1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION
AND RESEARCH
BIOLOGICAL RESPONSE MODIFIERS
ADVISORY COMMITTEE
MEETING #37
Friday, March 19,
2004
8:30 a.m.
Hilton Hotel
Silver Spring,
Maryland
2
PARTICIPANTS
MEMBERS
Mahendra S. Rao, M.D.,
Chairman
Gail Dapolito, Executive
Secretary
Bruce R. Blazar, M.D.
Katherine A. High, M.D.
Jonathan S. Allan, D.V.M
David M. Harlan, M.D.
Joanne Kurtzberg, M.D.
Anastasios A. Tsiatis, Ph.D.
James J. Mule, Ph. D.
Thomas H. Murray, Ph.D.
CONSULTANTS
Jeffrey S. Borer, M.D.
Jeremy N. Ruskin, M.D.
Michael Simons, M.D.
Susanna Cunningham, Ph.D.
Michael D. Schneider, M.D.
INDUSTRY REPRESENTATIVE
John F. Neylan, M.D.
NIH PARTICIPANTS
Richard O. Cannon, M.D.
Stephen M. Rose, Ph.D.
FDA PARTICIPANTS
Jesse L. Goodman, M.D., M.P.H.
Dwaine Rieves, M.D.
Stephen Grant, M.D.
Philip Noguchi, M.D.
Ellen Areman, M.S. SBB (ASCP)
Richard McFarland, Ph.D., M.D.
Mercedes Sarabian, M.S., D.A.B.T.
GUEST SPEAKERS
Stephen E. Epstein, M.D.
Robert J. Lederman, M.D.
Emerson C. Perin, M.D.,
V.A.C.C.
Silviu Itescu, M.D.
Phillipe Menasche, M.D.
Doris A. Taylor, Ph.D.
3
C O N T E N T S
Page
Call to Order
Chairman Rao 4
FDA Opening Remarks
Philip Noguchi 8
Open Committee Discussion-Cellular
Therapies for
Cardiac Disease
Open Public Hearing 9
FDA Charge to Committee--Introduction of
Questions
Stephen Grant, M.D. 37
Committee Discussion of Questions 53
Closing Remarks/Adjourn 270
4
1 P R O C E E D I N G S
2 Call to Order
3 CHAIRMAN RAO: Welcome to the discussion
4
part of the meeting today. As is
usual with all of
5
these meetings, we have to go around and
6
re-introduce the people who are on the committee,
7
and then open it up for public questions
8
subsequently.
9
So I'm going to ask Dr.
Neylan to start by
10
introducing himself again, and then we'll just go
11
around the table.
12 DR. NEYLAN: I'm John Neylan. I'm vice
13
president of clinical research and development and
14
Wyeth Research, and I sit on the committee as
15
industry representative.
16 CHAIRMAN RAO: All right.
17 DR. SIMONS: Michael Simons of Dartmouth
18
Medical School. I'm a vascular
biologist and also
19 a
cardiologist.
20
DR. SCHNEIDER: Michael Schneider, Center
21
for Cardiovascular Development, Baylor College of
22
Medicine. I'm a cardiologist and
molecular
23
biologist with an interest in cardiac growth and
24
cardiac progenitor cells.
25 DR. CUNNINGHAM: Susanna Cunningham from
5
1
the University of Washington School of Nursing in
2
Seattle, and I am the consumer representative,
3
usually with the Cardiovascular-Renal Advisory
4
Committee.
5
DR. BORER: I'm Jeff Borer. I'm a
6
cardiologist from New York. I am
chief of the
7
Cardiovascular Pathophysiology Division at Cornell,
8
and the head of the Howard Gillman Institute at
9
Cornell, and chair of the Cardio-Renal Advisory
10
Committee of the FDA.
11 DR. HARLAN: I'm David Harlan. I'm chief
12
of the Islet and Autoimmunity Branch at the NIDDR,
13
within the NIH. My interests are
immunotherapies
14
for diabetes and islet transplantation.
15 DR. TSIATIS: I'm Butch Tsiatis. I'm a
16
professor of statistics at North Carolina State
17
University.
18 DR. MULE: Jim Mule, associate center
19
director, H. Lee Moffitt Cancer Center in Tampa. I
20
oversee cell-based therapies for the treatment of
21
cancer.
22 DR. MURRAY: Tom Murray, resident of the
23
Hastings Cents Center; a long interest in ethical
24
issues in medicine and science.
I write a lot
25
about genetics and some of these new cellular and
6
1
gene-based therapies.
2 CHAIRMAN RAO: Dr. Ruskin, we missed
3
you--can you--
4 DR. RUSKIN: Jeremy Ruskin--I'm a
5
cardiologist and electrophysiologist, and I direct
6
the Cardiac Arrhythmia Service at Massachusetts
7
General Hospital.
8 CHAIRMAN RAO: I'm Mahendra Rao. I'm at
9
the National Institute of Aging, and I'm a stem
10
cell biologist.
11 MS. DAPOLITO: Gail Dapolito, Executive
12
Secretary for the Committee. And
I'd also like to
13
introduce the Committee Management Specialist,
14
Roseanna, Harvey.
15 Thank you.
16 DR. KURTZBERG: I'm Joanne Kurtzberg. I'm
17 a
pediatric hematologist-oncologist, and I run the
18
pediatric bone marrow transplant program at Duke,
19
and the Carolinas Cord-blood Bank, and I have an
20
interest in cord-blood stem cells;
21
transdifferentiation and plasticity.
22 DR. HIGH: My name is Kathy High. I'm a
23
hematologist at the University of Pennsylvania, and
24
my research interests are in gene transfer as a
25
means of treating bleeding disorders.
7
1 DR. ALLAN: I'm John Allan. I'm a
2
virologist at the Southwest Foundation in San
3
Antonio. My area is non-human
primate models for
4
AIDS pathogenesis. I also sit on
the HHS
5
Secretary's Advisory Committee on
6
Xenotransplantation.
7 DR. BLAZAR: My name is Bruce Blazar. I'm
8
at the University of Minnesota in the Department of
9
Pediatric Bone Marrow Transplantation.
Our lab is
10
focused on the immunobiology of bone marrow
11
transplantation and its complications.
In
12
addition, we're using non-hematopoietic cell
13
therapy to treat organ tissue injury after bone
14
marrow transplantation.
15 DR. CANNON: I'm Richard Cannon. I'm
16
clinical director of NHLBI. I'm
a clinical
17
cardiologist by training.
18 DR. AREMAN: I'm Ellen Areman. I'm a
19 product
reviewer with CBER, Office of Cellular,
20
Tissue and Gene Therapy.
21 DR. McFARLAND: I'm Richard McFarland. I'm
22 a
pre-clinical reviewer in the Pharm-Tox Branch in
23
the Office of Cellular, Tissue and Gene Therapy.
24
And my training background is immunopathology and
25
toxicology.
8
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
9
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
10
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
11
1
in all of them.
2 The second concurrently running--run CABG
3
study was a cohort of dose-escalation study; 12
4
patients. All of these patients
had EF's less than
5
30 percent, and the injection of myoblasts was done
6
concurrent with their bypass grafting.
7 The third--the most current study--was a
8
cohort of 10 evaluable patients.
All of these
9
patients, however, had injection of 300 million
10
myoblasts. However, this group
had a much more
11
extensive--and I should say expensive--preoperative
12
evaluation and follow-up using core laboratories
13
standardized protocols for Echo, MRI, PET and
14
multiple, multiple 24-hour Holter examinations.
15 Next slide, please.
16 [Slide.]
17 In slightly more detail, this is the six
18
patients--probably should call it "LVAD" instead of
19
the CHF patients. Three of the
patients received
20
heart transplantations. Two
died, and one is still
21
awaiting transplant after over two years.
22 Histologic--as part of the informed
23
consent, the explanted hearts were to be made
24
available for histologic evaluation, and that has
25
been completed in five evaluable patients. That
12
1
was recently published, last year, in JAC. You can
2
see the reference there.
3 We couldn't identify any related SAEs.
4 Next slide, please.
5 [Slide.]
6 This is the dose-escalation study in four
7
separate cohorts. You can see
the number of cells
8
was much smaller than was mentioned yesterday in
9
the Paris study. The initial
three only got 10
10
million, then 30 million, 100 million, and the
11
final three got the 300 million myoblasts. Seven
12
have completed 24-month follow-up.
Five are still
13
within that time period.
And, again, we didn't
14
really find any obviously related SAEs in this
15
group.
16 Next slide, please.
17 [Slide.]
18 In the most recent and current study,
19
which has just--I think the last patient is just
20
being enrolled--all these patients received the 300
21
million myoblast cells. There
was one early
22
death--an elderly gentleman, bad re-do, bad
23
targets. He died seven days
post-op. He was
24
already out of the hospital two days, and a
25
question of primary arrhythmia versus an infarct.
13
1
And on autopsy, he had fresh thrombus in a
2
right--and a sequential graft going to two branches
3
of the right. We suspect that
that fit his
4
clinical pattern and he had a primary MI.
5 And, again, all these patients are getting
6
thoroughly evaluated by serial MRIs, echo, PETs,
7
multiple Holters, by standardized core labs.
8 Next slide, please.
9 [Slide.]
10 And in slightly closer focus--as obviously
11
the AICD, and the arrhythmias is significant issue,
12
both clinically and from a regulatory
13
perspective--let me just tell you a little bit
14
about all these folks.
15 The first--the first patient listed there
16
had an AICD placed prophylactically at week two.
17
He had non-sustained V-tach, and some new kind of
18
chest pain within a week after being discharge.
19
Urgently re-cathed; had significant kinks in his
20
mammary graft; question of flow limitation. Placed
21 on Amyoterone, resolved his arrhythmias, but he had
22
an AICD placed prophylactically anyway.
23 The next two patients are very similar,
24
both at month 10 and month 15.
Both patients had
25
AICDs placed, essentially due to progressive heart
14
1
failure. There was no
improvement after
2
the--cardiac function after their grafts. Neither
3
patient ever had VT--and I don't believe any of
4 these
three have had a shock.
5 And then, the last group, one patient had
6
an AICD week three, who had non-sustained V-tach,
7
also severe LV dysfunction. His
pre- and
8
post-operative Holters, however, were not really
9 different, but he had an AICD placed. And the very
10
last one had it, again, placed prophylactically for
11 a
position T-wave alternans test, which some
12
cardiologists feel has significant prognostic
13
significance.
14 So my conclusion from evaluating this is
15
that it's really patient-related variables, rather
16
than specific procedure-related variables, and do
17
reflect some expanding indications for the use of
18
AICDs in this problematic patient group, over just
19
the four years that these have been running.
20 And the last slide, please.
21 [Slide.]
22 Thus, the total enrollment is 28 patients
23
over four years. The average
follow-up, as you can
24
see, for the CABG patients is a year-and-a-half;
25
for the LVAD patients it's been three months. We
15
1
could not identify any specific procedure,
2
rejection-related complications; really no
3
definitive SAEs--that one possibility, but probably
4
not.
5 Histologic evidence for cell survival is
6
currently available. And the
standardized core lab
7
assessment for all the things mentioned, including
8
Holters, are ongoing. So both I,
independently,
9
and GenVec thank you for the opportunity to present
10
this data to the committee and the FDA.
11 Thank you very much.
12 [Applause.]
13
CHAIRMAN RAO: There's just
one question
14
for you from the committee, Dr. Salomon.
15 DR. BORER: Borer.
I guess when you say
16
the results are pending from the core labs, there
17
really aren't any results yet available. But, let
18
me ask anyway.
19 If I understood properly, one of your
20
studies--I guess it's CABG 002--was a dose-response
21
study--
22 DR. SALOMON: Dose escalation, yes.
23 DR. BORER: Well--escalation, but you had
24
one dose given to four different groups; one dose
25
to each group. That's right?
16
1 Okay. So you
can define a dose-response
2
curve from those data, albeit the numbers are
3
small, you could.
4 Do I understand correctly we don't know if
5
cell survival varied among the doses used in any
6
dose-related way, and we don't know if there was
7
any functional parameter that was altered by the
8
treatment in a dose-related way?
9 And the reason I ask, obviously, is that
10
this is the only study that has, in essence, a
11
control. I mean, it's a
dose-response study, which
12
could provide a great deal of information, you
13
know, if the information become available. So
14
that's why I'm asking specifically about that
15
study.
16 The others are, you know, observational
17
studies with millions of confounds.
This one has
18
confounds, too. But, you know,
in addition to the
19
surgery that everybody had, there was a
20
dose-response design--a parallel group, differing
21
dose design.
22 Can you tell us anything about results in
23
that group? Or they're just not
available.
24 DR. SALOMON: You know, this was really
25
confined--with no allusion to efficacy whatsoever,
17
1
of course, in terms of functional alterations. I
2
haven't addressed that whatsoever.
So--
3 DR. BORER: But you made measurements. You
4
have echo, you have PET, you have--
5 DR. SALOMON: Oh, sure.
6 DR. BORER: You have stuff.
7 DR. SALOMON: Sure.
Sure.
8 DR. BORER: And I wasn't suggesting you
9
could look at efficacy. I was
just asking about
10
functional concomitants of treatment.
11 DR. SALOMON: Right.
No--I understand.
12 No--the answer is no obvious correlation;
13
no dose-related correlation.
Correct. Too many
14
variables.
15 DR. EPSTEIN: I'd like to ask a
16
question--Steve Epstein. I'd
like to ask a
17 question of the FDA.
18 I don't mean to be critical of this study,
19
but in light of what Dr. Manasche said yesterday,
20
if you have concomitant CABG, and you're putting
21
cells in, there is no way you're going to get any
22
information. None.
23 So here are patients who are being exposed
24
to some risk, with the expectation of having no
25
information, because there's a CABG.
18
1 What is the FDA policy on something like
2
this.
3 CHAIRMAN RAO: Let's leave that question
4
for later, then, Dr. Epstein.
5 Yes?
6 DR. SCHNEIDER: I have a question for you
7
about patient recruitment for the Diagran GenVex
8
study.
9 How many recruiting centers were involved?
10
What was the average number of patients recruited
11
in each? And what was the range
in the number of
12
patients recruited by each?
13 DR. SALOMON: By each center?
14 DR. SCHNEIDER: By each center. Because
15
one of the issue in a trial like this is
16
reproducibility, hands-on experience.
I'm trying
17
to get a feeling for what the range was in the
18
level of participation and recruitment by the
19
centers.
20 DR. SALOMON: Yes--excellent question.
21 There was a predominance of--I guess I
22
shouldn't say names of centers, so I won't. But
23 there was a predominance in both of
the--well,
24
actually, all the trials, with just maybe--we had a
25
total, I believe, in opportunities for eight to 10
19
1
centers, but virtually 80 percent of the patients
2
came from three to four of the centers.
3 DR. SCHNEIDER: And the other 20 percent
4
came from centers that were doing one or two
5
patients each?
6 DR. SALOMON: Had fewer patients
7
each--correct. Correct.
8 CHAIRMAN RAO: Thank you, Dr. Salomon.
9 DR. CUNNINGHAM: What were the genders of
10
the patients?
11 DR. SALOMON: Only--of all these--of the 28
12
patients, only two female.
13 DR. CUNNINGHAM: Thank you.
14 CHAIRMAN RAO: Thank you.
15 Dr. Reiss?
16 DR. REISS: My name is Russ Reiss. I don't
17
have any slides prepared. I've
just been sitting
18
at this meeting for the last day and am somewhat
19
frustrated.
20 I'm a clinical heart surgeon at the
21
University of Utah who--we also have a very active
22
basic science laboratory, and we are also planning
23
to do cardiac trials will cellular therapy.
24 But what I wanted to say--actually, I'm
25
glad that Dr. Salomon did just give a little bit of
20
1
information from the cardiac surgeon side--and a
2
little bit of rebuttal to Dr. Epstein.
3 I do not believe that just because we can
4
put these in with catheters that that is the actual
5
safest way to do this; and that maybe in the
6
operating room, with the heart under diastolic
7
arrest, completely in a controlled setting that is
8
probably the most controlled, most sterile setting
9
we have from clinicians today is the cardiac
10
operating room. And just some of
the quick points
11 I
just wanted to let the FDA know, that in response
12
to putting a CABG graft on a heart and saying that
13
you can't tell any difference, I don't agree with
14
that at all. Because we've all
revascularized a
15
heart and seen no difference in wall motion,
16
because that area is not graftable, or there's an
17
area there that's thin but not dead.
