we have to worry about the

12 immune-suppressed state, and that there are some

13 disagreements on whether you can use an

14 immuno-compromised model as a xeno-model, where you

15 can transplant, say, human cells into a small

16 animal model.

17 And, otherwise, the field seemed to think

18 that one should be doing comparable cells. So you

19 take, you know, bone marrow cells from the same

20 animal and put it back in a syngenic field.

21 Does that seem to be a fair summary? And

22 maybe I\'ll ask Doris that question\--just as a yes,

23 no.

24 \[Laughter.\]

25 DR. TAYLOR: I think that\'s accurate.

117

1 I think devices\--obviously, you\'ve got to

2 do in large animals. And some of the other

3 things\--cells you can do in small animals.

4 CHAIRMAN RAO: Dr. Epstein? Or Dr. Itescu,

5 can you\--would you say yes or no to that summary?

6 DR. ITESCU: Yes.

7 CHAIRMAN RAO: So, keeping that as a

8 background, maybe we can look at specifics in some

9 of these models. And, again, that hopefully gives

10 us a clear-cut breakdown into small and large

11 animal models\--right?

12 And maybe we can start off with Dr.

13 Borer\'s point about: you have to integrate

14 information\--right? And that you have to collect

15 data. So, maybe if you take a large animal model\--

16 maybe, Dr. Borer, would you like to say what one

17 would like to collect, and what kind of animal

18 model? Would there be any preference, or an

19 absolute requirement for a particular model?

20 DR. BORER: Sure. I don\'t\--well, yes,

21 okay. I\'ll tell you what was an absolute

22 requirement. An absolute requirement are hard

23 natural history endpoint collection; death, major

24 clinical events in the animal: myocardial

25 infarction, stroke, what have you. I mean, we

118

1 could define a list\--infection, whatever.

2 But can I just say one more thing? And

3 maybe I\'m going beyond what you\'re asking me, but a

4 point that was raised yesterday\--and I want to

5 raise it again here\--is that there are several

6 different things that are happening in the

7 myocardium. Putting in cells that differentiate in

8 a way so that they can generate force is wonderful,

9 but there has to be a remodeling process that goes

10 on.

11 And the cellular remodeling\--cellular

12 remodeling\--differs among species. So that while

13 there are certain things that I think we can look

14 for in small animals, over and above the generic

15 stuff I just said, there are other issues that

16 really probably cannot be judged in mice, for

17 example, because the myocytes and the fibroblasts

18 in mice do different things than the myocytes and

19 fibroblasts in species closer to humans.

20 And I would just, again, bookmark the

21 issue of cellular remodeling. We heard a little

22 while ago from Dr. Taylor that the heterogeneity of

23 the product that\'s injected probably is important.

24 I think it probably is, too. I think it\'s very

25 important. I think it\'s very important because of

119

1 the points that Dr. Epstein made yesterday; that is

2 that the cells are secreting stuff. We don\'t know

3 what they are, but they\'re probably crucial to the

4 whole system working well. And, again, those

5 processes differ among species.

6 So I think when you start to look at the

7 global issue, and the remodeling issue, you really

8 have to be closer to people than to mice.

9 CHAIRMAN RAO: Can I ask you one question

10 just as an extension of this?

11 Is there a sense, then, that since animals

12 are not like humans, for example, and that there

13 are going to be species\' differences and these are

14 physiology differences which are critical, that you

15 can\'t just do animal studies that will match? Or

16 should you be doing both xeno- as well as syngenic

17 studies? Or that\'s not something that the

18 committee thinks is a good thing to do?

19 DR. BORER: Well, I mean, I\'m not\--I hope

20 I\'m answering the appropriate question here, and

21 that I understood it properly\--but, we can\'t answer

22 all the preliminary questions that we need to

23 answer to be able to go forward with clinical

24 trials by doing clinical trials. There have to

25 be\--there has to be some information that is at

120

1 least intuitively reasonably predictive to suggest

2 that you\'re going to do something good and you\'re

3 not going to do something bad once you start

4 working in people.

5 There are many examples of animal studies

6 done in species closer to man than to mouse; you

7 know, on dogs and in pigs and even rabbits\--and

8 primates, of course\--which have been reasonably

9 predictive of the general response that you see in

10 people. Will that lead to a clinical benefit, or

11 will it not? I don\'t know. That\'s what clinical

12 trials are for.

13 But I think that you can and must do

14 certain animal studies to at least suggest that

15 it\'s reasonable to infer that there might be a

16 benefit, and might not be excessive harm

17 outweighing the benefit if you go to people. So I

18 think that there are studies that should be done in

19 animals. The assay for potency that Mike and

20 others have talked about I think is key, and that

21 probably can be done in small animals.

22 And I\'m probably getting much more

23 specific than you wanted me to. But I think that

24 several animal models have a place here; that it\'s

25 crucial to do preclinical studies before you do

121

1 clinical studies. My only argument was that in all

2 species we look at, we have to look at deaths,

3 infarctions, strokes and other major events, and

4 that we shouldn\'t forget about the remodeling

5 issues because, as Steve pointed out yesterday,

6 these cells know better than we do what they\'re

7 supposed to be doing, and they do it, and we don\'t

8 know what they\'re doing.

9 CHAIRMAN RAO: Bruce? And then Dr.

10 Schneider.

11 DR. BLAZAR: One question I haven\'t heard

12 answered is the role and function of human cells in

13 rodents. It\'s been implied that you could use

14 human cells in rodents to assay biological

15 function. We know for some cell types\--core blood

16 in non-SKD mice, you can get some assessments,

17 whereas human t-cells put into rodents in general

18 don\'t function well.

19 There are certainly non-cellular sources

20 in rodents that don\'t receive the right inductive

21 or survival signals, and I guess the question is

22 whether the fraction of cells that survive, are

23 they biologically functional if you put human cells

24 in rodents?

25 I didn\'t hear a lot of discussion about

122

1 that. And given the heterogeneity of the

2 population, between myoblasts, fibroblasts,

3 macrophages, SP cells\--to what extent, and where is

4 the barrier drawn for being able to assess

5 biological function in either small or large

6 animals, of the actual human product?

7

8 CHAIRMAN RAO: Before I ask one of the

9 cardiologists to answer, I\'m just going to ask

10 if\--Dr. Schneider, is your question similar to

11 Bruce\'s?

12 DR. SCHNEIDER: I was actually going to

13 follow up on that.

14 CHAIRMAN RAO: So should we, then, have

15 that question so that maybe the cardiologists can

16 answer that together\--other cardiologists.

17 \[Laughter.\]

18 The presentations can answer that. Maybe

19 I should make that clear. So go ahead, Dr.

20 Schneider.

21 DR. SCHNEIDER: I was going to say, in

22 response to Jeff\'s point about the balance of large

23 and small mammals, that I would probably draw the

24 line of preference at a slightly different point.

25 I think there\'s clearly a need\--and an

123

1 unambiguous need\--for large-mammal models, where

2 delivery systems are to be studied, such as

3 catheters or, conceivably, specific complex

4 surgical procedures beyond the kind that we heard

5 about in yesterday\'s presentations; that,

6 inherently, because of geometry could never be

7 adequately tested in a smaller mammal.

8 If the question is: does the biology of

9 the smaller mammal allow complete predictability of

10 the human situation, the answer would be no. My

11 point is that that also would be true for the large

12 mammal. The large mammal studies are not done in

13 aged animals. They\'re not done in animals with

14 disseminated atherosclerosis. So there always will

15 be a gap between what we can learn\--even in the

16 best of circumstances\--from the large mammal and

17 from the human.

18 CHAIRMAN RAO: Would you add to that about

19 safety, as opposed to efficacy?

20 DR. SCHNEIDER: Safety issues as well.

21 What I would do is to try to emphasize the

22 point that the job of the preclinical data is not

23 to predict the outcome of a Phase III trial. The

24 job of the preclinical data is to predict the

25 safety of a Phase I trial. And from that point of

124

1 view, I think a preponderance of small-mammal data

2 is more than sufficient, with the exceptions that I

3 noted, where complex devices are concerned.

4 It\'s to show the reasonableness of a

5 benefit, and the reasonableness of safety.

6 Ultimately, those have to be judged in Phase I

7 trials. And if Phase I trials work, the more

8 complex larger trials later.

9 CHAIRMAN RAO: Joanne.

10

11 DR. KURTZBERG: I was just going to add

12 that I think the allogeneic models are important.

13 I don\'t think we know what direction this will

14 ultimately take. And I think they\'re important to

15 ask question about tolerance induction and whether

16 the use of allogeneic cells will be

17 feasible\--because it may be that, in the long run,

18 it will be technically more straightforward to have

19 the cells ready when the patient needs them, and it

20 may be timing is important to get it right away or,

21 you know, shortly after the MI\--or whatever. And

22 with autologous cells, you may not have that

23 option.

24 CHAIRMAN RAO: Dr. Cannon.

25 DR. CANNON: This is really a follow-up to

125

1 Dr. Borer\'s and Dr. Schneider\'s comment about the

2 limitations of large animals, as far as safety and

3 efficacy.

4 And a good example is estrogen therapy.

5 Hormone replacement therapy was believed to be safe

6 and efficacious in all animal models tested;

7 virtually all tested, including primates. And yet

8 it did not predict the response in individuals with

9 diffuse atherosclerosis and its risk factors.

10 So I think there are major limitations to

11 even large animals.

12 CHAIRMAN RAO: Dr. Ruskin, and then Dr.

13 Epstein.

14 DR. RUSKIN: Just a comment about the

15 safety question and animal models.

16 I thin, with regard to cardiac safety, and

17 particularly this issue of arrhythmagenesis, the

18 small animal models are not going to be useful.

19 They may be\--they\'re very useful from a biological

20 perspective, and potency, and other elements that

21 people have raised. But I think that given the

22 relative infancy of this field, that having

23 experience in some of the well established

24 large-animal models\--particularly dogs, but also in

25 pigs; dog models have been around now for three

126

1 decades of acute and sub-acute and chronic

2 infarction, for example and, more recently, some

3 heart failure models\--can be very useful. And I

4 would never suggest that the information obtained

5 from these studies would be dispositive, but they

6 can be informative from a safety standpoint,

7 particularly if safety issues arise; that is, they

8 tend to be rather insensitive. But if you see a

9 major safety question with regard to arrhythmagenic

10 effects in a canine model, that should be a red

11 flag for whether or not one moves forward, and how

12 one moves forward into Phase I.

13 So I would make a plea for doing work in

14 large-animal models fairly early on\--certainly well

15 before considering Phase I trials with an aspect of

16 these new therapies.

17 CHAIRMAN RAO: I\'ll have Dr. Epstein and

18 Doris make quick comments.

19 DR. EPSTEIN: Yes. Bruce, just in answer

20 to your question: if you wanted to test either

21 safety or efficacy of human cells in an animal

22 model\--immunosuppressed\--I mean, I guess the bottom

23 line is there\'s no\--as everyone has said\--there\'s

24 no perfect animal model. Because the effect of the

25 cells you\'re injecting may not be primarily a

127

1 direct effect of the cells, but their ability to

2 orchestrate, for example, an inflammatory response.

3 So if there\'s no inflammatory\--host

4 inflammatory response, that could either be

5 efficacious or it could be\--lead to adverse

6 effects. So it\'s not a perfect model but,

7 nonetheless, it could provide some important

8 information.

9 So the bottom line is, I think that large

10 animals, small animals\--none of them are perfect.

11 All of them can provide some important information.

12 What should be required is obviously going to

13 depend on what the specific question being asked,

14 and what the specific cells are that one is

15 thinking of injecting.

16 DR. BLAZAR: So can I\--just before you

17 leave the microphone, just ask you: what\--is there

18 a different frequency\--if you put human cells in

19 rodents, dogs, pigs, what fraction of those cells

20 have any biological function or survival in the

21 different species? Because while it may not

22 correlate directly in each individual species, if

23 the fraction of cell survival and being able to

24 function in vivo is extraordinarily low in rodents

25 and increases as you go up the ladder\--

128

1 DR. EPSTEIN: You mean in the absence of

2 immunosuppression.

3 DR. BLAZAR: However. To me, it\'s still

4 whether there are appropriate inductive and

5 survival signals. Forget, necessarily, the host

6 immune response, but are there just signals so the

7 cells just don\'t sit there. Because I know you can

8 engraft human MSCs and MAPCs etcetera in rodents,

9 but the frequency is extraordinarily low in many

10 cases, without the necessary inductive signals.

11 DR. BLAZAR: Well, I guess the bottom line

12 is that studies have been done, and published in

13 excellent journals, demonstrating that you get a

14 biologic effect. And as Dr. Borer has been

15 emphasizing, you know, that is what you\'re

16 interested in.

17 Now, what percentage of cells survive, and

18 which specific cells survive is an important

19 question. But there is important biologic activity

20 when you put in human cells in a rodent model.

21 CHAIRMAN RAO: Go ahead, Doris.

22 DR. TAYLOR: I\'m sorry, I just wanted to

23 say very quickly that one of the slides I showed

24 yesterday, in terms of comparing myoblasts and

25 myoblasts plus\--angiogenic myoblasts were human

129

1 myoblasts transplanted into SCD mice. And we saw a

2 biologic effect. So\--and I didn\'t emphasize that.

3 But I think, in terms of injecting human

4 cells in small-animal models to test function, I

5 think that\'s fine. I think to test safety, you

6 have to move up the tree.

7 You know, nobody wants this field to move

8 forward more rapidly or more quickly than\--or more

9 safely and quickly than I, but I think we have to

10 answer the safety questions. We didn\'t anticipate

11 them all with myoblasts, and now we have the

12 opportunity to do it differently.

13 CHAIRMAN RAO: So before we get to you, is

14 there anybody who strongly disagrees with the

15 statement that Doris made?

16 Just\--Doris said that, you know, for

17 safety studies it seems to be quite important that

18 you might want to consider larger animal models as

19 well. That was her point. She said that\--I\'m

20 summarizing, but\--

21 DR. SCHNEIDER: If the operative word is

22 \"consider\" rather than \"implement,\" I think\--

23 CHAIRMAN RAO: Yes.

24 DR. SCHNEIDER: \--I think that\'s the

25 distinction.

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1 I mean, Dr. Ruskin makes a very good point

2 about the safety issue with respect to arrhythmias.

3 But it\'s one point that needs to be balanced

4 against other considerations. If I were asked to

5 weigh the predictive power of dog cells re-injected

6 into the dog, versus human cells injected into a

7 mouse as indicative of what human cells would do

8 when injected into a patient, I\'d rather know what

9 the human cells do.

10 In many cases, the markers don\'t exist to

11 isolate the cells from some of these large mammals.

12 And as Steve Epstein pointed out, if one wants to

13 use an immuno-compromised dog, sheep or pig, one is

14 obliged to use drugs that have many confounding

15 effects. Cyclosporin is used routinely in the

16 transplantation field, but in heart failure studies

17 many of us have been looking, for the last six

18 years, at complex molecular effects of

19 calcinurine-dependent signals.

20 So, from an immunological point of view, a

21 mutant mouse is cleaner and more predictive than a

22 cyclosporin-treated pig.

23 DR. MULE: So I\'ve been hearing almost a

24 consensus of the\--not necessity for animal models,

25 but the preference for animal models, perhaps.

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1 What I haven\'t been hearing is what are we

2 asking these animal models to provide us with

3 information? I\'ve been hearing a lot about the

4 weaknesses of small animal models, large animal

5 models, xeno-transplants, human cells into

6 immuno-compromised mice\--and, again, layering the

7 complexity of the disease, which has not been

8 replicated in any of these animal models. I\'ve

9 heard that one cannot necessarily predict the

10 toxicity of the cell-based therapy in perhaps

11 large-animal models.

12 So I guess the issue is: if we have

13 myoblasts as sort of the therapy to be considered

14 here\--as one of the therapies, and we can

15 conceivably understand that if we put certain

16 parameters on that population, that in vitro will

17 produce myotubes, for instance.

18 What are we asking of these animal models?

19 Are we asking that 90 percent of the cells will die

20 when they\'re injected? I think we already know

21 that. And so what I have not heard\--other than

22 weaknesses in all these models\--is what precisely

23 we\'re asking these animal models to provide us with

24 information that will help us to go to the clinic.

25 CHAIRMAN RAO: Hold that thought, and I\'ll

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1 maybe ask you to re-phrase it again in the next

2 five minutes or so.

3 Go ahead, Dr. Murray.

4 DR. MURRAY: Well, actually, Jim asked, in

5 a broad frame, the same kind of question I wanted

6 to ask. And I\'ve been trying to listen carefully

7 to the various things that have been said, and the

8 questions that we\'re being asked to help the FDA

9 address.

10 So, I\'ve been trying to create a

11 conceptual map to help myself understand what\'s at

12 issue here. So let me just\--what some elements

13 are: we want to know something about the basic

14 biology; what happens to these cells; what are

15 these cells; what happens to them if you stick them

16 in a heart\--by various routes, by various

17 means\--you know, with all the various different

18 ways people prepare these.

19 And you want to know about autologous

20 cells, you want to know about\--and you want to know

21 how human cells behave in, you know, in an animal

22 model, so you\'ve got to have an immuno-compromised

23 animal model. And there are all kinds of

24 disadvantages there.

25 The hearts differ in these different

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1 animal models, and their anatomy, the cell type

2 functions; the geometry, physiology and

3 electrophysiology. The disease\--the disease models

4 differ. You\'ve mostly got fresh experimental

5 lesions, rather than a good model of chronic

6 congestive heart failure. Plus, in humans, you\'ve

7 got this background of long-term disease, with all

8 the stuff that\'s happened, plus the drugs and other

9 treatments and other interventions that have gone

10 on\--all of which make it difficult.

11 The hearts differ in these animal models

12 and what you can measure. You know, a mouse heart

13 beats\--what?\--600 times a minute? Is that what I

14 learned yesterday? And it\'s probably a little hard

15 to catch what\'s going on in those 600 beats per

16 minute. Larger animals beat more slowly, or more

17 like humans\--allow more measurements.

18 So this is the sort of map I\'ve been

19 putting on this. And it\'s pretty clear that no

20 single model is right. There are a lot of

21 different questions you ask in different ways.

22 We\'re going to learn about

23 the\--ultimately, you want to learn about the safety

24 issues involved with doing the sort of

25 interventions that people are proposing to do, and

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1 almost certainly that will involve some use of

2 larger animals that are closer to the human.

3 CHAIRMAN RAO: Deborah?

4 AUDIENCE: I run a large primate program

5 involving hematopoietic stem-cell biology, and I\'ve

6 also worked quite a bit in xenograft with mice.

7 I would stress that, like Bruce said, I

8 don\'t think, if you have no efficacy in a xenograft

9 you necessarily know if that is going to predict no

10 efficacy in a large animal or human. The homing

11 and engraftment of cells, if we\'re going to give

12 them intravenously, or look at cytokine

13 mobilization in a xenograft is, I think, completely

14 useless.

15 Mouse spleens behave extremely differently

16 from human and large animal spleens. The cells all

17 go there. For most of the hematopoiesis studies,

18 you have to splenectomize mice to get any

19 information out that\'s going to apply to humans.

20 Non-human primates\--we have lots of

21 reagents like cytokines and cell service molecules,

22 and the ability to culture cells that are very

23 analogous to humans. What we don\'t have is

24 cardiologists and cardiac surgeons who\'ve worked in

25 these models.

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1 So as we tried at the NIH to bring some of

2 these cell therapies into the non-human primate to

3 test them, there just isn\'t very much known, and

4 there\'s not a lot of comfort with the surgeons and

5 the cardiologists in knowing how these animals

6 react, in terms of arrhythmias and everything else.

7 On the other hand, dogs, where you do know a lot,

8 and pigs where you know a lot, you can\'t have any

9 idea if the cell populations are correct. So, I

10 either would try to put resources at an extramural

11 level into better defining reagents, antibodies and

12 cytokines for dogs and pigs, or get some

13 cardiologists and cardiac surgeons more comfortable

14 with working in non-human primates. Because for

15 highly manipulated products, like MSCs, you\'re

16 going to over-express AKTN, or MAPCs, I really

17 don\'t think that you would want to put those into

18 humans without having some long-term safety studies

19 in a large animal saying where the cells go, how

20 long they last, do they form tumors? You know,

21 labeling them with iron or other moieties to try to

22 figure out exactly what\'s happening to them, both

23 acutely and sub-acutely I think would be pretty

24 important.

