FOOD AND DRUG ADMINISTRATION








                              MEETING #37







                         Friday, March 19, 2004


                               8:30 a.m.




                              Hilton Hotel

                        Silver Spring, Maryland








                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

                            Cardiac Disease


      Open Public Hearing                                        9


      FDA Charge to Committee--Introduction of Questions

                Stephen Grant, M.D.                             37


      Committee Discussion of Questions                         53


      Closing Remarks/Adjourn                                  270




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


  2                          Call to Order


  3             CHAIRMAN RAO: Welcome to the discussion


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


  5   these meetings, we have to go around and


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


  7   and then open it up for public questions


  8   subsequently.


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


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


 11   around the table.


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


 13   president of clinical research and development and


 14   Wyeth Research, and I sit on the committee as


 15   industry representative.


 16             CHAIRMAN RAO: All right.


 17             DR. SIMONS: Michael Simons of Dartmouth


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


 19   a cardiologist.


 20            DR. SCHNEIDER: Michael Schneider, Center


 21   for Cardiovascular Development, Baylor College of


 22   Medicine.  I'm a cardiologist and molecular


 23   biologist with an interest in cardiac growth and


 24   cardiac progenitor cells.


 25             DR. CUNNINGHAM: Susanna Cunningham from




  1   the University of Washington School of Nursing in


  2   Seattle, and I am the consumer representative,


  3   usually with the Cardiovascular-Renal Advisory


  4   Committee.


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


  6   cardiologist from New York.  I am chief of the


  7   Cardiovascular Pathophysiology Division at Cornell,


  8   and the head of the Howard Gillman Institute at


  9   Cornell, and chair of the Cardio-Renal Advisory


 10   Committee of the FDA.


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


 12   of the Islet and Autoimmunity Branch at the NIDDR,


 13   within the NIH.  My interests are immunotherapies


 14   for diabetes and islet transplantation.


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


 16   professor of statistics at North Carolina State


 17   University.


 18             DR. MULE: Jim Mule, associate center


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


 20   oversee cell-based therapies for the treatment of


 21   cancer.


 22             DR. MURRAY: Tom Murray, resident of the


 23   Hastings Cents Center; a long interest in ethical


 24   issues in medicine and science.  I write a lot


 25   about genetics and some of these new cellular and




  1   gene-based therapies.


  2             CHAIRMAN RAO: Dr. Ruskin, we missed


  3   you--can you--


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


  5   cardiologist and electrophysiologist, and I direct


  6   the Cardiac Arrhythmia Service at Massachusetts


  7   General Hospital.


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


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


 10   cell biologist.


 11             MS. DAPOLITO: Gail Dapolito, Executive


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


 13   introduce the Committee Management Specialist,


 14   Roseanna, Harvey.


 15             Thank you.


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


 17   a pediatric hematologist-oncologist, and I run the


 18   pediatric bone marrow transplant program at Duke,


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


 20   interest in cord-blood stem cells;


 21   transdifferentiation and plasticity.


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


 23   hematologist at the University of Pennsylvania, and


 24   my research interests are in gene transfer as a


 25   means of treating bleeding disorders.




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


  2   virologist at the Southwest Foundation in San


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


  4   AIDS pathogenesis.  I also sit on the HHS


  5   Secretary's Advisory Committee on


  6   Xenotransplantation.


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


  8   at the University of Minnesota in the Department of


  9   Pediatric Bone Marrow Transplantation.  Our lab is


 10   focused on the immunobiology of bone marrow


 11   transplantation and its complications.  In


 12   addition, we're using non-hematopoietic cell


 13   therapy to treat organ tissue injury after bone


 14   marrow transplantation.


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


 16   clinical director of NHLBI.  I'm a clinical


 17   cardiologist by training.


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


 19   product reviewer with CBER, Office of Cellular,


 20   Tissue and Gene Therapy.


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


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


 23   the Office of Cellular, Tissue and Gene Therapy.


 24   And my training background is immunopathology and


 25   toxicology.




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


  2   I'm a medical officer at the FDA.


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


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


  5   reviewer, and I'm also a cardiologist.


  6             DR. NOGUCHI: Phil Noguchi, acting director


  7   of the Office of Cellular, Tissue and Gene


  8   Therapies.


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


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


 11   remarks.


 12                       FDA Opening Remarks


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


 14   short, because we have a lot to accomplish.


 15             The first acknowledgment I'd like to do is


 16   we neglected yesterday to say that this is Dr.


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


 18   the BRMAC committee, and we gave him an easy


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


 20   today.


 21             [Laughter.]


 22             And to pick up with apologies to Gandhi,


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


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


 25   have some laughs yesterday, but it was not laughs




  1   about the absurdity of the approach but, really,


  2   about all the nuances that we see.


  3             There was a quote today in the Washington


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


  5   instead of fighting, I would say we are fulfilling


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


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


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


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


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


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


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


 13   be time for opening the Open Public Hearing.


 14             Thank you.


 15             CHAIRMAN RAO: We have a couple of people


 16   who wanted to make comments.  And I want to


 17   emphasize right now that if anybody else from the


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


 19   time to make it.  Sometimes making comments at the


 20   time when the committee is deliberating becomes


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


 22   given the time constraints as well.


 23                       Open Public Hearing


 24             CHAIRMAN RAO: The first speaker is going


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




  1   about five minutes.


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


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


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


  5   medical director for Parexel, a large CRO based in


  6   Waltham, Massachusetts.  During this time I"ve


  7   worked with GenVec, formerly known to us as


  8   Diacrin, as both a medical monitor and a consultant


  9   in the implementation of their clinical trials,


 10   using autologous myoblast transplantation.


 11             I would like to very briefly summarize the


 12   currently updated results of the three Phase I


 13   pilot safety and feasibility studies--as I believe


 14   that GenVec currently has the largest clinical


 15   experience in the United States.


 16             Next slide, please.


 17             [Slide.]


 18             This is just a brief overview.  And all


 19   subjects in these studies have received their


 20   multiple epicardial injections in the region of


 21   maximal transmural myocardial, epicardial scar.


 22             The first study was just six patients, all


 23   of whom received 300 million myoblasts concurrent


 24   with LVAD replacement as a bridge to heart


 25   transplantation.  I believe that HeartMate was used




  1   in all of them.


  2             The second concurrently running--run CABG


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


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


  5   30 percent, and the injection of myoblasts was done


  6   concurrent with their bypass grafting.


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


  8   cohort of 10 evaluable patients.  All of these


  9   patients, however, had injection of 300 million


 10   myoblasts.  However, this group had a much more


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


 12   evaluation and follow-up using core laboratories


 13   standardized protocols for Echo, MRI, PET and


 14   multiple, multiple 24-hour Holter examinations.


 15             Next slide, please.


 16             [Slide.]


 17             In slightly more detail, this is the six


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


 19   the CHF patients.  Three of the patients received


 20   heart transplantations.  Two died, and one is still


 21   awaiting transplant after over two years.


 22             Histologic--as part of the informed


 23   consent, the explanted hearts were to be made


 24   available for histologic evaluation, and that has


 25   been completed in five evaluable patients.  That




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


  2   see the reference there.


  3             We couldn't identify any related SAEs.


  4             Next slide, please.


  5             [Slide.]


  6             This is the dose-escalation study in four


  7   separate cohorts.  You can see the number of cells


  8   was much smaller than was mentioned yesterday in


  9   the Paris study.  The initial three only got 10


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


 11   final three got the 300 million myoblasts.  Seven


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


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


 14   really find any obviously related SAEs in this


 15   group.


 16             Next slide, please.


 17             [Slide.]


 18             In the most recent and current study,


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


 20   being enrolled--all these patients received the 300


 21   million myoblast cells.  There was one early


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


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


 24   already out of the hospital two days, and a


 25   question of primary arrhythmia versus an infarct. 




  1   And on autopsy, he had fresh thrombus in a


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


  3   of the right.  We suspect that that fit his


  4   clinical pattern and he had a primary MI.


  5             And, again, all these patients are getting


  6   thoroughly evaluated by serial MRIs, echo, PETs,


  7   multiple Holters, by standardized core labs.


  8             Next slide, please.


  9             [Slide.]


 10             And in slightly closer focus--as obviously


 11   the AICD, and the arrhythmias is significant issue,


 12   both clinically and from a regulatory


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


 14   about all these folks.


