DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
BIOLOGICAL RESPONSE MODIFIERS ADVISORY COMMITTEE
Friday, March 19, 2004
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.
Jeffrey S. Borer, M.D.
Jeremy N. Ruskin, M.D.
Michael Simons, M.D.
Susanna Cunningham, Ph.D.
Michael D. Schneider, M.D.
John F. Neylan, M.D.
Richard O. Cannon, M.D.
Stephen M. Rose, Ph.D.
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.
Stephen E. Epstein, M.D.
Robert J. Lederman, M.D.
Emerson C. Perin, M.D., V.A.C.C.
Silviu Itescu, M.D.
Phillipe Menasche, M.D.
Doris A. Taylor, Ph.D.
C O N T E N T S
Call to Order
Chairman Rao 4
FDA Opening Remarks
Philip Noguchi 8
Open Committee Discussion-Cellular Therapies for
Open Public Hearing 9
FDA Charge to Committee--Introduction of Questions
Stephen Grant, M.D. 37
Committee Discussion of Questions 53
Closing Remarks/Adjourn 270
1 P R O C E E D I N G S
2 Call to Order
3 CHAIRMAN RAO: Welcome to the discussion
4 part of the meeting today. As is usual with all of
5 these meetings, we have to go around and
6 re-introduce the people who are on the committee,
7 and then open it up for public questions
9 So I'm going to ask Dr. Neylan to start by
10 introducing himself again, and then we'll just go
11 around the table.
12 DR. NEYLAN: I'm John Neylan. I'm vice
13 president of clinical research and development and
14 Wyeth Research, and I sit on the committee as
15 industry representative.
16 CHAIRMAN RAO: All right.
17 DR. SIMONS: Michael Simons of Dartmouth
18 Medical School. I'm a vascular biologist and also
19 a cardiologist.
20 DR. SCHNEIDER: Michael Schneider, Center
21 for Cardiovascular Development, Baylor College of
22 Medicine. I'm a cardiologist and molecular
23 biologist with an interest in cardiac growth and
24 cardiac progenitor cells.
25 DR. CUNNINGHAM: Susanna Cunningham from
1 the University of Washington School of Nursing in
2 Seattle, and I am the consumer representative,
3 usually with the Cardiovascular-Renal Advisory
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
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
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
about genetics and some of these new cellular and
1 gene-based therapies.
2 CHAIRMAN RAO: Dr. Ruskin, we missed
3 you--can you--
4 DR. RUSKIN: Jeremy Ruskin--I'm a
5 cardiologist and electrophysiologist, and I direct
6 the Cardiac Arrhythmia Service at Massachusetts
7 General Hospital.
8 CHAIRMAN RAO: I'm Mahendra Rao. I'm at
9 the National Institute of Aging, and I'm a stem
10 cell biologist.
11 MS. DAPOLITO: Gail Dapolito, Executive
12 Secretary for the Committee. And I'd also like to
13 introduce the Committee Management Specialist,
14 Roseanna, Harvey.
15 Thank you.
16 DR. KURTZBERG: I'm Joanne Kurtzberg. I'm
17 a pediatric hematologist-oncologist, and I run the
18 pediatric bone marrow transplant program at Duke,
19 and the Carolinas Cord-blood Bank, and I have an
20 interest in cord-blood stem cells;
21 transdifferentiation and plasticity.
22 DR. HIGH: My name is Kathy High. I'm a
23 hematologist at the University of Pennsylvania, and
24 my research interests are in gene transfer as a
means of treating bleeding disorders.
1 DR. ALLAN: I'm John Allan. I'm a
2 virologist at the Southwest Foundation in San
3 Antonio. My area is non-human primate models for
4 AIDS pathogenesis. I also sit on the HHS
5 Secretary's Advisory Committee on
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
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
9 CHAIRMAN RAO: Thank you, Phil. I'll turn
10 the mike over to you so you can make the opening
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
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
have some laughs yesterday, but it was not laughs
1 about the absurdity of the approach but, really,
2 about all the nuances that we see.
3 There was a quote today in the Washington
4 Post about the success of CNN. And, actually,
5 instead of fighting, I would say we are fulfilling
6 that; and that is the public's business is best
7 done in the public, which this is a very elegant
8 example of. And I'm sure today will be even more
9 of an example. And the goal, of course, is to make
10 sure that when we leave that we do so with a better
11 knowledge of how we can actually win in the end.