25 With non-manipulated cells, and

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1 mononuclear cells from the bone marrow that you\'re

2 shooting into coronaries and things that have

3 already been done, maybe that\'s not necessary, and

4 maybe you can do it in dogs. But for the

5 manipulated populations, I think you need to try to

6 improve the primate models\--potentially.

7 CHAIRMAN RAO: Go ahead. Just introduce

8 yourself.

9 DR. KELLY: Ralph Kelly. I\'m from Genzyme

10 Corporation. And I wanted to follow up with Dr.

11 Ruskin about the comment regarding arrhythmias.

12 For the MAGIC trial that Phillipe

13 Menaasche is currently running, the protocol

14 specifies that the skeletal myoblasts\--autologous

15 skeletal myoblasts\--be placed not only in the

16 center of the scar, but also in the border zone

17 surrounding the scar, which obviously brings in

18 issues such as reentry. And you discussed the

19 canine model, for example, but then just sticking

20 them in a dog and then doing Holter monitor studies

21 and so forth may not be practical, or at least

22 efficient way to do it.

23 Can you comment on optical mapping

24 techniques, for example? Other measurements that

25 might give us an idea how pro-arrhythmic these

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1 cells might be?

2 DR. RUSKIN: That\'s a good question, and a

3 difficult one to answer.

4 The technique of optical mapping is very

5 useful for mechanism and for characterizing the

6 electrophysiologic properties of the tissues, but

7 doesn\'t tell you very much about arrhythmagenic

8 potential. So I think you would probably end up

9 doing continuous monitoring with implanted devices,

10 and also electrophysiologic studies.

11 And I suspect that the yield would

12 probably be quite low. And the concern, obviously,

13 in these models always is that they are

14 insensitive. So if one sees nothing, you can\'t

15 take much away from it.

16 If you say a signal\--for example, a high

17 sudden-death rate among the animals\--that would be

18 a red flag, obviously, for a major concern. And

19 that was my only point.

20 I don\'t think that ;there\'s a highly

21 specific probe that we can use that\'s going to

22 answer the question in an animal model as to what\'s

23 going to happen in the human situation.

24 CHAIRMAN RAO: Dr. Harlan?

25 DR. HARLAN: You started the session with

138

1 the question: are animal models required before we

2 move to the clinic, or should we do both

3 concurrently. And then Dr. Mule asked about what

4 question are we asking from the animal models.

5 I think the answer to the latter question,

6 and then to your question, is that we\'re\--in all

7 cases, we\'re gathering data; that we don\'t know

8 what we don\'t know. And, to me, I don\'t think

9 there is any ideal animal model. We learn

10 something from each one. And I think we learn

11 stuff in the clinic that we can\'t possibly learn

12 from any animal model, and so that you need to do

13 both, and that then the question is: how do you do

14 the clinical trial in the way that is least likely

15 to do harm. And that will be, I think, the major

16 topic of discussion.

17 CHAIRMAN RAO: I guess it\'s you, me and

18 Rumsfeld\--right? There are known knowns and known

19 unknowns, I guess.

20 DR. ITESCU: I\'d just like to add a little

21 bit about the small animal models, and disagree

22 with one of the earlier speakers\--that, in fact,

23 we\'ve done a lot of work looking at homing and

24 cytokines and chemokines in mice and rats\--those

25 immuno-compromised animals. And, in fact, it looks

139

1 like they\'re excellent models for being able to

2 predict the ability of human cells to home and

3 target the myocardium; that many of the chemokines

4 and cytokines produced in these rodent models do,

5 in fact, interact with the receptors on human

6 cells.

7 So I think, in fact, they\'re very adequate

8 models to study many of these processes. And

9 perhaps the biggest difference between these models

10 and the primate models, obviously, are the immune

11 responses. And we just need to keep that in mind.

12 But, otherwise, many biological questions

13 can be addressed pretty adequately.

14 DR. BLAZAR: I wasn\'t saying that the

15 models were inadequate. I was not clear as to what

16 ;you all had as a consensus as to the relative use

17 of these xenogeneic system to get where you wanted

18 to go\--the way Jim phrased.

19 So if the consensus is that this does

20 provide you the necessary readouts, despite the

21 limitations of a xenogeneic environment, I think

22 that\'s fine. But it did not come out in the

23 presentations as to whether that was necessarily

24 the case.

25 DR. ITESCU: Yes, I didn\'t show yesterday,

140

1 but we\'ve got some pretty convincing data on a

2 variety of cytokines and chemokines made by

3 rodents, and how they interact with the human cells

4 in a similar way to what happens in man.

5 DR. HARLAN: I just want to quickly comment

6 that when you look at your cells and they do home

7 appropriately, what you don\'t know is what other

8 cells might not work in that model, but would work

9 in a different model. So it\'s just the same point:

10 we don\'t know what we don\'t know.

11 And so I think it\'s important to not rule

12 out the possibility that a cell that doesn\'t work

13 in a non-SKD mouse might work in a different

14 species.

15 DR. ALLAN: Yes, I just wanted to come back

16 to what animal model is appropriate. Because, I

17 mean, I\'m not in this field. So I sit here and I

18 go, \"Gee, you know, I don\'t hear that much about

19 non-human primates.\" You know, because to me it\'s

20 a no-brainer. You want to be using non-human

21 primates.

22 And then\--so it was interesting to hear

23 what some of the reasons are why people aren\'t

24 using non-human primates. It\'s a comfort zone:

25 cardiologists never used\--haven\'t used non-human

141

1 primates very often for this. Maybe it\'s also a

2 question of cost, and numbers of animals\--things

3 like that\--which I can understand.

4 And in this particular case it seems to me

5 that what you\'re dealing with is basically

6 cost-benefit\--or risk-benefit, and that is, well,

7 if you\'re shooting cells into humans, you probably

8 aren\'t going to kill them, and therefore you don\'t

9 have to use non-human primates because you\'re not

10 sweating as much. Because in xenotransplantation,

11 they have a bar, and you\'ve got to do

12 pig-to-primate transplants and show that the organ

13 survives for more than, you know, five days or 10

14 days before, you know, they let you go into humans.

15 Whereas here, you know, you shoot a few cells, and

16 you probably are not going to kill the patient.

17 And so therefore maybe you don\'t need to use

18 non-human primates.

19 But to me, I mean, it\'s like\--I mean, the

20 non-human primates, it\'s not a perfect

21 model\--obviously it\'s not a perfect model, but it\'s

22 a better model than any of the other models, in

23 terms of you\'ve got cytokines that you can use. I

24 mean, this GCSF study, you know, they probably

25 could have done some of that work in non-human

142

1 primates and would have got some ideas.

2 And it doesn\'t mean that that wouldn\'t

3 happen anyway because, I mean, you look at gene

4 therapy trials. Some of the studies in macaques

5 show that if you give them too much virus you kill

6 them, and yet, you know, they still went into

7 humans with the same dosage and there were some

8 adverse reactions there.

9 So I\'m just\--I\'m not trying to promote the

10 use of non-human primates, but I was just sort of

11 like curious as to why people aren\'t using that

12 more often.

13 DR. BORER: I\'d like to get back to the

14 issues raised by Dr. Mule and Dr. Murray, because I

15 think they\'re very important issues. And let me

16 try and take a crack at an answer.

17 CHAIRMAN RAO: Dr. Borer, can we hold off,

18 then, on that\--

19 DR. BORER: Sure.

20 CHAIRMAN RAO: \--because I want to try and

21 complete this\--it\'s part of the question we want to

22 address which is Question 4, but I want to try and

23 get this whole idea of do we absolutely need

24 models, and which kinds of models, and is there any

25 absolute criteria that we should use first.

143

1 DR. BORER: That is what I was going to

2 respond to, actually. I think that\'s the crux of

3 what the question was: do we really need animals if

4 we don\'t know how to interpret the results?

5 CHAIRMAN RAO: I think Dr. Murray\'s point

6 was what kind of readouts, and what are you really

7 using the models for? And I want to wait on that

8 just for a couple more minutes if we can.

9 DR. BORER: Okay. Maybe I wasn\'t

10 responding to Dr. Murray\'s question.

11 CHAIRMAN RAO: Okay, then.

12 DR. SCHNEIDER: So you don\'t want a

13 response to Dr. Mule\'s question: why do we use the

14 animal models?

15 CHAIRMAN RAO: Yes\--not just yet.

16 DR. SCHNEIDER: Okay. Let me respond to

17 why cardiologists\--

18 \[Laughter.\]

19 \--don\'t use non-human primates.

20 Apart from the fact of expense, lack of

21 experience in most of the university medical

22 centers, we are also cognizant of the fact that the

23 non-human primate models are, to the public, an

24 abomination.

25 CHAIRMAN RAO: Kathy?

144

1 DR. HIGH: So\--maybe I have to wait, too,

2 because I wanted to respond to Dr. Mule\'s question.

3 \[Laughter.\]

4 CHAIRMAN RAO: So maybe we can really list

5 these as comments that can be made\--give me a

6 minute, then, to try and see if we have some sense

7 of consensus on this minimal first part.

8 From what I heard from everyone here was

9 that nobody thinks you should rush to go and do

10 human trials without doing some sorts of animal

11 studies\--right? That seemed to be pretty clear.

12 And what also seemed to be pretty clear to

13 me from listening to everyone was that there\'s no

14 perfect animal model for the disease. So we\'re not

15 trying to mimic a particular disease, but you\'re

16 really trying to look at sort of some kind of

17 critical issues on the cell type that you will use,

18 and the choice really depends on the cell type that

19 you\'re going to use, and that\'s why you have to

20 vary between choices of models.

21 And there seems to be clear-cut consensus

22 that for certain things you have to use a

23 large-animal model. So, for physiology, sort of

24 geometry, imaging issues and so on, it doesn\'t seem

25 that you can answer those questions with a small

145

1 model.

2 But there are other issues where, maybe

3 because of speed, maybe because the behavior has

4 already been demonstrated, or there\'s a whole

5 history in terms of sort of bone marrow studies

6 which can be addressed in small-animal models\--and

7 there\'s no reason why they shouldn\'t be addressed

8 in small-animal models.

9 So, ultimately, you may have to choose

10 which model you use, depending on the type of cell

11 you choose, and what type of readout you\'re looking

12 at. And such models exist for doing that. But

13 clearly there\'s no perfect model which will clearly

14 answer all of these studies.

15 There still seemed to me a little bit of

16 dissension\--and I want to make sure that I haven\'t

17 missed that\--is there seemed to be some argument

18 that safety studies could only be done in a

19 large-animal model. And I wasn\'t absolutely

20 sure\--maybe some types of safety issues are really

21 critical and can only be done in a large-animal

22 model such as, you know, tachycardia perhaps,

23 geometry and reentries phenomenon. But other

24 studies may be simply more important in

25 small-animal models\--right? You know, where we

146

1 have\--if you\'re looking at immuno-compromised

2 animals and so on.

3 The last piece that seemed to come through

4 from everybody was that animal cells are animal

5 cells, and there are many, many reasons why they

6 will be different. And we already know that

7 they\'re different, so that though you can do

8 syngenic, they\'re not going to be absolutely

9 predictive of what will happen when you take human

10 cells and put them into human patients, and you

11 have to keep that view in mind. And if that\'s the

12 case, then there might be certain times\--or

13 depending, at certain stages\--where doing either

14 xeno-models, or correlating it with\--as Dr. Harlan

15 pointed out\--with clinical trials which are

16 happening at the same time might be quite critical.

17 Is that\--at least for part of

18 choosing\--we\'ve not yet talked about what the Hell

19 are you going to learn from a model\--and I

20 apologize for my language, I guess\--

21 \[Laughter.\]

22

23 \--but at least it sets up the fact that we

24 need some kind of model. That seems to be

25 irrespective\--that we need something, and we nee to

147

1 get some information, and we need to collect a

2 large amount of data from it.

3 And, Dwaine\--

4 DR. RIEVES: But, Dr. Rao, those are

5 excellent points, and it\'s very difficult to talk

6 in generalities.

7 But if in the discussion the committee

8 members could also consider something Dr. Dunbar

9 touched on, is whether, as witnesses, or reviewers

10 or production of development programs, we should

11 consider flexibility with respect to the nature of

12 the cellular product itself, as to how it\'s

13 manufactured\--these heavily manipulated products,

14 the cultured products.

15 Should the preclinical testing for those

16 type products be different from the many academic

17 investigators across the country who say, \"I\'m

18 harvesting bone marrow in the operating room suite,

19 and I\'m filtering it to get the specules out, and

20 I\'m administering it.\" When those

21 sponsor-investigators come to us, they\'re going to

22 ask is there some need for pre-clinical study. Or

23 is it inherently safe because it\'s autologous and

24 minimally manipulated.

25 If you could consider those type issues in

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1 the discussion, too.

2 CHAIRMAN RAO: As soon as we start talking

3 now, and hopefully, just next is what do we want to

4 learn from an animal model, and why do you want to

5 put cells in.

6 DR. TAYLOR: \[Off mike\] When I said the

7 word \"safety\" I meant arrhythmia. I didn\'t

8 mean\--so there\'s really not dissension. When I

9 said \"safety\" I meant electrical safety.

10 CHAIRMAN RAO: So maybe we can go with Dr.

11 Borer, who was trying to summarize or respond, and

12 then go with Kathy, and then Dr. Schneider, since

13 you wanted to respond, too, sir.

14 DR. BORER: First let me say I agree with

15 everything you said.

16 \[Laughter.\]

17 I think that where we may be going here,

18 and what seems like a little dissension that I

19 don\'t think really is dissension, is that what

20 everybody wants is a preclinical construct that

21 would be perfectly predictive so that you really

22 knew what the problems are, and you really knew

23 what the potential benefits were, or what the

24 functional changes in the heart might be so that

25 you could then give your therapy in patients and be

149

1 concerned, really, only about clinical outcome; you

2 know, is there a clinical benefit, is there not, or

3 does the benefit outweigh the risk.

4 There is no such preclinical construct for

5 any disease\--in cardiology. I mean, in other

6 disease there may be. I don\'t know. But certainly

7 there isn\'t in cardiology.

8 So I think what we want from the animal

9 studies is two types of information. First of all,

10 one would like to have some confidence that there

11 isn\'t an overwhelming show-stopper lurking out

12 there, safety-wise. Jeremy made the point: animal

13 studies are not highly sensitive, in general, for

14 cardiac events, but when cardiac events of certain

15 types occur, one should take note of that and be

16 cognizant of that in designing clinical studies if,

17 indeed, it even seems reasonable to do that after

18 you know about the major potential risks that one

19 might have picked up in animals.

20 With regard to the minimally manipulated

21 cells that are taken out of the bone marrow,

22 filtered and put into a person\--into the same

23 person from which they came\--is there any need for

24 preclinical studies? Well, I would argue that you

25 would at least want to test the implements that

150

1 you\'re going to use to take and do, to make sure

2 you haven\'t changed the cells that you\'ve taken out

3 in such a way that they clump, form emboli and, you

4 know, block arteries, for example.

5 I mean, so some kind of preclinical

6 testing relevant to the specific situation would be

7 appropriate, but here we\'re talking more about

8 mechanical, I think, than biological

9 problems\--although there may be biological

10 problems, too, with the minimal manipulation\--I

11 don\'t know.

12 But, anyway, that\'s one type of

13 information one seeks from preclinical studies.

14 The second is some evidence that it\'s

15 reasonably likely that a benefit might occur if

16 used as therapy. You know, we can\'t test animals

17 for clinical benefit, per se. I mean\--or at least

18 it would be very difficult to do it\--unless we

19 learned how to talk to the monkeys or, you know,

20 followed the animals for a longer period of time

21 than we usually do to look at outcomes of other

22 sorts. But at least one can look at surrogates

23 that seem, from a tremendous amount of prior

24 experience, to be at least reasonably predictive of

25 the likelihood that something good clinically may

151

1 result.

2 And for that purpose, I would say you

3 would want to see some consistency among different

4 types of models, properly selected for functional

5 markers of one sort or another. And I don\'t want

6 to get very much more specific.

7 Now, at the end of the day you\'ve done all

8 that, and you still may be wrong\--as Richard

9 pointed out. I mean, you know, all the animal

10 studies can look great and you put the product into

11 people and it doesn\'t work, or it does bad things

12 that you didn\'t expect. That can happen.

13 But I think it would be wrong to expose

14 human beings to a putative therapy without at least

15 having done some reasonable screening so that you

16 could\--so that a bunch of reasonable people sitting

17 around a table who had experience could say it

18 seems as if we are unlikely to cause great harm,

19 and it seems reasonable to infer that we may cause

20 good.

21 Yu know, I think that\'s the basis of doing

22 these studies. There\'s no perfect predictor, but

23 without the kinds of evidence that I\'ve been

24 talking about, I don\'t think we could reasonably go

25 to humans.

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1 CHAIRMAN RAO: Kathy?

2 DR. HIGH: So, I just want to make two

3 points, and I think I can be fairly brief because I

4 want to agree with some of the points that Dr.

5 Borer has made.

6 But just that, to me, the point of the

7 preclinical studies\--part of the critical goals of

8 those is to define a safe starting dose and at

9 least get a bracket around what would be an

10 efficacious starting dose. And from everything I

11 heard yesterday, that means work in large animals.

12 And the same point can be made about the

13 deliver system. So that\'s one point.

14 The second point I want to make is to

15 respond to Dr. Rieves\' point about need for

16 preclinical studies for single-site investigators

17 who are doing small trials. As far as I\'m

18 concerned, they need to be held to the same

19 standard. They need to show that the way they

20 process the cells, and the way that they deliver

21 the cells has some reasonable expectation in their

22 preclinical studies. And I don\'t think that they

23 should be able to avoid that responsibility.

24 CHAIRMAN RAO: Did you have a point, Dr.\--

25 DR. CUNNINGHAM: Yes, I just wanted to

153

1 comment that there is a subset of the population

2 who do not like primate studies, but the large

3 segment of the population expects the FDA to

4 ascertain safety. And so there\'s a large segment

5 of the population who would also expect everything

6 that was reasonable to be done to ascertain safety

7 be done.

8 CHAIRMAN RAO: We\'re still trying to focus

9 on the point that: what do we want in the readouts,

10 and it is specific to specific cell types, so that

11 Dr.\--you know, that we address some of these

12 issues. So if you can try and\--

13 DR. SCHNEIDER: Yes. With respect to

14 skeletal myoblasts, I think the goal in the

15 preclinical data, along with the safety issues, is

16 more straightforward than for some of the other

17 cell types that we\'ve talked about. The goal in

18 skeletal muscle therapy is to replace cardiac

19 myocytes with another contractile cell type which,

20 regardless of the presence or absence of electrical

21 coupling, does have strong animal data\--as Doris

22 and Phillipe showed yesterday\--suggesting that they

23 improve pump function in the regions of the

24 ventricular wall that receive the cells, and also

25 global pump function.

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1 So, to your point and Jeff\'s I would say:

2 the skeletal myoblast trials are very simple. What

3 they\'re trying to treat is heart failure, and it\'s

4 functional correlates as measured by MVO2, or

5 ejection fraction, or pressure volume loops; and in

6 patients\--but not in the animals\--symptomatology,

7 and whether or not they also have the other kind of

8 clinical correlates\--reduction of hospitalizations,

9 reduction of the need for transplantation,

10 reduction of mortality. That\'s one of the things

11 that the animal models just won\'t answer.

12 For me, the goals in the angiogenesis\--or

13 in the pleuripotent cells is more complex. And

14 maybe Steve or Silviu could comment. Many of those

15 are also being done with pump function as a major

16 endpoint. These studies are done in a different

17 setting clinically, typically, with treatment

18 within the first days of myocardial infarction, and

19 it\'s likely that the mechanisms of efficacy include

20 at least some cytoprotective effect on jeopardized

21 myocardium, plus angiogenesis, plus\--and this point

22 is highly controversial in the field\--the

23 conversion of the bone marrow or circulating cells

24 into cardiac myocytes.