And you may
18
not see anything at all.
19 If you put cells in that area that you did
20
not put a graft on, you can follow that. And we've
21
seen some very nice images--Dr. Lederman yesterday
22
showed beautiful cardiac MRI images with very
23
specific areas of the heart and the walls that can
24
be followed with high definition.
We can see what
25
happens to the area that is not revasculizable with
21
1 a
CABG graft.
2 And I would say that all the concerns that
3
have been raised with catheters--we heard yesterday
4
that the catheter was very safe, and nothing ever
5
happens in the cath lab. We'll
that's not true.
6
Cardiac surgeons repair valves, we repair aortas.
7
That thin transverses the groin, the aortic arch.
8
There's all kinds of misadventures that happen with
9
catheters that cardiac surgeons have to fix.
10 So I would just say to the FDA that, you
11
know, it's going to be done with a catheter one
12
day. It's already being done
outside this country.
13 I
think that is going to be eventually how the
14
majority of cellular therapy is going to be
15
delivered. But, as far as
safety, some of these
16
trials probably should be also considered in the
17
cardiac setting, in the operating room, where much
18
of the pre-clinical data has been done with direct
19
injection, under arrested heart.
20 And the last thing, about safety: all our
21
patients also go to the ICU, and they're under the
22
most monitoring on a daily basis that you can have.
23
And we can also apply what other types of safety
24
monitoring the FDA would like to see us do. But
25
often the catheter patients do not get the same
22
1
level of post-operative monitoring.
2 So, just a plug for the cardiac surgery
3
side, since it seems that we're a little bit
4
under-represented.
5 CHAIRMAN RAO: Thank you, Dr. Reiss.
6 Dr. O'Callaghan?
7
8 DR. O'CALLAGHAN: My name is Michael
9
O'Callaghan, and I"m the vice president of
10
pre-clinical biology at Genzyme.
I'm responsible
11
for many of the pre-clinical studies that are to
12
look after safety and efficacy for the cell
13
products and many other products at Genzyme.
14 I'd like to thank the FDA for, first,
15
allowing us to speak and, secondly, for putting on
16
this two-day series of seminars, because I think
17
it's critical to the way we move forward.
18 I would remind people of this document
19
called "Innovation and Stagnation," which is a
20
document that just recently came out from the FDA.
21
And if you look at the graph which is on Figure 2,
22
you will see that in 1993, there were 17 BLAs
23
submitted to the FDA, and progressively over the
24
next 10 years to 2003, there was virtually a
25
straight line downward plunge to 14 last year. If
23
1
you continue that, that's 5 BLA losses per year.
2
So by 2007, there won't be any.
3 So, I think what we're talking about
4
today--and some of the things that we're talking
5
about today--is how do we get to a better process
6
or procedure or strategy that will allow industry
7
and the FDA to come to a more transparent, perhaps,
8
and faster or more efficient approach to this.
9 If you think about some of the issues
that
10
have been discussed and the complexity of what
11
we're dealing with, you may recall from much of
12
yesterday's conversation that many of the
13
procedures that we are using to deliver cells--in
14
fact all of them--invoke some sort of pathology of
15
themselves. So if you think
about the emboli that
16
were produced in the intra-coronary delivery, or
17
you think about needle tracks or catheter delivery
18
systems that ago through the wall or travel through
19
the heart, there is a primary pathology created by
20
that.
21 On top of that, there is the pathology
22
that is behind the infarct itself; whether it's a
23
recent infarct or an old infarct, which complicates
24
interpretation, and complicates the safety and
25
efficacy issues we're trying to deal with.
24
1 A third variable, of course, is the cell
2
death that we all heard about, obviously invokes
3
some sort of pathology. And, on
top of that, we
4
have our understanding of the pathological, or
5
physiological processes that we have in great
6
abundance in the literature, and that's our sort of
7
background in trying to understand how to provide
8
studies that answer the safety questions or the
9
efficacy questions.
10 And then on top of this background, we're
11
attempting--with the few surviving cells that are
12
there, and presumably the ones that are going t o
13
give benefit to the patient--out of that morass,
14
try to find out whether there is a safety issue, or
15
efficacy, on top of many of the other things, like
16
CABG.
17 So, how does that translate to dealing
18
with the regulatory authorities in trying to
19
demonstrate that there is safety and that there is
20
efficacy? The difficulty, of
course, is that
21
background. I think the other
difficulty is
22
outlined, in part, in this document: and that is
23
that the process as it is at the moment is an
24
iterative one, where it's almost like a five-year
25
poker game, where each one is holding the cards
25
1
against their own chest and only giving out the
2
card that matters. And that goes
on for several
3
years, and as you play your card, or pick up a new
4
card to try and strengthen your hand, you end up
5
spending a lot of money in the process and, in the
6
end, many of these products shown on this graph die
7
very slowly.
8 So my plea at the moment, or to this body,
9
is that we need to think about how we are going to
10
make the process more transparent so that quicker
11
decisions can be made. And I
think it has to be
12
translated at two levels: one is at the level of
13
policy and strategy--how the FDA is going to
14
interact with industry. And,
secondly, what was
15
pointed out yesterday by Dr. Noguchi and McFarland,
16
how to translate that down to the individual case,
17
where the sponsor and the FDA are having to work
18
out, between them, on that one individual case, how
19
to get to a satisfactory solution as quickly as
20
possible.
21 Thank you.
22 CHAIRMAN RAO: Thank you, Dr. O'Callaghan.
23 I
think the FDA shares the frustration--and all the
24 stem-cell
biologists also, in how can one translate
25
some of these things into an appropriate
26
1
methodology that can be used.
2 I'm going to ask Dr. Noguchi to maybe say
3 a
couple of words on what a BLA is so that people
4
who may not be familiar with it are aware of what a
5
BLA application is.
6 DR. NOGUCHI: Okay.
Yes--BLA stands for
7
"Biologics License Application." It's given under
8
the authority of a section of the Public Health
9
Service Act that we call "Section 351," and it is
10
in a parallel situation to the Food, Drug and
11
Cosmetic Act. The main
distinction, from the legal
12
point of view, is that if you have an approved
13
NDA--new drug application--you don't need a
14
simultaneous BLA, and vice versa.
15 The basic requirements for a license
16
application is that you have a product--let's give
17 a
hypothetical example of a cellular product for
18
future cardiac repair--that can be made in a manner
19
that is consistent; that is, for many biologics, we
20
do not need to have an ultimately precise
21
definition and specification for a pure entity,
22
however we want you to be able to make it the same,
23
time after time after time, within certain limits.
24 If we go back to the original law--1902
25
law--the legislative history is basically states:
27
1
what we want is something that's safe relative to
2
the indication; that's pure as possible; and that
3
is potent, so that the practicing physician, in his
4
or her capacity, will have some confidence that
5
when this product is given that their patient will
6
have some expectation of therapy; that is, they'll
7
be better after than before.
8 So I think--that's sort of more of a
9
philosophical thing, but the end game is really: if
10
you have something that we know works, and can
11
be--works in a manner that it can be convincing,
12
which is usually based on planned clinical
13
trials--occasionally we may have historical data
14
that can be used in terms of an approval. But,
15
clearly, for experimental products such this--we
16
heard yesterday, eloquently--that without a placebo
17
how do you know that this is actually working,
18
since all the non-controlled trials say they all
19
work.
20 So if it's effective in a reproducible
21
way, and you can make the product the same again
22
and again and again, so that, again, the practicing
23
physician gets a vial of cells, says, "Okay, I know
24
this is pretty potent. This is
the dating period.
25 I
can give it. Or, if it's past the
dating period,
28
1
maybe I'll give a little bit more." It's to give
2
the physician the maximum flexibility in
3
prescription, as well as to validate and provide
4
that assurance that the product actually works and
5
can be made consistently. That's
what the BLA is
6
all about.
7 It can be done by a major pharmaceutical
8
company. It has actually been done, in a few cases,
9
by universities and by state public health
10
entities. So it's a very
flexible approach. It
11
can go all the way from the very largest
12
multi-center, multi-national, hundreds of thousand
13
patient trials down to even those with about five
14
to 10.
15 So it's a flexible mechanism. But, again,
16
the end game is: does it work?
If it does, we'll
17
approve it.
18 CHAIRMAN RAO: Thank you.
19 I think a couple of people have questions
20
for you, sir.
21 DR. MURRAY: Phil, what's your response to
22
Dr. O'Callaghan's claim that we've gone from having
23
rather a large number of these BLA applications in
24 a
year, to a declining trend? Is that--if
that's
25
the data--I have no reason to doubt the data, but
29
1
the interpretation of it was what is not clear to
2
me.
3 DR. NOGUCHI: Yes, myself not having all
4
the primary data at hand--but it is--like anything
5
else, it depends on what is put into the
6
publication. We do, for example,
license blood
7 banks,
and those, literally, will be coming in at a
8
much higher rate. We do not
necessarily count
9
those as new molecular entities.
10 It is true, but it's not just for
11
biologics applications, but also for molecular
12 entities--for drug molecular entities--that in a
13
very real sense there has been a tremendous set of
14
developments and follow-through of things that are
15
known. And we have entered,
somewhat
16
asynchronously, a time where there a lot of things
17
that have been solved, in a somewhat prosaic way.
18
All the easier diseases really have been done, and
19
now we're dealing with the ones that are very hard.
20
Cancer, as an entity, sounds like it's not just
21
one, it's a very hard disease in order to make
22
progress above and beyond extension of live for
23
several months, or--and so forth.
24 So a lot of what we're seeing is: what's
25
known has been done for those diseases for which we
30
1
know how to treat. But what we
are now seeing is
2
all the rest of them here: cardiovascular disease,
3
congestive heart failure. We saw
how the cascade
4
is just a very long one, and we're trying to
5
intervene at perhaps a point where it's a little
6
bit hard to reverse years of damage.
Likely it can
7
be done, but how we get there is very dependent, to
8 a
great degree, on what the science and knowledge
9
of disease is.
10 So, I think what we are seeing is that we
11
are seeing fewer applications in the whole drugs
12
and biologics arena. And part of
that is that our
13
scientific knowledge, on the one hand, for making
14
products is expanding rapidly, but our
15
understanding of the--quote--"simplicity" of
16
disease is proving to be--well, it may be very
17
simple, but, boy, that's pretty darn hard compared
18
to what we already know.
19 There are no easy solutions to any
of
20
these diseases that we see right at the moment.
21
And that's part of the lag we're seeing.
22 Dr. McClellan's emphasis on the
23
critical-path initiative is really to try to help
24
everyone to come back and focus as to what are
25
those things that will make a difference, and then
31
1
what are those things that are simply going to be
2
increments and improvements that may only give us a
3
little bit of extension of life, a little bit
4
longer acting drug, but may not be actually
5
altering the fundamental disease.
6 CHAIRMAN RAO: Joanne?
7 DR. KURTZBERG: I have a question that goes
8
back to the cardiac transplantation issue at
9
hand--or the cellular therapy issue at hand.
10 In the current proposed tissue regs,
11
minimally manipulated or non-manipulated products
12
are not really candidates for BLA or licenses. So,
13
for example, if you take bone marrow from a sibling
14
and you transplant it directly into the patient,
15
there's no license involved with doing that.
16 And some of the therapies that both are
17
being done now and are being proposed involve what
18
we've done with bone marrow for years; taking it
19
and putting it somewhere else--in this case,
20
usually autologous, or mobilized blood, or even
21
CD34 AC133-- selected products for which there
22
already are devices that are either under IND or
23
licensed.
24 So how would the FDA--you know, so this
25
therapy crosses a bridge between using things that
32
1
we use already, but just putting them in a
2
different place; and then, also, modifying
3
those--some things, ex vivo, with culturing and
4
other technology.
5 You could interpret the regs as they are
6
proposed as saying the minimally manipulated
7
product doesn't need a license or a BLA, and only
8
the ex vivo manipulated or culture, transfected,
9
etcetera and so forth products do.
10 What's the FDA's view of that.
11 DR. NOGUCHI: Well, we really did not have
12
this meeting to try to focus on the question of
13
whether we need this approach versus that approach.
14
However, I'll just quickly say a couple of things.
15 First, the tissue regulations are
still in
16
the process of being finalized.
However, the
17
point--one part of the regulations does say that if
18
you use something that would otherwise be
19
considered to be not manipulated beyond its normal
20
biological characteristics, if it's used in a
21
manner that inherently does not seem that it
22
logically follows--which is what happens in this
23
case--we've already heard yesterday, and we see
24
throughout the past year, in terms of the active
25
literature, if bone marrow cells of whatever never,
33
1
however purified, are put into the heart by means
2
of devices, or by direct injection, or by surgical
3
procedures, that, in fact, either you get
4
regeneration of heart, you get vascularization, you
5
get transdifferentiation--none of which have been
6
proven by any means, in any clinical trial, let
7
alone in any animal studies that have been done--we
8
term that a "non-homologous use," because it has
9
not been shown, and the current science does not
10
show that any of those possibilities are actually,
11
in fact, what happens.
12
And so, for that reason, we
are saying
13
these are highly experimental procedures they're
14
using in addition to the product itself, which is
15
experimental. We're using
products--other products
16
such as catheters in an experimental way--and, all
17
put together, clearly merit the justification and
18
the overview of FDA regulation at the IND level.
19 DR. KURTZBERG: I'm not questioning that.
20
But--
21 CHAIRMAN RAO: I'm going to cut this here,
22
because this is not part of the whole mandate for
23
the committee. And these
questions--this whole
24
idea of--I just wanted people to know about the
25
BLA.
34
1 DR.
KURTZBERG: But it is important.
2
Because if it works, do you then have to go have a
3
BLA, or a license to use bone marrow for this, when
4
you wouldn't have a license to use bone marrow for
5
the other indication therapy.
6 CHAIRMAN RAO: And that's certainly an
7
important issue, but I don't think we want to
8
address it in this committee because it's not part
9
of our mandate for the question.
10 [Pause.]
11 Are there any additional comments from the
12
audience? Anyone?
13 Go ahead. Just
make sure you identify
14
yourself, and if you have any financial--
15 DR. GRANT: My name is Stephan Grant. I'm
16
working with Viacel in Boston, and I'm running the
17
European branch of Viacel--a small company named,
18
Curion.
19 I would like to make a comment to the
20
issue of immunosuppression in animal studies.
21
There has been a position by Dr. Itescu yesterday
22
saying, well, it doesn't make sense to use
23
immuno-compromised animals treated with cyclosporin
24
or rapomycin, or whatever, in order to do our
25
studies.
35
1 I would like to challenge that position a
2
little bit, because I think we also heard that stem
3
cells are quite heterogeneous, and we see the
4
problem that how can we make sure that an animal
5
stem cell preparation is really very homologous to
6
the human stem cell preparation, which may carry
7
the same name but could be different, in terms of
8
the cell composition or other factors.
And we
9
don't have the tools in our hands to discriminate,
10
or to decide whether the animal stem cells are
11
really the same--have the same quality, the same
12
properties, the same purities as the human product.
13 So we had made a conscious decision to
14
work with immunosuppressed animals,
15
immuno-compromised porcine--pigs, treated with
16
cyclosporin, and tested our stem cells, human stem
17
cells in that setting, with good results so far.
18 And I think taking that strategy, we are
19
on the safe side with respect to testing our
20
products in terms of efficacy and safety, because
21
we don't have to make this transition or
22
translation of the animal that, say, the animal
23
data generated with animal stem cells then into the
24
human setting.
25 And somehow, I--I mean, I think it's fine
36
1
if the authorities accept the, let's say known
2
xenograft, or xenograft-avoiding strategy, but it
3
would be--I think it would be a pity if we would
4
now have a dogma that studies with
5
immuno-suppressed animals would make sense in this
6
context.
7 CHAIRMAN RAO: Thank you.
8 DR. ITESCU: I accept that point. That's a
9
valid point.
10 The point that I was making simply is if
11
you're going to use immuno-suppression in an animal
12
model with human cells, you've got to take into
13
account the potential effects of the drugs on the
14
cells you're studying. And as
long as you've got
15
appropriate controls, as long as you've taken that
16
into account, it's reasonable to look at those sort
17
of models.
18 CHAIRMAN RAO: We're going to move on.
19 Briefly? Is
this relevant.