12 And, with that, I think Dr. Rao, it will
13 be time for opening the Open Public Hearing.
14 Thank you.
15 CHAIRMAN RAO: We have a couple of people
16 who wanted to make comments. And I want to
17 emphasize right now that if anybody else from the
18 audience needs to make a comment, this is a good
19 time to make it. Sometimes making comments at the
20 time when the committee is deliberating becomes
21 much harder, and it's hard to recognize people,
22 given the time constraints as well.
23 Open Public Hearing
24 CHAIRMAN RAO: The first speaker is going
to be Dr. Neal Salomon, and he's going to speak for
1 about five minutes.
2 DR. SALOMON: Good morning. I'm Neal
3 Salomon. I'm a cardiac surgeon, and for the last
4 several years I've worked part-time as an associate
5 medical director for Parexel, a large CRO based in
6 Waltham, Massachusetts. During this time I"ve
7 worked with GenVec, formerly known to us as
8 Diacrin, as both a medical monitor and a consultant
9 in the implementation of their clinical trials,
10 using autologous myoblast transplantation.
11 I would like to very briefly summarize the
12 currently updated results of the three Phase I
13 pilot safety and feasibility studies--as I believe
14 that GenVec currently has the largest clinical
15 experience in the United States.
16 Next slide, please.
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
transplantation. I believe that
HeartMate was used
1 in all of them.
2 The second concurrently running--run CABG
3 study was a cohort of dose-escalation study; 12
4 patients. All of these patients had EF's less than
5 30 percent, and the injection of myoblasts was done
6 concurrent with their bypass grafting.
7 The third--the most current study--was a
8 cohort of 10 evaluable patients. All of these
9 patients, however, had injection of 300 million
10 myoblasts. However, this group had a much more
11 extensive--and I should say expensive--preoperative
12 evaluation and follow-up using core laboratories
13 standardized protocols for Echo, MRI, PET and
14 multiple, multiple 24-hour Holter examinations.
15 Next slide, please.
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
been completed in five evaluable patients. That
1 was recently published, last year, in JAC. You can
2 see the reference there.
3 We couldn't identify any related SAEs.
4 Next slide, please.
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
16 Next slide, please.
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
question of primary arrhythmia versus an infarct.
1 And on autopsy, he had fresh thrombus in a
2 right--and a sequential graft going to two branches
3 of the right. We suspect that that fit his
4 clinical pattern and he had a primary MI.
5 And, again, all these patients are getting
6 thoroughly evaluated by serial MRIs, echo, PETs,
7 multiple Holters, by standardized core labs.
8 Next slide, please.
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
AICDs placed, essentially due to progressive heart
1 failure. There was no improvement after
2 the--cardiac function after their grafts. Neither
3 patient ever had VT--and I don't believe any of
4 these three have had a shock.
5 And then, the last group, one patient had
6 an AICD week three, who had non-sustained V-tach,
7 also severe LV dysfunction. His pre- and
8 post-operative Holters, however, were not really
9 different, but he had an AICD placed. And the very
10 last one had it, again, placed prophylactically for
11 a position T-wave alternans test, which some
12 cardiologists feel has significant prognostic
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.
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;
for the LVAD patients it's been three months. We
1 could not identify any specific procedure,
2 rejection-related complications; really no
3 definitive SAEs--that one possibility, but probably
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.
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
22 DR. SALOMON: Dose escalation, yes.
23 DR. BORER: Well--escalation, but you had
24 one dose given to four different groups; one dose
to each group. That's right?
1 Okay. So you can define a dose-response
2 curve from those data, albeit the numbers are
3 small, you could.
4 Do I understand correctly we don't know if
5 cell survival varied among the doses used in any
6 dose-related way, and we don't know if there was
7 any functional parameter that was altered by the
8 treatment in a dose-related way?