25 Steve, I\'m not aware of any cell therapy

155

1 trial that\'s been aimed at intractable angina as

2 the\--

3 VOICE: I think there have been several.

4 DR. EPSTEIN: Yeah.

5 DR. SCHNEIDER: Okay. So I think what one

6 is asking of the animal models in those cases is

7 different, and not the same as for skeletal

8 myoblasts and chronic heart failure.

9 CHAIRMAN RAO: Dr. Epstein?

10 DR. EPSTEIN: Yes, and I would agree with

11 you\--

12 CHAIRMAN RAO: Before you answer, Dr.

13 Epstein\--

14 DR. EPSTEIN: Yes\--sorry.

15 CHAIRMAN RAO: Dr. Harlan, did you have\--

16 DR. HARLAN: Oh, I was just going to

17 respond to Dr. Rieves\' question that he asked about

18 should there be different standards of safety and

19 product release for cellular products that just

20 come out of the patient, versus those that get

21 manipulated.

22 And I would simply endorse what the FDA

23 does; that the further you get from what is taken

24 out of the patient, the more rigorous the testing.

25 I think what you guys do is right.

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1 CHAIRMAN RAO: Dr. Epstein?

2 DR. EPSTEIN: Yes, there have been, I

3 think, four studies published, including our

4 own\--and Dr. Perin\'s, really\--which are not an

5 acute myocardial infarction studies. They really

6 are angiogenesis trials. Even Dr. Perin looked at

7 patients with reduced ejection fraction.

8 But I think the goal there was to improve

9 perfusion of that ischemic myocardium. And our

10 study was in chronic stable angina.

11 So I think there are two approaches for

12 angiogenesis. One is in the acute myocardial

13 infarction setting, which may be part myogenesis,

14 part angiogenesis. But then there are

15 many\--several centers that are involved in sort of

16 chronic refractory angina.

17 And I completely agree with you. The

18 endpoints that one looks for in the animal models

19 for efficacy would be very different than for

20 myogenesis.

21 DR. KURTZBERG: I have two comments.

22 One, I want to really endorse what Kathy

23 said and just also say that I think if you define

24 all these things going forward, you will save time.

25 You will make progress more quickly. I think we

157

1 learned that in the bone marrow world after we

2 didn\'t do that. And it took us 15 years to get

3 together and agree what engraftment meant.

4 But if you have those common definitions

5 ahead of time, you can talk between your studies,

6 and you can compare things. And so I don\'t think

7 it matters whether it\'s a Phase I study at a single

8 institution, or it\'s a multi-institutional study.

9 I think having those agreements makes you be able

10 to talk and make progress much more quickly.

11 And I also think, you know, you may be

12 doing skeletal myoblasts now, but who knows what

13 other kind of myoblasts you\'ll do in a few years.

14 And if you don\'t agree to have the same common

15 terms and endpoints\--even though you\'ll modify

16 them\--you won\'t be able to compare one to the

17 other.

18 So I think that\'s really important.

19 And then the second thing I wanted to say

20 was just to clarify my comments about autologous,

21 unmanipulated cells. I think they should be

22 studied under IND for delivery, but I don\'t think

23 they should become a product. I don\'t think that

24 we should have to pay\--the patient should have to

25 pay extra for their own cells that are not

158

1 manipulated in any non-classical sort of standard

2 of care fashion.

3 So once they\'re proved to be efficacious,

4 and the delivery systems are defined, etcetera,

5 then I just don\'t want to see them turned into a

6 commercial product.

7 CHAIRMAN RAO: So, you know, there are a

8 couple of things that are still a little bit

9 confusing to me, and I\'m going to try and see if we

10 can focus on those as well.

11 So\--you know, to me, it\'s pretty clear

12 that one needs animal models to do some sort of

13 safety study. But, to me, what\'s not clear is what

14 kind of safety studies are absolutely critical, in

15 terms of when you put the cells into an animal

16 model?

17 For example, if I were to deliver cells by

18 IV, you know, I don\'t just want to look at the

19 heart and look at safety studies and look at

20 V-tach. You know, I really would like to know, for

21 example, what\'s happened to the cells where we

22 didn\'t want them to know. You know, probably a lot

23 of them go to the kidney and the spleen and the

24 lung. And should we be, in animal studies, be

25 worrying about where they are if that\'s the method

159

1 of delivery?

2 If we put cells in, you know, with a

3 catheter, and then that\'s the animal model that

4 you\'re studying in terms of safety, should we be

5 saying that, you know, you always want to have to

6 look at a leak\--right?\--because that happens with a

7 certain frequency. Is that a really specific thing

8 that we need to worry about? And are there

9 certain, sort of simple, obvious things like this

10 which need to be considered, or should be required

11 in an animal model?

12 I mean, Kathy pointed out one thing and,

13 you know, it came up with Dr. Murray and with

14 several people, is that we need something about

15 dose\--right? It doesn\'t matter whether they\'re

16 minimally manipulated or not, or whether they\'ve

17 been grown in culture. We really need to know

18 what\'s a safe dose when you deliver them, and we

19 need to know that in that animal model, and we need

20 to know where they are. And that came up when we

21 talked about it.

22 So are there any such other things that

23 one might want to consider, specifically with

24 taking a particular cell type which has been

25 manipulated in culture, you know, and that has been

160

1 put in by a certain methodology, that you would

2 absolutely want to highlight and say, you know, \"If

3 you do this, and you put in an animal model, we

4 really want to worry about this?\"

5 For example, in the nervous system, you

6 know, epogen cells which have maintained in

7 culture, I mean we really, really want to know

8 whether they continue dividing for up to six

9 months, and whether they form a proliferating mass.

10 I mean, we consider that a requirement when you put

11 the cells in\--right?\-- in terms of doing it.

12 Maybe there are some things like this that

13 should be clear to the whole cardiac community.

14 And maybe there\'s a consensus. And maybe the

15 cardiologists can tell us.

16 Who wants to take a first shot at that?

17 \[Laughter.\]

18 DR. SIMONS: You know, I find it very

19 difficult to speak about these models in such

20 general terms. I think we haven\'t gotten into any

21 amount of detail you need to sort of talk about it.

22 And I\'m not sure we have enough people

23 around the table, or in the room, who are

24 extensively familiar with these models\--of course,

25 we will get into the use of devices, the use of

161

1 cells. And if that\'s an important issue\--and I

2 believe it is\--maybe it should be a subject of a

3 separate discussion by a separate panel. I would

4 really like to suggest that that could be an

5 important step forward.

6 And we\'re talking about the cells sort of

7 transformed as if this was a single disease. It\'s

8 not. There are at least two different

9 circumstances in which this is going to be used

10 clinically, and each of the circumstances will

11 actually dictate a very different model and a very

12 different delivery strategy.

13 And we either have to get into a very

14 profound amount of detail to sort of go over it, or

15 we should maybe sort of postpone this.

16 CHAIRMAN RAO: That\'s an important

17 perspective and I think, unfortunately, the FDA

18 doesn\'t have that luxury. And so\--

19 \[Laughter.\]

20 \--we have to see whether\--that the

21 conclusion can be that this is all we know, that

22 there\'s some even generic sort of advice that one

23 can offer.

24 DR. TAYLOR: I\'m not a cardiologist, but

25 I\'ve been thinking about this for a long time.

162

1 And, obviously, moving into clinical trials is an

2 important step.

3 I think we\'re in a very early stage here.

4 When the first myoblast trial was designed, for

5 example, MRI was the surrogate marker that was used

6 as an efficacy endpoint. Partially through the

7 trials, people discovered that, in fact,

8 ventricular tachycardias were emerging, and that

9 people had to have AICDs implanted. And all of a

10 sudden the endpoint was no longer useable.

11 And I think it illustrates how dynamic

12 this field is right now, and how flexible we have

13 to be in terms of changing as more knowledge comes

14 forward. And I think that\'s what the FDA has to

15 keep in mind; that many of us who have been

16 thinking about this for 15 years haven\'t yet gotten

17 together and defined all the terms. We\'re doing

18 that now, but we don\'t know.

19 CHAIRMAN RAO: You\'re right. It\'s

20 important. You\'re echoing what Dr. Simons just

21 said.

22 But let me ask one specific question

23 before we get to Dr. Harlan.

24 Do you think that one could say that,

25 well, we really, really, absolutely, for safety,

163

1 need to know about cells, so they have to all be

2 labeled so that we can follow them\--in a reasonable

3 study.

4 Is that something that should be like a de

5 rigeur requirement\--you know, an observation. We

6 don\'t\--

7 DR. TAYLOR: In a clinical study? Or in a

8 preclinical study?

9 CHAIRMAN RAO: In a preclinical\--since

10 we\'re talking about animal models, and\--

11 DR. TAYLOR: I think right now it probably

12 depends, to some degree, on the cell type. The

13 short answer would be: I think we need to do

14 bio-distribution studies that we haven\'t done.

15 There are data that, you know\--we know

16 some of these cells track to bone marrow. We know

17 they then get recruited to other places that we

18 don\'t know anything about yet.

19 On the other hand\--and a lack of a label

20 has been a real issue, and that\'s one of the reason

21 small animals\--mice\--where you can use genetically

22 labeled cells are an incredibly important model to

23 be able to track these cells in vivo. That\'s a

24 situation where safety studies could very easily be

25 done in small-animal models and be important.

164

1 Do I think clinically we need to be able

2 to label and track these cells? No.

3 CHAIRMAN RAO: Dr. Harland?

4 DR. HARLAN: Well, I just want to respond

5 to your specific question about other potential

6 safety tests to consider, and to follow up on a

7 comment you asked about this morning about

8 karyotype.

9 I wonder if anybody is looking at, say,

10 cells that have been propagated in culture,

11 transplanted into a non-SKD mouse two years later?

12 You know, I think that may be\--it may be something

13 that\'s not being looked at right now: the

14 tumorgenicity of these cells. And I would suggest

15 that would be a good way to look for that.

16 Karyotype\'s one way, but an in vivo test would be

17 better.

18 CHAIRMAN RAO: But would you agree\--I think

19 it\'s a very valid point. But say, for example,

20 that that can\'t be generalized to all cell types

21 because there might be a lot of data on, say,

22 minimally manipulated bone marrow cells, for which

23 there\'s long history of operative reporting, but

24 may not be true for other cell types that are put

25 in.

165

1 I want to ask: do you feel that this sort

2 of addresses some of the issues that you had

3 raised, in terms of the kind of things that one

4 needs in an animal model?

5 DR. MULE: It does.

6 DR. TAYLOR: I slightly disagree with

7 regard to minimally manipulated bone marrow cells,

8 because of some rodent data that haven\'t fully been

9 explained yet, which are that GFP

10 transplanted\--animals were ablated and green

11 fluorescent protein cells were used to replenish

12 their bone marrow. Tumors were implanted in those

13 animals, Several weeks later the tumors were

14 explanted and the vessels were green in those

15 tumors.

16 I think we don\'t know exactly where

17 these\--we know these cells go where we want them.

18 We also suspect they go places we don\'t want them.

19 And until we started\--we do need to begin to

20 address that preclinically, I think.

21 At the same time, that\'s no different than

22 is already being required. I think people are

23 doing tumorgenicity studies with most of these cell

24 types before they have the ability to implant them.

25 CHAIRMAN RAO: On this note\--and I know

166

1 that there still is sort of sense that there\'s no

2 perfect model, and that we don\'t have a single

3 model that we can look at, and everything depends;

4 and that \"everything depends\" is sort of anathema

5 to, you know, the FDA\--I guess.

6 But let\'s add to that just one more issue

7 here so that we can see whether this sort of

8 uncertainty also extends to specific models of

9 ischemia.

10 So\--a lot of things that we\'ve looked

11 at\--there has been\--the data that we\'ve heard has

12 been about transplanting cells in the animal trials

13 and the human trials has been in some sort of

14 either ischemic infarct, or with low ejection

15 fraction where there has been damage.

16 Are there any merits to any specific

17 model, that you would say one is better than the

18 other, in terms of either the cryo model or the

19 banding model, or it\'s any species? And, again,

20 maybe I can ask one of the cardiologists who has

21 experience with this to make some general statement

22 and see.

23 DR. RUSKIN: There are a number of canine

24 models that are relevant to the human situation

25 with regard to ischemic left ventricular injury.

167

1 So, certainly, if I were given a choice, I would

2 choose one of those over a cryo model, which is

3 really not a physiologic model. Cryo produces very

4 uniform scarring, very discrete margins. It

5 doesn\'t bear any relationship to the architecture

6 of myocardial infarcts.

7 So I think if I had to pick a model\--

8 CHAIRMAN RAO: Dr. Ruskin, when you make

9 this, would you also sort of consider this in the

10 light of \"predominantly safety\" versus efficacy

11 studies, as well, in terms of a bias?

12 DR. RUSKIN: I think that it\'s relevant

13 with regard to both safety and efficacy.

14 The model that we developed in the late

15 70s, and continue to use, are the transmural

16 myocardial infarction in dogs. It is highly

17 analogous to some of the questions that are being

18 raised here in humans, in terms of wanting to treat

19 areas of myocardium that are truly dead. This is a

20 model of LAD occlusion with ligation of all the

21 collaterals, from the right and the left circumflex

22 coronary arteries to produce an aneurism at the

23 left ventricular apex. It produces a thin

24 transmural scar, with very little in the way of

25 islands of viable myocardium\--which would seem to

168

1 me to be an ideal substrate in which to test this

2 kind of question.

3 So, if you asked me to pick a model,

4 that\'s certainly one of them that I would pick.

5 And, generically, I would certainly pick a true

6 ischemic-induced injury over a cryo or some other

7 synthetic kind of injury, if you will.

8 CHAIRMAN RAO: Dr. Simons?

9 DR. SIMONS: I certainly agree with Dr.

10 Ruskin that the cryo injury model is probably not

11 the way to go, for a number of different reasons.

12 There are two standard ischemia models

13 that\'s been used as a basis for a lot of the

14 growth-factor trials. One is an amyloid model,

15 which is the most\--which, over the last 10 years

16 became the most common cause of coronary artery

17 disease in pigs. And we know a lot about this

18 model. We knowhow it works.

19 We also know that the drugs or devices or

20 cells or genes that work in that model don\'t work

21 in people\--which raises an issue of how useful that

22 is. It certainly can be useful for safety testing,

23 and a lot of other natural history. But it\'s clear

24 that if\--a pig, and if you have coronary disease,

25 we\'re going to fix you. And unfortunately that

169

1 doesn\'t happen in people. And this could be the

2 fact that these are young pigs, that are going to

3 grow. They don\'t have any lipid disease, and they

4 are not taking drugs. So, it\'s a hard one to

5 study.

6 As the other model that I think is getting

7 a lot of play now is the hind-limb ischemia in an

8 APE knockout, or an LD with a septal knockout mice,

9 because here you can mimic age, which you cannot do

10 in pigs and dogs. And here you can mimic a lot of

11 human disease.

12 And it\'s interesting that the data is sort

13 of emerging now is that none of the growth factors

14 actually work in that model, and that could well

15 explain why they actually don\'t work in people.

16 So I think you can use pigs or dogs with a

17 chronic ischemia model such as an anaberoid to

18 study how effective your devices are in getting the

19 desired cells in place, and you can use the

20 diseased-mice models to get more of a functional

21 readout of whether the desired therapies will work

22 in the setting of age and disease.

23 CHAIRMAN RAO: Can I ask one more question

24 here, is that even in terms of safety, is it really

25 important to study the effect of these cells in an

170

1 animal model\--in some kind of ischemia model?

2 Because the environment has changed; you know, the

3 cytokines have changed, the milieu has changed. So

4 when you look at safety studies, should you be

5 really doing it in some kind of model of ischemia

6 or not?

7 DR. SIMONS: I think the safety study in

8 animals should sort of mimic as close as possible

9 the clinical trial design. So, if this is going to

10 be a trial of cells injected in\-- that\'s how the

11 testing should be in animals, because of ischemic

12 milieu, and actually it has to work in ischemic

13 milieu, will have a different effect than if you\'re

14 doing it in healthy animals without it.

15 CHAIRMAN RAO: Dr. Schneider, then Dr.

16 Borer.

17 DR. SCHNEIDER: To follow up on Dr. Simons\'

18 comment about using ischemic models to mimic

19 ischemia, the harder part, I think, will be using

20 heart failure models to model heart failure.

21 And if one considers the heart failure

22 population that Dr. Perin was speaking of

23 yesterday, and which is nominally the substrate for

24 many of the skeletal myoblast trials and some of

25 the other therapies, many patients have heart

171

1 failure as the result of prior coronary artery

2 disease and infarction; not all of them do. Many

3 of them have longstanding hypertension as a

4 contributing cause, but not all of them do.

5 And what I would say is that a number of

6 animal models\--rather than seeing a limitation of

7 the field being that no one can agree on an animal

8 model which is perfect\--specifically, no one can

9 agree on an animal model which is perfect for all

10 clinical situations. I would also say no one can

11 agree on an animal model which is perfect for

12 either of the clinical situations.

13 You know, you\'ve heard convincing

14 allusions by Dr. Ruskin and Dr. Simons to one of

15 the best ischemic models, in the dog, and one of

16 the ischemic models, in the pig. And I personally

17 don\'t think that someone who comes to the FDA with

18 preclinical data should be precluded from using one

19 of those rather than the other. You know, a number

20 of alternatives are possible, as well.

21 The situation becomes more complex in

22 heart failure, where there is far less agreement on

23 what an adequate large mammal is. Some

24 investigators used rapid ventricular pacing in a

25 dog or some other species. I would say that the

172

1 smaller mammal models, or the rodent model\--Syrian

2 hamster model of cardiomyopathy, which one speaker

3 alluded to yesterday\--in fact mimic human heart

4 failure better than the pig or dog models that

5 currently exist.

6 CHAIRMAN RAO: Dr. Borer.

7 DR. BORER: Yes, unless Richard is going to

8 disagree, I think we\'re all in unanimity

9 here\--those who are cardiologists around the

10 table\--because I think the point is well made that

11 if the therapy is going to be given to people with

12 ischemic heart disease, then a physical injury

13 model is not appropriate, because the myocardial

14 milieu\--the response of the extracellular matrix,

15 etcetera, etcetera\--is going to be very different

16 in that setting than in an ischemia setting.

17 Having said that, of course, the animals

18 don\'t perfectly mimic people. So what one would

19 like to do would be to look at several models. The

20 dog model is the one that we used to use at the NIH

21 regularly, because it was easy to manipulate and

22 seemed to be predictive. And there\'s a god deal of

23 information about the predictive value of the dog

24 and the pig in certain situations.

25 The point I would make here, though, is

173

1 the one that Steve Epstein has mentioned again and

2 again: the selection is going\--the selection of

3 model is going to depend, in part, on whether

4 you\'re thinking about myocardial function alone, or

5 angiogenesis\--or arteriogenesis, to be politically

6 correct\--because the different species differ, for

7 example, in their collateral development response

8 to coronary occlusion, etcetera, etcetera.

9 So one would like to select the animal

10 depending upon what it is you want to look at.

11 Having said that, the point that mike made

12 is very important. There is no really\--you know,

13 there\'s no perfect model for heart failure. All of

14 them are deficient in one or another. And earlier

15 today Dr. Grant said that heart failure is the only

16 cardiac disease that\'s increasing in incidence over

17 time.

18 There\'s a subset of that: valvular

19 diseases are also increasing over time. And the

20 valvular\--the valve manipulation models produce

21 heart failure that mimics human disease as well.

22 The point is, there are several types of

23 models one could use. As Mike said, I think you

24 want to use several, and try to find some degree of

25 consistency of the effect of the therapy in the

174

1 different models, none of which is absolutely

2 perfect.

3 The only thing I think that I would avoid

4 is the physical injury model, which I don\'t think

5 has much relevance.