 15             The first--the first patient listed there


 16   had an AICD placed prophylactically at week two.


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


 18   chest pain within a week after being discharge.


 19   Urgently re-cathed; had significant kinks in his


 20   mammary graft; question of flow limitation.  Placed


 21   on Amyoterone, resolved his arrhythmias, but he had


 22   an AICD placed prophylactically anyway.


 23             The next two patients are very similar,


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


 25   AICDs placed, essentially due to progressive heart




  1   failure.  There was no improvement after


  2   the--cardiac function after their grafts.  Neither


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


  4   these three have had a shock.


  5             And then, the last group, one patient had


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


  7   also severe LV dysfunction.  His pre- and


  8   post-operative Holters, however, were not really


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


 10   last one had it, again, placed prophylactically for


 11   a position T-wave alternans test, which some


 12   cardiologists feel has significant prognostic


 13   significance.


 14             So my conclusion from evaluating this is


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


 16   than specific procedure-related variables, and do


 17   reflect some expanding indications for the use of


 18   AICDs in this problematic patient group, over just


 19   the four years that these have been running.


 20             And the last slide, please.


 21             [Slide.]


 22             Thus, the total enrollment is 28 patients


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


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


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




  1   could not identify any specific procedure,


  2   rejection-related complications; really no


  3   definitive SAEs--that one possibility, but probably


  4   not.


  5             Histologic evidence for cell survival is


  6   currently available.  And the standardized core lab


  7   assessment for all the things mentioned, including


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


  9   and GenVec thank you for the opportunity to present


 10   this data to the committee and the FDA.


 11             Thank you very much.


 12             [Applause.]


 13             CHAIRMAN RAO: There's just one question


 14   for you from the committee, Dr. Salomon.


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


 16   the results are pending from the core labs, there


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


 18   me ask anyway.


 19             If I understood properly, one of your


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


 21   study--


 22             DR. SALOMON: Dose escalation, yes.


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


 24   one dose given to four different groups; one dose


 25   to each group.  That's right?




  1             Okay.  So you can define a dose-response


  2   curve from those data, albeit the numbers are


  3   small, you could.


  4             Do I understand correctly we don't know if


  5   cell survival varied among the doses used in any


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


  7   any functional parameter that was altered by the


  8   treatment in a dose-related way?


  9             And the reason I ask, obviously, is that


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


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


 12   could provide a great deal of information, you


 13   know, if the information become available. So


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


 15   study.


 16             The others are, you know, observational


 17   studies with millions of confounds.  This one has


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


 19   surgery that everybody had, there was a


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


 21   dose design.


 22             Can you tell us anything about results in


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


 24             DR. SALOMON: You know, this was really


 25   confined--with no allusion to efficacy whatsoever,




  1   of course, in terms of functional alterations.  I


  2   haven't addressed that whatsoever.  So--


  3             DR. BORER: But you made measurements.  You


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


  5             DR. SALOMON: Oh, sure.


  6             DR. BORER: You have stuff.


  7             DR. SALOMON: Sure.  Sure.


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


  9   could look at efficacy.  I was just asking about


 10   functional concomitants of treatment.


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


 12             No--the answer is no obvious correlation;


 13   no dose-related correlation.  Correct.  Too many


 14   variables.


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


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


 17   question of the FDA.


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


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


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


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


 22   information.  None.


 23             So here are patients who are being exposed


 24   to some risk, with the expectation of having no


 25   information, because there's a CABG.




  1             What is the FDA policy on something like


  2   this.


  3             CHAIRMAN RAO: Let's leave that question


  4   for later, then, Dr. Epstein.


  5             Yes?


  6             DR. SCHNEIDER: I have a question for you


  7   about patient recruitment for the Diagran GenVex


  8   study.


  9             How many recruiting centers were involved?


 10   What was the average number of patients recruited


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


 12   patients recruited by each?


 13             DR. SALOMON: By each center?


 14             DR. SCHNEIDER: By each center.  Because


 15   one of the issue in a trial like this is


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


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


 18   level of participation and recruitment by the


 19   centers.


 20             DR. SALOMON: Yes--excellent question.


 21             There was a predominance of--I guess I


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


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


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


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




  1   centers, but virtually 80 percent of the patients


  2   came from three to four of the centers.


  3             DR. SCHNEIDER: And the other 20 percent


  4   came from centers that were doing one or two


  5   patients each?


  6             DR. SALOMON: Had fewer patients


  7   each--correct.  Correct.


  8             CHAIRMAN RAO: Thank you, Dr. Salomon.


  9             DR. CUNNINGHAM: What were the genders of


 10   the patients?


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


 12   patients, only two female.


 13             DR. CUNNINGHAM: Thank you.


 14             CHAIRMAN RAO: Thank you.


 15             Dr. Reiss?


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


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


 18   at this meeting for the last day and am somewhat


 19   frustrated.


 20             I'm a clinical heart surgeon at the


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


 22   basic science laboratory, and we are also planning


 23   to do cardiac trials will cellular therapy.


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


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




  1   information from the cardiac surgeon side--and a


  2   little bit of rebuttal to Dr. Epstein.


  3             I do not believe that just because we can


  4   put these in with catheters that that is the actual


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


  6   operating room, with the heart under diastolic


  7   arrest, completely in a controlled setting that is


  8   probably the most controlled, most sterile setting


  9   we have from clinicians today is the cardiac


 10   operating room.  And just some of the quick points


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


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


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


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


 15   heart and seen no difference in wall motion,


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


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


 18   not see anything at all.


 19             If you put cells in that area that you did


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


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


 22   showed beautiful cardiac MRI images with very


 23   specific areas of the heart and the walls that can


 24   be followed with high definition.  We can see what


 25   happens to the area that is not revasculizable with




  1   a CABG graft.


  2             And I would say that all the concerns that


  3   have been raised with catheters--we heard yesterday


  4   that the catheter was very safe, and nothing ever


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


  6   Cardiac surgeons repair valves, we repair aortas.


  7   That thin transverses the groin, the aortic arch.


  8   There's all kinds of misadventures that happen with


  9   catheters that cardiac surgeons have to fix.


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


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


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


 13   I think that is going to be eventually how the


 14   majority of cellular therapy is going to be


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


 16   trials probably should be also considered in the


 17   cardiac setting, in the operating room, where much


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


 19   injection, under arrested heart.


 20             And the last thing, about safety: all our


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


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


 23   And we can also apply what other types of safety


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


 25   often the catheter patients do not get the same




  1   level of post-operative monitoring.


  2             So, just a plug for the cardiac surgery


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


  4   under-represented.


  5             CHAIRMAN RAO: Thank you, Dr. Reiss.


  6             Dr. O'Callaghan?




  8             DR. O'CALLAGHAN: My name is Michael


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


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


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


 12   look after safety and efficacy for the cell


 13   products and many other products at Genzyme.


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


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


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


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


 18             I would remind people of this document


 19   called "Innovation and Stagnation," which is a


 20   document that just recently came out from the FDA.


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


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


 23   submitted to the FDA, and progressively over the


 24   next 10 years to 2003, there was virtually a


 25   straight line downward plunge to 14 last year.  If




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


  2   So by 2007, there won't be any.


  3             So, I think what we're talking about


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


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


  6   or procedure or strategy that will allow industry


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


  8   and faster or more efficient approach to this.


  9             If you think about some of the issues that


 10   have been discussed and the complexity of what


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


 12   yesterday's conversation that many of the


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


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


 15   themselves.  So if you think about the emboli that


 16   were produced in the intra-coronary delivery, or


 17   you think about needle tracks or catheter delivery


 18   systems that ago through the wall or travel through


 19   the heart, there is a primary pathology created by


 20   that.


 21             On top of that, there is the pathology


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


 23   recent infarct or an old infarct, which complicates


 24   interpretation, and complicates the safety and


 25   efficacy issues we're trying to deal with.




  1             A third variable, of course, is the cell


  2   death that we all heard about, obviously invokes


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


  4   have our understanding of the pathological, or


  5   physiological processes that we have in great


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


  7   background in trying to understand how to provide


  8   studies that answer the safety questions or the


  9   efficacy questions.