9 And the reason I ask, obviously, is that
10 this is the only study that has, in essence, a
11 control. I mean, it's a dose-response study, which
12 could provide a great deal of information, you
13 know, if the information become available. So
14 that's why I'm asking specifically about that
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
confined--with no allusion to efficacy whatsoever,
1 of course, in terms of functional alterations. I
2 haven't addressed that whatsoever. So--
3 DR. BORER: But you made measurements. You
4 have echo, you have PET, you have--
5 DR. SALOMON: Oh, sure.
6 DR. BORER: You have stuff.
7 DR. SALOMON: Sure. Sure.
8 DR. BORER: And I wasn't suggesting you
9 could look at efficacy. I was just asking about
10 functional concomitants of treatment.
11 DR. SALOMON: Right. No--I understand.
12 No--the answer is no obvious correlation;
13 no dose-related correlation. Correct. Too many
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
information, because there's a CABG.
1 What is the FDA policy on something like
3 CHAIRMAN RAO: Let's leave that question
4 for later, then, Dr. Epstein.
6 DR. SCHNEIDER: I have a question for you
7 about patient recruitment for the Diagran GenVex
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
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
total, I believe, in opportunities for eight to 10
1 centers, but virtually 80 percent of the patients
2 came from three to four of the centers.
3 DR. SCHNEIDER: And the other 20 percent
4 came from centers that were doing one or two
5 patients each?
6 DR. SALOMON: Had fewer patients
7 each--correct. Correct.
8 CHAIRMAN RAO: Thank you, Dr. Salomon.
9 DR. CUNNINGHAM: What were the genders of
10 the patients?
11 DR. SALOMON: Only--of all these--of the 28
12 patients, only two female.
13 DR. CUNNINGHAM: Thank you.
14 CHAIRMAN RAO: Thank you.
15 Dr. Reiss?
16 DR. REISS: My name is Russ Reiss. I don't
17 have any slides prepared. I've just been sitting
18 at this meeting for the last day and am somewhat
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
glad that Dr. Salomon did just give a little bit of
1 information from the cardiac surgeon side--and a
2 little bit of rebuttal to Dr. Epstein.
3 I do not believe that just because we can
4 put these in with catheters that that is the actual
5 safest way to do this; and that maybe in the
6 operating room, with the heart under diastolic
7 arrest, completely in a controlled setting that is
8 probably the most controlled, most sterile setting
9 we have from clinicians today is the cardiac
10 operating room. And just some of the quick points
11 I just wanted to let the FDA know, that in response
12 to putting a CABG graft on a heart and saying that
13 you can't tell any difference, I don't agree with
14 that at all. Because we've all revascularized a
15 heart and seen no difference in wall motion,
16 because that area is not graftable, or there's an
17 area there that's thin but not dead. And you may
18 not see anything at all.
19 If you put cells in that area that you did
20 not put a graft on, you can follow that. And we've
21 seen some very nice images--Dr. Lederman yesterday
22 showed beautiful cardiac MRI images with very
23 specific areas of the heart and the walls that can
24 be followed with high definition. We can see what
happens to the area that is not revasculizable with
1 a CABG graft.
2 And I would say that all the concerns that
3 have been raised with catheters--we heard yesterday
4 that the catheter was very safe, and nothing ever
5 happens in the cath lab. We'll that's not true.
6 Cardiac surgeons repair valves, we repair aortas.
7 That thin transverses the groin, the aortic arch.
8 There's all kinds of misadventures that happen with
9 catheters that cardiac surgeons have to fix.
10 So I would just say to the FDA that, you
11 know, it's going to be done with a catheter one
12 day. It's already being done outside this country.
13 I think that is going to be eventually how the
14 majority of cellular therapy is going to be
15 delivered. But, as far as safety, some of these
16 trials probably should be also considered in the
17 cardiac setting, in the operating room, where much
18 of the pre-clinical data has been done with direct
19 injection, under arrested heart.
20 And the last thing, about safety: all our
21 patients also go to the ICU, and they're under the
22 most monitoring on a daily basis that you can have.
23 And we can also apply what other types of safety
24 monitoring the FDA would like to see us do. But
often the catheter patients do not get the same
1 level of post-operative monitoring.
2 So, just a plug for the cardiac surgery
3 side, since it seems that we're a little bit
5 CHAIRMAN RAO: Thank you, Dr. Reiss.
6 Dr. O'Callaghan?
8 DR. O'CALLAGHAN: My name is Michael
9 O'Callaghan, and I"m the vice president of
10 pre-clinical biology at Genzyme. I'm responsible
11 for many of the pre-clinical studies that are to
12 look after safety and efficacy for the cell
13 products and many other products at Genzyme.