6 CHAIRMAN RAO: Would it be fair to say that

7 if you were looking at the behavior of cells which

8 are being transplanted, that it\'s far better to

9 look at them in an ischemia model\--preferably as

10 close to a human disease as possible\--and that that

11 would be better than looking at it in a wild-type

12 or a non-injured model?

13 DR. BORER: Absolutely.

14 CHAIRMAN RAO: Because the behavior would

15 be\--

16 DR. SCHNEIDER: Absolutely\--not only for

17 the reason that you cite\--that the milieu in which

18 those cells are required to function would be

19 different, but also for the reason\--going back to

20 Dr. Mule\'s more general question, \"What are we

21 looking for in the animal models?\"\--we\'re looking

22 for evidence of efficacy.

23 And so to rescue ischemic dysfunction, one

24 needs ischemia.

25 CHAIRMAN RAO: Can I ask one more question

175

1 before\--

2 DR. EPSTEIN: Just\--directly\--just to

3 support what you\'ve said, there was a very recent

4 and very interesting paper in Circulation, where

5 they were looking at adverse events of cells,

6 namely a pro-atherosclerotic effect. And they were

7 using the ischemic mouse hind-limb model.

8 Cells derived from APLE knockout mouse

9 increased atherosclerosis, but only in the presence

10 of hind-limb ischemia. So that\'s another point

11 that substantiates what you and the others have

12 been saying.

13 CHAIRMAN RAO: Did you have a comment?

14 DR. WEISS: Yes, I\'d like to make a

15 comment. My name is Judy Weissinger, of Weissinger

16 Solutions.

17 I wanted to make more of a philosophical

18 comment in the concept of agreeing on an animal

19 model, or requiring large animals for certain

20 things; requiring small animals for certain areas.

21 I think what I\'m hearing today is a lot of

22 people are identifying the question we need to

23 answer, and the considerations that we need to

24 address in developing these products, along with

25 the potential models, the studies, the methods that

176

1 we need to address.

2 And these questions and considerations are

3 really important for the sponsor to propose a plan

4 based on the product\--the uniqueness of the product

5 they\'re developing, and the clinical design of the

6 study.

7 And so I just want to caution again\--and

8 go along with the traditional biologics approach of

9 identifying the criteria that are needed to

10 evaluate a new therapy, as opposed to specifying

11 and requiring the exact studies that are needed.

12 Thank you.

13 CHAIRMAN RAO: That\'s a good point.

14 On that same\--I just want some sort of

15 general feeling from people is that, you know,

16 almost all the viral studies we think about, or any

17 other study, we also always have some sort of sense

18 of how long you want to follow\--right? Even in a

19 safety thing\--like we talked about tumors.

20 I mean, is there any sense in the

21 cardiology field, for example, that, you know, if

22 we do this animal study and, you know, you want to

23 look at an animal, and we have to look at

24 this\--should it be six months? Should it be one

25 year? Should it be\--you know, \"Well, three weeks

177

1 is enough?\"

2 DR. BORER: Let me try to answer that in

3 two ways.

4 First of all, you asked a question before

5 that\'s relevant to this point. And I don\'t think

6 it received a specific response.

7 You said given the fact that with some

8 forms of delivery cells will be distributed

9 systemically, leads to questions about whether you

10 should look at other issues besides cardiac issues.

11 And I think the answer is absolutely yes, but there

12 must be\--and I don\'t know what it is\--must be a

13 rich experience from hematology studies over the

14 years to tell us about how and what one should be

15 looking for. In that situation, I think one would

16 want to do that, in cardiac studies as well. And

17 that would drive the duration of follow-up in some

18 animal studies in a certain way.

19 In terms of the duration of follow-up for,

20 specifically, cardiac problems, that depends upon

21 the outcome you\'re interested in, and it depends

22 upon the model; and, specifically, it depends upon

23 the expected outcome of the animal naturally. You

24 know, mice don\'t live very long. I\'m not sure what

25 the duration of follow-up of a mouse would be that

178

1 would be meaningfully extrapolatable to people.

2 But, you know, the average life span of a

3 dog or a rabbit is known, and one would like to

4 follow the animal for a substantial period of that

5 life span that might be relevant to the natural

6 history of the disease, I think. That doesn\'t mean

7 that every study has to be done that way, but one

8 might like, for example, in a rabbit to be able to

9 follow it for two years, if you\'re looking at heart

10 failure issues.

11 I mean, I don\'t want to give a specific

12 number. But the principle is that the follow-up,

13 at least in some studies, should be relevant to

14 what you expect the outcome to be in people, I

15 would think.

16 CHAIRMAN RAO: So that seems to be the

17 consensus from a lot of other stem cell fields,

18 where you expect cells to persist for a long

19 period.

20 I mean, for example, when you think about

21 the nervous system, that seems to be the case;

22 where you say, well, we do it in mice, we want to

23 look at least 50 percent of the life span. They

24 live about two years, so you\'re going to follow at

25 least\--not \"at least\" in every study, but for

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1 particular studies, at least follow for a period of

2 a year\--but not in every study.

3 DR. TAYLOR: Talk about a hurdle! I mean,

4 we know that in most of our preclinical studies,

5 the function gets better in a month to two months,

6 and it doesn\'t get better after that. It stays

7 pretty level.

8 In patients, the data seem to suggest

9 there\'s an improvement at three months. It seems

10 to be maximal about six months, and it stays stable

11 after that.

12 I think requiring two-year follow-up in

13 these animal studies, in light of that, doesn\'t

14 make a lot of sense\--at least from what I can see.

15 CHAIRMAN RAO: Dr. Ruskin.

16 DR. RUSKIN: I was going to agree with

17 that. I\'m not sure\--I would say that it doesn\'t

18 make sense. I think that it\'s very difficult to

19 do, and part of this has to be tempered by the

20 patient populations that are going to be addressed

21 by the studies. And if it\'s going to be Class IV

22 heart failure, with ejection fractions less than 20

23 percent, I don\'t think you need, you know,

24 five-year follow-up unless we\'re talking about a

25 miracle here\--

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1 \[Laughter.\]

2 \--which would be wonderful.

3 So I suspect that the preclinical

4 requirements will evolve as the therapies evolve,

5 and as we begin to use them in earlier phases of

6 heart failure, if this pans out, then clearly the

7 preclinical requirements will become much more

8 rigid and demanding with regard to longevity of

9 follow-up.

10 CHAIRMAN RAO: Dr. Borer.

11 DR. BORER: Yes, I mean, I agree with what

12 Jeremy said, and I agree with what Dr. Taylor

13 said\--but, to me, the issue isn\'t whether

14 continuing improvement occurs, but whether

15 deterioration occurs. And you can\'t know that

16 unless you study\--at least at some point, in some

17 model, and in some way\--the natural history of the

18 treatment effect; you know, which may not persist.

19 And I think we ought to know that somehow before we

20 start giving it to people.

21 Jeremy is, of course, quite right. If

22 somebody is expected to live six months and they

23 live two years because of the therapy, that may be

24 a clinically acceptable benefit and you don\'t have

25 to know any more. But still, at the outset, I

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1 think you\'d like to know the natural history of the

2 effect of the treatment.

3 DR. ITESCU: I think that the barrier

4 should be set exactly the same as you would set it

5 for any other pharmaceutical product or biological

6 compound that the FDA requires for testing at the

7 present time.

8 And an example\--it depends on which cell

9 you\'re using, and what type of outcome you\'re

10 looking for. Some of the cells\--as Dr. Epstein

11 presented yesterday\--simply are agents that release

12 preformed effect, and you\'re looking for an

13 immediate cytoprotective effect that may be fairly

14 short-lived, and the cells themselves may not

15 engraft, may not survive beyond the first couple of

16 days.

17 So I think you\'ve got to keep those things

18 in mind, and not expect a more rigorous approach

19 here than you would with any other type of an

20 approach.

21 DR. BORER: I think that may be correct,

22 but I\'d like to point out that the approach to

23 testing with pharmaceuticals is aimed primarily at

24 other issues\--at least in cardiac diseases\--because

25 we give the drugs every day. So the issue there is

182

1 development of tolerance, or tactiphylaxis, and

2 there are\--you know, we know from trial and error

3 that if an anti-anginal drug continues to work for

4 three months, the patients will continue to

5 benefit, you know, for a long time\--who knows how

6 long?\--but for a long time.

7 Same thing with drugs for heart failure,

8 etcetera, etcetera, where the follow-up has been

9 even longer. But the drug is given every day.

10 Here we\'re giving one treatment, once.

11 And we don\'t know about its persistence.

12 So I would say that while what Dr. Itescu

13 says is absolutely right, I do think that there is

14 a slightly different standard here because of the

15 differences in administration, and expectations of

16 the administration regimen.

17 CHAIRMAN RAO: I\'m going to ask the FDA\--go

18 head\--

19 DR. McFARLAND: I was just going to\--from a

20 practical standpoint\--I mean, I\'ve really enjoyed

21 the discussion, the way you\'ve been managing it,

22 and the scientific points that have come out.

23 From a practical perspective, what I\'m

24 getting\--and I want to see if this is the correct

25 consensus\--let\'s say next week when I have a

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1 pre-IND meeting and they ask what preclinical

2 trials should we do? What preclinical studies?\--it

3 would be reasonable\--a degree of flexibility, I

4 mean, on what particular model people choose; that

5 it should be a model that if you\'re looking at an

6 ischemic disease, it should be a model that

7 clinically monitors ischemia; that there isn\'t

8 really a consensus on versus cell types, versus a

9 myoblast product versus a hematopoietically-derived

10 product, in terms of what kind of preclinical

11 models people should suggest.

12 And there\'s not definitive consensus on

13 chronicity of the study, except that it should be

14 long enough to cover the period where we would

15 expect maximal time of safety readouts; and that,

16 you know, given the fact that none of the animal

17 models\--particularly double-sided models\--a point

18 Dr. Ruskin\'s made and others have made, is that a

19 positive signal is very important, but a lack of a

20 positive safety signal shouldn\'t give us over

21 assurance.

22 And\--is this sort of the consensus of\--

23 CHAIRMAN RAO: I would add two more points,

24 which I thought were emphasized. And one is that

25 bio-distribution, at least to some extent, in a

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1 particular model is really quite critical, and that

2 a dose escalation of any kind is really quite

3 important in terms of being able to do it. And

4 that\'s irrespective of cell type\--that\'s important.

5 DR. McFARLAND: And one specific question

6 that I don\'t have an idea of a consensus on: the

7 point was made that large models are important for

8 monitoring delivery systems, and you would expect

9 to see animal models when you\'re doing innovative

10 catheter delivery systems.

11 There was no comment on, you know,

12 chronicity of the model with respect to that. I

13 mean, we\'ve heard various viewpoints outside of the

14 room about\--well, from an hour to six weeks to\--and

15 I would like some discussion on that particular

16 specific point related to the catheter delivery

17 systems.

18 CHAIRMAN RAO: How long to follow?

19 DR. McFARLAND: What sort of a length of

20 time in an animal study of a catheter, in a large

21 model. Is it any different\--I mean\--there are

22 problems with acute toxicity with the procedure

23 itself\--potentially. And then, you know, problems

24 with somewhat of chronicity, and I haven\'t heard

25 discussion about that.

185

1 CHAIRMAN RAO: Should we be considering

2 that point when we talk about devices and delivery

3 in the next question?

4 DR. McFARLAND: Oh, right. Okay.

5 CHAIRMAN RAO: Does the committee feel

6 we\'ve captured some of this discussion in a

7 reasonable summary? That we really can\'t be

8 specific, but we need more than one kind of model.

9 It\'s important that we have models that are run in

10 parallel when we\'re doing this, and that they are

11 important for safety, even if you\'re using

12 minimally manipulated cells\--what you require.

13 DR. SCHNEIDER: I wanted to reiterate Dr.

14 Borer\'s point that a reasonable duration of

15 follow-up is advisable, even for interventions like

16 angiogenic cells, where the expected mechanism of

17 action might be over a short period of time.

18 I think it\'s logical to insist, before

19 going into a clinical trial, to ascertain, in a

20 relevant animal, that the benefit of induced

21 angiogenesis is persistent rather than transient.

22 CHAIRMAN RAO: Did you have a comment?

23 DR. SERABIAN: My name is Mercedes

24 Serabian. I\'m the branch chief for the Pharm-Tox

25 Branch, and also Soft Tissue and Gene Therapy.

186

1 I just have a couple of comments, real

2 quick. I mean, the more I\'m hearing with respect

3 to all the animal models that are potentially

4 possible is I stress early communication with

5 FDA\--pre-IND; what we call \"pre-pre-IND\" even;

6 connect with us early. You\'re deciding you\'re

7 going into preclinical studies, because these are

8 very resource intensive studies, and we want to

9 make sure that we\'re in agreement with what you\'re

10 planning on doing. I think that\'s really, really

11 important, the more I hear the conversation.

12 And just one more general comment. Again,

13 with all these models that we\'re talking

14 about\--these disease models, specifically. I

15 always question the potential validity of the

16 model. I mean, whose\--is it a lab that\'s doing it?

17 Is it a\--you know, a model that\'s been used before?

18 Is it published in the literature?

19 Even more important than the number of

20 animals that are used, the controls that are used;

21 the potential blinding for the study. Again, just

22 because if this is your efficacy as well as your

23 safety study, that\'s really, really important for

24 us.

25 CHAIRMAN RAO: On that note, I think we can

187

1 break for lunch. And the committee has some lunch

2 for it already ready.

3 \[Off the record.\]

4 CHAIRMAN RAO: Back on the record.

5 So now that everybody\'s well fed, I think

6 we\'re going to have a much shorter discussion.

7 \[Laughter.\]

8 We\'ll see. No, I think it will be shorter

9 just because many of the points have been discussed

10 throughout\--from yesterday and today.

11 Before we start, Dr. Cunningham wanted to

12 make a statement, and I think this might be a good

13 time to make it.

14 DR. CUNNINGHAM: Thank you.

15 I just wanted to make a comment that

16 doesn\'t fit any of the questions that we\'ve been

17 asked today, and yet I think it\'s important to

18 include. And that is the importance of looking at

19 both genders when we study this issue; that I think

20 that Dr. Taylor has indicated\--her data indicated

21 that there\'s a signal that there may be a

22 significant difference between the genders.

23 There may be more differences than that,

24 and I think that, overall, in the long term, we

25 want the populations to be studied to be

188

1 representative of the populations that we wanted to

2 treat. But if we\'re talking even just a Phase I, I

3 think at least we should begin with being sure that

4 the safety data includes both men and women, and

5 then from there on we\'d like to have more diversity

6 as possible.

7 CHAIRMAN RAO: So, I\'m going to set up two

8 extreme positions for this next question, and

9 that\'s in terms of devices.

10 And you heard one relatively extreme

11 position, I guess, which was that if you\'ve got a

12 device and it\'s already approved, and it\'s been

13 approved for use, and there\'s a lot of studies and

14 data on the safety of that particular device, then

15 you don\'t need to worry, as long as you have some

16 simple tests on saying that you can use those\--give

17 cells, and that the cells are viable, then that\'s

18 fine.

19 And then the other extreme is that, you

20 know, there are many, many things we don\'t know,

21 and we\'ll never know about how they interact, and

22 so we can\'t really make sure that we understand

23 this in any simplistic way, and so we need lots of

24 detailed studies; and that lots of detailed studies

25 often is a red flag.

189

1 And perhaps there is a happy medium. But

2 let\'s maybe sort of think about it, and try and set

3 this up and whether it all makes sense to the

4 committee as well.

5 To me it seems that catheters can be used

6 to deliver in a variety of ways. And whether

7 you\'re doing it through the venous end, or you\'re

8 doing it through the arterial end, there are going

9 to be differences. And so can\'t generalize from

10 one site of delivery to another.

11 There\'s another thing that I felt that one

12 can\'t generalize at all\--and which, I think, Doris

13 Taylor raised in her talk, too\--is that a lot of

14 the data in delivering cells has been using a

15 needle which is at right-angles to the orientation

16 of the fibers. And that\'s important. Orientation

17 is really important. While a lot of catheters,

18 when they deliver it with a needle, may be

19 delivering it at right-angles to the epicardium, or

20 delivering at a different angle than what we have

21 studies on.

22 So, keeping those sort of thoughts in

23 mind, maybe we can have people think about what

24 should be studied, if somebody came to the FDA and

25 said, you know, here is a device. It\'s already

190

1 approved, or we know how to use it and we\'ve used

2 it for hundreds of years. And, you know, here are

3 cells. And we\'ve already got a lot of data on

4 cells.

5 What would be sort of really important in

6 consideration that we\'d have to worry about?

7 And one obvious thing has already been

8 talked about, and that\'s pressure effects, and size

9 and gauge of the needle; and, you know, how you\'re

10 going to give it; and issues of vessel wall and

11 pressure on the catheter.

12 So those are all straightforward things

13 which are obvious. But there are also particular

14 interactions between cells and reagents, and the

15 FDA already raised them when they talked about

16 things like the lubricants which coat, and so on.

17 So there are probably things that we who

18 are not familiar with the field don\'t understand.

19 And maybe some of the cardiologists can enlighten

20 us, or raise red flags on this as well.

21 DR. KURTZBERG: I have a real simplistic

22 question for the interventional cardiologists.

23 As I think about it, you\'re in there with

24 a catheter, in a beating heart, trying to be

25 precise about delivering whatever many cells in a

191

1 very small volume to an exact perimeter. I mean,

2 how realistic is that, to think that you really can

3 do that?

4 DR. SIMONS: I actually think that\'s the

5 easiest part. There are lots of systems for doing

6 this with any degree of sort of precision that you

7 want. And I\'m not sure that you want an extreme

8 degree of, you know, precision. You can do it

9 with, you know, a millimeter accuracy. If that\'s

10 not good enough with a biosense system, you can do

11 it with 100 micron accuracy. If that\'s not good

12 enough, with\--you can probably do it even better

13 than that.

14 I think that really is the easy part.

15 DR. KURTZBERG: Even if you\'re moving a

16 needle\--

17 DR. SIMONS: Oh, yes. Absolutely.

18 DR. KURTZBERG: \--through, that\'s causing

19 trauma as it\'s going\--

20 DR. SIMONS: Yes. Mm-hmm.

21 \[Laughter.\]

22 CHAIRMAN RAO: Dr. Borer?

23 DR. BORER: I think there are two sets of

24 questions\--maybe\--

25 CHAIRMAN RAO: Will you hit the button?

192

1 DR. BORER: \--or maybe six sets of

2 questions here. But let me dispense with one that

3 I think is important, first, and then move on to

4 the second.

5 The issue of the safety of the catheter

6 does depend, obviously, on the prior\--the issue of

7 how much testing you have to do about safety,

8 placement, etcetera, depends upon prior experience.

9 And I think, you know, there\'s a lot that can be

10 done with catheters. And I should tell you I speak

11 from the point of view of someone who did several

12 thousand, first at the NIH, and then when I was

13 running the cath lab at Cornell. There are a lot

14 of things you can do with catheters.

15 The issue I would think, however, with a

16 device that\'s already been approved for something

17 else is, first, where are you going to put it? Are

18 you going to put it in the same place that you\'ve

19 put it in for a hundred years, or are you putting

20 it someplace new?

21 Manipulating the catheter can be

22 relatively simple, but if you\'re putting it into a

23 new location, you have to be reasonably certain you

24 can do that safely; and not nine times out of 10.

25 It probably has to be 99 times out of 100, or maybe

193

1 better than that. I don\'t know. And so some

2 experience might be necessary there.

3 And then I would say, too, for the

4 applications we\'re talking about, there probably

5 will be multiple new devices with potential and

6 putative advantages developed as better delivery

7 systems than the already available delivery

8 systems. And there, I would say that it is not\--I

9 don\'t think it\'s actually right to believe\--and you

10 said this yesterday, Dr. Rao\--to believe that

11 testing at the bench a few mechanical parameters is

12 quite enough. You actually have to feel the

13 implement, and to know how easily it turns, and

14 torques, and da-da-da-da-da. And in gaining that

15 experience, you have to keep count of the serious

16 and non-serious adverse events.