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


 11   attempting--with the few surviving cells that are


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


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


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


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


 16   CABG.


 17             So, how does that translate to dealing


 18   with the regulatory authorities in trying to


 19   demonstrate that there is safety and that there is


 20   efficacy?  The difficulty, of course, is that


 21   background.  I think the other difficulty is


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


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


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


 25   poker game, where each one is holding the cards




  1   against their own chest and only giving out the


  2   card that matters.  And that goes on for several


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


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


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


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


  7   very slowly.


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


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


 10   make the process more transparent so that quicker


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


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


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


 14   interact with industry.  And, secondly, what was


 15   pointed out yesterday by Dr. Noguchi and McFarland,


 16   how to translate that down to the individual case,


 17   where the sponsor and the FDA are having to work


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


 19   to get to a satisfactory solution as quickly as


 20   possible.


 21             Thank you.


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


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


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


 25   some of these things into an appropriate




  1   methodology that can be used.


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


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


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


  5   BLA application is.


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


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


  8   the authority of a section of the Public Health


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


 10   in a parallel situation to the Food, Drug and


 11   Cosmetic Act.  The main distinction, from the legal


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


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


 14   simultaneous BLA, and vice versa.


 15             The basic requirements for a license


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


 17   a hypothetical example of a cellular product for


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


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


 20   do not need to have an ultimately precise


 21   definition and specification for a pure entity,


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


 23   time after time after time, within certain limits.


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


 25   law--the legislative history is basically states:




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


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


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


  4   or her capacity, will have some confidence that


  5   when this product is given that their patient will


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


  7   be better after than before.


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


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


 10   you have something that we know works, and can


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


 12   which is usually based on planned clinical


 13   trials--occasionally we may have historical data


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


 15   clearly, for experimental products such this--we


 16   heard yesterday, eloquently--that without a placebo


 17   how do you know that this is actually working,


 18   since all the non-controlled trials say they all


 19   work.


 20             So if it's effective in a reproducible


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


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


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


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


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




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


  2   the physician the maximum flexibility in


  3   prescription, as well as to validate and provide


  4   that assurance that the product actually works and


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


  6   all about.


  7             It can be done by a major pharmaceutical


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


  9   by universities and by state public health


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


 11   can go all the way from the very largest


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


 13   patient trials down to even those with about five


 14   to 10.


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


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


 17   approve it.


 18             CHAIRMAN RAO: Thank you.


 19             I think a couple of people have questions


 20   for you, sir.


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


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


 23   rather a large number of these BLA applications in


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


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




  1   the interpretation of it was what is not clear to


  2   me.


  3             DR. NOGUCHI: Yes, myself not having all


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


  5   else, it depends on what is put into the


  6   publication.  We do, for example, license blood


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


  8   much higher rate.  We do not necessarily count


  9   those as new molecular entities.


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


 11   biologics applications, but also for molecular


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


 13   very real sense there has been a tremendous set of


 14   developments and follow-through of things that are


 15   known.  And we have entered, somewhat


 16   asynchronously, a time where there a lot of things


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


 18   All the easier diseases really have been done, and


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


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


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


 22   progress above and beyond extension of live for


 23   several months, or--and so forth.


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


 25   known has been done for those diseases for which we




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


  2   all the rest of them here: cardiovascular disease,


  3   congestive heart failure.  We saw how the cascade


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


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


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


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


  8   a great degree, on what the science and knowledge


  9   of disease is.


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


 11   are seeing fewer applications in the whole drugs


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


 13   scientific knowledge, on the one hand, for making


 14   products is expanding rapidly, but our


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


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


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


 18   to what we already know.


 19             There are no easy solutions to any of


 20   these diseases that we see right at the moment.


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


 22             Dr. McClellan's emphasis on the


 23   critical-path initiative is really to try to help


 24   everyone to come back and focus as to what are


 25   those things that will make a difference, and then




  1   what are those things that are simply going to be


  2   increments and improvements that may only give us a


  3   little bit of extension of life, a little bit


  4   longer acting drug, but may not be actually


  5   altering the fundamental disease.


  6             CHAIRMAN RAO: Joanne?


  7             DR. KURTZBERG: I have a question that goes


  8   back to the cardiac transplantation issue at


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


 10             In the current proposed tissue regs,


 11   minimally manipulated or non-manipulated products


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


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


 14   and you transplant it directly into the patient,


 15   there's no license involved with doing that.


 16             And some of the therapies that both are


 17   being done now and are being proposed involve what


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


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


 20   usually autologous, or mobilized blood, or even


 21   CD34 AC133-- selected products for which there


 22   already are devices that are either under IND or


 23   licensed.


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


 25   therapy crosses a bridge between using things that




  1   we use already, but just putting them in a


  2   different place; and then, also, modifying


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


  4   other technology.


  5             You could interpret the regs as they are


  6   proposed as saying the minimally manipulated


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


  8   the ex vivo manipulated or culture, transfected,


  9   etcetera and so forth products do.


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


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


 12   this meeting to try to focus on the question of


 13   whether we need this approach versus that approach.


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


 15             First, the tissue regulations are still in


 16   the process of being finalized.  However, the


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


 18   you use something that would otherwise be


 19   considered to be not manipulated beyond its normal


 20   biological characteristics, if it's used in a


 21   manner that inherently does not seem that it


 22   logically follows--which is what happens in this


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


 24   throughout the past year, in terms of the active


 25   literature, if bone marrow cells of whatever never,




  1   however purified, are put into the heart by means


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


  3   procedures, that, in fact, either you get


  4   regeneration of heart, you get vascularization, you


  5   get transdifferentiation--none of which have been


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


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


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


  9   not been shown, and the current science does not


 10   show that any of those possibilities are actually,


 11   in fact, what happens.


 12             And so, for that reason, we are saying


 13   these are highly experimental procedures they're


 14   using in addition to the product itself, which is


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


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


 17   put together, clearly merit the justification and


 18   the overview of FDA regulation at the IND level.


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


 20   But--


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


 22   because this is not part of the whole mandate for


 23   the committee.  And these questions--this whole


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


 25   BLA.




  1             DR. KURTZBERG: But it is important.


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


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


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


  5   the other indication therapy.


  6             CHAIRMAN RAO: And that's certainly an


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


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


  9   of our mandate for the question.


 10             [Pause.]


 11             Are there any additional comments from the


 12   audience?  Anyone?


 13             Go ahead.  Just make sure you identify


 14   yourself, and if you have any financial--


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


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


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


 18   Curion.


 19             I would like to make a comment to the


 20   issue of immunosuppression in animal studies.


 21   There has been a position by Dr. Itescu yesterday


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


 23   immuno-compromised animals treated with cyclosporin


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


 25   studies.




  1             I would like to challenge that position a


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


  3   cells are quite heterogeneous, and we see the


  4   problem that how can we make sure that an animal


  5   stem cell preparation is really very homologous to


  6   the human stem cell preparation, which may carry


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


  8   the cell composition or other factors.  And we


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


 10   or to decide whether the animal stem cells are


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


 12   properties, the same purities as the human product.


 13             So we had made a conscious decision to


 14   work with immunosuppressed animals,


 15   immuno-compromised porcine--pigs, treated with


 16   cyclosporin, and tested our stem cells, human stem


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


 18             And I think taking that strategy, we are


 19   on the safe side with respect to testing our


 20   products in terms of efficacy and safety, because


 21   we don't have to make this transition or


 22   translation of the animal that, say, the animal


 23   data generated with animal stem cells then into the


 24   human setting.


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




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


  2   xenograft, or xenograft-avoiding strategy, but it


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


  4   now have a dogma that studies with


  5   immuno-suppressed animals would make sense in this


  6   context.


  7             CHAIRMAN RAO: Thank you.


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


  9   valid point.


 10             The point that I was making simply is if


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


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


 13   account the potential effects of the drugs on the


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


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


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


 17   of models.


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


 19             Briefly?  Is this relevant.


 20             AUDIENCE MEMBER: I'm very sorry to


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


 22   get a response--at least from me.


 23             And the other issue is the clinical trial


 24   design, with human subject protection.  And these


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




  1   stand-alone procedure, because clearly you have to


  2   get safety and feasibility first.


  3             So, it's really difficult to do cell


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


  5   procedure, and they had to be done concomitantly


  6   with bypass grafting.  I think that was really the


  7   rational; not to prove efficacy.


  8             Thank you.


  9             CHAIRMAN RAO: Thank you.


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


 11   questions.


 12             Dr. Grant?


 13                     FDA Charge to Committee


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


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


 16   cardiologist.