20 AUDIENCE MEMBER: I'm very sorry to
21
re-comment, but Dr. Epstein's query didn't really
22
get a response--at least from me.
23 And the other issue is the clinical trial
24
design, with human subject protection.
And these
25
pilot studies weren't designed--efficacy as a
37
1
stand-alone procedure, because clearly you have to
2
get safety and feasibility first.
3 So, it's really difficult to do cell
4
implantation studies, I think, as a stand-alone
5
procedure, and they had to be done concomitantly
6
with bypass grafting. I think
that was really the
7
rational; not to prove efficacy.
8 Thank you.
9 CHAIRMAN RAO: Thank you.
10 I'm going to ask the FDA to pose the
11
questions.
12 Dr. Grant?
13 FDA Charge to Committee
14 DR. GRANT: Hi--I'm Steve Grant. I'm one
15
of the clinical reviewers here at FDA.
I'm also a
16
cardiologist.
17 I wanted to start out today by thanking
18
the members of the committee and the invited
19 speaker--as
well as the speakers who were kind
20
enough to join us during the open public
21
hearing--for coming here and sharing their time.
22
We know they all have very busy and very productive
23
professional lives, and we thank you for joining us
24
today to discuss these very important issues.
25 I'm going to briefly review why we've
38
1
asked you to come here yesterday and today. And
2
I'll then review the questions that we've asked you
3
to discuss.
4 Next slide, please.
5 [Slide.]
6 We have asked you to discuss certain
7
safety concerns that need to be addressed to
8
initiate human trials of cellular therapies for
9
cardiovascular diseases. These
concerns are part
10
of our mission to promote and protect public
11
health. We are, however, also
responsible for
12
facilitating the development of safe and effective
13
therapies--and I've put up here an addition that
14
was made to the FDA Mission Statement in August
15
2003.
16 This revision explicitly states that "the
17
FDA is responsible for advancing the public health
18
by helping to speed innovations that make medicines
19
and foods more effective, safer and more
20
affordable."
21 Although this was made explicit in the
22
2003 revision, facilitating the development of safe
23
and effective therapies does promote the public
24
health, so I would argue that this was always
25
implicit in our mission statement.
39
1 We have convened the committee to solicit
2 advice about certain issues that have delayed the
3
development of potential therapies for
4
cardiovascular disease.
5 Next slide, please.
6 [Slide.]
7 Here's one of the clinical challenges that
8
exists in cardiology--I think you've heard about it
9
from several speakers yesterday.
There's--very
10
simply stated--there's over a million people in the
11
United States who acute myocardial infarction every
12
year.
13
For those of us who have a bit
of gray
14
hair, they can remember when taking care of MIs
15
consisted essentially of putting people to bed.
16
The mortality rate for MI has been declining fairly
17
rapidly. It's gone down 30
percent over the last
18
two decades. And this has been
due, at least in
19
large part, to the advent of reperfusion therapy;
20
both thrombolysis and percutaneous coronary
21
intervention. However, these
therapies are not
22
entirely effective. Most
patients who will suffer
23
acute myocardial infarction will be left with a
24
variable amount of left ventricular dysfunction.
25 Because increasing numbers of these
40
1
patients are surviving, there are many, many more
2
patients each year that have diminished cardiac
3
reserve. It fact, congestive
heart failure is the
4
only cardiovascular diagnosis whose absolute
5
incidence is increasing year by year.
And it's
6
partially due to the aging of the population, but
7
it's also, in large part, due to this phenomenon.
8 And therefore we are very interested in
9
facilitating cellular therapies because they may
10
benefit these growing numbers of patients with
11
congestive heart failure.
12 Now, I don't want to suggest that this is
13
the only indication for which I think these
14
products might be used, or that even for sure, that
15
this is an appropriate indication.
Conceptually,
16
there are many, many other types of cardiac disease
17
that could be benefitted by cellular therapy.
18 Next slide, please.
19 [Slide.]
20 I'm going to talk a bit about the
21
regulatory requirements. Before
a new product is
22
administered to humans, FDA is required to conduct
23
an independent and detailed assessment of the risk
24
to human subjects. The
regulations provide the
25
mechanism by which we conduct this assessment.
41
1
They provide the framework wherein we can answer
2
this question--which is never trivial, I don't
3
think, for any trial, but most certainly is not
4
trivial for novel therapies such as these--and that
5
is: how do we balance individual subject safety
6
against the potential public health benefits of new
7
therapy?
8 The risks are borne by the few, and the
9
benefits go to the many. And our
society has
10
designed a mechanism, and provide a framework, and
11
charged us to make this assessment.
And the
12
regulations are how we do that.
13 This risk assessment must be
14
sufficiently--must include sufficiently detailed
15
information regarding the following: product
16
characterization and safety testing.
And I think
17
it's fairly obvious--safety testing, that we
18
wouldn't transmit, for example, infectious agents
19
in a product.
20 Product characterization--as Dr. Noguchi
21
has already discussed--is a bit more difficult for
22
cellular therapies than it is for a drug. A drug,
23
you know the--you can characterize the reagents
24
that go into it. You know and
understand precisely
25
the manufacturing processes. You
can chemically
42
1
characterize what comes out. You
understand--you
2
manufacture the pill.
3 We talk about manufacturing with cellular
4
therapies as well, although even to my ear it still
5
always sounds a little strange to talk about
6
"manufacturing." I
mean, we're really--it's a
7
process that we use to produce these cells, and
8
that process, in some ways, is the way we
9
characterize them. But, still,
there are certain
10
concerns that we have to be able to characterize
11
that end product in some way that's
12
meaningful--because you can't run a clinical trial
13
if you don't understand what you're giving to the
14
patients. I think it's kind of
self-evident that
15
if you don't understand, or don't have a way of
16
characterizing what you've done, you don't have a
17
trial you have a case series of a group of people
18
who are given something you don't understand.
19 You have to provide supportive
20
pre-clinical or clinical data.
You have to provide
21
data that allows us to independently assess the
22
risk to the subjects as best as can be done. I
23
mean, we've heard already about the difficulties of
24
finding appropriate pre-clinical models. That
25
doesn't--because they're difficult doesn't excuse
43
1
you from not having any.
2 And you need to be able to identify a safe
3
starting dose. And then you need
to have a
4
monitoring plan that suggests that you're going to
5
be able to detect the adverse events in a timely
6
fashion, so that any subject that suffers those
7
adverse events can be identified and treated
8
quickly, and so that subsequent subjects will not
9
be exposed to the same adverse events.
10 Next slide, please.
11 [Slide.]
12 And with that as the background, I want to
13
go through the common issues that have delayed
14
initiation of clinical trials in this area--and
15
I've probably seen most of the submissions to the
16
FDA, And these are the four
things that we have
17
identified as being problems.
18 One: the cellular product that is
19
administered--or the cellular product that's
20
proposed for the clinical trial is different from
21
that that's used in pre-clinical studies. You
22
know, we--some people, I think, would advocate--we
23
certainly heard yesterday people who would say once
24
you've seen one bone-marrow mononuclear cell you
25
may have seen them all. But
there may be
44
1
differences within these preparations.
2 Secondly: insufficiently detailed safety
3
data--and particularly, we will sometimes get, as a
4
safety data base, just published reports. It's
5
very difficult to get, from a publication, the kind
6
of detail. We have to be able to
do an independent
7 analysis and,
generally, publications will not
8
include a detailed protocol, which will include all
9
the protocol-specified assessments, and it won't
10
include either the case report forms for a clinical
11
study, the line item of raw data for a pre-clinical
12
or non-clinical study.
13 Three: limited information about the
14
compatibility of the cellular product and the
15
delivery device.
16 Four: an inadequate plan for monitoring of
17 subjects during and after product
administration.
18 And I think you'll see that the questions
19
that we've asked you, with the exception of the
20
seventh, which is just a bit different--but the
21
first six clearly all are derived from these
22
issues. We'd like to get advice
about these issues
23
so that we can help understand how to resolve
24
these, and so the investigator community can help
25
understand, so that we can get submissions that
45
1
will go forward.
2 Next slide, please.
3 [Slide.]
4 So the advice that we seek from you are
5
general comments and recommendations about certain
6
manufacturing issues, certain preclinical testing
7
issues, and about pilot clinical design, with
8
respect to certain issues that need to be addressed
9
to permit safe initiation of clinical
10
development--which we are quite anxious to see
11
happen.
12 Next slide, please.
13 [Slide.]
14 Question 1--well, these first two
15
questions are going to relate to safety in
16
characterization of the cellular product.
17
Question 1: we know that because
the
18
specific cells, mechanism of action and cell-device
19
interactions are still in very early stages of
20
investigation, the appropriate and adequate safety
21
testing and characterization have not yet been
22
defined, and may conceptually vary, based on the
23
cell source and type of manipulation.
24 We would like you to discuss the intrinsic
25
safety concerns for cellular products for the
46
1
treatment of cardiovascular diseases, and the
2
testing that should be performed to ensure
3
administration of a safe product.
Among the
4
factors that you might consider are tissue source,
5 manufacturing
process, formulation, storage, route
6
and site of administration.
7 In your printed version, in the briefing
8
document, these came out as "a, b, c, d." We by no
9
means think that you have to discuss each of those
10
as a separate subpoint, but consider them, instead,
11
in your discussion of the overall question. And I
12
would caution the committee to try to remember that
13
we're talking here about treatments of cardiac
14
diseases. The larger field of
cell therapy is
15
quite a broad one, and we would like to stay to the
16
specifics of cardiac therapy today.
17 Question 2--
18 Next slide, please.
19 [Slide.]
20 --these products are all heterogeneous, in
21
terms of cell types contained and, in some of them,
22
the biomarkers also are different on different cell
23
types; the degree of heterogeneity present in
24
administered cellular products may be an important
25
variable in characterization or in determining
47
1
their safety or efficacy.
2 Therefore, please comment on the elements
3
of product identity and characterization necessary
4
to generate meaningful data about safety and
5
efficacy. And, conceptually, we
think that these
6
may include comments about specific
7
biomarkers--that would be most particularly with
8
the bone marrow-derived products--and the types and
9
percentages of cell types that would apply to both
10
the products derived from muscle biopsies, as well
11
as those derived from bone marrow or from
12
peripheral blood.
13 And there may be other parameters that you
14
would identify as being important.
And we would
15
ask for your comments.
16 Next slide, please.
17 [Slide.]
18 Question No. 3--the next couple of
19
questions, 3 and 4, concern the kinds of
20
pre-clinical data needed to assess safety, and
21
identify a safe starting dose prior to initiating
22
human clinical trials.
23 Various--we've already had part of a
24
discussion of this. Various
animal models have
25
been proposed to support the safety of cellular
48
1
products used in the treatment of cardiac disease.
2
These include studies of both small and large
3 species; studies utilizing either immune-competent
4
or immuno-compromised animals.
5 Each model has some advantages and
6
limitations, which have been reviewed by the
7
speakers and previously discussed.
For instance,
8
human cellular products can be tested in
9
genetically immuno-compromised rodents, but these
10
animals provide limited clinical monitoring of
11
cardiac function, and cannot be used to assess the
12
safety of devices. Large animals
allow for more
13
extensive monitoring of cardiac function and the
14
use of the same delivery device intended for
15
clinical use.
16 Please discuss the merits and limitations
17
of various large and small animal species for
18
providing pharmacologic, physiologic and
19
toxicologic support for cellular products used in
20
the treatment of cardiac disease, and please
21
consider the following: the intended human clinical
22
cellular product; the delivery system that's
23
proposed in the clinical trial; and extrapolation
24
of study results from animals to humans.
25 Question No. 4: Please discuss the merits
49
1
of animal models of ischemic disease with respect
2
to ability to generate proof of concept data, and
3
generate toxicologic data of relevance to the
4
clinical disease. And,
conceptually, animal models
5
of ischemic disease could include normal
6
animals--or no ischemic disease--as Dr. Vouye
7
presented a very interesting study with essentially
8
normal dogs.
9 The models--again, the models of ischemia
10
that are available are many; cryoablation,
11
ligation, ligation-reperfusion, ameroids.
12 Question No. 5, please
13 [Slide.]
14 The next question concerns the types of
15
evacuations needed to assess the compatibility of
16
the cellular product with the delivery device.
17
Please discuss evaluation of potential interactions
18
between cellular products and cardiac catheters;
19
adverse effects of catheters on the viability and
20
functionality of a specific cellular product;
21
factors other than cell concentration and simple
22
viscosity that might contribute to clogging or
23
other adverse events; injection of cells into
24
system circulation, the pericardial space, thoracic
25
space via needle catheter; effects of depth or
50
1
spread of injection into they myocardium on either
2
the safety or, potentially, the efficacy.
3 Question No. 6--these last two questions
4
are about two design elements of early-phase
5
clinical trials. The theoretical
risk of these
6
products include the generation of non-cardiac
7
tissues, abnormal cardiac tissue and/or local
8
inflammation. These outcomes
potentially could
9
lead to myocardial dysfunction, arrhythmias, or
10
conduction abnormalities.
11 Also, these products are administered
12
because some of the cells contained are
13
self-renewing and possess developmental plasticity;
14 that
is, they can differentiate into cells not
15
found in the tissue from which they were obtained.
16
Since uncontrolled cellular proliferation may
17
result in tumor genesis, these products could
18
theoretically result in subjects' developing
19
neoplasia.
20 So, please discuss the appropriate
21
frequency and duration of follow-up.
In addition
22
to any other events, please consider the following
23
potential adverse pathological and clinical events
24 in
your discussion items: scar formation, left
25
ventricular dysfunction, ventricular arrhythmias,
51
1
and neoplasia.
2 Next question, please.
3 [Slide.]
4 Some adverse--this is the question that's
5
not--that is a little bit different than the
6
previous six, but I think it's important to
7
discuss. Some adverse events
potentially due to
8
administration of these products, such as
9
ventricular arrhythmia, worsening left ventricular
10
contractility and death may be identical to events
11
that occur during the natural history of the
12
underlying disease. The subjects
in these
13
trials--in many of these trials--have been quite
14
sick. So a high proportion may
suffer one or more
15
of these adverse events.
16 Consequently, adverse events related to
17
the cellular product or its administration might
18
not be discernible without concomitant controls.
19
However, invasive procedures are frequently
20
utilized to deliver these cellular products.
21 Please discuss the pros and cons of using
22
control groups in these early clinical studies,
23
including any need for randomization or masking.
24
Within your discussion, please also comment on the
25
use of placebos in these studies; for example,
52
1
transendocardial injection of saline into the
2
heart.
3 I would like to make a couple of points
4
that aren't on my slide--one specifically about
5
this. I want to make absolutely
crystal clear that
6
there is no--nothing in the regulations that
7
prevent the use of controls in Phase I studies, and
8
there have been many Phase I studies that did have
9
controls. So there is no
regulatory prohibition of
10
this, nor is there any unstated policy of the
11
agency that we don't allow controls in Phase I.
12
I've heard that stated many places.
I just want to
13
make that absolutely clear.
14 Secondly, I would--these questions, any
15
one of them, would allow for several hours, I
16
think, of very useful and intelligent discussion.
17
To get through them is going to be a challenge. I
18
would encourage the committee to remember that
19
these are issues that need to be dealt with so that
20
we can resolve certain safety issues to allow
21
initiation of early-phase clinical trials. I would
22
discourage you--the discussion yesterday was quite
23
interesting, but I would discourage you from
24
discussion of issues that are dealt with in
25
later-phase clinical trial: appropriate end-points,
53
1
eventual populations for therapy.
These are things
2
about which we haven't presented any data.
3 And I will note that--as you will note in
4
the agenda--that FDA is always asked the questions,
5
after all the FDA speakers, we never leave any time
6
for us to be asked question--for good reason.
7 [Laughter.]
8 Committee Discussion of Questions
9 CHAIRMAN RAO: Thank you, Dr. Grant.
10 So, I guess now we come to the hard part.
11
Many questions, very little time.
And we're going
12
to try and get through all of them so that we give
13
the last few questions also fair discussion.
14 I'm going to try and see if we can try and
15
focus the discussion a little bit, and focus on the
16
manufacturing question, and try and get that
17
addressed before the break.
18 So I'm going to make some blanket
19
statements and ask the committee to see whether
20
they agree or disagree with them, and then sort of
21
go from there.