14 I'd like to thank the FDA for, first,
15 allowing us to speak and, secondly, for putting on
16 this two-day series of seminars, because I think
17 it's critical to the way we move forward.
18 I would remind people of this document
19 called "Innovation and Stagnation," which is a
20 document that just recently came out from the FDA.
21 And if you look at the graph which is on Figure 2,
22 you will see that in 1993, there were 17 BLAs
23 submitted to the FDA, and progressively over the
24 next 10 years to 2003, there was virtually a
straight line downward plunge to 14 last year. If
1 you continue that, that's 5 BLA losses per year.
2 So by 2007, there won't be any.
3 So, I think what we're talking about
4 today--and some of the things that we're talking
5 about today--is how do we get to a better process
6 or procedure or strategy that will allow industry
7 and the FDA to come to a more transparent, perhaps,
8 and faster or more efficient approach to this.
9 If you think about some of the issues that
10 have been discussed and the complexity of what
11 we're dealing with, you may recall from much of
12 yesterday's conversation that many of the
13 procedures that we are using to deliver cells--in
14 fact all of them--invoke some sort of pathology of
15 themselves. So if you think about the emboli that
16 were produced in the intra-coronary delivery, or
17 you think about needle tracks or catheter delivery
18 systems that ago through the wall or travel through
19 the heart, there is a primary pathology created by
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
efficacy issues we're trying to deal with.
1 A third variable, of course, is the cell
2 death that we all heard about, obviously invokes
3 some sort of pathology. And, on top of that, we
4 have our understanding of the pathological, or
5 physiological processes that we have in great
6 abundance in the literature, and that's our sort of
7 background in trying to understand how to provide
8 studies that answer the safety questions or the
9 efficacy questions.
10 And then on top of this background, we're
11 attempting--with the few surviving cells that are
12 there, and presumably the ones that are going t o
13 give benefit to the patient--out of that morass,
14 try to find out whether there is a safety issue, or
15 efficacy, on top of many of the other things, like
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
poker game, where each one is holding the cards
1 against their own chest and only giving out the
2 card that matters. And that goes on for several
3 years, and as you play your card, or pick up a new
4 card to try and strengthen your hand, you end up
5 spending a lot of money in the process and, in the
6 end, many of these products shown on this graph die
7 very slowly.
8 So my plea at the moment, or to this body,
9 is that we need to think about how we are going to
10 make the process more transparent so that quicker
11 decisions can be made. And I think it has to be
12 translated at two levels: one is at the level of
13 policy and strategy--how the FDA is going to
14 interact with industry. And, secondly, what was
15 pointed out yesterday by Dr. Noguchi and McFarland,
16 how to translate that down to the individual case,
17 where the sponsor and the FDA are having to work
18 out, between them, on that one individual case, how
19 to get to a satisfactory solution as quickly as
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
some of these things into an appropriate
1 methodology that can be used.
2 I'm going to ask Dr. Noguchi to maybe say
3 a couple of words on what a BLA is so that people
4 who may not be familiar with it are aware of what a
5 BLA application is.
6 DR. NOGUCHI: Okay. Yes--BLA stands for
7 "Biologics License Application." It's given under
8 the authority of a section of the Public Health
9 Service Act that we call "Section 351," and it is
10 in a parallel situation to the Food, Drug and
11 Cosmetic Act. The main distinction, from the legal
12 point of view, is that if you have an approved
13 NDA--new drug application--you don't need a
14 simultaneous BLA, and vice versa.
15 The basic requirements for a license
16 application is that you have a product--let's give
17 a hypothetical example of a cellular product for
18 future cardiac repair--that can be made in a manner
19 that is consistent; that is, for many biologics, we
20 do not need to have an ultimately precise
21 definition and specification for a pure entity,
22 however we want you to be able to make it the same,
23 time after time after time, within certain limits.
24 If we go back to the original law--1902
law--the legislative history is basically states:
1 what we want is something that's safe relative to
2 the indication; that's pure as possible; and that
3 is potent, so that the practicing physician, in his
4 or her capacity, will have some confidence that
5 when this product is given that their patient will
6 have some expectation of therapy; that is, they'll
7 be better after than before.