 17             I wanted to start out today by thanking


 18   the members of the committee and the invited


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


 20   enough to join us during the open public


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


 22   We know they all have very busy and very productive


 23   professional lives, and we thank you for joining us


 24   today to discuss these very important issues.


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




  1   asked you to come here yesterday and today.  And


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


  3   to discuss.


  4             Next slide, please.


  5             [Slide.]


  6             We have asked you to discuss certain


  7   safety concerns that need to be addressed to


  8   initiate human trials of cellular therapies for


  9   cardiovascular diseases.  These concerns are part


 10   of our mission to promote and protect public


 11   health.  We are, however, also responsible for


 12   facilitating the development of safe and effective


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


 14   was made to the FDA Mission Statement in August


 15   2003.


 16             This revision explicitly states that "the


 17   FDA is responsible for advancing the public health


 18   by helping to speed innovations that make medicines


 19   and foods more effective, safer and more


 20   affordable."


 21             Although this was made explicit in the


 22   2003 revision, facilitating the development of safe


 23   and effective therapies does promote the public


 24   health, so I would argue that this was always


 25   implicit in our mission statement.




  1             We have convened the committee to solicit


  2   advice about certain issues that have delayed the


  3   development of potential therapies for


  4   cardiovascular disease.


  5             Next slide, please.


  6             [Slide.]


  7             Here's one of the clinical challenges that


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


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


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


 11   United States who acute myocardial infarction every


 12   year.


 13             For those of us who have a bit of gray


 14   hair, they can remember when taking care of MIs


 15   consisted essentially of putting people to bed.


 16   The mortality rate for MI has been declining fairly


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


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


 19   large part, to the advent of reperfusion therapy;


 20   both thrombolysis and percutaneous coronary


 21   intervention.  However, these therapies are not


 22   entirely effective.  Most patients who will suffer


 23   acute myocardial infarction will be left with a


 24   variable amount of left ventricular dysfunction.


 25             Because increasing numbers of these




  1   patients are surviving, there are many, many more


  2   patients each year that have diminished cardiac


  3   reserve.  It fact, congestive heart failure is the


  4   only cardiovascular diagnosis whose absolute


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


  6   partially due to the aging of the population, but


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


  8             And therefore we are very interested in


  9   facilitating cellular therapies because they may


 10   benefit these growing numbers of patients with


 11   congestive heart failure.


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


 13   the only indication for which I think these


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


 15   this is an appropriate indication.  Conceptually,


 16   there are many, many other types of cardiac disease


 17   that could be benefitted by cellular therapy.


 18             Next slide, please.


 19             [Slide.]


 20             I'm going to talk a bit about the


 21   regulatory requirements.  Before a new product is


 22   administered to humans, FDA is required to conduct


 23   an independent and detailed assessment of the risk


 24   to human subjects.  The regulations provide the


 25   mechanism by which we conduct this assessment. 




  1   They provide the framework wherein we can answer


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


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


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


  5   is: how do we balance individual subject safety


  6   against the potential public health benefits of new


  7   therapy?


  8             The risks are borne by the few, and the


  9   benefits go to the many.  And our society has


 10   designed a mechanism, and provide a framework, and


 11   charged us to make this assessment.  And the


 12   regulations are how we do that.


 13             This risk assessment must be


 14   sufficiently--must include sufficiently detailed


 15   information regarding the following: product


 16   characterization and safety testing.  And I think


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


 18   wouldn't transmit, for example, infectious agents


 19   in a product.


 20             Product characterization--as Dr. Noguchi


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


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


 23   you know the--you can characterize the reagents


 24   that go into it.  You know and understand precisely


 25   the manufacturing processes.  You can chemically




  1   characterize what comes out.  You understand--you


  2   manufacture the pill.


  3             We talk about manufacturing with cellular


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


  5   always sounds a little strange to talk about


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


  7   process that we use to produce these cells, and


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


  9   characterize them.  But, still, there are certain


 10   concerns that we have to be able to characterize


 11   that end product in some way that's


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


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


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


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


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


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


 18   who are given something you don't understand.


 19             You have to provide supportive


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


 21   data that allows us to independently assess the


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


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


 24   finding appropriate pre-clinical models.  That


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




  1   you from not having any.


  2             And you need to be able to identify a safe


  3   starting dose.  And then you need to have a


  4   monitoring plan that suggests that you're going to


  5   be able to detect the adverse events in a timely


  6   fashion, so that any subject that suffers those


  7   adverse events can be identified and treated


  8   quickly, and so that subsequent subjects will not


  9   be exposed to the same adverse events.


 10             Next slide, please.


 11             [Slide.]


 12             And with that as the background, I want to


 13   go through the common issues that have delayed


 14   initiation of clinical trials in this area--and


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


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


 17   identified as being problems.


 18             One: the cellular product that is


 19   administered--or the cellular product that's


 20   proposed for the clinical trial is different from


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


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


 23   certainly heard yesterday people who would say once


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


 25   may have seen them all.  But there may be




  1   differences within these preparations.


  2             Secondly: insufficiently detailed safety


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


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


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


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


  7   analysis and, generally, publications will not


  8   include a detailed protocol, which will include all


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


 10   include either the case report forms for a clinical


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


 12   or non-clinical study.


 13             Three: limited information about the


 14   compatibility of the cellular product and the


 15   delivery device.


 16             Four: an inadequate plan for monitoring of


 17   subjects during and after product administration.


 18             And I think you'll see that the questions


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


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


 21   first six clearly all are derived from these


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


 23   so that we can help understand how to resolve


 24   these, and so the investigator community can help


 25   understand, so that we can get submissions that




  1   will go forward.


  2             Next slide, please.


  3             [Slide.]


  4             So the advice that we seek from you are


  5   general comments and recommendations about certain


  6   manufacturing issues, certain preclinical testing


  7   issues, and about pilot clinical design, with


  8   respect to certain issues that need to be addressed


  9   to permit safe initiation of clinical


 10   development--which we are quite anxious to see


 11   happen.


 12             Next slide, please.


 13             [Slide.]


 14             Question 1--well, these first two


 15   questions are going to relate to safety in


 16   characterization of the cellular product.


 17             Question 1: we know that because the


 18   specific cells, mechanism of action and cell-device


 19   interactions are still in very early stages of


 20   investigation, the appropriate and adequate safety


 21   testing and characterization have not yet been


 22   defined, and may conceptually vary, based on the


 23   cell source and type of manipulation.


 24             We would like you to discuss the intrinsic


 25   safety concerns for cellular products for the




  1   treatment of cardiovascular diseases, and the


  2   testing that should be performed to ensure


  3   administration of a safe product.  Among the


  4   factors that you might consider are tissue source,


  5   manufacturing process, formulation, storage, route


  6   and site of administration.


  7             In your printed version, in the briefing


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


  9   means think that you have to discuss each of those


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


 11   in your discussion of the overall question.  And I


 12   would caution the committee to try to remember that


 13   we're talking here about treatments of cardiac


 14   diseases.  The larger field of cell therapy is


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


 16   specifics of cardiac therapy today.


 17             Question 2--


 18             Next slide, please.


 19             [Slide.]


 20             --these products are all heterogeneous, in


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


 22   the biomarkers also are different on different cell


 23   types; the degree of heterogeneity present in


 24   administered cellular products may be an important


 25   variable in characterization or in determining




  1   their safety or efficacy.


  2             Therefore, please comment on the elements


  3   of product identity and characterization necessary


  4   to generate meaningful data about safety and


  5   efficacy.  And, conceptually, we think that these


  6   may include comments about specific


  7   biomarkers--that would be most particularly with


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


  9   percentages of cell types that would apply to both


 10   the products derived from muscle biopsies, as well


 11   as those derived from bone marrow or from


 12   peripheral blood.


 13             And there may be other parameters that you


 14   would identify as being important.  And we would


 15   ask for your comments.


 16             Next slide, please.


 17             [Slide.]


 18             Question No. 3--the next couple of


 19   questions, 3 and 4, concern the kinds of


 20   pre-clinical data needed to assess safety, and


 21   identify a safe starting dose prior to initiating


 22   human clinical trials.


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


 24   discussion of this.  Various animal models have


 25   been proposed to support the safety of cellular




  1   products used in the treatment of cardiac disease.


  2    These include studies of both small and large


  3   species; studies utilizing either immune-competent


  4   or immuno-compromised animals.