22 The first statement I'm going to make is
23
that: a cell is a cell is a cell is not true. Even
24
though in the heart you can put them in and they
25
all seem to have the same effect, it's still not
54
1
true, in terms of how they have an effect and what
2
you need to do in terms of the numbers that you put
3
in and so on. So cells have to
be treated
4
differently.
5 That's one statement.
6 The second statement I'm going to make is
7 that it seems the FDA and pharmaceutical companies
8
know about how to manufacture cells to some extent.
9
That's generic in terms of cells.
I mean, Genzyme
10
presented data on what their GMP facilities look
11
like. They aren't the only
company--and I'm sure
12
there will be many other companies who will be
13
willing to tell us how they are much better at
14
doing it.
15 [Laughter.]
16 So it does seem to me that the general
17
issues about cells, in terms of, you know, "Well,
18
we have to look at viral testing, and we have to
19
look at micoplasma, and we have to see that, you
20
know, when we look at cells that the supplies are
21
okay." And that's not
something that we need to
22
worry about in terms of the discussion today.
23
Right?
24 So, we know how to make cells--or some
25
people know how to make cells.
And we know that
55
1
each cell is different, so we can broadly divide
2
this and say that: are there specific issues to a
3
particular cell type in a particular disease, or as
4
it's applied to the transplanting into the heart,
5
irrespective of the mechanism that you use.
6 And I'm going to further subdivide this
7
into two broad categories. And I
think we should
8
focus on allogenic, because there's very little--we
9
shouldn't focus on allogenic, because there's very
10
little data on it, and we've not heard any data on
11
whether that's going to be the same, except to make
12 a
statement that allogenic is different from using
13
autologous cells.
14 And, broadly, I think for cells--at least
15
in my experience with growing cells in
16
cultures--there's a very big difference between
17
cells which are freshly harvested over a short time
18
period and put back, versus cells which have been
19
grown in culture, have been manipulated in culture.
20
So there will be criteria which will be uniquely
21
different between those two cell types.
And we'd
22
keep those sort of generic points in mind, unless
23
people specifically disagree with any one of those
24 statements.
25 [Pause.]
56
1 So--great.
It's amazing that we could
2
start with a common basis, then.
3 [Laughter.]
4 So let's--
5 DR. MULE: I just have one comment, which
6
relates not necessarily to the use of fresh cells.
7 I
think many of us would argue that there are less
8
regulatory hurdles involved with using fresh cells
9
as opposed to using cultured cells--with the
10
proviso, of course, that with fresh cells it's a
11
well-defined population that is being introduced
12
into patients.
13 With cultured cells, what I heard
14
yesterday, I think, is the issue of using fetal
15
calf serum, which raises the point: if we can avoid
16
fetal calf serum, that is a good thing.
17 CHAIRMAN RAO: If you could talk about some
18
of these specifics--can we just hold that thought
19
for a second. I can come back to
that.
20 DR. MULE: Okay.
21 CHAIRMAN RAO: It's the second point, also,
22
on some edition-specific--
23 DR. MULE: It just relates to the product
24
characterization of using in vitro cultured cells.
25 CHAIRMAN RAO: Hold that thought, and we'll
57
1
come back to it.
2 Joanne, do you have something on--
3 DR. KURTZBERG: Yes, I had just one general
4
addition. I mean, I agree with
everything you
5
said.
6 I think it would be a sad comment if we
7
came out of here with anything that recommended or
8
facilitated a company making a product as an
9
autologous non-manipulated bone marrow or
10
peripheral blood-derived cell--much as you would
11
with an organ. And I think
that's important.
12 CHAIRMAN RAO: So, given that viewpoint-and
13
it's clearly going to be a contentious one--let's
14
start at the other end--and look at cells which
15
have been cultured for a long time period.
16 Does anybody here feel specifically--like
17
you made the point about serum--are there specific
18 things
that you need to worry about that are unique
19
to cultures which have been in culture for a long
20
time period, and which are going to be transplanted
21
in the heart. And, you know,
some of them were
22
raised in issues before. There
was this idea of
23
not differentiating, and there was this idea of
24
cells changing, in terms of the different
25
satienability, and only using the third and fourth
58
1 batches. You heard all of that, right?
2 So anybody--specifically on those
3
comments, on sort of long-term culture?
4 Dr. Schneider?
5 DR. SCHNEIDER: Well, we heard about that
6
from a useful from limited point of view. We heard
7
that part of the efficacy monitoring in the process
8
of manufacturing--the skeletal myoblasts, and
9
propagating them to a quantity sufficient for human
10
trials--was to make sure that over time they did
11
not get overgrown by a sub-population that was
12
differentiation-defective.
That's clearly
13
important.
14 What we did not hear as part of that
15
presentation was that in vivo efficacy also is
16
tested over time, or is tested for consistency
17
between patient subgroups. There
are good clinical
18
data now, at least from the trials in Frankfurt,
19
that heart failure patients, or diabetic patients
20
have bone marrow-derived and circulating progenitor
21
cells which are less functional in human grafting
22
than other patients do. And
there are some cell
23
culture and in vitro correlates of that. The
24
cell-culture correlates of that are decreased cell
25
mobility and invasiveness. The
in vivo correlate
59
1
of that is that if those human cells are put into
2
an immuno-compromised rodent model of hind-limb
3
ischemia, with patient cells that don't work, don't
4
rescue hind-limb ischemia in a rodent.
So there
5
are predictive models, both for clinical
6
heterogeneity, or for potential heterogeneities
7
introduced in the manufacturing process.
8 So I would say that what we heard, in
9
terms of the characterization of culture not
10
introducing a distortion to the potential
11
biological properties of the cells was nicely
12
raised yesterday, but there are other elements to
13
that, including cell heterogeneity over time, and
14
cell function by other measures, that we'll need to
15
talk about this morning.
16 CHAIRMAN RAO: So, clearly, one issue is
17
that if you grow cells for some time in culture,
18
you should be testing them at the stage that you
19
would use them, to figure out whether they have the
20
appropriate characteristics and properties that you
21
want to use them for; and that these methodologies
22
exist--right? You said mobility
assays, some other
23
assay.
24 And there was one other sort of issue on
25
this long-term thing--Dr. Borer, go ahead.
60
1 DR. BORER: I'd like to--this is Borer.
2
I'd like to follow on to what Mike said, because
3
it's appropriate to separate out the different
4
categories of the process as these questions have
5
done. But I think it would be
unfortunate to
6
completely separate them and forget that they
7
overlap in many important ways.
8 Steve Epstein suggested this in his
9
comment about conditioned medium yesterday, and I
10
want to restate it in another way.
11 We track and we study what we know about.
12
We don't track and study what we don't know about.
13
And it's easy to become fixated on your theory of
14
pathophysiology, or my theory of pathophysiology,
15
and study those things and miss other, or even more
16
important, characteristics and factors.
17 So what we need to do is to combine the
18
characterization of the product with the parameters
19
that we know to look at with some integrator
20
further down the road; that is, injecting these
21
items into animals, or ultimately into people, and
22
look at outcomes. And I don't
mean just whether
23
the cells survive or not, I mean it's important to
24
track meaningful endpoints, even in small studies,
25
so that you can pick up a's, so you can pick up
61
1
signals about survival--if they're there.
2 You'll never find those in small studies.
3
Therefore, that statement--that concept--argues in
4
favor of the FDA--maybe not in this committee
5
today--but ultimately defining standards for data
6
collection so that small data sets can be pooled in
7
some way, so that signals can be amplified.
8
Because, ultimately, if we try to define a list of
9
characteristics that ought to be looked at to
10
characterize a product, it will be a lovely list,
11
but it may not be the right list.
And the only way
12
we're going to know that is by looking at the
13
outcomes.
14 So I would just make that point: that we
15
have to be thinking about data collection
16
strategies to allow us to pool the small data sets
17
into large data sets that allow one to pick up
18
signals that will tells us there's something else
19
we should have looked at.
20 CHAIRMAN RAO: I completely agree with you,
21
Dr. Borer, and I think it's really important
22
that--it's this general idea of what is required is
23 much more important than any specific list that's
24
developed.
25 Doris?
62
1 DR. TAYLOR: Have a question that I don't
2
want to see get ignored in this process, which is
3
definition of the cells, and definition of any
4
given product, when a group claims that they're
5
injecting--and the heterogeneity of that product.
6
How do you define potency of a given cell
7
population? Is it permissible
for it to be less
8
than half of what you're delivering?
Or does it
9
have to be the majority of what you're giving.
10 If you say, "Okay, we're going to give
11
CD34 cells," does it have to be a hundred percent
12
CD34? Can it be 50 percent CD34,
with a mixture
13
you don't know about? And that
may change in
14
culture.
15 And so I'd like to--
16 CHAIRMAN RAO: So, the important point is
17
that we need a better defined product, and that's
18
what is going to be some of the issues that we
19
discuss in this Question 2, as well.
Would that be
20 a
fair way of stating it?
21 DR. TAYLOR: Yes--and what's an acceptable
22
range.
23
DR. HIGH: I have a
question about skeletal
24
myoblast processing. For
material derived from
25
humans, is expansion to a set number ever a
63
1
limiting factor, or can every subject, no matter
2
what his age, be expanded to 10
9
cells, and our
3
cell numbers are lot release criteria.
4 CHAIRMAN RAO: Doris, do you want to answer
5
that?
6 DR. TAYLOR: Yes, I'll be glad--Doris
7
Taylor. I'll be glad to answer
that.
8 There are a limited number of patients
9
from whom you cannot grow cells--for reasons we
10
don't understand. Philippe has
published data, and
11
other groups have published data, looking at age.
12
And there doesn't seem to be a direct correlation
13
with age and an inability to grow cells.
14
Occasionally we end up with a patient where we
15
can't grow the cells and we don't know why.
16
They're just not there.
17 Now, can you grow
10
9
cells? Generally
18
the question is how long it will take to do that.
19 CHAIRMAN RAO: Go ahead, Joanne.
20 DR. KURTZBERG: I think whenever you work
21
with biologic products there is always an element
22
of unpredictability, and that you can never count
23
on every patient growing the same number of cells,
24
every patient biologically acting the same way.
25
And if you try to design a trial that assumes that,
64
1
you'll never finish your trial.
2 So there has to be some understanding that
3
biology is variable.
4 DR. HIGH: But should there be some minimum
5
number that goes into--on injecting?
6 DR. KURTZBERG: I don't--I think that a lot
7
of these questions are very premature.
I just--we
8
can't define the cell type today--we, you--anybody.
9 I
mean, I think what we have to do is do the
10
studies to get some more data, to have some more
11
general idea of some of this.
And maybe the answer
12
will be that--you know, if a certain kind of cell
13
is beneficial, and you've done a collection from a
14
patient and only collected 80 percent, are you
15
going to deny that patient that 80 percent?
16
Probably not. I don't know.
17 CHAIRMAN RAO: Again, I want to
18
emphasize--and this is maybe just general, for
19
information: this is historically a problem for all
20
cell therapies--right? And you
have to worry about
21
cellular therapy when it's a single
22
lot--right?--it's a one-unit dose that you're
23
making, and it's from one patient, and you can't
24
really do it for each patient.
And as you all
25
pointed out, it's going to be different from each
65
1
case.
2 And so what Dr. Borer pointed out is that
3
we can't come up with a really absolute, specific
4
list--as you said--that you can't.
5 So what--how do people do this in
any of
6
these systems? And from my
limited experience has
7
been that you either say that they're the same,
8
because you have some definition of markers, or
9
sets of things that you put together for cells, or
10
you say they're the same in terms of some
11
substitute assay in culture.
12 So, for example, if you're looking at
13
pancreatic islets, you say they all release this
14
much in terms of the number of cells that you give
15
in terms of insulin release. Or,
you know, in
16
Parkinson's patients you say, well, this is how
17
much dopamine is released by this particular number
18
of cells, and you say that's an equivalency sort of
19
measure.
20 And what, to me, from looking at--or
21
hearing conversations seems to be that it's pretty
22
clear that there's going to be that same sort of
23
variability, and that there must be some kind of
24
equivalency measure that must be looked at if you
25
want to collect any kind of data.
66
1 Go ahead.
2 DR. BLAZAR: That was the point I was also
3
going to make is it's--listening to the data
4
yesterday, it looks like multiple cell types may,
5
in fact, be additive or synergistic, so these
6
preparations that are not 100 percent pure may, in
7
fact, have some advantageous--potentially
8
advantageous aspects to it.
9 So I think if it's well characterized, it
10
doesn't necessarily have to be 100 percent pure.
11
The dilemma is that if the in vivo readout is the
12
critical final denominator, then the in vitro
13
assays might simply just characterize the product,
14
provide the information to the literature, which is
15
then correlated with the clinical outcomes, and
16
then in retrospect then define, potentially,
17
product limitations.
18
I just don't know if you'd be
able to, up
19
front, say that "this is a desired product," so
20
much as "this is the characterization of that
21
product," to the best that we can characterize it,
22
and then try to retrospectively do the clinical
23
outcomes measurement, and then have that define the
24
field of a useful product.
25 CHAIRMAN RAO: Go ahead.
67
1 DR. BORER: This may be a little premature,
2
because I think it will be covered in another
3
question. But the discussion
that Dr. High and Dr.
4
Kurtzberg just had I think is important, and I just
5
want to put a bookmark in here.
6 What's being raised here is the issue of
7
dose-response. And I would point
out--and you all
8
know this--that the shelves and the libraries are
9
filled with expired patents of wonderful drugs that
10
were never used, because the dose-response wasn't
11
adequately characterized, and the drugs were
12
developed at the wrong dose.
13 Now, I think we're--not with unprocessed
14
bone marrow, but with cultured cells, there is
15
incumbent upon investigators the need to define the
16
dose-response in a broad, and as complete as
17
possible way, because ultimately the application of
18
at least that type of therapy will depend on the
19
adequacy of dose.
20 So I just put that bookmark in. We'll be
21
taking about it later.
22 CHAIRMAN RAO: I was actually kind of
23
surprised--one issue that didn't come up with
24
cultured cells was nobody seems to worry about
25
looking at karyotypic stability of cells. And even
68
1
when people talked about this, nobody presented
2
data where they said, well, you know, when we put
3
in 100 million cells, that these cells were
4
all--you know, we tested an aliquot, or we looked
5
at it.
6 What does the committee feel about
7
karyotypic assessment?
8 DR. BORER: Yes, I must say I had that
9
written down here, but I thought since nobody
10
mentioned it, it was probably silly.
11 The fact is, with multiple passages, I
12
would have thought one would like to know how the
13
error rate increases; that is the replication
14
errors increase, because that's going to
15
characterize the population, as well, and one could
16
easily wind up with cells that have all the surface
17
markers that we look for, and the antigenic markers
18
we look for, and, you know, they look like what
19
we're interested in, and yet you inject them and
20
you come up with a cell rest in the myocardium that
21
doesn't do what you think it should have done.
22 So I would think that it would be very
23
important to assess the karyotype in the final
24
product, as well as in the initial set of cells
25
that you put in.
69
1 CHAIRMAN RAO: Joanne?
2 DR. KURTZBERG: I agree with you, but I
3
have an unrelated point about administration--and
4
it wasn't mentioned yesterday.
But there
5
were--during the talks about the devices, the
6
needle gauge size came up a couple of times, and I
7
heard numbers like 27-gauge, 29-gauge thrown
8
around.
9 And, as a transplanter of hematopoietic
10
cells, we would never put those cells through that
11
small a needle, because they lyse, get crushed, get
12
smashed, break apart. And then
you're talking
13
about doing it under high pressure, which only
14
increases the probably of cell damage.
15 I understand there are other technical
16
issues related to the heart and getting catheters
17
in there, but I think it's really important to talk
18
about that, and at least require some kind of bench
19
testing that would demonstrate that cells can
20
be--you know, aren't damaged when they go through
21
that small a hole under high pressure.
22 CHAIRMAN RAO: Dr. Murray?
23
DR. MURRAY: If we're going to
worry about
24
dose response--that's if we need a numerator and a
25
denominator--right?--the denominator's going to be
70
1
response. We're not talking
about that right now,
2
we're talking about the numerator, which--what do
3
we count as being part of the dose?
Is it how many
4
hundreds of millions of cells?
Is it how many
5
millions of myoblasts in a set-up preparation? Is
6
it how millions of cells with the normal karyotype
7
of a particular cell type?
8 I feel very uncomfortable with the
9
tremendous uncertainty of what it is we think we're
10
looking at, and what subsets of that--the
11
collections of cells we're looking at, etcetera.