8 So I think--that's sort of more of a
9 philosophical thing, but the end game is really: if
10 you have something that we know works, and can
11 be--works in a manner that it can be convincing,
12 which is usually based on planned clinical
13 trials--occasionally we may have historical data
14 that can be used in terms of an approval. But,
15 clearly, for experimental products such this--we
16 heard yesterday, eloquently--that without a placebo
17 how do you know that this is actually working,
18 since all the non-controlled trials say they all
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.
can give it. Or, if it's past the
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
the data--I have no reason to doubt the data, but
1 the interpretation of it was what is not clear to
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
known has been done for those diseases for which we
1 know how to treat. But what we are now seeing is
2 all the rest of them here: cardiovascular disease,
3 congestive heart failure. We saw how the cascade
4 is just a very long one, and we're trying to
5 intervene at perhaps a point where it's a little
6 bit hard to reverse years of damage. Likely it can
7 be done, but how we get there is very dependent, to
8 a great degree, on what the science and knowledge
9 of disease is.
10 So, I think what we are seeing is that we
11 are seeing fewer applications in the whole drugs
12 and biologics arena. And part of that is that our
13 scientific knowledge, on the one hand, for making
14 products is expanding rapidly, but our
15 understanding of the--quote--"simplicity" of
16 disease is proving to be--well, it may be very
17 simple, but, boy, that's pretty darn hard compared
18 to what we already know.
19 There are no easy solutions to any of
20 these diseases that we see right at the moment.
21 And that's part of the lag we're seeing.
22 Dr. McClellan's emphasis on the
23 critical-path initiative is really to try to help
24 everyone to come back and focus as to what are
those things that will make a difference, and then
1 what are those things that are simply going to be
2 increments and improvements that may only give us a
3 little bit of extension of life, a little bit
4 longer acting drug, but may not be actually
5 altering the fundamental disease.
6 CHAIRMAN RAO: Joanne?
7 DR. KURTZBERG: I have a question that goes
8 back to the cardiac transplantation issue at
9 hand--or the cellular therapy issue at hand.
10 In the current proposed tissue regs,
11 minimally manipulated or non-manipulated products
12 are not really candidates for BLA or licenses. So,
13 for example, if you take bone marrow from a sibling
14 and you transplant it directly into the patient,
15 there's no license involved with doing that.
16 And some of the therapies that both are
17 being done now and are being proposed involve what
18 we've done with bone marrow for years; taking it
19 and putting it somewhere else--in this case,
20 usually autologous, or mobilized blood, or even
21 CD34 AC133-- selected products for which there
22 already are devices that are either under IND or
24 So how would the FDA--you know, so this
therapy crosses a bridge between using things that
1 we use already, but just putting them in a
2 different place; and then, also, modifying
3 those--some things, ex vivo, with culturing and
4 other technology.
5 You could interpret the regs as they are
6 proposed as saying the minimally manipulated
7 product doesn't need a license or a BLA, and only
8 the ex vivo manipulated or culture, transfected,
9 etcetera and so forth products do.
10 What's the FDA's view of that.
11 DR. NOGUCHI: Well, we really did not have
12 this meeting to try to focus on the question of
13 whether we need this approach versus that approach.
14 However, I'll just quickly say a couple of things.
15 First, the tissue regulations are still in
16 the process of being finalized. However, the
17 point--one part of the regulations does say that if
18 you use something that would otherwise be
19 considered to be not manipulated beyond its normal
20 biological characteristics, if it's used in a
21 manner that inherently does not seem that it
22 logically follows--which is what happens in this
23 case--we've already heard yesterday, and we see
24 throughout the past year, in terms of the active
literature, if bone marrow cells of whatever never,
1 however purified, are put into the heart by means
2 of devices, or by direct injection, or by surgical
3 procedures, that, in fact, either you get
4 regeneration of heart, you get vascularization, you
5 get transdifferentiation--none of which have been
6 proven by any means, in any clinical trial, let
7 alone in any animal studies that have been done--we
8 term that a "non-homologous use," because it has
9 not been shown, and the current science does not
10 show that any of those possibilities are actually,
11 in fact, what happens.