17 So I think one has to have some experience

18 with a new product, just in terms of the mechanical

19 viability and ease of handling, and safety of

20 putting a device into a body\--as opposed to an old

21 device that\'s being dealt with with new use. And

22 there, I think the issue is a little simpler, but

23 you do have to be sure that putting it in the new

24 place is viable.

25 Now, once you get past that set of issues,

194

1 there is the major issue, it seems to me, of the

2 viability of the product after it\'s extruded

3 through the catheter. I was surprised\--I tell you,

4 honestly, I was surprised to hear about the

5 27-gauge needle. And you already made the point,

6 Dr. Kurtzberg. You know, you do have to know that

7 the product, once it\'s extruded through the

8 delivery system, is not fragmented; that it is

9 viable; that there are cells there, and not, you

10 know, junk.

11 And, of course, there\'s the whole issue of

12 the interaction of the\--chemical, as well as

13 physical interaction, of the product with the

14 substance from which the device is made. You know,

15 I mean, you\'ve said it already. I don\'t want to

16 belabor the point. But, you know, there are so

17 many examples\--not just with biological materials,

18 but with simple drugs\--where the drug is adsorbed

19 to catheter materials. If some key component of

20 the diluent, or the excipient, or something was

21 adsorbed to the catheter, who knows what would

22 happen when the product is delivered into the

23 myocardium?

24 So, there are several different levels of

25 questions, beginning with the safety of the device

195

1 mechanically, through the effectiveness of

2 mechanically delivering a viable product, through

3 the issue of chemically or biologically delivering

4 a viable product.

5 And I separate the mechanical and the

6 biological or chemical\--or biochemical, or

7 whatever\--because the fragmentation of the product

8 can raise safety issues by itself. And it would be

9 naive to believe, in this latter context\--that is,

10 the interaction of the product with the

11 device\--again, that bench testing can tell you

12 about safety issues beyond the viability of the

13 product. I\'m thinking specifically of

14 thrombogenesis, for example. I mean, there are two

15 different heart valves that, you know, meet the

16 mechanical\--valve prostheses that meet all the

17 specifications. Both are approved, made by

18 different companies. And it wasn\'t know until

19 multiple years of experience that one of them

20 turned out to be more thrombogenic than the

21 other\--importantly so, changing the recommendations

22 for anticoagulation of one versus the other. It

23 wasn\'t known until clinical testing.

24 Now, how much clinical testing you need so

25 that you can be reasonably safe in a population as

196

1 sick as the population we\'re talking about is a

2 different set of issues, and we can\'t solve that

3 here. But that some information is necessary from

4 direct testing\--to some extent in animals, to some

5 extent in patients\--about the mechanical safety,

6 the safety of manipulating the device in the heart

7 and in the patient; the mechanical\--the physical

8 viability of the product, and the chemical and

9 biological viability of the product, I think must

10 be defined before you can approve the device.

11 CHAIRMAN RAO: Before Dr. Ruskin, I just

12 want o make a statement and ask you to comment on

13 it as well.

14 So, from what you said\--or what I heard

15 from this\--was that it almost seemed that you would

16 want to test this in an animal model. Is that what

17 it seemed like?

18 DR. BORER: Absolutely. And before

19 approval, I would think you\'d want a certain amount

20 of patient experience. But\--sure.

21 CHAIRMAN RAO: Dr. Ruskin.

22 DR. RUSKIN: First, I\'d like to just second

23 Dr. Borer\'s comments about the need for getting

24 hands on experience with any catheter design.

25 Bench testing tells you a great deal, but it

197

1 doesn\'t tell you how it\'s going to perform in the

2 body. And that can only be answered in large

3 animal models, and in early clinical trials.

4 I want to come back to Dr. Kurtzberg\'s

5 first question, though\--or previous question\--and

6 expand a little bit on the answer that Jeff gave,

7 and also Mike Simons. I think he was kidding, by

8 the way, when he told you we could do this with 100

9 micron accuracy.

10 \[Laughter.\]

11 I think there are couple of components to

12 the question as I heard it. One is mapping

13 substrate, which we can do pretty well. We can

14 delineate, by voltage mapping and other criteria

15 the presence of what we believe to be scar, and we

16 can do it with a reasonable precision, and we can

17 do it reproducibly.

18 Getting the catheter where you want it to

19 go is also achievable with current mapping systems,

20 but I must emphasize something that Nick Jensen

21 brought up yesterday, which is that catheters are

22 inherently unstable in terms of holding a position

23 in the left ventricle, and that problem has not

24 been overcome yet. The mapping systems do help you

25 mark spots and get back to them, but it doesn\'t

198

1 ensure that your catheter will stay there.

2 The other is the deliver, which is a

3 needle of some sort. And I think that is a huge

4 challenge, and one which is not yet solved. And I

5 don\'t think we know where we\'re putting materials

6 when we inject through needles via catheters. And

7 we\'ve done some of this with gene delivery, and I\'m

8 not at all convinced that much of the time we get

9 anything into the tissue; or, if we do, I suspect

10 it\'s a small amount.

11 So I view that, right now, as an area of

12 enormous challenge, and not a problem that is

13 solved, from a technological standpoint.

14 CHAIRMAN RAO: Dr. Lederman, you had a

15 statement?

16 DR. LEDERMAN: I think I agree with most of

17 the points made, except in the execution. So,

18 sure, we\'d probably need to know most of the

19 information mentioned before deploying

20 drug-delivery devices in early clinical studies.

21 But let\'s take the example of cells.

22 Let\'s say than in animal models we have proof of

23 principle for a given cell preparation that we\'d

24 like to deliver by direct myocardial injection.

25 And let\'s say that those data come from small

199

1 mammals, and that there\'s no satisfactory

2 large-mammal model of that cell.

3 What is it that we need to know about the

4 catheter device before we can declare it adequate

5 to deliver cells into humans? Would it not be

6 satisfactory to measure a simple index, like tripan

7 blue exclusion after passage, or after some dwell

8 time? Do we really need to push cells through and

9 then show preserved biological activity by some

10 more complex in vivo measure? Doesn\'t that seem

11 excessive?

12 CHAIRMAN RAO: So\--before Dr. Simons\--I

13 think that\'s a point we want to try and really get

14 to here is that are there certain minimum things?

15 Is there a consensus on what\'s excessive or not?

16 And I think from the earlier part of what

17 we looked at, we said that cells themselves need to

18 be characterized in quite a lot of detail, and that

19 we need to characterize them when they get there,

20 in the heart. And that\'s why you needed to do them

21 in animal studies.

22 So we have to keep that in mind and say:

23 that\'s absolutely true, that what we need to study

24 about catheters in general is true, and that those

25 are simple things, and maybe we can look at them

200

1 and you can also get an answer to how you deliver.

2 But then subsequently we really need to know, once

3 they\'ve been delivered from the catheter, what are

4 the characteristics of the cell.

5 And\--Dr. Simons?

6 DR. SIMONS: Well, you just said what I was

7 going to say. Because you can damage cells at

8 several different points when you use a catheter to

9 put them in. One is in a physical contact with the

10 catheter polymers; second when it goes through the

11 27-gauge needle. And, actually, most cell types

12 will not get damaged by passage through the

13 27-gauge needle.

14 But a lot of damage occurs when the cells

15 contact tissue at high sort of pressure, and you

16 are not going to model that in vitro. You really

17 have to model this in vivo, and you need to know

18 what happened to the cells once they\'re in the

19 tissues.

20 CHAIRMAN RAO: Perhaps even that could be

21 modeled, say, in an animal prep, you know, where

22 you\--you have a heart prep, and you can look at

23 those sorts of pressure\--maybe.

24 So, I\'m not arguing that we have to

25 absolutely make it specific. I just want people to

201

1 keep in mind that there are certain criteria that

2 you\'d really want to worry about in terms of

3 characteristics of cells.

4 Dr. Harlan, and then Dr.\--

5 DR. HARLAN: Well, my only comment with

6 regard to Dr. Lederman\'s question was: implicit in

7 your scenario as you presented it was that here was

8 no animal model to test the viability of these

9 cells in. So I think what the FDA continually\--my

10 read of it is that they say, \"Do all the testing

11 that\'s reasonable to expect.\" If there is no way

12 to test the hypothetical cell that you\'re talking

13 about, then I think the FDA would be reasonable, if

14 you identified the patient population

15 appropriately.

16 DR. KURTZBERG: I was going to just comment

17 on the tripan blue question.

18 I don\'t think tripan blue is enough of a

19 measure to tell you that your cells will preserve

20 function and viability later. If you see a lot of

21 cell death that\'s important. But you can have

22 cells that will not exclude tripan blue five

23 minutes later, but who will still die, you know,

24 several days later.

25 So if you have a functional assay like a

202

1 colony assay or something like that, that would be

2 a better measure.

3 CHAIRMAN RAO: Dr. Borer.

4 DR. BORER: Yes, I would like to agree with

5 what Dr. Simons said, that you do need\--I think you

6 need an in vivo assay. I don\'t think it\'s a heart

7 prep, because there is a difference\--an important

8 physical difference, I think\--or there may

9 be\--between the outcome, in terms of the adequacy

10 of delivery and the state of what\'s delivered, if

11 you place the delivery device within turbulent

12 flowing blood and a beating heart, than in a

13 preparation that\'s external to the body, that\'s not

14 subjected to those same mechanical stresses\--even

15 if it were a beating heart on a Langendorf

16 apparatus or something\--or something analogous to

17 that.

18 So I think you do need some in vivo

19 experience. I don\'t want to say how much, what

20 model, how much in people. Those are degrees of

21 specificity that I don\'t think we can get to here.

22 But I agree with the point that Dr. Simons made

23 that you do need in vivo experience.

24 CHAIRMAN RAO: Phillip?

25 DR. NOGUCHI: Not to comment specifically

203

1 on these particular catheters, but I will point

2 out, since our device colleague is not here right

3 at the moment, that under the device law you have

4 something like this\--this happens to be a

5 blackberry. But as a manufacturer makes it, they

6 are not restricted to always manufacturing

7 everything themselves. So, for example, they may

8 have several suppliers for the steel that\'s being

9 used, or several suppliers for any of the

10 lubricants, or for the tubing.

11 And so, from a real practical point of

12 view, while rare, we do have experience where

13 substitutions that are made by the manufacturer on

14 a reasonable basis, based on their specifications

15 and qualifications, can sometimes lead to fairly

16 distinctive changes in the same device\--let alone a

17 comparable device\--that can have severe adverse

18 reactions.

19 And, again, we won\'t be talking about

20 specifics, but let\'s just say that on a rare

21 occasion, the fact that a device is made through

22 multiple suppliers can lead to the question, and

23 the realization, that sometimes we find it hardest

24 to, off the shelf, just say: \"This catheter is

25 equivalent to this catheter,\" or \"This device is

204

1 equivalent to this device,\" because it\'s not always

2 quite the same supplied material.

3 CHAIRMAN RAO: We\'ve had all of these

4 experiences with tissue-culture plastic, and the

5 same manufacturer changing the manufacturing

6 protocol, and then the cells wouldn\'t grow. So, I

7 mean, I completely agree with you that that\'s an

8 issue to worry about.

9 Dr. Neylan?

10 DR. NEYLAN: I would love to take the

11 opportunity to segue your comments to, I think, a

12 closely related but perhaps still sidebar issue.

13 And that is that just as the conversations here

14 have demonstrated the importance of the interaction

15 between the device and the constituents being

16 delivered, I think there\'s another analogy that can

17 be made within VDA about the importance that this

18 instance brings up\--and others like the

19 drug-eluting stints\--about perhaps finding new ways

20 of working so that the different divisions can work

21 more synchronously\--CBER, and the devices

22 division\--so that it doesn\'t fall into some more

23 prolonged review process, or step-wise review

24 process, but perhaps could be done in a more

25 consultative fashion.

205

1 DR. NOGUCHI: Just to quickly respond,

2 that\'s exactly why we had Dr. Jensen throughout all

3 the preparation for this, and he\'s been involved in

4 all the reviews of all the products.

5 So\--that point is well taken ,and we

6 strongly endorse it.

7 CHAIRMAN RAO: Here\'s another question for

8 the cardiologists, related to device\--and I think

9 Dr. Borer alluded to this already\--is: though we

10 can be accurate, we\'re not a hundred percent

11 perfect in terms of delivering things. And with

12 cells, then, that means if you deliver it into the

13 cavity, or you deliver it into the epicardium, or

14 you do that, then there\'s going to be a whole

15 different effect of what you\'ve delivered.

16 And should there be, when one does some

17 sort of study like this, some way of monitoring

18 that so that, you know\--you\'re assessing a device

19 and the cell, and should one be looking at

20 bio-distribution after this has been done to worry

21 about it? Or hopefully those things are

22 discovered, because you\'ve already looked at cells.

23 DR. BORER: Yes, I\'ll take the first crack

24 at that.

25 At some point I was going to make the

206

1 suggestion that we should do just that. You know,

2 nobody knows how much difference it makes.

3 Jeremy\'s point is, of course, very well taken. We

4 don\'t absolutely know where these things are being

5 delivered with the best of implements. You know,

6 there\'s reasonable accuracy but not total accuracy.

7 But we also don\'t know where they should

8 be delivered. We don\'t know whether there is a

9 difference in outcome if you deliver to the

10 mid-wall, or whether you deliver to the endocardium

11 or the epicardium. We don\'t know whether one part

12 of the ventricle is more important than another; we

13 don\'t whether the border zone or the center of an

14 infarct\--of a scar is important. We don\'t know any

15 of those things. And information needs to be

16 obtained.

17 Now, does that mean that all the

18 information has to be available by the time a

19 product may be ready for clinical use? I think

20 perhaps not. It depends on the outcome from

21 clinical studies. But information that would allow

22 one to know these things would be very important

23 if, for nothing else, for improvement of a

24 product\--even if a product were approved.

25 And I think that, therefore\--getting back

207

1 to the point we all made earlier\--there must be a

2 data collection protocol set up that will allow

3 data to be used from all the studies that are done,

4 to allow us to answer questions like that. And I

5 do believe that bio-distribution is very

6 important\-- knowing about it\--not only throughout

7 the whole body, but throughout the heart, so that

8 we can somehow retrospectively relate the outcome

9 to the location of what\'s been delivered. So I

10 think it\'s very important.

11 CHAIRMAN RAO: Go ahead Joanne.

12 DR. KURTZBERG: I agree with everything you

13 said. But I don\'t know, right now, of any safe way

14 to label human cell and see them\--on whatever you

15 want to look at them with.

16 I mean, you can do things with iron and

17 fluorescent dyes in animals, but those things are

18 not safe for the cells, and there is no material

19 that allows us to track human cells yet. We need

20 one. It would be terrific. But I don\'t think it\'s

21 there yet.

22 CHAIRMAN RAO: So would you say, Joanne,

23 that this is true for animal studies when you\'re

24 looking at them, or in preclinical studies, that

25 there should be a way, but we can\'t necessarily

208

1 expect that that be done?

2 DR. KURTZBERG: I mean, it\'s just not ready

3 for prime time in humans.

4 DR. BORER: Yes, I think that\'s a critical

5 point. I think studies should be done in animals.

6 But, I don\'t know whether the methods I\'m going to

7 describe are appropriate for the purpose.

8 But radio-nucleide based molecular imaging

9 is becoming a reality. And it may be possible to

10 monitor the presence and location of cells with

11 label that can be administered after the fact to

12 localize cells with certain characteristics. I

13 mean, there would need to be enabling research to

14 allow this to happen, but the imaging techniques

15 have developed to the point where I think this may

16 be a viable issue.

17 I think it\'s an important issue, so some

18 time should be spent at some point looking at the

19 various methods that can be used to identify cell

20 types within the myocardium. But it may be that

21 newer techniques for imaging could be used.

22 CHAIRMAN RAO: Dr. Simons, and then\--

23 DR. SIMONS: I would like to come back to

24 the safety issues of the needle-based material

25 delivery.

209

1 Essentially, with all the needle devices

2 now, there will be some loss\--there will be some

3 loss of the material. And, you know, depending on

4 what the material is and what the catheter is, that

5 it could be up to 50 or 70 percent of the dose.

6 And it could be lost either in the left ventricular

7 chamber, or it can be lost then through the

8 coronary\--into the myocardial vasculature and will

9 immediately get washed out. And that happens to

10 cells, too.

11 So I think it\'s something to sort of

12 consider, because depending on the cell type used,

13 you would clearly have a number of cells injected

14 essentially in the left ventricular cavity.

15 Whether that\'s a risk, I think, needs to be

16 assessed. And this would be assessed, and it

17 should be assessed, I think, in an animal model.

18 CHAIRMAN RAO: Here are a couple more

19 questions for the cardiologists.

20 We heard that when you infuse cells in a

21 long vessel\--whether it\'s venous or arterial\--that

22 there are some specific complications of putting

23 cells in; one was this idea of micro-emboli, and

24 the other one was that you have ventricular changes

25 in the echocardiogram.

210

1 Is this something that\'s of sufficient

2 concern from experience, or that\'s something that

3 one can learning by doing the experiment in an

4 animal model? Or it\'s something that should be

5 required or, you know, considered of urgent

6 criteria? In any of things, in general?

7 DR. TAYLOR: Can I directly speak to that?

8 We know for years of our preclinical

9 studies with surgical delivery, that we lose a

10 relatively large percentage of the cells after we

11 deliver them. And we may very well lose those both

12 epicardially and into the left ventricular cavity.

13 So I don\'t think it\'s that different for catheters

14 than it is for surgical deliver in terms of the

15 loss of cells.

16 More recently we have begun to develop

17 some radio-nucleide labeling that lets us start to

18 follow the bio-distribution of these cells. And I

19 think what we\'re finding is size matters. The

20 larger the cell, the more likely it is to be in the

21 lungs; the smaller the cell, the more likely it is

22 to be in the spleen or the liver\--and that\'s not

23 particularly surprising.

24 So I think\--there probably is a whole lot

25 of data already out there from surgical delivery of

211

1 these cells, and also from the delivery of bone

2 marrow cells for other situations, that would

3 directly feed into this, and we don\'t have to

4 re-create that wheel.

5 CHAIRMAN RAO: Specifically, though,

6 related to catheter delivery, though, one can\'t

7 assume that it\'s going to be the same\--right?\--in

8 terms of distribution.

9 DR. TAYLOR: No, but we do know that we\'ve

10 lost\--we lose a significant number surgically into

11 the ventricle as well.

12 DR. EPSTEIN: I\'d like to just recall Bob

13 Lederman\'s comments yesterday: we know that we\'re

14 going to lose cells into the general circulation.

15 So you could take an animal model and just inject

16 the cells into the left atrium. You don\'t need a

17 catheter. I mean, you know that cells are going to

18 be lost into the circulation. And then, by

19 whatever technique you may have, you could track

20 them. But then what?

21 So, you know that the cells will be in the

22 brain, in the spleen. But are you going to follow

23 those animals for a year or two to see if there\'s

24 an oncogenic\--I mean, you know, that that\'s going

25 to happen, and then you have to ask yourself, \"What

212

1 do you do with that information?\"

2 And I would have real questions as to how

3 important that information is. Because you know

4 what the answer is going to be.

5 Your other question is a very important

6 one, and that is: the intra-coronary injection of

7 cells\--and I\'ve forgotten the name of the gentleman

8 who presented yesterday, with the dogs, showing

9 small areas\--

10 CHAIRMAN RAO: Mule.

11 DR. EPSTEIN: Yes\--and we did a study like

12 that\--Dr. Unger of the FDA many years ago\--where we

13 injected endothelial cells that were harvested from

14 the carotid arteries of dogs. These were

15 autologous cells. And these were dogs with an

16 amyloid constrictor around the circumflex coronary

17 artery. We genetically altered those cells and we

18 thought that we were going\--it was really a smart

19 experiment, injecting the genetically altered cells

20 into the LAD to enhance collateral development.

21 And all we did was kill dogs.

22 Because if you think about the situation,

23 the LAD\--the circumflex is totally occluded, and

24 the LAD is feeding the entire left ventricle,

25 essentially. And these cells embolize. I mean

213

1 they\'re too big to go through the capillaries.