12
Some clarity on that I think would be helpful.
13 CHAIRMAN RAO: Doris?
14 DR. TAYLOR: Specifically, with regard to
15
myoblasts, I think one of the issues is the assays
16
you design for your cells. And
with myoblasts--I
17
can't say that we've looked at the karyotype of our
18
cells over time. What I can say
is that we've
19
looked at the ability of our cells to fuse and
20
terminally differentiate and form myotubes; and
21
that that's used as a potency measurement of these
22
cells.
23 And I think that is the kind of assay that
24
makes a lot of sense in this particular setting,
25
because once they're terminally differentiated,
71
1
they're not going to continue to divide in the
2
myocardium.
3 I will say that--I didn't present these
4
data yesterday, but we have preclinical data over a
5
number of years showing that if we purify the cells
6
to too great a degree of homogeneity they are less
7
effective than if there is a mixture of cells
8
present. And that doesn't
surprise me, given the
9 mitogens
that, I think, are delivered by the
10
fibroblasts and other cells that are there.
11 CHAIRMAN RAO: Dr. Borer, did you have a
12
comment?
13 DR. BLAZAR: Yes.
I think the issue of
14
passage numbers and serum requirements is really
15
critical, and as these studies go forward, even
16
with characterizations, if the products look the
17
same at three passages, and you're using them at
18
five or six passages, the cells may well
19
differentiate in a way that can't be well monitored
20
in vitro.
21 And I don't know necessarily that there's
22
an optimal passage number, but I think as the
23
studies report their results, it will be very
24
important to discuss those two issues which may
25
affect in vivo survival and differentiation, as
72
1
well as karyotype stability.
2 CHAIRMAN RAO: That's a really important
3
point, and maybe I can try and summarize what I
4
felt was the sense of just this specific point:
5
that when you keep cells in long-term culture, it's
6
really critical to look at passage number. And
7
that's more an absolute rather than just saying,
8
"Well, you know, I used passage eight and it has
9
the same apparent phenotype as an early passage,"
10
but that you really want to keep track of the
11
passage number. And you can't
just automatically
12
assume one will be the other.
13 DR. BLAZAR: I think even added to that is
14
cell density. We know that cell
density is a
15
critical influencer of differentiation potential,
16
and minor changes in cell density can have
17
significant abilities, not only to look at the
18
growth rate, but can differentiate cells in ways
19
that may be picked up in later passages because of
20
the cell contact and growth-factor issues
21
that--where one population influences another.
22 So I think, again, as we go forward,
as
23
much information in the reports as possible, to try
24
to look at these effects, and if they are going to
25
vary in even individual patients, so that there can
73
1
be a net body of information in the literature, it
2
would be helpful retrospectively in evaluating the
3
outcomes.
4 CHAIRMAN RAO: It's a good time to sort of
5
consider also what you raised as an issue of the
6
growth-factors in serum, and cytokines, which
7
should be used in the manufacturing process
8
perhaps. And if you have a
specific comment--
9 AUDIENCE: Actually, it was back on the
10
unmanipulated cells--I just wanted to make a
11
comment on those.
12 CHAIRMAN RAO: We're going to come back.
13
Hold it and see if you need to make that comment at
14
that time.
15 Go ahead.
16 DR. SCHNEIDER: Michael Schneider.
17 I wanted to state that with respect to
18
heterogeneity, skeletal muscle-derived cells over
19
time in culture, in addition to the issue that
20
Doris mentioned about the variable percentage of
21
fibroblasts, there are two other specific
22
populations to be vigilant about in the skeletal
23
muscle preparations.
24 One of them is the so-called side
25
population, or SP cells, which are very small in
74
1
number, but--as many members of this panel know--in
2
bone marrow account for much, if not all, of the
3
long-term self-renewal potential.
And so it would
4
be important to know whether the manipulation of
5
the skeletal muscle cells in culture over time
6
might be depleting that from the starting
7
population; or, alternatively, enriching for that
8
relative to the starting population.
9 There also has been described in rodents,
10
by several labs, a SCA positive population, similar
11
to the progenitor cells that we see in adult rodent
12
hearts. SCA-1 is an allelic
variant in rodents
13
that doesn't have a precise equivalent in humans.
14
But as Dr. Itescu alluded to yesterday, markers
15
such as STOW-1, indicative of the pericyte might
16
well be good indicators of the SCA-1 equivalent in
17
the skeletal muscle preparations.
18 And so my point is that, in terms of the
19
drift in time over culture, it's important to know
20
in a consistent and reliable way what is happening
21
to these other sub-populations that may be
22
contributing to the in vivo efficacy.
23 CHAIRMAN RAO: So that's really--it seems
24
to be a really quite important point, is that since
25
we don't know what is the--and it's the point you
75
1
made, as well--is that we may not know the
2
effective cell, and we need to know both about the
3
concentration of the effective cell, in terms of
4
whatever you think its mechanism is, as well as the
5
other cells that are going to present in the media,
6
because we may or may not know how useful or how
7
bad they may be-- whatever may be the case.
8 DR. SCHNEIDER:
It's not that these would
9
be necessarily contributing to the skeletal muscle
10
formation in large number, but they may be
11
producing cytokines, growth factors, acting on the
12
other injecting cells or, as several speakers
13
alluded to yesterday, having some other kind of
14
favorable effect on the host.
15 DR. MULE: If it's true that 90 percent of
16
the injected cells are dying, it's hard for me to
17
imagine, first of all, how one can do an
18
appropriate dose-response. And
secondly, we may
19
spend an enormous amount of time trying to
20
understand the makeup of the culture before it goes
21
into a patient. But not having
an understanding of
22
whether certain subsets of cells within that
23
heterogeneous population are dying off in
24
vivo--with a 90 percent overall die-off, it's a
25
struggle to understand--and it gets back to Dr.
76
1
Borer's concern about having appropriate endpoints
2
in the trial that will allow you to get some
3
biologic information about the cells that not only
4
go in, but those that survive.
5 DR. MURRAY: This is Tom Murray.
6 My friend Carol Greider was once trying to
7
teach me about Belgian beers.
And the lesson
8
didn't particularly take. But
apparently--they go
9
through multiple fermentations, and they utterly
10
change their character, depending upon whether it's
11
the first, second, third, fourth--I don't know how
12
many times they do it.
13 And I heard yesterday--and maybe a little
14
bit even today--the possibility that in different
15
passages the cells' properties change.
And it
16
seems to me there are just--crudely, three
17
possibilities. One is it doesn't
matter how many
18
passages, at least up to a certain limit, but the
19
cells are the same all the way through.
And that
20
does not seem to be the case. I
don't hear anybody
21
saying that that's the case.
22 The second possibility is: they change,
23 but
in a continuous fashion. That is,
whatever
24
changes there are, they simply--they're additive,
25
so the changes in each passage, they become more
77
1
extreme.
2
A third is--and this is
what I thought I
3
heard yesterday--was that, in fact, they change in
4
interesting ways, such that three and five may be
5
more alike than four. I may have
the specific
6
numbers wrong.
7 It would be very helpful for the FDA, I
8
think, to ascertain what the best scientific
9
evidence is as to which of those three models is
10
the correct one, and then that will have
11
implications for whatever you decide.
12
CHAIRMAN RAO: So--I want to get
back to
13
the point that Dr. Murray made, and that is that
14
all of this assessment that one considers, you need
15
to consider not just at the time that you've got
16
the cells into a wire, but really have to have some
17
assessment of what that means when you get them
18
into the heart. Is that the
emphasis that you've
19
been making?
20 So if you're going to have deaths, then
21
you need to know that you're going to have 90
22
percent die each time, because that's going to
23
significantly change your dose, if you do something
24
with it. Is that a fair--
25 DR. TAYLOR: I think one of the issues that
78
1
you need to think about in considering that is that
2
the geometry of the injections, and the number of
3
injections is really going to probably change the
4
number of cells that die. If you
inject a giant
5
bolus of cells, it doesn't take a rocket scientist
6
to figure out the fact that more are likely to die
7
than if you inject 10 smaller populations
8
throughout the scar, based on the nutrients they
9
receive.
10 So I think you have to factor into trial
11
design the injection patterns for these cells as
12
well.
13 CHAIRMAN RAO: Dr. Borer?
14 DR. BORER: I thought that the issue I'm
15
about to raise really would be subsumed under the
16
preclinical studies area, but I looked at the
17
question, and it's really not only.
18 And that is--and that follows from some
19
points Dr. Itescu raised yesterday which broadly
20
involve drug-biologic interaction.
These products
21
will be given to patients who have--who will have
22
multiple drugs in their bodies at the time the
23
products are given. And I don't
think we know--I
24
mean, I don't know the research in the field, but I
25
didn't hear much about it yesterday--I don't think
79
1
we know how the drugs that routinely are given to
2
patients who have the target diseases affect the
3
growth and development of the cell products.
4 And I think this needs to be
5
characterized. I don't know what
we'll learn, but
6
one could just, for example, learn that maybe you
7
have to stop beta blockers for a few weeks in
8
people with heart failure who are being given
9
cells, because the cells won't grow properly--or
10
optimally.
11 And I think that characterization has to
12
begin before one gets to the in vivo experimental
13
model studies, that it really does require some
14
benchwork to look at the effect of drugs on the
15
cell population.
16 So, again, just to bookmark--but we
17
haven't talked about drug-biologic interactions,
18
and I think that's an important area that we need
19
to consider throughout these discussions.
20 CHAIRMAN RAO: Bruce?
21 DR. BLAZAR: I wanted to come back to the
22
cell death rate. I think one
possibility is, of
23
course, mechanical, and the cells don't survive
24
when they've been removed from an in vitro culture,
25
and they're undergoing cytokine withdrawal,
80
1
etcetera. Another possibility is
that they're just
2 not receiving the proper inductive signals in
vivo.
3 If it was the latter case, then a
4
dose-response curve would actually help, because
5
it's still going to be the same fraction of cells
6
that is not receiving the appropriate inductive
7
signals. And I think there is
ample data in
8
animals, with a variety of cell types, to say that
9
if there is not a stimulus for proliferation the
10
cells will either sit there or they will undergo
11
cytokine withdrawal, or other apoptotic cell death
12
pathways.
13 So I think despite the death rate, it's
14
critical to evaluate the dose response because we
15
do not know, as you remove these cells from the in
16
vitro environment, what proportion of cells would
17
survive in any location, given under any
18
conditions. And while it's
important to evaluate
19
the cell death rate, I believe that several of
20
these may relate to just inappropriate environment
21
to be induced to proliferate the way that they are
22
in vitro.
23 DR. MULE: I
agree with you, Bruce.
24 My concern is that it will not allow you
25
to achieve the highest dose
81
1
response--conceivably--limited by practicality, for
2
instance. I mean, if you go up
to 10
10 cells,
and
3
you're losing 90 percent of those cells,
4
realistically, how many cells can you generate over
5 a
given period of time, given the injections that
6
are needed. Those type of
issues--
7 DR. BLAZAR: We don't know how many is
8
necessary--what fraction of surviving cells is
9
necessary for a clinical benefit.
10 If you look at bone marrow infusions, most
11
of those cells die. The vast
majority of them are
12
terminally differentiated myeloid cells, and, you
13
know, we're injecting products where the cell
14
survival rate is extraordinarily low.
And, again,
15 I
think it's the inductive signals that are
16
required.
17 Once it is known how best to manufacture
18
cells to receive the appropriate inductive signals
19
and to put them in the appropriate inductive
20
environment, then we'll realize more of the
21
clinical benefit. But even for
now, I think, that
22
as the dose response curves are done, since we
23
don't know the fraction of cells surviving
24
necessary for clinical benefit, those studies just
25
have to be done and looked at the data
82
1
retrospectively.
2
CHAIRMAN RAO: Dr. Allan?
3 DR. ALLAN: The comment I'd like to make is
4
when I read Question 1 what I see is safety. And
5
most of the discussion here seems to be on
6
efficacy; what's the right formulation in order to
7
get the right response, or dose response. And to
8
me, what I see the question is is mostly safety.
9
And so therefore it's like the preparations, that
10
if it's 80 percent fibroblasts maybe you don't want
11
to give it, but if it's, you know, 80 percent
12
myoblasts, then--what are the safety
13
considerations? And so for a lot
of this, it's
14
really--because we're going to be stuck on Question
15 1
for the rest of the morning if we keep
16
introducing efficacy into the discussion.
17 And I would say we just want to stick to
18
safety.
19 CHAIRMAN RAO: Yes--I, in fact, would even
20
say that we want to stick to manufacturing right
21
now--you know. So--meaning, at
the product. So
22
all we're looking at is that can we define a
23
product in light of what it will be, with some
24
reasonable criteria, in terms of--
25 DR. ITESCU: Yes, and I think that was
83
1
really my point to Dr. Borer.
Whilst I agree that
2
there are many scientifically valid questions to be
3
asked, I think the cell product that's being
4
defined by whatever is being addressed needs to be
5
viewed no differently than a pharmaceutical
6
composition. And I think that's
really the job of
7
the FDA, to ask questions about, obviously, safety,
8
but also dose-response questions, about efficacy,
9
about production, manufacturing--scientifically
10
valid questions then follow on from that.
11 But the definition of the product is the
12
key, I think. And that can be
based on surface
13
phenotype or function.
14 CHAIRMAN RAO: Go ahead.
15 DR. WENTWORTH: Yes, my name is Bruce
16
Wentworth from Genzyme Corporation.
I just want to
17
make a small observation.
18 There's been a number of suggestions of
19
tests and assays that might be performed on cells.
20
Some of those are, in fact, done in the normal and
21
routine monitoring of cells in production. Every
22
production facility will set limits on the number
23
of passages that are used. I
would point out that
24
it is actually population doubling is perhaps the
25
more relevant figure, rather than passage number;
84
1
and the conditions under which cells are passaged.
2 However, in cell therapy, really, it can
3
never be quite like pharmaceuticals.
Cells are
4
inherently variable. There's no
way around that.
5
And I would ask you, in a moment of quiet
6
reflection, to look at the back of your hand. You
7
will see warts, cells that are dark, skin that's
8
light, hair, no hair--it's all the product of
9
karotynocites. Every one of them
works. All of
10
them are different.
11 You can make a useful product from that
12
that actually saves the lives of burn patients. So
13
if we spend a great deal of time analyzing the
14
karyotypic difference, which is inherent to the
15
back of your hand, we'll get nowhere and you'll
16
have no new product.
17 Thank you.
18 CHAIRMAN RAO: Dr. Borer, and then Dr.
19
Harlan.
20 DR. BORER: Just a philosophical point. As
21
Dr. Allan points out, we're talking primarily here
22
about preserving safety, but first of all, there
23 are dose responses for safety endpoints as
well as
24
for efficacy endpoints. And so
you have to know
25
these things. And, in addition,
I think it's very
85
1
artificial to talk about "safety," and not consider
2
other effects--other effects of the product--that
3
might contribute to clinical effectiveness because,
4
at the end of the day, the issue isn't absolute
5
safety, it's safety that's acceptable for the
6
intended use.
7 So, one really has to keep the equation in
8
mind always between effectiveness and toxicity. So
9 I
think it's reasonable to characterize the product
10
in all these ways, even though it sounds like
11
"effectiveness," in fact the safety
12
characterization and the efficacy characterization
13
are really different ways of looking at exactly the
14
same characteristics.
15 CHAIRMAN RAO: And I'm going to try and ask
16
everyone that let's try and focus on this first two
17
sets of questions, which is: we've got cells--some
18
kind of cell--and right now we''ve only focused on
19
the cells that you've got in long-term passage, and
20
that we've got some specific issues that we might
21
want to consider when they're there, and one of the
22
issues was that passage number is important, and
23
the second issue was that you really should look at
24
karyotypic stability as well, and that you should
25
have some readout on what that composition of the
86
1
cell type is, and that none of these can be done
2
just in culture. You really need
to do them after
3
you've implanted the cell in some fashion so that
4
you have some readout of what you're actually
5
delivering in terms of a product.
6 And Joanne made the really important
7
point, I felt, was that what that means is that you
8
have to include in this whole process is how you're
9
going to deliver--right? That
gauge of the needle
10
that you deliver through; the method of delivery is
11
going to be as important in that whole process as
12
anything else, because 27-gauge for somebody is
13
going to lyse their cell type, and if you use a
14
30-gauge, it's certainly going to give you based,
15
and maybe that will be effective, but the mechanism
16
will be different, you know.