12 And so, for that reason, we are saying
13 these are highly experimental procedures they're
14 using in addition to the product itself, which is
15 experimental. We're using products--other products
16 such as catheters in an experimental way--and, all
17 put together, clearly merit the justification and
18 the overview of FDA regulation at the IND level.
19 DR. KURTZBERG: I'm not questioning that.
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
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.
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,
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
1 I would like to challenge that position a
2 little bit, because I think we also heard that stem
3 cells are quite heterogeneous, and we see the
4 problem that how can we make sure that an animal
5 stem cell preparation is really very homologous to
6 the human stem cell preparation, which may carry
7 the same name but could be different, in terms of
8 the cell composition or other factors. And we
9 don't have the tools in our hands to discriminate,
10 or to decide whether the animal stem cells are
11 really the same--have the same quality, the same
12 properties, the same purities as the human product.
13 So we had made a conscious decision to
14 work with immunosuppressed animals,
15 immuno-compromised porcine--pigs, treated with
16 cyclosporin, and tested our stem cells, human stem
17 cells in that setting, with good results so far.
18 And I think taking that strategy, we are
19 on the safe side with respect to testing our
20 products in terms of efficacy and safety, because
21 we don't have to make this transition or
22 translation of the animal that, say, the animal
23 data generated with animal stem cells then into the
24 human setting.
25 And somehow, I--I mean, I think it's fine
1 if the authorities accept the, let's say known
2 xenograft, or xenograft-avoiding strategy, but it
3 would be--I think it would be a pity if we would
4 now have a dogma that studies with
5 immuno-suppressed animals would make sense in this
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
pilot studies weren't designed--efficacy as a
1 stand-alone procedure, because clearly you have to
2 get safety and feasibility first.
3 So, it's really difficult to do cell
4 implantation studies, I think, as a stand-alone
5 procedure, and they had to be done concomitantly
6 with bypass grafting. I think that was really the
7 rational; not to prove efficacy.
8 Thank you.
9 CHAIRMAN RAO: Thank you.
10 I'm going to ask the FDA to pose the
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
17 I wanted to start out today by thanking
18 the members of the committee and the invited
19 speaker--as well as the speakers who were kind
20 enough to join us during the open public
21 hearing--for coming here and sharing their time.
22 We know they all have very busy and very productive
23 professional lives, and we thank you for joining us
24 today to discuss these very important issues.
25 I'm going to briefly review why we've
1 asked you to come here yesterday and today. And
2 I'll then review the questions that we've asked you
3 to discuss.
4 Next slide, please.
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
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
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
implicit in our mission statement.
1 We have convened the committee to solicit
2 advice about certain issues that have delayed the
3 development of potential therapies for
4 cardiovascular disease.
5 Next slide, please.
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
13 For those of us who have a bit of gray
14 hair, they can remember when taking care of MIs
15 consisted essentially of putting people to bed.
16 The mortality rate for MI has been declining fairly
17 rapidly. It's gone down 30 percent over the last
18 two decades. And this has been due, at least in
19 large part, to the advent of reperfusion therapy;
20 both thrombolysis and percutaneous coronary
21 intervention. However, these therapies are not
22 entirely effective. Most patients who will suffer
23 acute myocardial infarction will be left with a
24 variable amount of left ventricular dysfunction.
25 Because increasing numbers of these
1 patients are surviving, there are many, many more
2 patients each year that have diminished cardiac
3 reserve. It fact, congestive heart failure is the
4 only cardiovascular diagnosis whose absolute
5 incidence is increasing year by year. And it's
6 partially due to the aging of the population, but
7 it's also, in large part, due to this phenomenon.
8 And therefore we are very interested in
9 facilitating cellular therapies because they may
10 benefit these growing numbers of patients with
11 congestive heart failure.
12 Now, I don't want to suggest that this is
13 the only indication for which I think these
14 products might be used, or that even for sure, that
15 this is an appropriate indication. Conceptually,
16 there are many, many other types of cardiac disease
17 that could be benefitted by cellular therapy.
18 Next slide, please.
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
mechanism by which we conduct this assessment.