2 So you probably wouldn\'t see any

3 hemodynamic perturbations if you gave those cells to

4 an animal with normal coronary arteries. But if

5 you have a collateral dependent\--if you inject them

6 into a feeder vessel, then you\'ll see what, you

7 know, you saw yesterday.

8 So the clinical studies that have been

9 done to date\--acute myocardial infarction, total

10 occlusion of an artery, opening up the artery, and

11 then several days later injecting cells\--in that

12 situation, I think you\'re okay, because you\'ll

13 never be worse off than with the situation you were

14 in five days before, with a totally occluded

15 artery.

16 But now if you extend that and say, okay,

17 let\'s take patients with chronic coronary disease,

18 where you\'re injecting cells into a vessel that may

19 feed collaterals to the rest of the heart\--you

20 know, I think you really need animal studies for

21 that, for safety, but you have to model it very

22 carefully.

23 And my prediction is that it would be very

24 dangerous. So, you know, once again it depends on

25 the clinical situation.

214

1 CHAIRMAN RAO: Go ahead, Dr. Lederman.

2 DR. LEDERMAN: I think that\'s a very good

3 point. Alternatively, you could model this\--since

4 we have very sensitive biomarkers\--of myonecrosis,

5 both imaging-based or biochemical. And these can

6 be testing in healthy animals.

7 And if we\--as I say, again, there are

8 fairly high-sensitive biomarkers. We could

9 administer whatever cell prep we\'re interested in

10 by intra-coronary infusion under different

11 conditions, and if there is no myonecrosis, I think

12 that\'s probably a satisfactory test.

13 Do other members of the committee agree,

14 or do they disagree?

15 You gave us a much more

16 difficult-to-achieve test.

17 VOICE: \[Off mike\] But those are the

18 patients \[inaudible\].

19 DR. LEDERMAN: I\'m not disagreeing. I\'m

20 wondering if others have other opinions. It\'s not

21 self-evident to me that your system, which is much

22 more harder to accomplish, has more

23 predictive\--necessarily have more predictive value.

24 And I just wonder what other opinions

25 might be?

215

1 CHAIRMAN RAO: Dr. Harlan, did you have a

2 comment to make? Okay.

3 Let me see if I have a sense here\--and

4 nobody mentioned anything about monitoring, in

5 terms of looking at arrhythmias of any sort. Is

6 that something that one would consider as an

7 important thing to do? And would that be something

8 one would consider as a routine thing to do when

9 one is testing?

10 DR. RUSKIN: Actually, I had mentioned

11 something in response to one of the questions that

12 was raised. And I would think if you were to

13 pursue any of this work in a canine

14 model\--hopefully a relevant infarct model\--that

15 chronic monitoring with implanted telemetric

16 devices would be appropriate, as would

17 electrophysiologic testing\--invasive testing\--and

18 just routine clinical monitoring for the kinds of

19 adverse events that Jeff Borer described.

20 And I think those would be important to

21 do, based on concerns about creating what may be a

22 highly arrhythmagenic substrate. I\'m not convinced

23 that we know that happens, because of the kinds of

24 patients in whom these procedures have been done.

25 But at least the potential for doing that certainly

216

1 seems to be there, and it would have to be pursued,

2 I think, pretty aggressively\--including monitoring.

3 CHAIRMAN RAO: So\--go ahead, Dr. Simons.

4 DR. SIMONS: If I can just amplify this

5 point, because the concern of an arrhythmic even

6 has been raised with skeletal myoblasts.

7 To my knowledge, this has not been raised

8 with different cell types. So, do people around

9 the table feel that this kind of monitoring is

10 required for all cell types, or just for skeletal

11 myoblasts?

12 CHAIRMAN RAO: I think we\'re just looking

13 at delivery through a catheter, either through

14 venous\--or putting it in, not like a long-term

15 thing\--one week later monitoring, or\--I\'m just

16 wondering about whether it\'s important, when you do

17 the procedure\--just like you would with dye or

18 something\--

19 DR. SIMONS: Oh, if you\'re talking about

20 acute settings, it\'s standard to monitor. I mean,

21 that\'s a standard of practice.

22 CHAIRMAN RAO: It would be something one

23 would consider really important, you said.

24 DR. RUSKIN: I\'d just like to respond to

25 Dr. Simons\' question.

217

1 My own bias would be in the beginning to

2 be rather conservative and cautious with regard to

3 monitoring in any of these models; my answer being,

4 to his question: yes, I would be inclined to, even

5 with other cell types\--only because I think the

6 potential exists for creating a substrate that is

7 very dangerous.

8 I\'m not at all convinced that happens.

9 But introducing cells that morph into myofibers of

10 any sort, in a situation in which we don\'t know how

11 they line up, how they communicate, what the

12 intracellular substrate looks like, what their

13 action potential characteristics are, what their

14 ion channel properties are\--is one of the ways that

15 I would, if you asked me to invent an

16 arrhythmagenic substrate, that\'s one of the things

17 I would think\--one of the ways I would think of

18 doing it.

19 So I think that the bar ought to be pretty

20 high early on for some form of careful vigilance.

21 The problem is that the sensitivity of these models

22 is going to be low. And I would take no

23 reassurance from the fact that nothing adverse was

24 observed.

25 But, on the other hand, if adverse

218

1 outcomes are observed, it raises a very important

2 issue, in terms of how one proceeds.

3 CHAIRMAN RAO: Go head, Dr. Schneider.

4 DR. SCHNEIDER: I\'d like to follow up on

5 Dr. Ruskin\'s cautionary note, and ask him how best

6 might the FDA, or should the FDA take into account

7 the established safety as demonstrated in Phase I

8 trials elsewhere? I think that the nightmare

9 scenario is appropriate, if it hasn\'t been done or

10 60 or 100 patients already. But once its been done

11 in 60 or 100 patients already, it seems to me that,

12 without cutting corners, and without jeopardizing

13 safety, the information has an applicability.

14 DR. RUSKIN: I think that\'s a very

15 important point. And electrophysiologists have

16 sledgehammer answer for all of that, and it\'s

17 called an ICD.

18 And my own bias is that, yes, I think

19 there is information that\'s quite reassuring

20 already, and that given the nature of the patient

21 population being studied, it would be relatively

22 easy, I would think, to do your Phase I studies in

23 patients who are already recipients of implantable

24 defibrillators\--because of the primary prophylaxis

25 trials that have recently been completed and that

219

1 point out, I think, quite clearly that most of the

2 patients we\'re talking about here are already ICD

3 candidates.

4 So that\'s the ultimate protection. And I

5 think given the data that\'s already available, it\'s

6 quite reasonable to move ahead\--with appropriate

7 caution, and the protection of a defibrillator.

8 CHAIRMAN RAO: So this maybe gets back to

9 what Dr. Lederman raised, then, that if that\'s the

10 case, and that\'s how you\'re going to do your Phase

11 I clinical trials, why is it necessary to worry

12 about it in the animal model?

13 DR. RUSKIN: Because I think we can learn a

14 great deal from animal models, and if we\--my

15 sense\--and, again, I\'m naive about this, but I get

16 the sense that we don\'t know exactly what the right

17 cell type is, how to deliver it, in what kind of

18 media. There are all sorts of unanswered

19 questions. Are the cells going to be genetically

20 modified, and so on, and are there going to be ways

21 of ensuring that they lay down appropriately and

22 form connections?

23 These are all unanswered questions. And I

24 think until they\'re answered, the more information

25 you get from preclinical models, the smarter you\'ll

220

1 be.

2 CHAIRMAN RAO: Dr. Cannon, you had a point

3 you want to make?

4 DR. CANNON: I was just thinking, listening

5 to Steve\'s comments, I would take exception, Steve,

6 to your lack of concern about cells\--large cells,

7 now, not the peripheral blood mononuclear cells, by

8 the myoblasts, the larger cells\--about whether they

9 go to the brain or not, and will that matter,

10 I think it might matter\--after looking at

11 what happens in the coronary circulation of dogs

12 when these cells are injected, if a similar

13 phenomenon were to occur in the brain, I would be

14 worried that the patient may be different

15 cognitively after the procedure than before the

16 procedure, even though there may be benefit to the

17 pump function of the heart.

18 So I think it would be important to know,

19 in an animal model, injecting cells into the left

20 ventricle, the left atrium, if they do lodge in the

21 brain, and for how long. And, if so, certainly

22 that would raise concerns for cognitive monitoring

23 in this kind of application.

24 CHAIRMAN RAO: Joanne?

25 DR. KURTZBERG: You know, if you had been

221

1 here for the neural stem-cell meeting, they would

2 be so happy if you could put cells into the left

3 ventricle and get them into the brain.

4 \[Laughter.\]

5 I mean, that\'s very hard to do unless you

6 have some kind of connection you\'re not supposed to

7 have.

8 So, I mean, realistically, that probably

9 is the one thing you don\'t have to worry about.

10 They\'ll go all over the place, but to go into the

11 brain at the time you inject them into the blood is

12 not a worry, I don\'t think. It\'s actually a

13 challenge for the people who want to get cells into

14 the brain.

15 CHAIRMAN RAO: But it\'s a general problem,

16 right? Anything which is in artery circulation

17 essentially\--where they might be distributed might

18 be something to worry about, right?

19 DR. TAYLOR: I actually wanted to address

20 the point of whether\--Dr, Ruskin\'s point about

21 whether or not we need to deal with\--when 60 or 100

22 patients have already been treated, whether or not

23 we need to still demand preclinical information.

24 And I guess what we have to get back to is whether

25 or not the cells are identical.

222

1 If the cells are not identical\--just

2 because one group can grow appropriate endothelial

3 progenitor cells for three days in a dish doesn\'t

4 mean if somebody else tries it they\'re going to get

5 the same cells. So I think the data have to be

6 fairly convincing that you\'re working with the same

7 cell population, or it\'s not appropriate to base

8 that on previous data.

9 And just calling it the same thing doesn\'t

10 mean it is the same thing. The markers have to be

11 the same.

12 CHAIRMAN RAO: Do you have a comment? Go

13 ahead, Dr. Lederman.

14 DR. LEDERMAN: I also want to comment on

15 Dr. Ruskin\'s point.

16 Certainly, it\'s defensible to advocate a

17 strategy\--in fact, European investigators have

18 already sometimes applied a strategy of

19 prophylactic defibrillator implantation before

20 testing cell therapies for various applications.

21 But to mandate that I think is a bit extreme in a

22 way that would hurt the field, and patients in

23 that, our most sensitive, surrogate markers of

24 myocardial performance would then be unavailable

25 for our patients. And that means MRI endpoint

223

1 assessment.

2 So, unfortunately, that\'s a very high

3 price. And I think to mandate it is\--

4 CHAIRMAN RAO: Remember, the committee

5 doesn\'t mandate, and the committee\'s only advisory,

6 and it\'s not looking at any specific applications.

7 DR. LEDERMAN: But, unfortunately\--this is

8 not a compromise.

9 DR. RUSKIN: Yes, your point\'s very well

10 taken, and Mike Sunn has made the same point with

11 regard to how it compromises imaging.

12 I didn\'t mean to suggest that anybody even

13 think about mandating a population in whom this is

14 done, or mandating the use of a prophylactic ICD.

15 What I was suggesting was that there\'s a very large

16 patient population that already exists that have

17 ICDs implanted for appropriate clinical

18 indications, who have severe congestive heart

19 failure, and are at the end of the road, and have

20 had CRT therapy, and might provide an appropriate

21 population in which to begin to do some of these

22 studies\--if the question of arrhythmagenesis

23 remains high on the list.

24 I understand that that involves

25 compromises in terms of imaging. Nor do I mean to

224

1 suggest at all that that be the only group in whom

2 one ought to consider appropriate trials.

3 DR. BORER: I think that several important

4 points have been made, and I\'d like to comment on

5 three of them.

6 First of all, I agree with what Jeremy

7 said about conservativism in doing these studies,

8 and would just amplify by saying that

9 arrhythmias\--potentially lethal arrhythmias\--could

10 occur at several points after the administration of

11 cell therapy, and the mechanism in each case could

12 be different. So you have to watch at many points

13 in time. I don\'t know when the watching needs to

14 end. Again, it may be beyond the scope of this

15 meeting, and maybe in the too-hard box.

16 But the important point is that there is

17 the potential for problems with the initial

18 mechanical perturbation, with the initial physical

19 injury of the myocardium. Then, subsequently,

20 there are problems when the cells begin to grow

21 before they have fully defined their

22 interconnections with the surrounding tissue. And

23 then there are other problems that could occur when

24 they have made those connections.

25 So one has to monitor. And I would

225

1 suggest that we do need that information.

2 I think that Jeremy was absolutely right

3 in indicating that the availability of ICDs reduces

4 the risk compared to what it might be, but there a

5 couple of points that we have to keep in

6 mind\--without negating in any way what he said. I

7 think Dr. Lederman\'s point is a good one. If you

8 use that population, you can minimize the capacity

9 to make certain measurements you want to make.

10 But, more importantly, the fact that an

11 ICD is in place doesn\'t mean that someone has been

12 made immortal. \[Laughs.\] So, if you create

13 arrhythmias and they are sufficiently severe, they

14 may override the ICD, and we wouldn\'t want to do

15 that. So we\'d want to know if that was a potential

16 problem\--number one.

17 Number two, even if the ICD was

18 successful, people don\'t like to be shocked. I

19 mean, it hurts\--they tell me. So, you know, one

20 would like to know about that problem. And, you

21 know, I\'m not saying anything different from what

22 Jeremy said\--and he could say it better than I.

23 But I think you have to keep that in mind.

24 So we\'d still like to know about the

25 arrhythmias, their likelihood, etcetera.

226

1 Now, how much do we know because 60 to 100

2 patients have been studied? I have a statistician

3 sitting two seats to my right, and he should answer

4 this. But I think\--and you\'ll correct me if I\'m

5 wrong Dr. Tsiatis\--that the power we have from zero

6 out of 100 doesn\'t rule out a heck of a lot. There

7 could still be a lot of events. And so we should

8 have, I think, some preclinical data to help us in

9 this situation.

10 So I think those are just three

11 observations on the important points that have been

12 made.

13 CHAIRMAN RAO: Dr. Schneider.

14 DR. SCHNEIDER: In part, to follow up with

15 Jeff\'s cautionary note in terms of the numbers\--I

16 think it\'s either naive or disingenuous for someone

17 to suggest, as Dr. Lederman did, that it would harm

18 patients for any of the conservative precautions

19 being imposed as they\'re being discussed here.

20 Since Phase I trials haven\'t been done

21 there\'s no proof yet of safety in humans in the

22 U.S., much less of efficacy in humans. So to wrap

23 yourself in the mantle of protecting patients by

24 speeding the trials along is preposterous.

25 CHAIRMAN RAO: Let\'s see if I can try and

227

1 summarize and see whether we have some consensus on

2 some basic statements here.

3 So, it seemed to me from just listening to

4 everyone was that everybody thought that one needs

5 animal studies. And since this is with the device,

6 it seemed very clear that one needed animal studies

7 in a large animal\--of some kind, right?

8 And that you couldn\'t extrapolate from one

9 type of delivery to another, because there were

10 issues with it. And you couldn\'t extrapolate from

11 one type of catheter to another, because there are

12 issues with doing that, or if you\'re using it in a

13 different way than what it was supposed to be used.

14 And that if people in different centers

15 used one device, they should have some sort of

16 hands-on experience, because things change when

17 you\'re using it in a different fashion\--if I have

18 paraphrased that right.

19 And that once you deliver cells, you

20 really need to look at the function of the cells as

21 they\'ve been delivered, and so that they need to be

22 delivered in vivo in some fashion because simple

23 models will not be adequate in terms of doing it.

24 And you have to look at their behavior

25 where they\'ve been delivered; and that monitoring

228

1 has to be of a reasonable length of time, in terms

2 of that behavior in terms of safety of what you\'d

3 look at.

4 And that during that process\--especially

5 if you\'re doing it into arteries and veins, that

6 there are issues of monitoring because of what\'s

7 known about micro-emboli and what\'s known about

8 that; that you need studies to look at whether

9 that\'s going to cause ischemia or an infarct, or

10 it\'s going to cause arrhythmias, and that that

11 needs to be monitored for at least some period of

12 time in a critical way; and those would be unique

13 or specific to delivery via the cardiac route.

14 Does that seem like a\--have we missed

15 something? I mean, there was some issue that we

16 did not really look at in terms of long-term

17 follow-up, and that wasn\'t absolutely clear. Dr.

18 Borer seemed to point that you might need to worry

19 about it on a longer basis, and one might need to.

20 DR. BORER: Can I just come back to the

21 point Richard Cannon made? And I\'m asking a

22 question here. I don\'t know anything about cell

23 delivery to the brain, or whatever.

24 But I think there may be an important

25 difference between delivery of functional

229

1 progenitor cells to the brain that might cause a

2 benefit, and delivering a bolus of something that

3 might obstruct an artery, even though it couldn\'t

4 grow into a new part of the brain.

5 So I would continue to have Richard\'s

6 concern about the embolization\--the importance of

7 potential embolization to the brain, despite the

8 fact that, apparently, the neurologists have a hard

9 time developing a therapy by delivering cells that

10 way.

11 Am I wrong about that? Is that\--

12 DR. KURTZBERG: It can\'t cross the

13 blood-brain barrier\--okay?

14 DR. BORER: But you don\'t have to. All you

15 have to do is block an artery.

16 DR. CANNON: I\'m worried about plugging the

17 microcirculation, much as the microcirculation of

18 the dog heart was plugged by these cells. And

19 these are large cells. They\'re not like stem cells

20 that are small and deformable and that circulate

21 very easily. These are large\--I\'m talking about

22 the myoblasts, now, not the stem cells.

23 And, certainly, we send patients to

24 surgery, and even to the cath lab, and they

25 sometimes come back differently because of things

230

1 that are dislodged during the course of the

2 procedure that make their way to the brain. So,

3 certainly, the circulation can carry debris to the

4 brain.

5 It\'s just a concern. And I would think an

6 animal model, perhaps\--just injecting the cells

7 into the cavity of the left ventricle to see if

8 they do, indeed, lodge in the brain for a period of

9 time that might be anticipated to cause some damage

10 would be a worthwhile thing to look at\--for the

11 large cells, not the mononuclear\--the stem cells or

12 the peripheral blood mononuclear cells. I don\'t

13 think that\'s a concern. It\'s the large cells.

14 CHAIRMAN RAO: Dr. Grant, you had a

15 comment?

16 DR. GRANT: Yes, I just want to just speak

17 to this third point, the injection of cells into

18 systemic circulation.

19 And the question that would be consequent

20 to your discussion is: do you think that an animal

21 study\--that an additional animal study needs to be

22 done in which the cells are specifically injected

23 into the systemic circulation to see about the

24 systemic effects? Or do you think that these kinds

25 of effects that you\'re worried about would be

231

1 picked up in the other animal model\--in other

2 animal studies?

3 Because there would be enough systemic

4 distribution we\'d need to do additional studies?

5 That\'s, I think, what that third question was

6 about.

7 CHAIRMAN RAO: Let me see if this was

8 summarized from what people said: is it depended on

9 the cell type; that bone marrow cells, we have a

10 lot of experience with in terms of putting them in

11 systemic circulation, but that\'s not true for, say

12 myoblasts, or for some of the other cells.

13 And for myoblasts, maybe we have some

14 experience because that\'s been done in some of the

15 animal models already, but that\'s not true for some

16 of the other sorted cells or the passage cells.

17 DR. SCHNEIDER: Michael Schneider\--but to

18 deal with Dr. Grant\'s question specifically, it

19 would be my expectation that the kinds of

20 information that would be useful to address this

21 point about embolic risk would come about as part

22 of the natural dose-ranging studies that would

23 occur. I don\'t envision that it would

24 scientifically advance a protocol to inject

25 non-physiological numbers, or non-therapeutic

232

1 numbers of those cells into the systemic

2 circulation to see what happens.

3 And I share Dr. Cannon\'s cardiologists\'s

4 view of the nervous system as a sponge that vessels

5 go to.