17 And so those points seem to be pretty
18
clear from what needs to be done.
And I thought
19
that another point that came up was that when you
20
think about composition you're not just thinking
21
about the effective composition of the cells, but
22
you're really thinking about the total composition
23
of a cell, because heterogeneity may be important
24
in its function, but also what the other cells are
25
doing may be equally important in what they might
87
1
not do--right?--or what they might worsen.
2 And we need to have that information. And
3
the points you made about collecting that data is
4
really critical in terms of having that sort of
5
data in terms of defining a product.
6 So let's see if we can add to that,
7
specifically in terms of these cells, because I'd
8
like to try and extend this to also the non-passage
9
cells as well and see if there's anything, really,
10
that's specifically different in those as well.
11 DR. KURTZBERG: Well, I think you can learn
12
lessons from cell therapy that's already in
13
progress. And there are some
simple things that
14
are always done, like viability, sterility--and
15
those--especially for the long-term passage cells,
16
there has to be a protocol for determining
17
sterility that doesn't involve setting up a culture
18
the day you deliver the cells, because that's not
19
going to be useful information.
20 I think in most settings you would
21
characterize the population by phenotype or
22
whatever other method you have, and maybe the
23
potency assay would be a colony-forming assay, or a
24
cytokine-production assay, or whatever.
But
25
whatever is decided would be done on all products.
88
1 I think, also--
2 CHAIRMAN RAO: Joanne, let me add just one
3
point what you made--just make sure that I've got
4
that appropriate.
5 Whatever surrogate assay you use has to
6
match, or you have to have some data that it's a
7
representative assay for what function you're going
8
to use. Is that--
9 DR. KURTZBERG: To the best of your
10
ability.
11 CHAIRMAN RAO: To the best of your ability.
12 DR. KURTZBERG: I mean, again, what Bruce
13
said is that it may just characterize the cell,
14
rather than directly correlate with your efficacy.
15
But it's the best you can do at the time.
16 And then, finally--and this may have more
17
relevance in the future--but there will be other
18
contaminating cells in some of these populations,
19
like t-cells, or macrophages.
And while it may or
20
may not have relevance, I think that at least
21
knowing what immune-mediating kinds of cells are
22
there could be important, and they should be
23
characterized as well.
24 CHAIRMAN RAO: Dr. Simons.
25 DR. SIMONS: I would like to raise the
89
1
issue that the effects observed in all of the
2
studies may have nothing to do with the cells that
3
have been actually injected--at least with the live
4
cells--and it's the dead cells that are having this
5
effect.
6 With 90 percent of the cells dying, I find
7
it hard to believe that whatever is left is really
8
responsible for most of the biological effects
9
observed. And that could be
different in a setting
10
of an acute myocardial ischemia, versus the setting
11 of sort of chronic CHF patients. But I think, in
12
talking about what this material is, it is
13
important to consider that it could be t he dying
14
cells, or the dead cells, that are the active sort
15
of ingredients here, which I think sets a very
16
different set of issues than if the active material
17
is what's going to be left of the dividing cells.
18 And I would like to hear what people think
19
about that.
20 CHAIRMAN RAO: I thought before we go into
21
discussion--comments from some of the other people.
22 DR. HARLAN: I think you were making this
23
point, Dr. Rao, but I believe that we don't know if
24
any of these surrogate characterization tests that
25
we wish to do are true North. I
think we need a
90
1
"true-North" assay.
For bone marrow
2
transplantation we've had a lethally irradiated
3
mouse, where we can test the various assays to see
4
where they're predicative of anything.
5 What I heard yesterday is that we don't
6
necessarily have a true-North assay in the clinic,
7
or even in animal models, to say that this cell
8
population is doing what want it to do.
And
9
without that, all of the characterization is
10
difficult to judge.
11 CHAIRMAN RAO: A really important point,
12
and let's keep that in mind. And
I think it's good
13
that you brought it on the table.
14 Go ahead.
15 DR. SCHNEIDER: I would disagree with Dr.
16
Harlan's point because I think that the true North
17
is there. We don't know why the
true North is
18
working.
19 The true North would be to inject the
20
human cells proposed for use in human patients into
21
an immuno-compromised rodent and show efficacy, as
22
Dr. Itescu did. That could be
done most directly
23
by intra-cardiac injections or, as a surrogate for
24
their angiogenic capacity in vivo, as rescue of
25
hind-limb ischemia. And I think
both of those are
91
1
perfectly appropriate assays to test for the
2
angiogenic potential, or the myogenic potential of
3
the proposed populations.
4 What I wanted to comment on, prompted by
5
Bruce Wentworth's remarks, is to point out that the
6
FDA, I think, has to anticipate some very different
7
kinds of protocols in terms of manufacturing coming
8
down the pike. Some of those
will be large, very
9
centralized studies using GMP facilities such as
10
what we heard about from Genzyme, and as Dr. Rao
11
alluded to--other companies with large, long-term
12
experience in cell production of many kinds.
13 What I as an academic investigator see as
14
one of the potential risks to the field is the
15
illusion among academic investigators that cell
16
therapy is easy, because of the proliferation of
17
clinical trials that have been reported with high
18
visibility. And as trials move
or propose to move
19
from a single, highly experienced center into half
20 a
dozen, or a dozen, or two dozen centers with
21
variable degrees of experience, both in cell
22
production and in cell administration, that's, in
23
my mind, one of the principal issues for defining
24
the criteria in terms of purity of cells and in
25
vitro surrogates, and even in vivo surrogates
92
1
before a given trial be given a green light.
2 CHAIRMAN RAO: Can I expand on that
3
statement before we get the comments.
4
I think what you've said is
somehow also
5
representative of what Dr. Grant started with, in
6
terms of the frustration for the FDA; or, how can
7
you really use data from one trial or the other to
8
pool it when you have large numbers of small
9
samples?
10 And I think what's coming through here is
11
that you can't pool that data unless you really
12
have very clear-cut description of what you really
13
have put in--right?--in terms of the quality of the
14
cells, or the number, or--you know, the markers
15
that they exist, or some clear-cut surrogate
16
marker. You know, it may be--as
you pointed
17
out--that it has to be done in an animal model, or
18
it has to be done--but unless you have a common set
19
of readouts which are all consistent, you won't be
20
able to pull the data across many of the clinical
21
trials, and you won't be able to extrapolate from
22
one trial to the other.
23 And I think that was true, even when Dr.
24
Menasche, when he presented the data that they had
25
shown that, you know, when--even if you take
93
1
skeletal muscle and you look at different labs, if
2
they do it slightly differently, you get different
3
results. And so you really have
to be very
4
critical, in terms of how you can compare and not
5
compare and it won't be okay.
6 DR. SCHNEIDER: It's the second of those
7
aspects that I was trying to emphasize; the risk of
8
extreme variability, even with a single trial,
9
between different production sites.
10 CHAIRMAN RAO: Go ahead--you've been
11
waiting for a long time, and then Dr. Itescu.
12 DR. GRANT: Thank you.
Stephan Grant from
13
Viacel.
14 My question relates to the testing of the
15
finished products. Do you
think--would the
16
committee support a position saying that in vitro
17
or in vivo differentiation studies would not be
18
part of the final specification of the finished
19
products, because certainly, I think, if we just
20
transfer what we are doing with the small-molecule
21
drugs, or even with recombinant proteins, we are
22
normally not testing, for example, the receptor
23
binding or a biological assay for potency or for
24
efficacy for the batch release.
25 So the question is basically: would the
94
1
committee support a position saying, well,
2
differentiation assays, in vitro, in vivo, are good
3
for profiling of the product, but not mandatory for
4
the release of the finished goods?
5 CHAIRMAN RAO: I'm going to try and take
6
the liberty of answering for the committee, and if
7
people disagree--
8 I think that that's not--the sense from
9
the committee that I got was that, you know, it's
10
really important. It's important
that you know.
11
And from what Dr. Murray has said, and what other
12
people said, that you really need to have some
13
potency equivalent--right?--that has to be--
14 DR. GRANT: May I just add a comment?
15 I was not--I'm not saying that we don't
16
need such assays to be performed, but the question
17
is if we have to test batches of finished products,
18
batches to be released for clinical trials, or
19 later
for the market? The question is whether
a
20
differentiation assay should be part of every
21
batch-release specification?
22 CHAIRMAN RAO: I don't want to be too
23
specific, so we'll leave that topic on the table
24 right
now.
25 Go ahead, Dr. Itescu, and then--
95
1 DR. ITESCU: I just wanted to add to what
2
Dr. Schneider said. I agree with
him
3
entirely--that I think that we do have good
4
immunosuppressive models--small models--where you
5
can test whatever human cell type you want. And I
6
think that could easily be a surrogate outcome for
7
potency for any given product that you're
8 interested in.
9 I think, in addition to that, we would be
10
able to put together some sort of consensus on what
11
constitutes cardiac improvement.
We really barely
12
touched on that, really, yesterday, but I think, as
13 a
group, you'd find some sort of consensus about,
14
maybe, systolic improvement. And
I think if you
15
had those two combinations, in terms of
16
differentiation in vivo plus functional
17
improvement, you've got potency.
18
CHAIRMAN RAO: Dr. Cannon, and
Dr.
19
Kurtzberg.
20 DR. CANNON: I wanted to follow up on Dr.
21
Kurtzberg's comment about immuno-reactive cells.
22 I think it's also important for us to
23
consider how the cells are obtained.
I think there
24
is interest in cytokine mobilization of cells, and
25
certainly the experience in giving GCSF by our
96
1
transplanter colleagues has been very favorable.
2
They really haven't seen much in the way of
3
complications--a few.
4 But it may be very different in our
5
patient populations that we want to treat. And the
6
point I want to make is I think it will be
7 important for us to characterize these cells as to
8
whether they contain activated immuno-competent
9
cells that might destabilize plaque.
10 CHAIRMAN RAO: Hold the thought, I'm going
11
to try and summarize that and just make sure that
12
I've captured it, if it turns out I haven't.
13 DR. KURTZBERG: I'd just like to propose--I
14
think you need a cardiac therapy study group. I
15
think the people who are interested need to come
16
together, build a consensus, decide on how you're
17
going to monitor your products and characterize
18
your products; decide on what your endpoints are
19
going to be for your clinical trials.
20 Because you have several products, and
21 several
endpoints, and several diseases--and
22
there's models to do this in cancer therapy, in
23
transplant therapy. And I think
that's what has to
24
happen now in order to pull this all together.
25 CHAIRMAN RAO: Can I try and extend--if you
97
1
have a comment, is it specific to this?
2 DR. TAYLOR: It is--it's specific to
3
actually two things: one, to Dr. Schneider's
4
comment about different groups coming forward.
5 One of the things that frightens me most
6
about he field--and that I hope the FDA is going to
7
be the regulatory body on--is the number of phone
8
calls I get from physicians saying, "I can take
9
cells out of the bone marrow," or "I can grow cells
10
in a dish." "I can do
a study, and here's the
11
study I'm going to do." And
it concerns--with no
12
experience, necessarily, preclinically, in terms of
13
understanding the vagaries of cell therapy, or the
14
vagaries of growing cells, or measuring cells.
15 And so I really am concerned about that.
16 In terms of pulling together a cardiac
17
study group, one of the commitments that I and a
18
couple of other people in the field have made is to
19
get all the thought leaders, in terms of academic
20
investigators who are doing this work
21
internationally, together to try to come to a
22
consensus this year about what endpoints we need to
23
be measuring, preclinically and clinically.
24 DR. RIEVES: Dr. Rao, we appreciate all the
25
comments. They're very useful.
98
1
But in your summary,
could you also
2
incorporate the perspective of overall product
3
development? Characterization,
for example, is
4
usually regarded as a continuum.
As you've heard,
5
we need some details in early clinical development,
6
but our regulations, our acting procedures, allow a
7
great deal of flexibility, such that flexibility
8
for initiating a Phase I clinical study may be
9
considerable with respect to manufacturing,
10
compared to the flexibility that might be
11
reasonable prior to initiating a Phase III study.
12 So, in your summary and discussion could
13
you also incorporate the stages of product
14
development? And specifically,
we're interested in
15 early stages.
16 CHAIRMAN RAO: Before we get to that, can I
17
try and also--in the interest of time--try and
18
extrapolate from all this discussion?
19 You know, we looked at long-term passage
20
cells, and I want to say that many of these issues
21
apply, but to a lesser extent if you've directly
22
harvested the cells. And you
can't extrapolate
23
from one cell type to the other if the mode of
24
selection is different.
25 And as has been already pointed out from
99
1
the data that's available, that if you mobilize
2
bone marrow cells it's not that one mononuclear
3
cell population is the same as another mononuclear
4
population, because we don't know the mechanism of
5
action, and we don't know the cell type. So that
6
each cell type used in cardiac therapy, in some
7
sense, irrespective of whether operatively you call
8
it the same, is different because you have to
9
define that particular product in terms of how it
10
was isolated, and from what patient population it
11
was done. So even though it's a
one-shot dose, you
12
can only compare it with a single one-shot dose
13
from another patient where it was made and
14
harvested much the same way.
15 So many of the issues that we raised here
16
for passage cells apply to these cells in a generic
17
way, but there will be specific concerns which are
18
specific to each of those modalities.
19 Does that seem like a fair statement?
20 DR. HARLAN: If it's true--and one thing--I
21
agree with what you said, but one thing that was
22
stated, and if it's true I think it's a great
23
outcome of this session, is that if the community
24
agrees that injecting the cell of interest, or the
25
cell gamish of interest into immuno-compromised
100
1
mice with an infarcted or dysfunctional myocardium,
2
and the endpoint is an improvement in systolic
3
function--if the community agrees that that's
4
true-North and a good bio-assay, then that's a
5
wonderful outcome of this session to use as a
6
surrogate gold standard.
7 If it doesn't--
8 CHAIRMAN RAO: Dr. Harlan, we're going to
9
come back to models, and so I really want to--
10 DR. HARLAN: Okay.
11
CHAIRMAN RAO: --try and keep that--
12 DR. HARLAN: But it if doesn't, then I
13
endorse what Dr. Kurtzberg said about a working
14
group to try to come up with--
15 CHAIRMAN RAO: Yes.
Specifically to
16
manufacturing.
17 DR. HARLAN: Specifically to
18
manufacturing--and to Dr. Rieves' comment--a number
19
of benchmarks were discussed, including some
20
potentially onerous ones--were they to be applied
21
to every patient's cells. And,
in fact, some of
22
the assays that I was suggesting, such as testing
23
for in vivo efficacy in hind-limb ischemia clearly
24
could not be applied in a workable timeframe to
25
testing an individual patient's cells prior to
101
1
giving those cells back to the same patient.
2 So, in part of our recommendations to the
3
FDA, some of the benchmarks that we were alluding
4
to are benchmarks for the overall consistency and
5
quality of a production facility, rather an
6
benchmarks to be assayed on every lot of cells,
7
given to every patient.
8 CHAIRMAN RAO: So, to go back to what you'd
9
said, then--so is it true, for the sense--for early
10
studies, as Dwaine pointed out, that when you're
11
looking at Phase III trials, and you're looking at
12 a
company, and you're releasing a product where you
13
have a long history, there's a different set of
14
requirements. But when you're
doing this early,
15
you want to have a definite cell type which you can
16
then take reasonably to a Phase III trial if you
17
were going to do it. What would
be sort of a
18
minimal criteria that people would consider as
19
important in terms of how you look at product
20
development?
21 And, to me, it still seems--and, again, I
22
would have the committee weigh in on this, is that
23
we still need a minimal definition of what's in
24
that cell type. And we clearly
still need how it
25
was isolated--as, clearly, distinction, because
102
1
that's a different cell type.
And we need to know
2
the passage number and the karyotypic stability of
3
the cells when they've been grown in culture, and
4
that's irrespective of whether you're doing it
5
early or late, because otherwise you won't be able
6
to compare.
7
And you need a lot of the
data and
8
information so that if you have any of the small
9
trials, that you can actually see if you can truly
10
extrapolate--like you pointed out--from one trial
11
to the other, so that you have that.