1 They provide the framework wherein we can answer
2 this question--which is never trivial, I don't
3 think, for any trial, but most certainly is not
4 trivial for novel therapies such as these--and that
5 is: how do we balance individual subject safety
6 against the potential public health benefits of new
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
the manufacturing processes. You
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
doesn't--because they're difficult doesn't excuse
1 you from not having any.
2 And you need to be able to identify a safe
3 starting dose. And then you need to have a
4 monitoring plan that suggests that you're going to
5 be able to detect the adverse events in a timely
6 fashion, so that any subject that suffers those
7 adverse events can be identified and treated
8 quickly, and so that subsequent subjects will not
9 be exposed to the same adverse events.
10 Next slide, please.
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
may have seen them all. But
there may be
1 differences within these preparations.
2 Secondly: insufficiently detailed safety
3 data--and particularly, we will sometimes get, as a
4 safety data base, just published reports. It's
5 very difficult to get, from a publication, the kind
6 of detail. We have to be able to do an independent
7 analysis and, generally, publications will not
8 include a detailed protocol, which will include all
9 the protocol-specified assessments, and it won't
10 include either the case report forms for a clinical
11 study, the line item of raw data for a pre-clinical
12 or non-clinical study.
13 Three: limited information about the
14 compatibility of the cellular product and the
15 delivery device.
16 Four: an inadequate plan for monitoring of
17 subjects during and after product administration.
18 And I think you'll see that the questions
19 that we've asked you, with the exception of the
20 seventh, which is just a bit different--but the
21 first six clearly all are derived from these
22 issues. We'd like to get advice about these issues
23 so that we can help understand how to resolve
24 these, and so the investigator community can help
understand, so that we can get submissions that
1 will go forward.
2 Next slide, please.
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
12 Next slide, please.
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
safety concerns for cellular products for the
1 treatment of cardiovascular diseases, and the
2 testing that should be performed to ensure
3 administration of a safe product. Among the
4 factors that you might consider are tissue source,
5 manufacturing process, formulation, storage, route
6 and site of administration.
7 In your printed version, in the briefing
8 document, these came out as "a, b, c, d." We by no
9 means think that you have to discuss each of those
10 as a separate subpoint, but consider them, instead,
11 in your discussion of the overall question. And I
12 would caution the committee to try to remember that
13 we're talking here about treatments of cardiac
14 diseases. The larger field of cell therapy is
15 quite a broad one, and we would like to stay to the
16 specifics of cardiac therapy today.
17 Question 2--
18 Next slide, please.
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
variable in characterization or in determining
1 their safety or efficacy.
2 Therefore, please comment on the elements
3 of product identity and characterization necessary
4 to generate meaningful data about safety and
5 efficacy. And, conceptually, we think that these
6 may include comments about specific
7 biomarkers--that would be most particularly with
8 the bone marrow-derived products--and the types and
9 percentages of cell types that would apply to both
10 the products derived from muscle biopsies, as well
11 as those derived from bone marrow or from
12 peripheral blood.
13 And there may be other parameters that you
14 would identify as being important. And we would
15 ask for your comments.
16 Next slide, please.
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
been proposed to support the safety of cellular
1 products used in the treatment of cardiac disease.
2 These include studies of both small and large
3 species; studies utilizing either immune-competent
4 or immuno-compromised animals.
5 Each model has some advantages and
6 limitations, which have been reviewed by the
7 speakers and previously discussed. For instance,
8 human cellular products can be tested in
9 genetically immuno-compromised rodents, but these
10 animals provide limited clinical monitoring of
11 cardiac function, and cannot be used to assess the
12 safety of devices. Large animals allow for more
13 extensive monitoring of cardiac function and the
14 use of the same delivery device intended for
15 clinical use.
16 Please discuss the merits and limitations
17 of various large and small animal species for
18 providing pharmacologic, physiologic and
19 toxicologic support for cellular products used in
20 the treatment of cardiac disease, and please
21 consider the following: the intended human clinical
22 cellular product; the delivery system that's
23 proposed in the clinical trial; and extrapolation
24 of study results from animals to humans.
25 Question No. 4: Please discuss the merits
1 of animal models of ischemic disease with respect
2 to ability to generate proof of concept data, and
3 generate toxicologic data of relevance to the
4 clinical disease. And, conceptually, animal models
5 of ischemic disease could include normal
6 animals--or no ischemic disease--as Dr. Vouye
7 presented a very interesting study with essentially
8 normal dogs.