  5             Each model has some advantages and


  6   limitations, which have been reviewed by the


  7   speakers and previously discussed.  For instance,


  8   human cellular products can be tested in


  9   genetically immuno-compromised rodents, but these


 10   animals provide limited clinical monitoring of


 11   cardiac function, and cannot be used to assess the


 12   safety of devices.  Large animals allow for more


 13   extensive monitoring of cardiac function and the


 14   use of the same delivery device intended for


 15   clinical use.


 16             Please discuss the merits and limitations


 17   of various large and small animal species for


 18   providing pharmacologic, physiologic and


 19   toxicologic support for cellular products used in


 20   the treatment of cardiac disease, and please


 21   consider the following: the intended human clinical


 22   cellular product; the delivery system that's


 23   proposed in the clinical trial; and extrapolation


 24   of study results from animals to humans.


 25             Question No. 4: Please discuss the merits




  1   of animal models of ischemic disease with respect


  2   to ability to generate proof of concept data, and


  3   generate toxicologic data of relevance to the


  4   clinical disease.  And, conceptually, animal models


  5   of ischemic disease could include normal


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


  7   presented a very interesting study with essentially


  8   normal dogs.


  9             The models--again, the models of ischemia


 10   that are available are many; cryoablation,


 11   ligation, ligation-reperfusion, ameroids.


 12             Question No. 5, please


 13             [Slide.]


 14             The next question concerns the types of


 15   evacuations needed to assess the compatibility of


 16   the cellular product with the delivery device.


 17   Please discuss evaluation of potential interactions


 18   between cellular products and cardiac catheters;


 19   adverse effects of catheters on the viability and


 20   functionality of a specific cellular product;


 21   factors other than cell concentration and simple


 22   viscosity that might contribute to clogging or


 23   other adverse events; injection of cells into


 24   system circulation, the pericardial space, thoracic


 25   space via needle catheter; effects of depth or




  1   spread of injection into they myocardium on either


  2   the safety or, potentially, the efficacy.


  3             Question No. 6--these last two questions


  4   are about two design elements of early-phase


  5   clinical trials.  The theoretical risk of these


  6   products include the generation of non-cardiac


  7   tissues, abnormal cardiac tissue and/or local


  8   inflammation.  These outcomes potentially could


  9   lead to myocardial dysfunction, arrhythmias, or


 10   conduction abnormalities.


 11             Also, these products are administered


 12   because some of the cells contained are


 13   self-renewing and possess developmental plasticity;


 14   that is, they can differentiate into cells not


 15   found in the tissue from which they were obtained.


 16   Since uncontrolled cellular proliferation may


 17   result in tumor genesis, these products could


 18   theoretically result in subjects' developing


 19   neoplasia.


 20             So, please discuss the appropriate


 21   frequency and duration of follow-up.  In addition


 22   to any other events, please consider the following


 23   potential adverse pathological and clinical events


 24   in your discussion items: scar formation, left


 25   ventricular dysfunction, ventricular arrhythmias,




  1   and neoplasia.


  2             Next question, please.


  3             [Slide.]


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


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


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


  7   discuss.  Some adverse events potentially due to


  8   administration of these products, such as


  9   ventricular arrhythmia, worsening left ventricular


 10   contractility and death may be identical to events


 11   that occur during the natural history of the


 12   underlying disease.  The subjects in these


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


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


 15   of these adverse events.


 16             Consequently, adverse events related to


 17   the cellular product or its administration might


 18   not be discernible without concomitant controls.


 19   However, invasive procedures are frequently


 20   utilized to deliver these cellular products.


 21             Please discuss the pros and cons of using


 22   control groups in these early clinical studies,


 23   including any need for randomization or masking.


 24   Within your discussion, please also comment on the


 25   use of placebos in these studies; for example,




  1   transendocardial injection of saline into the


  2   heart.


  3             I would like to make a couple of points


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


  5   this.  I want to make absolutely crystal clear that


  6   there is no--nothing in the regulations that


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


  8   there have been many Phase I studies that did have


  9   controls.  So there is no regulatory prohibition of


 10   this, nor is there any unstated policy of the


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


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


 13   make that absolutely clear.


 14             Secondly, I would--these questions, any


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


 16   think, of very useful and intelligent discussion.


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


 18   would encourage the committee to remember that


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


 20   we can resolve certain safety issues to allow


 21   initiation of early-phase clinical trials.  I would


 22   discourage you--the discussion yesterday was quite


 23   interesting, but I would discourage you from


 24   discussion of issues that are dealt with in


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




  1   eventual populations for therapy.  These are things


  2   about which we haven't presented any data.


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


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


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


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


  7             [Laughter.]


  8                Committee Discussion of Questions


  9             CHAIRMAN RAO: Thank you, Dr. Grant.


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


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


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


 13   the last few questions also fair discussion.


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


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


 16   manufacturing question, and try and get that


 17   addressed before the break.


 18             So I'm going to make some blanket


 19   statements and ask the committee to see whether


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


 21   go from there.


 22             The first statement I'm going to make is


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


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


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




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


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


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


  4   differently.


  5             That's one statement.


  6             The second statement I'm going to make is


  7   that it seems the FDA and pharmaceutical companies


  8   know about how to manufacture cells to some extent.


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


 10   presented data on what their GMP facilities look


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


 12   there will be many other companies who will be


 13   willing to tell us how they are much better at


 14   doing it.


 15             [Laughter.]


 16             So it does seem to me that the general


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


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


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


 20   know, when we look at cells that the supplies are


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


 22   worry about in terms of the discussion today.


 23   Right?


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


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




  1   each cell is different, so we can broadly divide


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


  3   particular cell type in a particular disease, or as


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


  5   irrespective of the mechanism that you use.


  6             And I'm going to further subdivide this


  7   into two broad categories.  And I think we should


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


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


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


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


 12   a statement that allogenic is different from using


 13   autologous cells.


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


 15   in my experience with growing cells in


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


 17   cells which are freshly harvested over a short time


 18   period and put back, versus cells which have been


 19   grown in culture, have been manipulated in culture.


 20   So there will be criteria which will be uniquely


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


 22   keep those sort of generic points in mind, unless


 23   people specifically disagree with any one of those


 24   statements.


 25             [Pause.]




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


  2   start with a common basis, then.


  3             [Laughter.]


  4             So let's--


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


  6   relates not necessarily to the use of fresh cells.


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


  8   regulatory hurdles involved with using fresh cells


  9   as opposed to using cultured cells--with the


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


 11   well-defined population that is being introduced


 12   into patients.


 13             With cultured cells, what I heard


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


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


 16   fetal calf serum, that is a good thing.


 17             CHAIRMAN RAO: If you could talk about some


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


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


 20             DR. MULE: Okay.


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


 22   on some edition-specific--


 23             DR. MULE: It just relates to the product


 24   characterization of using in vitro cultured cells.


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




  1   come back to it.


  2             Joanne, do you have something on--


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


  4   addition.  I mean, I agree with everything you


  5   said.


  6             I think it would be a sad comment if we


  7   came out of here with anything that recommended or


  8   facilitated a company making a product as an


  9   autologous non-manipulated bone marrow or


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


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


 12             CHAIRMAN RAO: So, given that viewpoint-and


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


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


 15   have been cultured for a long time period.


 16             Does anybody here feel specifically--like


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


 18   things that you need to worry about that are unique


 19   to cultures which have been in culture for a long


 20   time period, and which are going to be transplanted


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


 22   raised in issues before.  There was this idea of


 23   not differentiating, and there was this idea of


 24   cells changing, in terms of the different


 25   satienability, and only using the third and fourth




  1   batches.  You heard all of that, right?


  2             So anybody--specifically on those


  3   comments, on sort of long-term culture?


  4             Dr. Schneider?


  5             DR. SCHNEIDER: Well, we heard about that


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


  7   that part of the efficacy monitoring in the process


  8   of manufacturing--the skeletal myoblasts, and


  9   propagating them to a quantity sufficient for human


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


 11   not get overgrown by a sub-population that was


 12   differentiation-defective.  That's clearly


 13   important.