And that in
12
the readout you need some sort of potency-type
13
assay where you can say--which is a maybe generic
14
substitute, and it may be the best that one can
15
have, given the limitations in the field on what
16
can be there. And maybe for
myoblasts it can
17
diffuse and form myoblasts because that's the
18
mechanism of action, and that's what you use each
19
time; and that for the overall generic product that
20
you have--so let's say it's myoblasts from
21 different
patients--you should have some kind of
22
biomarkers and assays that have been defined in a
23
more rigorous fashion.
24 Is that--
25 DR. SCHNEIDER: May I play the Devil's
103
1
advocate for a moment with respect to karyotyping?
2 I'm curious how one would use the data
3
from karyotyping if an abnormality were to be found
4
after three or four weeks of what I consider to be
5
relatively short-term culture, if there were no
6
objective evidence for tumor formation in animals
7
following six to 12 months of follow-up in
8
preclinical data? I mean, are
you using
9
karyotyping as a surrogate endpoint for tumor
10
formation even in the absence of data that tumors
11
would occur?
12 CHAIRMAN RAO: Hold that thought, and I
13
think maybe Bruce is going to take about what we
14
missed in saying this is the dose.
15
DR. BLAZAR: No, I wanted to
follow up on
16
your point as well. I think part
of the issue as
17
you go to define the products is if you're going to
18
call something a skeletal myoblast, it has to have
19
certain proportion of cells--which I haven't heard
20
what that is--that are defined as skeletal
21
myoblasts. It should have some
limitations as to
22
what the other cells are.
23 For karyotyping--which I think is
24
important--we need to know whether there are
25
unstable karyotypes, even if retrospectively to go
104
1
back and say "this culture was a different culture
2
than another culture," regardless as to the
3
tumorgenic risk.
4 And for the assays, I think if you're
5
going to use in vivo assays as readouts, then they
6
have to be able to reproduced from lab to lab with
7
some sort of standardized ability to say that this
8
cell has a certain potency. With
islets, that can
9
be shown; that many different labs can come up with
10
the same sort of readouts.
11 But the difficulty for me in listening to
12
this discussion as outside the field is I'm still
13
walking away with saying I don't know what kind of
14
product definitions are going to be required, other
15
than recording the data. What is
a reasonable
16
composition of matter? And are
there potency
17
assays that are exportable and evaluable in
18
multiple different laboratories for assessing some
19
level of potency that can be reported in the
20
literature to correlate with clinical outcomes?
21 DR. KURTZBERG: I agree with that, and I
22
also don't think a panel of non-experts should be
23
the people deciding the potency assay.
I think
24
that people who are experts in the field ought to
25
decide that and come back and say this is what we
105
1
think is the best we can offer.
2 CHAIRMAN RAO: Dr. Epstein?
3 DR. EPSTEIN: Dr. Rao, I think you
4
summarized the issues brilliantly.
I'd just like
5
to make two points.
6
I think a consensus panel of
experts would
7
be critical to define in vitro and in vivo assays.
8 I
think it's critically important to make certain
9
we understand that myogenesis is different from
10
angiogenesis, so that you have two consensus
11
panels.
12 But then I would suggest--because the
13
point just raised is excellent--not everybody has
14
the ability--not every laboratory, not every
15
facility has the ability to do a reliable in vivo
16 assay. And I would suggest that the FDA consider
17
the possibility--perhaps in collaboration with
18
NIH--of developing a core laboratory so that
19
products can be sent to that core laboratory and
20
tested in an absolutely uniform way.
21 And Michael made a very important point.
22
The in vivo assay is not going to really be helpful
23
in the acute situation. But we
can retrospectively
24
analyze the results, and try to correlate an in
25
vivo assay with a beneficial effect or a
106
1
non-beneficial effect. But I
think for some of
2
these assays, they're rather sophisticated. You do
3
have to have experience with it, and I would
4
think--and I don't know if it's financially
5
feasible--but that development of a core laboratory
6
where specimens can be sent would be a very
7
important part and role for FDA to play in
8
characterizing what we're giving these patients.
9 CHAIRMAN RAO: Dr. Mule, did you have a
10
comment?
11 DR. MULE: I just wanted to get back to Dr.
12
Rieves' point about the stages of product
13
development as it relates to the complexity or the
14
outgrowth of trials associated with cell-based
15
therapies. And there is a
history here from other
16
cell-based therapies, not necessary, of course, in
17
treatment of heart disease.
18 But the point, again, is that if one is
19
running a Phase I trial and it's limited to a
20
single institution, it's inconceivable to me that
21
that individual should be held responsible for a
22
transportable assay that other sites not affiliated
23
with the single-site study should be given the
24
stamp of approval, for instance.
I think that
25
comes later.
107
1 I think for these limited Phase I studies
2
that are single institution, to me it would almost
3
be a barrier to require that investigator to have a
4
robust enough assay that's transportable. That's
5
my point.
6 CHAIRMAN RAO: I want to ask the FDA: do
7
you feel that you've heard enough about Question 1
8
and Question 2, in terms of a generic picture on
9
these things, or just left too open in your mind in
10
terms of what can be done?
11 Go ahead.
12 DR. AREMAN: Well, I just wanted to make
13
one point that--people have been discussing potency
14
assays. And we really do not
require that there be
15 a
potency assay in place when you start doing a
16
Phase I or a pilot study. You
should be
17
considering what you might use as a potency assay
18
when you get to your Phase III trial.
But that
19
definitely is not--should not be a barrier to
20
initiating a Phase I trial.
21 CHAIRMAN RAO: Yes, I think all the
22
committee members, in one sense, were trying to say
23
that if you have to take these cells and
24
extrapolate them, you have to know some measure of
25
what they're doing, and so you need that. You
108
1 don't
necessarily have a direct dose-response or
2
potency that you need, but you need to be able to
3
say that when I take this lot, and I want to put
4
them in, because I think that this is the
5
mechanism, that these cells do fuse and form
6
myotubes and at passage four, this is what they do.
7
Or, you know, in passage one, this is what they do.
8 And so it's just one more characterization
9
assay on what it's going to do, and that this lot
10
has that kind of phenotype. When
you have cells,
11
you have to define them in some fashion as a
12
phenotype, and we can't just do it with markers.
13 DR. ITESCU: I would just like to--the
14
conclusion that was just drawn about a barrier;
15
that increasing the data required to move into
16
Phase I being a barrier to a single center
17
initiating a trial being a bad thing.
I think, in
18
fact, it's exactly the opposite from my
19
perspective: it's a good thing.
20 I think we want to raise the barrier to
21
the level where you understand as much as you can
22
about the biology of the product, about the potency
23
of the product and about the safety of the product.
24 I
think we want to raise the barrier to prevent the
25
conclusions that we're coming to that every cell
109
1
type works, that many small trials have been
2
initiated. We can't conclude
anything at this
3
point in time because not enough product
4
understanding has occurred.
5 And I think to increase the barrier is a
6
good thing, not a bad thing.
7 CHAIRMAN RAO: I think the FDA always likes
8
to hear that--
9 [Laughter.]
10 --people are asking for regulations.
11 DR. MURRAY: I mean, I view this through
12
the prism of how we treat the human subjects in
13
these trials. And if--to the
extent that we can
14
actually draw meaningful data from the trial, we
15
just have a better justification for involving
16
human subjects. And even in
these Phase I trials.
17 To the extent that we have total
18
non-standardization, and, you know, we're letting a
19
thousand flowers bloom, I understand some might
20
favor that, but I think, at minimum, we want to be
21
able to have comparability, or at least to know the
22
bases for comparability from trial to trial. And
23
that's simply one way of showing respect for human
24
subjects.
25 Now how do you do that? It's not simple.
110
1 I
mean, I will return to this when we get to the
2
clinical--discussion of the clinical issues. But
3
that would be a reason I would advocate, you know,
4
any sort of cooperation, standardization, etcetera,
5
that we can ascertain at this time would be
6
desirable from that perspective.
7 CHAIRMAN RAO: I'm going to ask Dr. Grant
8
and Dr. Rieves--do you feel that you've got a sense
9
of what the community feels, basically, on the
10
whole manufacturing process and early stages?
11 DR. RIEVES: The information's been very
12
useful. If we understand
correctly--with my
13
confederates here--the feedback that we are getting
14
is largely consistent with what we have been trying
15
to apply to cellular product development--not only
16
in the cardiac field but in other fields in
17
general. Your comments are very
useful.
18 If we are understanding correctly, you are
19
not objecting to some flexibility in early product
20
characterization. You're
encouraging exploration,
21
but that has to be tempered by the need for
22
attempts at the most consistency as possible, such
23
that the data are interpretable.
And, basically,
24
we're not hearing objections to the procedures that
25
we've been using in cellular product development,
111
1
in terms of manufacturing information.
2 CHAIRMAN RAO: I think one important point
3
that came through, I think, as a caveat, at least
4
to me, was that one can't simply consider a product
5
at the level of "you've got it in a vial," because
6
that really doesn't define it in any fashion. And
7
so there has to be some information on what happens
8
when you put it into any model that you do. And if
9
there's going to be death, we need to know that
10
that's consistent, because if you have too little
11
death or too much, that will be a problem. If
12
you've selected for some sub-population that grows,
13
that's going to be a problem.
14 So that's going to be--and that the mode
15
at which you deliver it can't be extrapolated. So
16
you can't say, "Well, you know, today I used a
17
27-gauge needle, and that was how we defined this
18
product in the manufacturing that you're going to
19
use." It's got to be at
least factored in in terms
20
of what has to be done when you're comparing
21
anything, or when you look at the sense.
22 But, other than that, you look at what's
23
the best that can be done.
24 But, to me, it seemed that those were two
25
additional things that people don't normally
112
1
consider in drug release maybe.
But that needs to
2
be factored in to the cells. At
least that was my
3
sense.
4 DR. SCHNEIDER: To paraphrase Dr. Murray:
5
let a dozen flowers bloom.
6
[Laughter.]
7 I think that for many of us, the hazard,
8
as I've said, is the impression created by the high
9
visibility trials that this is easy; that this can
10
be done by any cardiologist or cardiac surgeon with
11
access to a blood bank. And
that's adamantly to be
12
discouraged.
13 CHAIRMAN RAO: Go ahead, Dr. Noguchi.
14 DR. NOGUCHI: Yes--I think this has been an
15
excellent discussion, and we appreciate the rigor
16
with which the committee and all the participants
17
here want to move the field forward.
18 I will point out that, to a large extent,
19
this is not FDA's field. It is
our job to look and
20
to evaluate independently what comes in. If,
21
indeed, you're talking about a dozen flowers, if we
22
get 4,000 applications I can guarantee you my staff
23
will review every single one of those applications.
24 We would prefer--
25 [Laughter.]
113
1 --that we get some selectivity, but that
2
is not our judgment. That is not
our duty, and
3
that is not our responsibility.
The responsibility
4
is clearly that of the community that is trying to
5
develop these products. That is
clearly
6
determining what may be true North or North by
7
Northwest, or even maybe giving you the first step
8
on the journey. It's not for FDA
to tell you, it's
9 for you all, together,
to come to consensus to
10
develop the scientific knowledge to consider the
11
subjects absolutely as the center of all your
12
discussions, and bring that, not just to us, but to
13
the public so that we can have a reasonable
14
discourse about it.
15 So I think, really, we've heard--for the
16
manufacturing, we've heard a lot of very good
17
suggestions. We've heard a lot
of preliminary
18
discussions. The refinement of
this we will help.
19
But it's up to all of you to provide the data so
20
that we can make the evaluation.
21 CHAIRMAN RAO: So, as Joanne pointed out,
22
somebody has to help formulate a committee of, you
23
know, cardiologists to look at that.
24 DR. TAYLOR:
Dr.--
25 CHAIRMAN RAO:
Is it a big comment?
114
1
Because you're keeping everybody from a break now.
2 [Laughter.]
3 DR. TAYLOR:
Dr. Rao, there is one issue
4
that I didn't hear at all, and that's vehicle. And
5 I
think vehicle is an important issue that we can't
6
ignore here: what the cells are injected in.
7 CHAIRMAN RAO: Yes--I think that's an
8
important point, and I sort of--people raise this
9
issue, and it was raised before in terms of whether
10
serum is good or bad, and whether there's a
11
serum-shock effect, depending on how much is there.
12
Dr. Epstein, for example, pointed that out. And
13
that excipients, just like in any drug, are also an
14
important component that has to be fully defined in
15
terms of doing this. And I think
that's going to
16
be important to do when you look at comparing
17
anything, or look at when you're delivering cells.
18 And you're absolutely right; it's even the
19
glucose, and the PBS that you put in when you
20
deliver cells, it's going to be important. And I
21
think that's an important thing that the committee
22
would suggest to the FDA as well, is that when you
23
define that product, that that information should
24
also be collected.
25 DR. SCHNEIDER: Very quick response to Dr.
115
1
Noguchi's suggestion about a process for consensus
2
development.
3 Betsy Knable and NHLBI have planned for
4
this coming September what promises to be the most
5
authoritative collection of investigators on the
6
subject of cardiac cell repair.
And it might be
7
useful to communicate with them that, as one
8
potential long-term outcome of that meeting, that
9
process of consensus committees be engendered.
10 CHAIRMAN RAO: So we'll take a 10-minute
11
break, and attack some of the next questions.
12 [Off the record.]
13 CHAIRMAN RAO: Back on the record.
14 It's time to get back to work, I guess.
15 [Pause.]
16 So this is going to be a little bit
17
easier, though not doubt as contentious, I guess.
18
And the only reason I think it's going to be a
19
little bit easier to consider this issue is that
20
we've discussed aspects of this already. And I'm
21
going to try again to see if we can summarize a
22
little bit of what people have already talked
23
about.
24 So there seems to be some consensus in the
25 field that if you're looking at physiology
and
116
1
overall global function, and you're looking at
2
certain of the tests which are non-invasive, it
3
seems that you are quite critical in terms of
4
needing some large animal models.
5 However there are some disadvantages to
6
large animal models, and there are alternatives in
7
terms of small animal models which may be useful
8
because they have certain specific advantages.
9 And one contentious issue seemed to be
10
that even though we have some advantages with small
11
animal models, we have to worry about the
12
immune-suppressed state, and that there are some
13
disagreements on whether you can use an
14
immuno-compromised model as a xeno-model, where you
15
can transplant, say, human cells into a small
16
animal model.
17 And, otherwise, the field seemed to think
18
that one should be doing comparable cells. So you
19
take, you know, bone marrow cells from the same
20
animal and put it back in a syngenic field.
21 Does that seem to be a fair summary? And
22
maybe I'll ask Doris that question--just as a yes,
23
no.
24 [Laughter.]
25 DR. TAYLOR: I think that's accurate.
117
1 I think devices--obviously, you've got to
2
do in large animals. And some of
the other
3
things--cells you can do in small animals.
4 CHAIRMAN RAO: Dr. Epstein? Or Dr. Itescu,
5
can you--would you say yes or no to that summary?
6 DR. ITESCU: Yes.
7 CHAIRMAN RAO: So, keeping that as a
8
background, maybe we can look at specifics in some
9
of these models. And, again,
that hopefully gives
10
us a clear-cut breakdown into small and large
11
animal models--right?
12 And maybe we can start off with Dr.
13
Borer's point about: you have to integrate
14
information--right? And that you
have to collect
15
data. So, maybe if you take a
large animal model--
16
maybe, Dr. Borer, would you like to say what one
17
would like to collect, and what kind of animal
18
model? Would there be any
preference, or an
19
absolute requirement for a particular model?
20 DR. BORER: Sure.
I don't--well, yes,
21
okay. I'll tell you what was an
absolute
22
requirement. An absolute
requirement are hard
23
natural history endpoint collection; death, major
24
clinical events in the animal: myocardial
25
infarction, stroke, what have you.
I mean, we
118
1
could define a list--infection, whatever.
2 But can I just say one more thing? And
3
maybe I'm going beyond what you're asking me, but a
4
point that was raised yesterday--and I want to
5
raise it again here--is that there are several
6
different things that are happening in the
7
myocardium. Putting in cells
that differentiate in
8 a
way so that they can generate force is wonderful,
9
but there has to be a remodeling process that goes
10
on.
11 And the cellular remodeling--cellular
12
remodeling--differs among species.
So that while
13
there are certain things that I think we can look
14
for in small animals, over and above the generic
15
stuff I just said, there are other issues that
16
really probably cannot be judged in mice, for
17
example, because the myocytes and the fibroblasts
18
in mice do different things than the myocytes and
19
fibroblasts in species closer to humans.