9 The models--again, the models of ischemia
10 that are available are many; cryoablation,
11 ligation, ligation-reperfusion, ameroids.
12 Question No. 5, please
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
space via needle catheter; effects of depth or
1 spread of injection into they myocardium on either
2 the safety or, potentially, the efficacy.
3 Question No. 6--these last two questions
4 are about two design elements of early-phase
5 clinical trials. The theoretical risk of these
6 products include the generation of non-cardiac
7 tissues, abnormal cardiac tissue and/or local
8 inflammation. These outcomes potentially could
9 lead to myocardial dysfunction, arrhythmias, or
10 conduction abnormalities.
11 Also, these products are administered
12 because some of the cells contained are
13 self-renewing and possess developmental plasticity;
14 that is, they can differentiate into cells not
15 found in the tissue from which they were obtained.
16 Since uncontrolled cellular proliferation may
17 result in tumor genesis, these products could
18 theoretically result in subjects' developing
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
ventricular dysfunction, ventricular arrhythmias,
1 and neoplasia.
2 Next question, please.
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
use of placebos in these studies; for example,
1 transendocardial injection of saline into the
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
later-phase clinical trial: appropriate end-points,
1 eventual populations for therapy. These are things
2 about which we haven't presented any data.
3 And I will note that--as you will note in
4 the agenda--that FDA is always asked the questions,
5 after all the FDA speakers, we never leave any time
6 for us to be asked question--for good reason.
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
all seem to have the same effect, it's still not
1 true, in terms of how they have an effect and what
2 you need to do in terms of the numbers that you put
3 in and so on. So cells have to be treated
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.
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.
24 So, we know how to make cells--or some
people know how to make cells.
And we know that
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
1 So--great. It's amazing that we could
2 start with a common basis, then.
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
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
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
satienability, and only using the third and fourth
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
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
mobility and invasiveness. The
in vivo correlate
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
24 And there was one other sort of issue on
this long-term thing--Dr. Borer, go ahead.
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,
so that you can pick up a's, so you can pick up
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
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
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
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
23 DR. HIGH: I have a question about skeletal
24 myoblast processing. For material derived from
humans, is expansion to a set number ever a
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
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.
And if you try to design a trial that assumes that,
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
pointed out, it's going to be different from each
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
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
want to collect any kind of data.
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.
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
looking at karyotypic stability of cells. And even
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
that you put in.
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
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
denominator--right?--the denominator's going to be
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
23 And I think that is the kind of assay that
24 makes a lot of sense in this particular setting,
because once they're terminally differentiated,
1 they're not going to continue to divide in the
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
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
affect in vivo survival and differentiation, as
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
vary in even individual patients, so that there can
1 be a net body of information in the literature, it
2 would be helpful retrospectively in evaluating the
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
population, or SP cells, which are very small in
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
we don't know what is the--and it's the point you
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
struggle to understand--and it gets back to Dr.
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,
so the changes in each passage, they become more
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
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
10 So I think you have to factor into trial
11 design the injection patterns for these cells as
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
didn't hear much about it yesterday--I don't think
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
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,
and they're undergoing cytokine withdrawal,
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
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
to achieve the highest dose
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
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
have to be done and looked at the data
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
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
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
more relevant figure, rather than passage number;
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.
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
these things. And, in addition,
I think it's very
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
have some readout on what that composition of the
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
doing may be equally important in what they might
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
whatever is decided would be done on all products.
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
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
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
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
we wish to do are true North. I
think we need a
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
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
hind-limb ischemia. And I think
both of those are
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
vitro surrogates, and even in vivo surrogates
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
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
shown that, you know, when--even if you take
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
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
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--
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.
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
certainly the experience in giving GCSF by our
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
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
comments. They're very useful.
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
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
cell gamish of interest into immuno-compromised
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
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
testing an individual patient's cells prior to
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
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
was isolated--as, clearly, distinction, because
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
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
unstable karyotypes, even if retrospectively to go
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
decide that and come back and say this is what we
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
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
vivo assay with a beneficial effect or a
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
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
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
what they're doing, and so you need that. You
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 for