 14             What we did not hear as part of that


 15   presentation was that in vivo efficacy also is


 16   tested over time, or is tested for consistency


 17   between patient subgroups.  There are good clinical


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


 19   that heart failure patients, or diabetic patients


 20   have bone marrow-derived and circulating progenitor


 21   cells which are less functional in human grafting


 22   than other patients do.  And there are some cell


 23   culture and in vitro correlates of that.  The


 24   cell-culture correlates of that are decreased cell


 25   mobility and invasiveness.  The in vivo correlate




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


  2   an immuno-compromised rodent model of hind-limb


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


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


  5   are predictive models, both for clinical


  6   heterogeneity, or for potential heterogeneities


  7   introduced in the manufacturing process.


  8             So I would say that what we heard, in


  9   terms of the characterization of culture not


 10   introducing a distortion to the potential


 11   biological properties of the cells was nicely


 12   raised yesterday, but there are other elements to


 13   that, including cell heterogeneity over time, and


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


 15   talk about this morning.


 16             CHAIRMAN RAO: So, clearly, one issue is


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


 18   you should be testing them at the stage that you


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


 20   appropriate characteristics and properties that you


 21   want to use them for; and that these methodologies


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


 23   assay.


 24             And there was one other sort of issue on


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




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


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


  3   it's appropriate to separate out the different


  4   categories of the process as these questions have


  5   done.  But I think it would be unfortunate to


  6   completely separate them and forget that they


  7   overlap in many important ways.


  8             Steve Epstein suggested this in his


  9   comment about conditioned medium yesterday, and I


 10   want to restate it in another way.


 11             We track and we study what we know about.


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


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


 14   pathophysiology, or my theory of pathophysiology,


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


 16   important, characteristics and factors.


 17             So what we need to do is to combine the


 18   characterization of the product with the parameters


 19   that we know to look at with some integrator


 20   further down the road; that is, injecting these


 21   items into animals, or ultimately into people, and


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


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


 24   track meaningful endpoints, even in small studies,


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




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


  2             You'll never find those in small studies.


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


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


  5   today--but ultimately defining standards for data


  6   collection so that small data sets can be pooled in


  7   some way, so that signals can be amplified.


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


  9   characteristics that ought to be looked at to


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


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


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


 13   outcomes.


 14             So I would just make that point: that we


 15   have to be thinking about data collection


 16   strategies to allow us to pool the small data sets


 17   into large data sets that allow one to pick up


 18   signals that will tells us there's something else


 19   we should have looked at.


 20             CHAIRMAN RAO: I completely agree with you,


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


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


 23   much more important than any specific list that's


 24   developed.


 25             Doris?




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


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


  3   definition of the cells, and definition of any


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


  5   injecting--and the heterogeneity of that product.


  6   How do you define potency of a given cell


  7   population?  Is it permissible for it to be less


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


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


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


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


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


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


 14   culture.


 15             And so I'd like to--


 16             CHAIRMAN RAO: So, the important point is


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


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


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


 20   a fair way of stating it?


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


 22   range.


 23             DR. HIGH: I have a question about skeletal


 24   myoblast processing.  For material derived from


 25   humans, is expansion to a set number ever a




  1   limiting factor, or can every subject, no matter


  2   what his age, be expanded to 10                                          

                                       9 cells, and our


  3   cell numbers are lot release criteria.


  4             CHAIRMAN RAO: Doris, do you want to answer


  5   that?


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


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


  8             There are a limited number of patients


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


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


 11   other groups have published data, looking at age.


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


 13   with age and an inability to grow cells.


 14   Occasionally we end up with a patient where we


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


 16   They're just not there.


 17             Now, can you grow  10                                          

                                       9 cells?  Generally


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


 19             CHAIRMAN RAO: Go ahead, Joanne.


 20             DR. KURTZBERG: I think whenever you work


 21   with biologic products there is always an element


 22   of unpredictability, and that you can never count


 23   on every patient growing the same number of cells,


 24   every patient biologically acting the same way.


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




  1   you'll never finish your trial.


  2             So there has to be some understanding that


  3   biology is variable.


  4             DR. HIGH: But should there be some minimum


  5   number that goes into--on injecting?


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


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


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


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


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


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


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


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


 14   patient and only collected 80 percent, are you


 15   going to deny that patient that 80 percent?


 16   Probably not.  I don't know.


 17             CHAIRMAN RAO: Again, I want to


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


 19   information: this is historically a problem for all


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


 21   cellular therapy when it's a single


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


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


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


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




  1   case.


  2             And so what Dr. Borer pointed out is that


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


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


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


  6   these systems?  And from my limited experience has


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


  8   because you have some definition of markers, or


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


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


 11   substitute assay in culture.


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


 13   pancreatic islets, you say they all release this


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


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


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


 17   much dopamine is released by this particular number


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


 19   measure.


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


 21   hearing conversations seems to be that it's pretty


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


 23   variability, and that there must be some kind of


 24   equivalency measure that must be looked at if you


 25   want to collect any kind of data.




  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


 25   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


 25   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


  8   around.


  9             And, as a transplanter of hematopoietic


 10   cells, we would never put those cells through that


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


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


 13   about doing it under high pressure, which only


 14   increases the probably of cell damage.


 15             I understand there are other technical


 16   issues related to the heart and getting catheters


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


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


 19   testing that would demonstrate that cells can


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


 21   that small a hole under high pressure.


 22             CHAIRMAN RAO: Dr. Murray?


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


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


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




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


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


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


  4   hundreds of millions of cells?  Is it how many


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


  6   it how millions of cells with the normal karyotype


  7   of a particular cell type?


  8             I feel very uncomfortable with the


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


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


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


 12   Some clarity on that I think would be helpful.


 13             CHAIRMAN RAO: Doris?


 14             DR. TAYLOR: Specifically, with regard to


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


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


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


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


 19   looked at the ability of our cells to fuse and


 20   terminally differentiate and form myotubes; and


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


 22   cells.


 23             And I think that is the kind of assay that


 24   makes a lot of sense in this particular setting,


 25   because once they're terminally differentiated,




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


  2   myocardium.


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


  4   data yesterday, but we have preclinical data over a


  5   number of years showing that if we purify the cells


  6   to too great a degree of homogeneity they are less


  7   effective than if there is a mixture of cells


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


  9   mitogens that, I think, are delivered by the


 10   fibroblasts and other cells that are there.


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


 12   comment?


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


 14   passage numbers and serum requirements is really


 15   critical, and as these studies go forward, even


 16   with characterizations, if the products look the


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


 18   five or six passages, the cells may well


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


 20   in vitro.


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


 22   an optimal passage number, but I think as the


 23   studies report their results, it will be very


 24   important to discuss those two issues which may


 25   affect in vivo survival and differentiation, as




  1   well as karyotype stability.


  2             CHAIRMAN RAO: That's a really important


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


  4   felt was the sense of just this specific point:


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


  6   really critical to look at passage number.  And


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


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


  9   the same apparent phenotype as an early passage,"


 10   but that you really want to keep track of the


 11   passage number.  And you can't just automatically


 12   assume one will be the other.


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


 14   cell density.  We know that cell density is a


 15   critical influencer of differentiation potential,


 16   and minor changes in cell density can have


 17   significant abilities, not only to look at the


 18   growth rate, but can differentiate cells in ways


 19   that may be picked up in later passages because of


 20   the cell contact and growth-factor issues


 21   that--where one population influences another.


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


 23   much information in the reports as possible, to try


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


 25   vary in even individual patients, so that there can




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


  2   would be helpful retrospectively in evaluating the


  3   outcomes.


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


  5   consider also what you raised as an issue of the


  6   growth-factors in serum, and cytokines, which


  7   should be used in the manufacturing process


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


  9             AUDIENCE: Actually, it was back on the


 10   unmanipulated cells--I just wanted to make a


 11   comment on those.


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


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


 14   that time.


 15             Go ahead.


 16             DR. SCHNEIDER: Michael Schneider.


 17             I wanted to state that with respect to


 18   heterogeneity, skeletal muscle-derived cells over


 19   time in culture, in addition to the issue that


 20   Doris mentioned about the variable percentage of


 21   fibroblasts, there are two other specific


 22   populations to be vigilant about in the skeletal


 23   muscle preparations.


 24             One of them is the so-called side


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




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


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


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


  4   be important to know whether the manipulation of


  5   the skeletal muscle cells in culture over time


  6   might be depleting that from the starting


  7   population; or, alternatively, enriching for that


  8   relative to the starting population.