6 \[Laughter.\]

7 DR. TAYLOR: I just want to make two quick

8 comments\--oh, I\'m sorry.

9 One is that myoblasts are not the only

10 large cells we\'re talking about here. Some of the

11 mazenchymal cells are as large or larger than

12 myoblasts, and we need to keep that in mind.

13 VOICE: \[Off mike\] What\'s\--

14 DR. TAYLOR: 10 microns. Yes. Rounded.

15 But the other issue is that we did studies

16 for different reasons, where we injected many of

17 these different bone marrow-derived cell

18 populations intravenously to try to treat vascular

19 injury. And we found that there were some negative

20 effects of some of those cells, and positive

21 effects of other of those cells. And we didn\'t

22 expect that.

23 And I think what we have to say is if

24 intravenous is going to be your preferred route of

25 administration, then obviously you have to do that.

233

1 But, otherwise, I think it\'s a waste.

2 CHAIRMAN RAO: Dr. Borer.

3 DR. BORER: In response to Dr. Grant\'s

4 specific question, I do think it may be worth doing

5 a specific animal study. I think Mike is right,

6 that the information may well fall out of the

7 studies that are done with dose-ranging in the

8 normal course of development.

9 But the problem I see here is that we

10 don\'t actually know how many cells are escaping

11 into the systemic circulation with the various of

12 routes of delivery we\'ve been talking about. And,

13 therefore, we may miss the information that we

14 want.

15 Doing what Steve said, which is to inject

16 some cells into the left atrium and, you know, see

17 what happens, seems to me to be a good idea because

18 ultimately what you wind up with is the lower bound

19 at which problems might be begin to develop. And

20 if, in fact, the lower bound of injectate size at

21 which problems would develop is above the size of

22 anything you\'re injecting, then it\'s a non-problem

23 and you don\'t have to worry about it anymore. If

24 it\'s not, then you have to worry about it a little

25 bit more, and maybe the strategy would change.

234

1 So I think it may be worth doing a

2 specific study to determine what happens to these

3 large cells.

4 DR. CUNNINGHAM: I also want to comment

5 that for when we do this in patients, that it\'s

6 going to be a risk they would at least want to know

7 about; that there was going to be a cognitive

8 change. That\'s something people tend to care a lot

9 about; either whether it\'s in themselves or it\'s in

10 a family member, that it\'s not a simple thing, and

11 you at least would want to know that was a risk,

12 and you might not choose to have the therapy if

13 that were going to be something you had to endure.

14 CHAIRMAN RAO: Quick comment, Dr. Lederman.

15 DR. LEDERMAN: Unfortunately, yet another

16 question.

17 If we are administering locally cells

18 derived from a patient by leukopheresis, for

19 example, how important are the questions we\'ve been

20 discussing about systemic distribution, or

21 mal-distribution of cells themselves recovered from

22 the circulation?

23 CHAIRMAN RAO: I mean, I thought we tried

24 to cover that, because we did try to point out that

25 there might be different criteria\--you can have a

235

1 standard criteria on the cell type. But even if

2 it\'s a cell which is endogenous, you know, if you

3 put RBCs back, there is an issue of the

4 concentration at which you\'re putting it relative

5 to the concentration at which they\'re circulating.

6 And that\'s always been an issue.

7 And so I don\'t know if it would change

8 specifically for leukopheresis versus any other

9 method, but I would still want to know what

10 happened when we put in cell by a particular

11 method, and how they went, and what they did.

12 DR. KURTZBERG: I mean, there is data about

13 the upper limit of safe cell dosing when you give

14 leukopheresed cells. I mean, it\'s way, way, way

15 above\--it\'s logs above the doses that you\'re

16 talking about for these injections\--even if the

17 whole injection escaped into the circulation. I

18 mean, we\'re talking 5 x 10

10 to 10 x 1010. And there

19 are rates per kilogram to infuse them to not have

20 leuko-agglutination. But you\'re two to thee logs

21 below that in the numbers that you\'re talking

22 about.

23 The other thing is that, I mean, in

24 leukemia, people have circulating blasts that are

25 large cells. They may be 20, 25, 30 microns in

236

1 diameter if they\'re certain kinds of blasts. And,

2 in general, they have high numbers of those cells,

3 and they\'re not clogging things\--until the white

4 count gets very high, and then they do clog\--you

5 know, decrease CNS perfusion.

6 But, I mean, you can learn some lessons

7 from those kinds of cells that may help sort some

8 of this out.

9 CHAIRMAN RAO: To me, the sense is that the

10 committee\'s telling people that one should be

11 cautious, and that testing is required.

12 Does that seem like a short summary?

13 And I\'m going to ask the FDA\--did they

14 feel that they had a sense for the kind of issues

15 that one needs to worry about?

16 DR. GRANT: Yes, we\'re ready to move on to

17 the next questions. But Richard had something he

18 wanted to say.

19 DR. McFARLAND: I don\'t want to spend a lot

20 of time on this, but one specific question\--just as

21 a ballpark\--for the studies that are to test safety

22 of catheter administration of a cell\--I don\'t\--at

23 this point it doesn\'t matter which cell\--how long

24 would one expect the studies to go out? Three

25 hours? Weeks? Four weeks? Three weeks?\--not

237

1 dealing with, necessarily, the biological

2 properties of the cells, but just the safety

3 related to administration.

4 CHAIRMAN RAO: Let me take a stab at this,

5 and then see if the committee aggress.

6 So, there are a whole set of studies that

7 we talked about which are related specifically to

8 cells\--right? And those are really in terms of the

9 safety of the cells and the long-term effect after

10 they incorporate and what happens with them. So,

11 really, when you\'re thinking of a combination of

12 cells with a device, you\'re looking at the

13 short-term effect of delivering those cells, and

14 the complications if they go to an inappropriate

15 place.

16 My feeling would be that that\'s the issue

17 that you would want to look at, which is relatively

18 short term rather than long term, in terms of

19 looking at it.

20 Does that seem like a reasonable\--

21 DR. BORER: I think that\'s reasonable, but

22 I would just\--you know, you\'re talking specifically

23 about device-related injury, I believe.

24 DR. McFARLAND: Correct.

25 DR. BORER: You know, my understanding of

238

1 this situation\--and you\'ll correct me if I\'m

2 wrong\--is that if you create a physical injury, it

3 takes a couple of weeks for the necrosis to be

4 maximal, and the scar to begin to form; and, you

5 know, a little bit longer until the scar is fully

6 mature.

7 It seems that those kinetics would define

8 the time\--the duration of the observation period,

9 because we are talking here about creating a

10 physically-mediated injury.

11 So, you know, just as a stab, if you

12 looked at some set of animals, or some experimental

13 preparation\--whatever it is\--for a month, I think

14 you would encompass all the device-related

15 problems. Probably you could do it in less time,

16 but I would be thinking about the kinetics of

17 injury, tissue necrosis and scar formation as the

18 basis for making that decision.

19 DR. SIMONS: I think I would be looking at

20 a much shorter time frame. I think the injury from

21 the needle-based devices is minimal. We have

22 pretty extensive experience with the devices in

23 animals. They\'re really benign, all of them.

24 And after what we did\--you know, to hearts

25 with lasers, what we can do with a 27-gauge needle

239

1 does not even come close. I would not really be

2 worried about the acute safety of a needle-based

3 device.

4 DR. NEYLAN: And I\'d just like to revisit

5 my sidebar issue of the need for close

6 communication between the divisions at FDA, because

7 this is an example where I think we would not like

8 to see one set of experiments go forward that

9 describe device-related safety, and another about

10 the delivery of the cells.

11 So I think it would be much better if we

12 create one set of experiments that answer both

13 questions.

14 DR. McFARLAND: No, I agree, and that was

15 part of the impetus for asking the question, so

16 that TDRH and CEBR can have a basis for discussion.

17 CHAIRMAN RAO: Now that we\'ve talked this

18 one through, shall we move on to the\--I guess the

19 clinicians have been waiting for this, I guess\--in

20 terms of the clinical aspects of these questions.

21 So I\'m going to read out that question,

22 and then I\'m going to just let people make

23 individual comments, and then see whether we can

24 put that together.

25 So the question was: Please discuss the

240

1 appropriate frequency and duration of follow-up.

2 In addition to any other events, please consider

3 the following potential adverse pathological and

4 clinical events in your discussion items: scar

5 formation, left ventricular dysfunction,

6 ventricular arrhythmias and neoplasia.

7 And I guess, here, I just want to make

8 sure that we are clear on this, is that we\'re

9 thinking about early clinical studies that will be

10 done, rather than looking at animal models here.

11 So this would be some kind of clinical study where

12 you\'ve done it, and you want to worry about whether

13 this makes appropriate sense, and what kind of

14 follow-up should one consider, and what are the

15 issues related to this?

16 VOICE: \[Off mike\] \[inaudible\].

17 CHAIRMAN RAO: Yes, I think that\'s an

18 important point, given what we\'ve already heard.

19 That\'s another important issue to worry about.

20 DR. CUNNINGHAM: How about cognitive

21 function, since we just discussed that; and also

22 stenosis.

23 CHAIRMAN RAO: Okay.

24 Go ahead, Dr. Borer.

25 DR. BORER: I\'d like to focus on left

241

1 ventricular function or dysfunction here. I mean,

2 we\'ve talked about arrhythmias and the duration of

3 observation that might be necessary for those. But

4 I want to point out something that has an impact

5 here.

6 If you replace an aortic valve in a person

7 with aortic regurgitation, it takes three years

8 until left ventricular function has maximized. If

9 you replace a mitral valve in someone with mitral

10 regurgitation, it takes three years for left

11 ventricular function to maximize\--systolic function

12 to maximize.

13 Now, forgetting about the whys and

14 wherefors, there are lot of processes\--and as Steve

15 said yesterday, we don\'t understand them all, but

16 the cells do. The fact is that a great deal of

17 remodeling goes on after you change the milieu; the

18 exogenous hemodynamic milieu and, I would suggest,

19 perhaps the cellular milieu in the scar, because

20 what you do in the scar is going to impact\--if it\'s

21 effective, it\'s going to impact on what\'s happening

22 in the non-scarred areas.

23 So, with that as a preamble, I would say

24 that at some point in some studies, you\'ve got to

25 look for a long time to know everything that may

242

1 happen. Is it necessary to look that long before

2 you approve a product? No, of course not\--at least

3 I don\'t think so, not if there are sufficient

4 animal studies and early clinical experience that

5 suggest you don\'t get deterioration. If you get

6 some improvement that\'s clinically relevant, you

7 know, at six months or whatever the time point

8 you\'re looking at is, one might approve a product.

9 But in terms of the duration that we

10 should make observations, ultimately, at some

11 point, either before or after approval of a

12 specific product, you have to look for a long time

13 if you\'re going to see the effects. And we don\'t

14 know the process that\'s going on here. We\'re

15 injecting cells. The cells may be

16 re-differentiating, transdifferentiating. They may

17 be doing all kinds of stuff. We don\'t know the

18 kinetics of those changes. We don\'t know what that

19 means. We know that\--I have to infer from the data

20 I saw yesterday that important changes in the

21 interaction between myocytes and extracellular

22 matrix is going on during this period; the kinetics

23 of extracellular remodeling is much slower than the

24 remodeling of myocytes\--on and on and on and on.

25 In order for us to fully understand the

243

1 biology here, if we\'re just talking about

2 mechanical function, it\'s necessary to look for a

3 long time. Again, that may not be necessarily in

4 order for a product to be approved\--there are other

5 issues there\--but to know the biology, monitoring

6 has to go on for a while. And although it\'s not my

7 field\--and Steve and others may want to comment on

8 this\--I think the same thing is probably true of

9 the angiogenesis-arteriogenesis issue.

10 CHAIRMAN RAO: Before you cede the mike can

11 you say, well, what kind of monitoring? I mean it

12 should be Holter monitoring for one month or, you

13 know\--

14 DR. BORER: Well, in terms of left

15 ventricular performance, you know, there are a

16 number of non-invasive techniques that easily can

17 be applied periodically over time; you know,

18 echocardiography, radio nuclide angiography, MRI if

19 you happen to have it available and the patient can

20 undergo MRI. There are a lot of techniques.

21 But there are global, left ventricular

22 function assessment techniques, and that\'s what we

23 really care most about. If we see improved wall

24 thickening someplace but the heart\'s not putting

25 out more blood and not pumping better, who cares?

244

1 So I would say that there are a variety of

2 standard, non-invasive techniques that can be used

3 to evaluate mechanical performance of the heart.

4 In terms of electrical performance, as

5 long as you\'re looking at the mechanical

6 performance, you may as well look at the

7 electrophysiologic aspects of what\'s going on\--and

8 there, yes, I think a Holter and a standard 12-lead

9 electrocardiogram would be the minimum.

10 In earlier studies\--as Jeremy pointed out

11 before\--during the first few months after an

12 intervention\--now I\'m talking about animals,

13 because you wouldn\'t re-do this in people\--I think

14 standard electrophysiologic testing\--invasive

15 electrophysiologic testing\--would be very

16 important. In people, I can\'t imagine that you

17 would want to do that very often. People don\'t

18 like to have that done to them.

19 I don\'t think you\'d want to do standard

20 electrophysiologic testing very often. There might

21 be some subset\--and, you know, Jeremy should

22 comment on this\--in whom a pair of standard

23 electrophysiologic studies might be done, separated

24 by an interval of, you know\--whatever the interval

25 is; whatever the preclinical data and the 24-hour

245

1 ambulatory electrocardiogram suggest is correct;

2 maybe a month, maybe two months\--I don\'t know.

3 But I think you do have to look at certain

4 aspects of the electrical function of the heart.

5 It\'s simple to do that with electrocardiography,

6 because if the electrocardiogram\'s okay, if you\'re

7 not seeing arrhythmias, then, again, who cares

8 about what\'s going on in the substrate? And as

9 long as I was looking at mechanical function, I\'d

10 look at electrical function by these simple means.

11 CHAIRMAN RAO: Joanne?

12 DR. KURTZBERG: I would think it would be

13 important also to, if possible, require or strongly

14 suggest an autopsy for any patients who die\--given

15 that you\'re saying this is such a high-risk

16 population. Because you may learn something about

17 the anatomic and histologic things you find in the

18 heart, even three years later, that will help you

19 optimize this.

20 DR. RUSKIN: I think, with regard to

21 follow-up, the issue of safety with regard to

22 ventricular arrhythmias is a very difficult

23 challenge. I think if we\'ve learned one thing in

24 the last 20 years it\'s that you don\'t follow

25 ventricular arrhythmias. You either stay out in

246

1 front of them, or people die.

2 And Holter monitoring, I think, in this

3 population is a waste of time because the

4 prevalence of spontaneous arrhythmias in this

5 patient group is somewhere between 60 and 80

6 percent\--talking about non-sustained ventricular

7 tachycardia. And the question then arises as to

8 what you would do about it if you saw it, because

9 anti-arrhythmic drugs\--talk about Dr. Epstein\'s

10 Janus effect\--you know, we might just as easily

11 kill people with the drugs that we use to try to

12 suppress these things as help them. And that\'s why

13 it brings me back, I think, to the issue of having

14 a group as protected as possible at the time that

15 they get the therapy, with an implantable

16 device\--at least early on; not that it\'s perfect,

17 but at least it offers a high level of protection

18 against anything other than an incessant VT or VF.

19 And I think that\'s really what the

20 follow-up is. It\'s having a protected patient with

21 a monitoring device that records events 24 hours a

22 day, seven days a week, 365 days a year. But the

23 real lessons will be learned from outcomes and, I

24 think, from the preclinical work that gets done.

25 And it\'s not going to get answered by ECGs and

247

1 Holter monitoring and other simple forms of

2 observation.

3 There are host of other risk

4 stratifiers\--like T-wave alternans, signal average

5 DCGs, and a number of other things\--all of which

6 would be of interest. The problem, again, will be

7 that the positivity rate is so high in this

8 population, even without the therapy, that I think

9 it\'s going to be very hard to distinguish the

10 treatment groups from the non-treatment

11 groups\--even if there\'s a pro-arrhythmic effect.

12 CHAIRMAN RAO: I\'ll ask this in a more

13 particular way, and it\'s really part of Question 7,

14 which sort of segues into this, and you\'ve already

15 raised that as a point.

16 So, once you\'ve chosen a patient

17 population\--and there\'s a caveat on how you choose

18 the population from the points of the worries that

19 one has with any kind of new therapy\--you have to

20 worry about monitoring them, and there\'s going to

21 be a certain basis of monitoring which is dependent

22 on the disease or the underlying process that they

23 have.

24 And then you want to have some kind of

25 additional monitoring\--maybe\--which is specific to

248

1 the therapy that you\'ve now introduced. In this

2 case is there anything which is new or unique that

3 has to be added on, or can one simply say that,

4 well, you\'ve chosen this patient population.

5 You\'re going to have to really be doing massive

6 monitoring anyway. Do you need anything else.

7 And, you know, Joanne pointed out that

8 even if you do all of this, one important thing one

9 should suggest is that they also do an autopsy,

10 which is not really monitoring on side effects but

11 is learning after the fact; and that one should be

12 looking at closely monitoring improvement in some

13 fashion, or at least it\'s function of the cells, by

14 looking at left ventricular ejection fraction in

15 some fashion, or left ventricular function in some

16 fashion.

17 Are there other sort of additional things

18 that one can use, and which would distinguish

19 between, say, the therapy\--like you pointed

20 out\--versus the underlying disease?

21 DR. SIMONS: If I can attempt to begin to

22 sort of address these issues\--and it really takes

23 us into, I think, Question 7.

24 As Dr. Ruskin points out, there is a very

25 high frequency of all sorts of events in these

249

1 people, given what these patients are. I really

2 think the only way you can find out how safe these

3 kinds of therapies are, if you do double-blind

4 randomized trials, and you have control group\--not

5 to assess efficacy but to actually assess safety,

6 because there will be a number of adverse events in

7 this patient group, and we will not be able to say

8 whether that is because of therapy or because of

9 natural history of disease if we don\'t have a

10 control group.

11 CHAIRMAN RAO: Dr. Perin.

12 DR. PERIN: In talking about monitoring LV

13 dysfunction, I think we probably should start from

14 the beginning, which is really\--obviously, we need

15 to see these people pretty often, in terms of

16 clinic visits because I think symptoms, even though

17 are not completely objective are an important thing

18 to assess in these people.

19 And in our limited clinical experience we

20 noticed that people really had a change in

21 improvement\--we presented this at ACC\--around the

22 seventh and eighth week. So that\'s something that

23 you might want to know.

24 Also, I think that echocardiographic

25 evaluation is simple\--because there is a problem of

250

1 doing MRI, because a lot of these people are going

2 to have a problem with having MRIs.

3 One other thing I would like to take note

4 is the issue of global versus regional improvement.

5 I think that\--I don\'t agree with what was said.

6 You don\'t have to have\--the meaning of global

7 improvement, it\'s great to have LV global

8 improvement, but we\'ve seen patients that have

9 regional improvement and this may translate in a

10 function way into a very significant improvement.

11 And so another way of looking at LV

12 function is really\--and I had said this before\--is

13 exercise capacity. And I think we need to be

14 evaluating these patients functionally as they go

15 along\--and this is a translation. So maybe if we

16 injected part of the heart we don\'t see a global

17 improvement in LV, but that patient may be able to

18 walk a lot further on a treadmill, be able to

19 exercise more, and that\'s important, as well.

20 DR. BORER: Yes, I think Dr. Perin\'s points

21 are very well taken. I didn\'t mean, in what I said

22 before, that in any way a clinical evaluation

23 should not be done, or should be precluded.

24 Obviously, that\'s the name of the game. The

25 patient has to feel better and/or live longer, or

251

1 you haven\'t done anything useful\--no matter what

2 the ejection fraction turns out to be.

3 So I would absolutely agree that clinical

4 evaluation has to be the key, and it\'s a given in

5 the follow-up of patients getting these kinds of

6 treatments.

7 I would also agree that there could be

8 clinically meaningful regional improvement without

9 much change in global left ventricular function.

10 I\'d sort of doubt that it would be very meaningful

11 if there wasn\'t any change, but I was thinking more

12 in terms of the kinds of echo studies that show

13 that with sonomicrography\--the ultrasonography, you

14 can see thickening in one small region. That

15 doesn\'t mean much to me.

16 But the point is well taken that you made,

17 and I don\'t disagree with it at all.

18 There\'s a sort of a more overarching issue

19 here about the various modalities that we might use

20 to evaluate patients. And, you know, Jeremy, of

21 course, is an expert in this area, and he\'s

22 undoubtedly absolutely right that the yield from

23 simple rhythm-monitoring studies would be pretty

24 low in people who are as sick as these people are,

25 and maybe that\'s the wrong example for me to take

252

1 here.

2 But, you know, in general if you don\'t

3 look you don\'t find something. There are simple

4 means of following patients, and I like Dr. Perin\'s

5 suggestion\--which I think should be part of any

6 follow-up\--clinical follow-up of people with heart

7 failure\--that is to assess exercise tolerance

8 formally.

9 There are lot of simple things that you

10 can do that are sort of part of a standard

11 armamentarium of researchers and clinicians who

12 follow patients who are very sick that I think

13 should be done. They may not show much, but unless

14 you look, you don\'t know.

15 So I just offer that. If, you know, it

16 gets back to we-know-what-we-know,

17 we-don\'t-know-what-we-don\'t-know, as Dr. Harlan

18 said before. Better to look with a wide compass

19 when our knowledge base is relatively small, then

20 we can eliminate things as we go along.

21 CHAIRMAN RAO: Dr. Ruskin.

22 DR. RUSKIN: Just a quick comment.

23 Jeff, I agree completely, and I didn\'t

24 mean to suggest that we shouldn\'t do the Holtering

25 or the routine ECGs. We would certainly do those,

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1 and it\'s possible one might see things that were

2 very surprising.

3 The issue that I raised really related to

4 safety; and that is that doing Holter monitoring as

5 a safety maneuver is not productive in this patient

6 population because, clearly, it\'s an icepick in

7 time, and you may see absolutely nothing and have a

8 dead patient 12 hours later, or see florid

9 arrhythmias that purport nothing ill with regard to

10 long-term outcome.

11 So the data would, I think, be necessarily

12 obtained, but it couldn\'t be used to ensure safety.

13 And that\'s really the reason for making the plea

14 that early on one consider populations that have

15 protective devices. They\'re not perfect, but

16 they\'re a lot better than not having them.

17 CHAIRMAN RAO: How about, you know,

18 monitoring for potential complications. I mean,

19 should people be worried about \"We are putting in

20 cells. There might be an inflammatory response

21 because of all the necrotic material.\" Should one

22 be looking at C-reactive peptide? Is that

23 something which should be over and above what one

24 would normally be doing in a sick patient?

25 Are there any other such tests that you\'d

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1 want to do, you know, to look at\--?

2 DR. BORER: I think you\'d do whatever you

3 can think of. It may not be worth anything. But,

4 again, if you don\'t look you don\'t find out.

5 I wouldn\'t particularly have picked

6 C-reactive protein, but it\'s fine. You know\--sure.

7 Why not look at systemic inflammatory markers?

8 Steve Epstein made the point yesterday\--I

9 have to backtrack for a moment. I\'ve referred to

10 Steve at least 20 times here\--and as you look

11 around the table\--well, one of them just left, but

12 there are three generations of Steve Epstein

13 trainees or underlings sitting at this table. So

14 it shouldn\'t be\--and, unfortunately, I am now the

15 most senior of those three.

16 \[Laughter.\]

17 Which, as Steve would say, what does that

18 make him? But\--what was I originally talking

19 about? \[Laughs.\]

20 \[Laughter.\]

21 There was a point here. Oh, yes\--about

22 atherosclerosis. You know, the inflammatory

23 milieu\--this is important because, remember\--I

24 mean, your point is very well taken. Steve pointed

25 out that some of these treatments we give could be

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1 good for the myocardium but, depending upon how we

2 give them, they could be atherogenic. That\'s very

3 important.

4 You know, undoubtedly, that the event

5 rate\--coronary event rate\--is substantially

6 higher\--two- to threefold higher among patients

7 with rheumatoid arthritis than among patients

8 without rheumatoid arthritis; that is, among

9 patients with rheumatoid arthritis with positive

10 markers of inflammation.

11 So there\'s some evidence that a systemic

12 inflammatory milieu somehow potentiates the

13 development of coronary disease.

14 Now, I don\'t want to talk about mechanisms

15 because we don\'t know them\--or at least I don\'t.

16 But I think, therefore, if we believe that there is

17 a likelihood that we\'re going to stimulate an

18 inflammatory response with what we\'re doing, we

19 should be looking for evidence of that so that we

20 can relate that\--even if retrospectively\--to other

21 events that occur in this population. So I think

22 the point is very well taken and we should be doing

23 that.

24 CHAIRMAN RAO: Given that this is a sick

25 population that would be the first sort of

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1 candidates for this, irrespective of how you select

2 them, would be anything you\'d suggest which will

3 change the frequency of monitoring from what you\'d

4 normally do for a sick population of this sort? Or

5 would it be more frequent? Or would it be longer,

6 in terms of the anticipated complications? Or

7 anything that one might imagine?

8 DR. SIMONS: I actually don\'t know what

9 patients\--or the population that we\'re talking

10 about. Because as we discussed several times,

11 there are really two different patient groups here.

12 One is an acute myocardial infarction patient, and

13 one is a patient who is chronic heart failure. And

14 I think you would monitor differently in these two

15 different groups because in acute MI, the

16 patients\--the risk is early. And once it\'s been

17 successfully treated, that\'s a pretty low-risk

18 group, with a very low mortality rate.

19 While, you know, Class IV heart failure

20 patient, who has a 20 percent ejection fraction has

21 a pretty high mortality rate. I think you would

22 sort of treat those things in a very different

23 manner.

24 CHAIRMAN RAO: Either of those groups\--so,

25 you know, you take acute MI, and you\'re trying to

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1 treat it with, say, bone marrow cells, and you

2 would monitor acute MI in a particular way.

3 Would it change now that you\'ve added

4 cells to the therapy?

5 DR. SIMONS: Probably would\--you\'d probably

6 want some sort of non-invasive imaging such as

7 echo. During the first two weeks you\'d probably

8 want it several times to see there\'s no pericardial

9 effusion, and there\'s\--if the left ventricular

10 function is not changing in sort of adverse

11 ways\--there\'s some adverse left ventricular sort of

12 remodeling.

13 But after two weeks I would go back to

14 pretty normal schedule; three months, six months.

15 CHAIRMAN RAO: If something changed, it

16 would change acutely.

17 And in a chronic disease model, would

18 there be anything that you\'d change?

19 DR. SIMONS: Once again, if this is a

20 catheter-based delivery, I think you need to

21 monitor more intensively within the first couple of

22 weeks.

23 CHAIRMAN RAO: Dr. Borer?

24 DR. BORER: Yes, I agree with what Dr.

25 Simons says. But I think you have to be aware\--you

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1 say, \"Should there be a difference compared with

2 what we usually do?\" There is no \"we.\" You know,

3 what someone who is working in an academic

4 institution, collecting data in a research milieu

5 might do is very different from what one might do

6 in private practice, or in primary care, or what

7 have you.

8 So what I would say is that we should

9 pre\--that people who set up these protocols should

10 pre-specify regular evaluation\--by objective

11 techniques that we\'ve all talked about here, at

12 some appropriate frequency, be it, you know, every

13 month for a few months, every six months after

14 that, every year after that\--whatever it is. I

15 don\'t know how the patients will live.

16 But I think that that kind of monitoring

17 probably should be continued for many years\--again,

18 given the fact that remodeling takes a long time.

19 CHAIRMAN RAO: Dr. Cannon, and then Kathy.

20 DR. CANNON: I would second Dr. Borer\'s

21 comments about long-term follow-up because,

22 particularly in thinking of this approach for the

23 chronic, intractable anginas, sort of an

24 angiogenesis or neovascularization approach. It\'s

25 conceivable to me that you could have a short-term

259

1 benefit, but not just a late failure, but maybe

2 even a worsening of the situation over time.

3 So perhaps putting cells in, either

4 directly or indirectly, stimulates new vessel

5 growth. But that may not be permanent in that

6 those cells will have to be replaced in time. They

7 don\'t live forever. And if that person\'s own

8 progenitor cells are very poor in function and few

9 in number, then the growth that was stimulated by

10 putting in a large number of perhaps activated or

11 genetically modified cells, or what have you, that

12 effect may go away in time, and the patient doesn\'t

13 have a way of replenishing or replacing the cells

14 that compose the new vessels. They could fail

15 fairly quickly, perhaps.

16 It\'s conceivable\--it\'s like the movie

17 Charlie. You know, there\'s short-term great

18 benefit, but then a deterioration that actually

19 makes the individual worse off than were had

20 nothing been done at all.

21 CHAIRMAN RAO: do you feel we have enough

22 information to point out how long?

23 DR. CANNON: No. No. I just raise that as

24 a possible concern, or a justification for

25 following them longer and perhaps more closely than

260

1 you ordinarily would someone with chronic stable

2 angina.

3 DR. HIGH: I just wanted to raise a

4 question to the cardiologists about one other

5 method of data capture, and just get your response

6 to this.

7 But, how often are these people

8 re-instrumented, or re-angio\'ed, or whatever? And

9 how much risk is it to do an endomyocardial biopsy

10 if they are?

11 CHAIRMAN RAO: Dr. Epstein, do you want to

12 take that?

13 DR. EPSTEIN: Well, my question was going

14 to be directly related to that.

15 I would like to raise a difficult

16 question, because it\'s very expensive. Given the

17 Lancet article of two weeks ago that was called\--it

18 was a very small number of patients, and I don\'t

19 know how much credibility to give it, but it raises

20 the interesting question that infusion of cells

21 into the coronary artery that had been harvested

22 after GCSF stimulation seemed to be associated with

23 a much higher incidence of re-stenosis than would

24 have been expected.

25 Should patients receiving cell therapy at

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1 the time or shortly after angioplasty\--should they

2 have a repeat coronary angiogram in six months to

3 rule out this very important possible adverse

4 effect?

5 What do you think, Richard?

6 DR. CANNON: You know, with the new

7 drug-eluting stents, it may be that that will not

8 be an issue in sort of the current environment now

9 that it was with the bare metal stents used in

10 that. So perhaps following more for

11 ischemia\--non-invasively, perhaps\--would be more

12 acceptable.

13 Doing repeat cardiac catheterizations

14 serially\--

15 DR. EPSTEIN: It\'s expensive\--

16 DR. CANNON: \--it would obviously add to

17 the expense\--

18 DR. EPSTEIN: \--and it\'s\--but that is, you

19 know it\'s a good question. And, you know, given

20 that recent study, you know, it\'s a very relevant

21 one.

22 CHAIRMAN RAO: Is biopsy dangerous, though?

23 DR. EPSTEIN: Oh, yes, I wouldn\'t think

24 about biopsy. And, also, I think you\'d have a

25 sampling. You couldn\'t be confident that you were

262

1 getting tissue in the area where you think you\'ve

2 done some.

3 DR. HIGH: \[Off mike\] Well, no, he said he

4 could do it within one micron\--

5 \[Laughter.\]

6 DR. EPSTEIN: Well, but Mike he was just

7 joking.

8 \[Laughter.\]

9 DR. RUSKIN: You know, about the\--if there

10 were a credible scientific question to ask from

11 repeat catheterization, I think the primary

12 question you\'re asking is: does the risk preclude

13 doing it?

14 The risk of a cardiac catheterization for

15 a major event, among all comers, is one in 500.

16 Now, it may be a little higher in a very sick

17 population, but, you know, I think that that risk

18 is\--not death, but some major event, stroke, MI,

19 death, bleeding, infection\--one in 500.

20 I think that if we had a credible

21 scientific question that was very important to

22 answer\--and I\'m not sure that we do. I think

23 Richard\'s point about doing non-invasive assessment

24 might suffice for the question about re-stenosis.

25 But if we had a question, I think that the risk

263

1 would be supportable, or could be supportable,

2 given what I\'ve just said.

3 In terms of biopsy, in fact the biopsy

4 data suggests that, in experienced hands, that\'s

5 reasonably safe, too. The big concern I would have

6 is exactly what Richard said\--you know, the

7 sampling error. I mean, a catheter-based biopsy is

8 a right ventricular biopsy. It\'s not anywhere near

9 where we\'re looking\--where the problem is, where

10 the cells were put in. To do it on the left side

11 would be very dangerous, I think.

12 So I would be concerned that we wouldn\'t

13 be able to get the information that we want to get.

14 And I would be interested in\--just with regard to

15 your question, which I think is a very good

16 one\--applying non-invasive methods, like MRI if it

17 were possible, or perhaps PET scanning to ask some

18 of the questions that you might have wanted to ask

19 with a biopsy.

20 CHAIRMAN RAO: Dr. Perin?

21 DR. PERIN: If we look at the population of

22 patients that are the chronic ischemic end-stage

23 patients, the reason they got there is they\'ve got

24 horrific coronary disease, have very aggressive

25 coronary disease. Their coronaries are already all

264

1 stopped up.

2 So I think it\'s really hard\--and we\'ve

3 done this\--but to re-angiogram these patients, it\'s

4 really hard to differentiate what\'s progression of

5 disease that they were going to have anyway; what\'s

6 do to the stem cell injection. So it\'s very

7 difficult to evaluate\--and which is completely

8 different in the acute MI population, where that

9 may actually be something that\'s important to look

10 at, because you have a target vessel, and a lot

11 different coronary situation.

12 DR. BORER: I think that that\'s a very good

13 point that leads to the point Dr. Simons made a few

14 minutes ago, and that Jeremy made yesterday, which

15 is Question 7, about controlled studies.

16 I think, Jeremy, what you said was that

17 from the earliest studies they should be

18 controlled. And I agree with that.

19 I think there\'s absolutely no way to

20 interpret the data in a very disparate, very sick

21 population\--very heterogeneous population. I don\'t

22 think that it\'s possible to interpret most of the

23 data that are of interest to us without some

24 comparator.

25 And I would go back to Dr. Murray\'s

265

1 earlier point. You know, you can not ethically

2 justify studying human subjects unless you can

3 interpret the data.

4 So I would say that Jeremy\'s point is a

5 very important one. I think controls have to be

6 built into these trials, even from the earliest

7 studies, and that probably it\'s not worth a heck of

8 a lot to do observational studies with no

9 comparator in most situations.

10 You know, the type of control could vary.

11 There are active controls, there are placebo

12 controls\--if you want to call it that. There are

13 dose\--different doses, in a dose-response design,

14 that could be used. But I think you do have to

15 have comparators.

16 CHAIRMAN RAO: That\'s an important point,

17 and I think it came up a couple of times before in

18 the past, too, and I\'ll just try and summarize

19 those few comments and then turn it over to you.

20 So, there seemed to be consensus in the

21 field\--in fact, almost everybody who talked about

22 it said that controls are important, or that

23 placebo controls are quite important.

24 And then I asked this question yesterday

25 was that is it possible to get controls. Will it

266

1 be possible to recruit them? And the answer was

2 yes\--as long as there was some kind of cross-over

3 option. And that seemed to be a possibility, so

4 that that wasn\'t an absolute limiting factor that

5 was there.

6 And you\'ve reiterated that point, that it

7 would be very hard to interpret these in small

8 studies without any kind of controls. So it seems

9 that that\'s one important thing that one should

10 keep in mind in any kind of clinical study that\'s

11 going to be done\--right?

12 Go ahead.

13 DR. MURRAY: From the point of view of

14 ethics\--and science, here\--there\'s one absolute

15 requirement: namely, the study would have to offer

16 interpretable results\--right? We\'ve talked about

17 that. You cannot justify doing trivial things to

18 human subjects if the design is basically never

19 going to yield anything of any value and you know

20 that going in.

21 The other thing you want to do\--and as I\'m

22 understanding the situation, is it\'s going to be

23 very difficult to get a good signal-to-noise ratio

24 so that you can actually pick out what the actual

25 effects of the intervention are. So there\'s a need

267

1 to maximize sensitivity to be able to pick those

2 out, and the discussion that\'s gone on about, you

3 know, what to look for here has been very helpful

4 for that.

5 Even in small numbers you\'d want to have

6 some sense\--we don\'t usually do power calculations

7 on small sizes, but we probably\--we ought to do the

8 best calculations we can in these so, again, so

9 that we have some assurance that we will have

10 interpretable results.

11 I don\'t think it will be easy to design

12 studies that will be ethically clearly acceptable

13 with the placebo design Phase I studies here. But

14 I suspect it\'s the way we have to try to go. And

15 I\'m going to count on the creativity of the

16 investigators and the courage of the subjects.

17 CHAIRMAN RAO: Go ahead, Dr. Borer. I

18 thought\--did you want to make a comment?

19 DR. BORER: About placebo, I did.

20 The issue of doing a placebo-controlled

21 study and then offering, as the benefit, a

22 crossover\--or I would\--it\'s not a crossover, it\'s a

23 dropout\--at the end of a certain period of time, if

24 the treated group actually shows benefit is very

25 attractive, but we may not have information that

268

1 would support doing that from early small trials,

2 or early small studies. So I\'m not sure that that

3 would be the out.

4 I think that one has to think creatively

5 about some other types of controls. And I do like

6 the multi-dose design, because that does allow you

7 to know, if you see a dose response, that, in fact,

8 there is, by definition, an effect. In that

9 situation, you know, everybody gets something.

10 And, of course, we don\'t know going in what\'s

11 better and what\'s worse; whether there is a dose

12 relation, whether there\'s a maximal dose that\'s

13 effective and above that you have safety problems.

14 You don\'t know that.

15 So I think that that might be some\--a

16 creative approach to dealing with this need for

17 comparators. And maybe a placebo-controlled

18 approach would be the appropriate way. I don\'t

19 know.

20 I\'m just suggesting that we have to be

21 more creative about the thinking about study design

22 to provide appropriate comparators. And then I\'d

23 get back to what we all discussed before, which is

24 that since multiple small studies will be done with

25 these agents, the designs and data collection

269

1 strategies should be compatible\--sufficient

2 compatible\--with one another so that you can pool

3 some data and eventually come up with some

4 information that might be more interpretable than

5 the data from any single study alone.

6 So, just sort of overarching thoughts.

7 CHAIRMAN RAO: In some ways we\'ve been

8 trying to answer this question but it\'s been a

9 little bit different from the way it\'s been set up

10 there.

11 I mean, it seems to me that, listening to

12 all the experts in the field, is that they seem to

13 feel that selection of patients, and the design of

14 the experiment, in terms of the controls, or the

15 placebo used, was really as critical as sort of the

16 readouts. And, in fact, nobody seemed to feel that

17 there weren\'t enough adequate readouts which were

18 non-invasive and that it would not be possible to

19 design them. It was just simply that you will have

20 to design them adequately, depending on the type of

21 patient you chose and the kind of, you know,

22 disease you were treating.

23 And I think the two points that were made

24 to me which were really important was that you\'re

25 going to have to follow up for certain things for a

270

1 long time. It\'s not an aggressive follow-up, but

2 you need to follow them up because you have to

3 learn something from these things. And that the

4 other was that in this trial itself there should be

5 some urgency, or some selection so that you could

6 have the option of performing an autopsy because

7 that might work really well, given that the choice

8 of patients is such that they are relatively sick,

9 and that that might be a really important thing to

10 keep in mind.

11 Does that seem to capture? Does the FDA

12 think that that addresses some of the issues on the

13 clinical trial?

14 DR. GRANT: Yes.

15 CHAIRMAN RAO: In that case, it\'s amazing.

16 We actually finished on time.

17 \[Laughter.\]

18 Well, thank you for all the people who

19 stuck out here to the bitter end. That was useful

20 And I thank all the experts who gave the time to

21 come to this. It couldn\'t have been done without

22 them.

23 \[Whereupon, at 3:00 p.m. the meeting was

24 adjourned.\]

25 - - -