  9             There also has been described in rodents,


 10   by several labs, a SCA positive population, similar


 11   to the progenitor cells that we see in adult rodent


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


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


 14   But as Dr. Itescu alluded to yesterday, markers


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


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


 17   the skeletal muscle preparations.


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


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


 20   in a consistent and reliable way what is happening


 21   to these other sub-populations that may be


 22   contributing to the in vivo efficacy.


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


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


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




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


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


  3   concentration of the effective cell, in terms of


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


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


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


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


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


  9   be necessarily contributing to the skeletal muscle


 10   formation in large number, but they may be


 11   producing cytokines, growth factors, acting on the


 12   other injecting cells or, as several speakers


 13   alluded to yesterday, having some other kind of


 14   favorable effect on the host.


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


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


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


 18   appropriate dose-response.  And secondly, we may


 19   spend an enormous amount of time trying to


 20   understand the makeup of the culture before it goes


 21   into a patient.  But not having an understanding of


 22   whether certain subsets of cells within that


 23   heterogeneous population are dying off in


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


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




  1   Borer's concern about having appropriate endpoints


  2   in the trial that will allow you to get some


  3   biologic information about the cells that not only


  4   go in, but those that survive.


  5             DR. MURRAY: This is Tom Murray.


  6             My friend Carol Greider was once trying to


  7   teach me about Belgian beers.  And the lesson


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


  9   through multiple fermentations, and they utterly


 10   change their character, depending upon whether it's


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


 12   many times they do it.


 13             And I heard yesterday--and maybe a little


 14   bit even today--the possibility that in different


 15   passages the cells' properties change.  And it


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


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


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


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


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


 21   saying that that's the case.


 22             The second possibility is: they change,


 23   but in a continuous fashion.  That is, whatever


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


 25   so the changes in each passage, they become more




  1   extreme.


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


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


  4   interesting ways, such that three and five may be


  5   more alike than four.  I may have the specific


  6   numbers wrong.


  7             It would be very helpful for the FDA, I


  8   think, to ascertain what the best scientific


  9   evidence is as to which of those three models is


 10   the correct one, and then that will have


 11   implications for whatever you decide.


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


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


 14   all of this assessment that one considers, you need


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


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


 17   assessment of what that means when you get them


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


 19   been making?


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


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


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


 23   significantly change your dose, if you do something


 24   with it.  Is that a fair--


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




  1   you need to think about in considering that is that


  2   the geometry of the injections, and the number of


  3   injections is really going to probably change the


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


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


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


  7   than if you inject 10 smaller populations


  8   throughout the scar, based on the nutrients they


  9   receive.


 10             So I think you have to factor into trial


 11   design the injection patterns for these cells as


 12   well.


 13             CHAIRMAN RAO: Dr. Borer?


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


 15   about to raise really would be subsumed under the


 16   preclinical studies area, but I looked at the


 17   question, and it's really not only.


 18             And that is--and that follows from some


 19   points Dr. Itescu raised yesterday which broadly


 20   involve drug-biologic interaction.  These products


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


 22   multiple drugs in their bodies at the time the


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


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


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




  1   we know how the drugs that routinely are given to


  2   patients who have the target diseases affect the


  3   growth and development of the cell products.


  4             And I think this needs to be


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


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


  7   have to stop beta blockers for a few weeks in


  8   people with heart failure who are being given


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


 10   optimally.


 11             And I think that characterization has to


 12   begin before one gets to the in vivo experimental


 13   model studies, that it really does require some


 14   benchwork to look at the effect of drugs on the


 15   cell population.


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


 17   haven't talked about drug-biologic interactions,


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


 19   to consider throughout these discussions.


 20             CHAIRMAN RAO: Bruce?


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


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


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


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


 25   and they're undergoing cytokine withdrawal,




  1   etcetera.  Another possibility is that they're just


  2   not receiving the proper inductive signals in vivo.


  3             If it was the latter case, then a


  4   dose-response curve would actually help, because


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


  6   that is not receiving the appropriate inductive


  7   signals.  And I think there is ample data in


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


  9   if there is not a stimulus for proliferation the


 10   cells will either sit there or they will undergo


 11   cytokine withdrawal, or other apoptotic cell death


 12   pathways.


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


 14   critical to evaluate the dose response because we


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


 16   vitro environment, what proportion of cells would


 17   survive in any location, given under any


 18   conditions.  And while it's important to evaluate


 19   the cell death rate, I believe that several of


 20   these may relate to just inappropriate environment


 21   to be induced to proliferate the way that they are


 22   in vitro.


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


 24             My concern is that it will not allow you


 25   to achieve the highest dose




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


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

                                                        10 cells, and


  3   you're losing 90 percent of those cells,


  4   realistically, how many cells can you generate over


  5   a given period of time, given the injections that


  6   are needed.  Those type of issues--


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


  8   necessary--what fraction of surviving cells is


  9   necessary for a clinical benefit.


 10             If you look at bone marrow infusions, most


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


 12   terminally differentiated myeloid cells, and, you


 13   know, we're injecting products where the cell


 14   survival rate is extraordinarily low.  And, again,


 15   I think it's the inductive signals that are


 16   required.


 17             Once it is known how best to manufacture


 18   cells to receive the appropriate inductive signals


 19   and to put them in the appropriate inductive


 20   environment, then we'll realize more of the


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


 22   as the dose response curves are done, since we


 23   don't know the fraction of cells surviving


 24   necessary for clinical benefit, those studies just


 25   have to be done and looked at the data




  1   retrospectively.


  2             CHAIRMAN RAO: Dr. Allan?


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


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


  5   most of the discussion here seems to be on


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


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


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


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


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


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


 12   myoblasts, then--what are the safety


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


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


 15   1 for the rest of the morning if we keep


 16   introducing efficacy into the discussion.


 17             And I would say we just want to stick to


 18   safety.


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


 20   say that we want to stick to manufacturing right


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


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


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


 24   reasonable criteria, in terms of--


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




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


  2   there are many scientifically valid questions to be


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


  4   defined by whatever is being addressed needs to be


  5   viewed no differently than a pharmaceutical


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


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


  8   but also dose-response questions, about efficacy,


  9   about production, manufacturing--scientifically


 10   valid questions then follow on from that.


 11             But the definition of the product is the


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


 13   phenotype or function.


 14             CHAIRMAN RAO: Go ahead.


 15             DR. WENTWORTH: Yes, my name is Bruce


 16   Wentworth from Genzyme Corporation.  I just want to


 17   make a small observation.


 18             There's been a number of suggestions of


 19   tests and assays that might be performed on cells.


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


 21   routine monitoring of cells in production.  Every


 22   production facility will set limits on the number


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


 24   it is actually population doubling is perhaps the


 25   more relevant figure, rather than passage number;




  1   and the conditions under which cells are passaged.


  2             However, in cell therapy, really, it can


  3   never be quite like pharmaceuticals.  Cells are


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


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


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


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


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


  9   karotynocites.  Every one of them works.  All of


 10   them are different.


 11             You can make a useful product from that


 12   that actually saves the lives of burn patients.  So


 13   if we spend a great deal of time analyzing the


 14   karyotypic difference, which is inherent to the


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


 16   have no new product.


 17             Thank you.


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


 19   Harlan.


 20             DR. BORER: Just a philosophical point.  As


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


 22   about preserving safety, but first of all, there


 23   are dose responses for safety endpoints as well as


 24   for efficacy endpoints.  And so you have to know


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




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


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


  3   might contribute to clinical effectiveness because,


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


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


  6   intended use.


  7             So, one really has to keep the equation in


  8   mind always between effectiveness and toxicity.  So


  9   I think it's reasonable to characterize the product


 10   in all these ways, even though it sounds like


 11   "effectiveness," in fact the safety


 12   characterization and the efficacy characterization


 13   are really different ways of looking at exactly the


 14   same characteristics.


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


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


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


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


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


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


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


 22   issues was that passage number is important, and


 23   the second issue was that you really should look at


 24   karyotypic stability as well, and that you should


 25   have some readout on what that composition of the




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


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


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


  4   you have some readout of what you're actually


  5   delivering in terms of a product.


  6             And Joanne made the really important


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


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


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


 10   that you deliver through; the method of delivery is


 11   going to be as important in that whole process as


 12   anything else, because 27-gauge for somebody is


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


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


 15   and maybe that will be effective, but the mechanism


 16   will be different, you know.


 17             And so those points seem to be pretty


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


 19   that another point that came up was that when you


 20   think about composition you're not just thinking


 21   about the effective composition of the cells, but


 22   you're really thinking about the total composition


 23   of a cell, because heterogeneity may be important


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


 25   doing may be equally important in what they might




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


  2             And we need to have that information.  And


  3   the points you made about collecting that data is


  4   really critical in terms of having that sort of


  5   data in terms of defining a product.


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


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


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


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


 10   that's specifically different in those as well.


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


 12   lessons from cell therapy that's already in


 13   progress.  And there are some simple things that


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


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


 16   there has to be a protocol for determining


 17   sterility that doesn't involve setting up a culture


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


 19   going to be useful information.


 20             I think in most settings you would


 21   characterize the population by phenotype or


 22   whatever other method you have, and maybe the


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


 24   cytokine-production assay, or whatever.  But


 25   whatever is decided would be done on all products.




  1             I think, also--


  2             CHAIRMAN RAO: Joanne, let me add just one


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


  4   that appropriate.


  5             Whatever surrogate assay you use has to


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


  7   representative assay for what function you're going


  8   to use.  Is that--


  9             DR. KURTZBERG: To the best of your


 10   ability.


 11             CHAIRMAN RAO: To the best of your ability.


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


 13   said is that it may just characterize the cell,


 14   rather than directly correlate with your efficacy.


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


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


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


 18   contaminating cells in some of these populations,


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


 20   may not have relevance, I think that at least


 21   knowing what immune-mediating kinds of cells are


 22   there could be important, and they should be


 23   characterized as well.


 24             CHAIRMAN RAO: Dr. Simons.


 25             DR. SIMONS: I would like to raise the




  1   issue that the effects observed in all of the


  2   studies may have nothing to do with the cells that


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


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


  5   effect.


  6             With 90 percent of the cells dying, I find


  7   it hard to believe that whatever is left is really


  8   responsible for most of the biological effects


  9   observed.  And that could be different in a setting


 10   of an acute myocardial ischemia, versus the setting


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


 12   talking about what this material is, it is


 13   important to consider that it could be t he dying


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


 15   of ingredients here, which I think sets a very


 16   different set of issues than if the active material


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


 18             And I would like to hear what people think


 19   about that.


 20             CHAIRMAN RAO: I thought before we go into


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


 22             DR. HARLAN: I think you were making this


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


 24   any of these surrogate characterization tests that


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




  1   "true-North" assay.  For bone marrow


  2   transplantation we've had a lethally irradiated


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


  4   where they're predicative of anything.


  5             What I heard yesterday is that we don't


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


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


  8   population is doing what want it to do.  And


  9   without that, all of the characterization is


 10   difficult to judge.


 11             CHAIRMAN RAO: A really important point,


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


 13   that you brought it on the table.


 14             Go ahead.


 15             DR. SCHNEIDER: I would disagree with Dr.


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


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


 18   working.


 19             The true North would be to inject the


 20   human cells proposed for use in human patients into


 21   an immuno-compromised rodent and show efficacy, as


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


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


 24   their angiogenic capacity in vivo, as rescue of


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




  1   perfectly appropriate assays to test for the


  2   angiogenic potential, or the myogenic potential of


  3   the proposed populations.


  4             What I wanted to comment on, prompted by


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


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


  7   kinds of protocols in terms of manufacturing coming


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


  9   centralized studies using GMP facilities such as


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


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


 12   experience in cell production of many kinds.


 13             What I as an academic investigator see as


 14   one of the potential risks to the field is the


 15   illusion among academic investigators that cell


 16   therapy is easy, because of the proliferation of


 17   clinical trials that have been reported with high


 18   visibility.  And as trials move or propose to move


 19   from a single, highly experienced center into half


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


 21   variable degrees of experience, both in cell


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


 23   my mind, one of the principal issues for defining


 24   the criteria in terms of purity of cells and in


 25   vitro surrogates, and even in vivo surrogates




  1   before a given trial be given a green light.


  2             CHAIRMAN RAO: Can I expand on that


  3   statement before we get the comments.


  4             I think what you've said is somehow also


  5   representative of what Dr. Grant started with, in


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


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


  8   pool it when you have large numbers of small


  9   samples?


 10             And I think what's coming through here is


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


 12   have very clear-cut description of what you really


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


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


 15   that they exist, or some clear-cut surrogate


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


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


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


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


 20   able to pull the data across many of the clinical


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


 22   one trial to the other.


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


 24   Menasche, when he presented the data that they had


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




  1   skeletal muscle and you look at different labs, if


  2   they do it slightly differently, you get different


  3   results.  And so you really have to be very


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


  5   compare and it won't be okay.


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


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


  8   extreme variability, even with a single trial,


  9   between different production sites.


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


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


 12             DR. GRANT: Thank you.  Stephan Grant from


 13   Viacel.


 14             My question relates to the testing of the


 15   finished products.  Do you think--would the


 16   committee support a position saying that in vitro


 17   or in vivo differentiation studies would not be


 18   part of the final specification of the finished


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


 20   transfer what we are doing with the small-molecule


 21   drugs, or even with recombinant proteins, we are


 22   normally not testing, for example, the receptor


 23   binding or a biological assay for potency or for


 24   efficacy for the batch release.


 25             So the question is basically: would the




  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.


 19   Kurtzberg.


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


 21   Kurtzberg's comment about immuno-reactive cells.


 22             I think it's also important for us to


 23   consider how the cells are obtained.  I think there


 24   is interest in cytokine mobilization of cells, and


 25   certainly the experience in giving GCSF by our




  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


 25   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


 25   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


 16   manufacturing.


 17             DR. HARLAN: Specifically to


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


 19   of benchmarks were discussed, including some


 20   potentially onerous ones--were they to be applied


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


 22   the assays that I was suggesting, such as testing


 23   for in vivo efficacy in hind-limb ischemia clearly


 24   could not be applied in a workable timeframe to


 25   testing an individual patient's cells prior to




  1   giving those cells back to the same patient.


  2             So, in part of our recommendations to the


  3   FDA, some of the benchmarks that we were alluding


  4   to are benchmarks for the overall consistency and


  5   quality of a production facility, rather an


  6   benchmarks to be assayed on every lot of cells,


  7   given to every patient.


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


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


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


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


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


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


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


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


 16   then take reasonably to a Phase III trial if you


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


 18   minimal criteria that people would consider as


 19   important in terms of how you look at product


 20   development?


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


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


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


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


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




  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


 25   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


 25   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


 11   panels.


 12             But then I would suggest--because the


 13   point just raised is excellent--not everybody has


 14   the ability--not every laboratory, not every


 15   facility has the ability to do a reliable in vivo


 16   assay.  And I would suggest that the FDA consider


 17   the possibility--perhaps in collaboration with


 18   NIH--of developing a core laboratory so that


 19   products can be sent to that core laboratory and


 20   tested in an absolutely uniform way.


 21             And Michael made a very important point.


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


 23   in the acute situation.  But we can retrospectively


 24   analyze the results, and try to correlate an in


 25   vivo assay with a beneficial effect or a




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


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


  3   have to have experience with it, and I would


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


  5   feasible--but that development of a core laboratory


  6   where specimens can be sent would be a very


  7   important part and role for FDA to play in


  8   characterizing what we're giving these patients.


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


 10   comment?


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


 12   Rieves' point about the stages of product


 13   development as it relates to the complexity or the


 14   outgrowth of trials associated with cell-based


 15   therapies.  And there is a history here from other


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


 17   treatment of heart disease.


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


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


 20   single institution, it's inconceivable to me that


 21   that individual should be held responsible for a


 22   transportable assay that other sites not affiliated


 23   with the single-site study should be given the


 24   stamp of approval, for instance.  I think that


 25   comes later.




  1             I think for these limited Phase I studies


  2   that are single institution, to me it would almost


  3   be a barrier to require that investigator to have a


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


  5   my point.


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


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


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


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


 10   terms of what can be done?


 11             Go ahead.


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


 13   one point that--people have been discussing potency


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


 15   a potency assay in place when you start doing a


 16   Phase I or a pilot study.  You should be


 17   considering what you might use as a potency assay


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


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


 20   initiating a Phase I trial.


 21             CHAIRMAN RAO: Yes, I think all the


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


 23   that if you have to take these cells and


 24   extrapolate them, you have to know some measure of


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




  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