20 And I would just, again, bookmark the
21
issue of cellular remodeling. We
heard a little
22
while ago from Dr. Taylor that the heterogeneity of
23
the product that's injected probably is important.
24 I
think it probably is, too. I think it's
very
25
important. I think it's very
important because of
119
1
the points that Dr. Epstein made yesterday; that is
2
that the cells are secreting stuff.
We don't know
3
what they are, but they're probably crucial to the
4
whole system working well. And,
again, those
5
processes differ among species.
6 So I think when you start to look at the
7
global issue, and the remodeling issue, you really
8
have to be closer to people than to mice.
9 CHAIRMAN RAO: Can I ask you one question
10
just as an extension of this?
11 Is there a sense, then, that since animals
12
are not like humans, for example, and that there
13
are going to be species' differences and these are
14
physiology differences which are critical, that you
15
can't just do animal studies that will match? Or
16
should you be doing both xeno- as well as syngenic
17
studies? Or that's not something
that the
18
committee thinks is a good thing to do?
19 DR. BORER: Well, I mean, I'm not--I hope
20
I'm answering the appropriate question here, and
21
that I understood it properly--but, we can't answer
22
all the preliminary questions that we need to
23
answer to be able to go forward with clinical
24
trials by doing clinical trials.
There have to
25
be--there has to be some information that is at
120
1
least intuitively reasonably predictive to suggest
2
that you're going to do something good and you're
3
not going to do something bad once you start
4
working in people.
5
There are many examples of
animal studies
6
done in species closer to man than to mouse; you
7
know, on dogs and in pigs and even rabbits--and
8
primates, of course--which have been reasonably
9
predictive of the general response that you see in
10
people. Will that lead to a
clinical benefit, or
11
will it not? I don't know. That's what clinical
12
trials are for.
13 But I think that you can and must do
14
certain animal studies to at least suggest that
15
it's reasonable to infer that there might be a
16
benefit, and might not be excessive harm
17
outweighing the benefit if you go to people. So I
18
think that there are studies that should be done in
19
animals. The assay for potency
that Mike and
20
others have talked about I think is key, and that
21
probably can be done in small animals.
22 And I'm probably getting much more
23
specific than you wanted me to.
But I think that
24
several animal models have a place here; that it's
25
crucial to do preclinical studies before you do
121
1
clinical studies. My only
argument was that in all
2
species we look at, we have to look at deaths,
3
infarctions, strokes and other major events, and
4
that we shouldn't forget about the remodeling
5
issues because, as Steve pointed out yesterday,
6
these cells know better than we do what they're
7
supposed to be doing, and they do it, and we don't
8
know what they're doing.
9 CHAIRMAN RAO: Bruce?
And then Dr.
10
Schneider.
11 DR. BLAZAR: One question I haven't heard
12
answered is the role and function of human cells in
13
rodents. It's been implied that
you could use
14
human cells in rodents to assay biological
15
function. We know for some cell
types--core blood
16
in non-SKD mice, you can get some assessments,
17
whereas human t-cells put into rodents in general
18
don't function well.
19 There are certainly non-cellular sources
20
in rodents that don't receive the right inductive
21
or survival signals, and I guess the question is
22
whether the fraction of cells that survive, are
23
they biologically functional if you put human cells
24
in rodents?
25 I didn't hear a lot of discussion about
122
1
that. And given the heterogeneity
of the
2
population, between myoblasts, fibroblasts,
3
macrophages, SP cells--to what extent, and where is
4
the barrier drawn for being able to assess
5
biological function in either small or large
6
animals, of the actual human product?
7
8 CHAIRMAN RAO: Before I ask one of the
9
cardiologists to answer, I'm just going to ask
10
if--Dr. Schneider, is your question similar to
11
Bruce's?
12 DR. SCHNEIDER: I was actually going to
13
follow up on that.
14 CHAIRMAN RAO: So should we, then, have
15
that question so that maybe the cardiologists can
16
answer that together--other cardiologists.
17 [Laughter.]
18 The presentations can answer that. Maybe
19 I
should make that clear. So go ahead,
Dr.
20
Schneider.
21 DR. SCHNEIDER: I was going to say, in
22
response to Jeff's point about the balance of large
23
and small mammals, that I would probably draw the
24
line of preference at a slightly different point.
25 I think there's clearly a need--and an
123
1
unambiguous need--for large-mammal models, where
2
delivery systems are to be studied, such as
3
catheters or, conceivably, specific complex
4
surgical procedures beyond the kind that we heard
5
about in yesterday's presentations; that,
6
inherently, because of geometry could never be
7
adequately tested in a smaller mammal.
8 If the question is: does the biology of
9
the smaller mammal allow complete predictability of
10
the human situation, the answer would be no. My
11
point is that that also would be true for the large
12
mammal. The large mammal studies
are not done in
13
aged animals. They're not done
in animals with
14
disseminated atherosclerosis. So
there always will
15
be a gap between what we can learn--even in the
16
best of circumstances--from the large mammal and
17
from the human.
18 CHAIRMAN RAO: Would you add to that about
19
safety, as opposed to efficacy?
20 DR. SCHNEIDER: Safety issues as well.
21 What I would do is to try to emphasize the
22
point that the job of the preclinical data is not
23
to predict the outcome of a Phase III trial. The
24
job of the preclinical data is to predict the
25
safety of a Phase I trial. And
from that point of
124
1
view, I think a preponderance of small-mammal data
2
is more than sufficient, with the exceptions that I
3
noted, where complex devices are concerned.
4 It's to show the reasonableness of a
5
benefit, and the reasonableness of safety.
6
Ultimately, those have to be judged in Phase I
7
trials. And if Phase I trials
work, the more
8
complex larger trials later.
9 CHAIRMAN RAO: Joanne.
10
11 DR. KURTZBERG: I was just going to add
12
that I think the allogeneic models are important.
13 I
don't think we know what direction this will
14
ultimately take. And I think
they're important to
15
ask question about tolerance induction and whether
16
the use of allogeneic cells will be
17
feasible--because it may be that, in the long run,
18
it will be technically more straightforward to have
19
the cells ready when the patient needs them, and it
20 may
be timing is important to get it right away or,
21
you know, shortly after the MI--or whatever. And
22
with autologous cells, you may not have that
23
option.
24 CHAIRMAN RAO: Dr. Cannon.
25 DR. CANNON: This is really a follow-up to
125
1
Dr. Borer's and Dr. Schneider's comment about the
2
limitations of large animals, as far as safety and
3
efficacy.
4 And a good example is estrogen therapy.
5
Hormone replacement therapy was believed to be safe
6
and efficacious in all animal models tested;
7
virtually all tested, including primates. And yet
8
it did not predict the response in individuals with
9
diffuse atherosclerosis and its risk factors.
10 So I think there are major limitations to
11
even large animals.
12 CHAIRMAN RAO: Dr. Ruskin, and then Dr.
13
Epstein.
14 DR. RUSKIN: Just a comment about the
15
safety question and animal models.
16 I thin, with regard to cardiac safety, and
17
particularly this issue of arrhythmagenesis, the
18
small animal models are not going to be useful.
19
They may be--they're very useful from a biological
20
perspective, and potency, and other elements that
21
people have raised. But I think
that given the
22
relative infancy of this field, that having
23
experience in some of the well established
24
large-animal models--particularly dogs, but also in
25
pigs; dog models have been around now for three
126
1
decades of acute and sub-acute and chronic
2
infarction, for example and, more recently, some
3
heart failure models--can be very useful. And I
4
would never suggest that the information obtained
5
from these studies would be dispositive, but they
6
can be informative from a safety standpoint,
7
particularly if safety issues arise; that is, they
8
tend to be rather insensitive.
But if you see a
9
major safety question with regard to arrhythmagenic
10
effects in a canine model, that should be a red
11
flag for whether or not one moves forward, and how
12
one moves forward into Phase I.
13 So I would make a plea for doing work in
14
large-animal models fairly early on--certainly well
15
before considering Phase I trials with an aspect of
16
these new therapies.
17 CHAIRMAN RAO: I'll have Dr. Epstein and
18
Doris make quick comments.
19 DR. EPSTEIN: Yes.
Bruce, just in answer
20
to your question: if you wanted to test either
21
safety or efficacy of human cells in an animal
22
model--immunosuppressed--I mean, I guess the bottom
23
line is there's no--as everyone has said--there's
24
no perfect animal model. Because
the effect of the
25
cells you're injecting may not be primarily a
127
1
direct effect of the cells, but their ability to
2
orchestrate, for example, an inflammatory response.
3 So if there's no inflammatory--host
4
inflammatory response, that could either be
5
efficacious or it could be--lead to adverse
6
effects. So it's not a perfect
model but,
7
nonetheless, it could provide some important
8
information.
9 So the bottom line is, I think that large
10
animals, small animals--none of them are perfect.
11
All of them can provide some important information.
12
What should be required is obviously going to
13
depend on what the specific question being asked,
14
and what the specific cells are that one is
15
thinking of injecting.
16 DR. BLAZAR: So can I--just before you
17
leave the microphone, just ask you: what--is there
18 a
different frequency--if you put human cells in
19
rodents, dogs, pigs, what fraction of those cells
20
have any biological function or survival in the
21
different species? Because while
it may not
22
correlate directly in each individual species, if
23
the fraction of cell survival and being able to
24
function in vivo is extraordinarily low in rodents
25
and increases as you go up the ladder--
128
1 DR. EPSTEIN: You mean in the absence of
2
immunosuppression.
3 DR. BLAZAR: However.
To me, it's still
4
whether there are appropriate inductive and
5
survival signals. Forget,
necessarily, the host
6
immune response, but are there just signals so the
7
cells just don't sit there.
Because I know you can
8
engraft human MSCs and MAPCs etcetera in rodents,
9
but the frequency is extraordinarily low in many
10
cases, without the necessary inductive signals.
11 DR. BLAZAR: Well, I guess the bottom line
12
is that studies have been done, and published in
13
excellent journals, demonstrating that you get a
14
biologic effect. And as Dr.
Borer has been
15
emphasizing, you know, that is what you're
16
interested in.
17 Now, what percentage of cells survive, and
18
which specific cells survive is an important
19
question. But there is important
biologic activity
20
when you put in human cells in a rodent model.
21 CHAIRMAN RAO: Go ahead, Doris.
22 DR. TAYLOR: I'm sorry, I just wanted to
23
say very quickly that one of the slides I showed
24
yesterday, in terms of comparing myoblasts and
25
myoblasts plus--angiogenic myoblasts were human
129
1
myoblasts transplanted into SCD mice.
And we saw a
2
biologic effect. So--and I
didn't emphasize that.
3 But I think, in terms of injecting human
4
cells in small-animal models to test function, I
5
think that's fine. I think to
test safety, you
6
have to move up the tree.
7 You know, nobody wants this field to move
8
forward more rapidly or more quickly than--or more
9
safely and quickly than I, but I think we have to
10
answer the safety questions. We
didn't anticipate
11
them all with myoblasts, and now we have the
12
opportunity to do it differently.
13 CHAIRMAN RAO: So before we get to you, is
14
there anybody who strongly disagrees with the
15
statement that Doris made?
16 Just--Doris said that, you know, for
17
safety studies it seems to be quite important that
18
you might want to consider larger animal models as
19
well. That was her point. She said that--I'm
20
summarizing, but--
21 DR. SCHNEIDER: If the operative word is
22
"consider" rather than "implement," I think--
23 CHAIRMAN RAO: Yes.
24 DR. SCHNEIDER:
--I think that's the
25
distinction.
130
1 I mean, Dr. Ruskin makes a very good point
2
about the safety issue with respect to arrhythmias.
3
But it's one point that needs to be balanced
4
against other considerations. If
I were asked to
5
weigh the predictive power of dog cells re-injected
6
into the dog, versus human cells injected into a
7
mouse as indicative of what human cells would do
8
when injected into a patient, I'd rather know what
9
the human cells do.
10 In many cases, the markers don't exist to
11
isolate the cells from some of these large mammals.
12
And as Steve Epstein pointed out, if one wants to
13
use an immuno-compromised dog, sheep or pig, one is
14
obliged to use drugs that have many confounding
15
effects. Cyclosporin is used
routinely in the
16
transplantation field, but in heart failure studies
17
many of us have been looking, for the last six
18
years, at complex molecular effects of
19
calcinurine-dependent signals.
20 So, from an immunological point of view, a
21
mutant mouse is cleaner and more predictive than a
22
cyclosporin-treated pig.
23 DR. MULE: So I've been hearing almost a
24 consensus
of the--not necessity for animal models,
25
but the preference for animal models, perhaps.
131
1 What I haven't been hearing is what are we
2
asking these animal models to provide us with
3
information? I've been hearing a
lot about the
4
weaknesses of small animal models, large animal
5
models, xeno-transplants, human cells into
6
immuno-compromised mice--and, again, layering the
7 complexity
of the disease, which has not been
8
replicated in any of these animal models. I've
9
heard that one cannot necessarily predict the
10
toxicity of the cell-based therapy in perhaps
11
large-animal models.
12 So I guess the issue is: if we have
13
myoblasts as sort of the therapy to be considered
14
here--as one of the therapies, and we can
15
conceivably understand that if we put certain
16
parameters on that population, that in vitro will
17
produce myotubes, for instance.
18 What are we asking of these animal models?
19
Are we asking that 90 percent of the cells will die
20
when they're injected? I think
we already know
21
that. And so what I have not
heard--other than
22
weaknesses in all these models--is what precisely
23
we're asking these animal models to provide us with
24
information that will help us to go to the clinic.
25 CHAIRMAN RAO: Hold that thought, and I'll
132
1
maybe ask you to re-phrase it again in the next
2
five minutes or so.
3 Go ahead, Dr. Murray.
4 DR. MURRAY: Well, actually, Jim asked, in
5 a
broad frame, the same kind of question I wanted
6
to ask. And I've been trying to
listen carefully
7
to the various things that have been said, and the
8
questions that we're being asked to help the FDA
9
address.
10 So, I've been trying to create a
11
conceptual map to help myself understand what's at
12
issue here. So let me just--what
some elements
13
are: we want to know something about the basic
14
biology; what happens to these cells; what are
15
these cells; what happens to them if you stick them
16
in a heart--by various routes, by various
17
means--you know, with all the various different
18
ways people prepare these.
19 And you want to know about autologous
20
cells, you want to know about--and you want to know
21
how human cells behave in, you know, in an animal
22
model, so you've got to have an immuno-compromised
23
animal model. And there are all
kinds of
24
disadvantages there.
25 The hearts differ in these different
133
1
animal models, and their anatomy, the cell type
2
functions; the geometry, physiology and
3
electrophysiology. The
disease--the disease models
4
differ. You've mostly got fresh experimental
5
lesions, rather than a good model of chronic
6
congestive heart failure. Plus,
in humans, you've
7
got this background of long-term disease, with all
8
the stuff that's happened, plus the drugs and other
9
treatments and other interventions that have gone
10
on--all of which make it difficult.
11 The hearts differ in these animal models
12
and what you can measure. You
know, a mouse heart
13
beats--what?--600 times a minute?
Is that what I
14
learned yesterday? And it's
probably a little hard
15
to catch what's going on in those 600 beats per
16
minute. Larger animals beat more
slowly, or more
17
like humans--allow more measurements.
18 So this is the sort of map I've been
19
putting on this. And it's pretty
clear that no
20
single model is right. There are
a lot of
21
different questions you ask in different ways.
22 We're going to learn about
23
the--ultimately, you want to learn about the safety
24
issues involved with doing the sort of
25
interventions that people are proposing to do, and
134
1
almost certainly that will involve some use of
2
larger animals that are closer to the human.
3 CHAIRMAN RAO: Deborah?
4 AUDIENCE: I run a large primate program
5
involving hematopoietic stem-cell biology, and I've
6
also worked quite a bit in xenograft with mice.
7 I would stress that, like Bruce said, I
8
don't think, if you have no efficacy in a xenograft
9
you necessarily know if that is going to predict no
10
efficacy in a large animal or human.
The homing
11
and engraftment of cells, if we're going to give
12
them intravenously, or look at cytokine
13
mobilization in a xenograft is, I think, completely
14
useless.
15 Mouse spleens behave extremely differently
16 from
human and large animal spleens. The
cells all
17
go there. For most of the
hematopoiesis studies,
18
you have to splenectomize mice to get any
19
information out that's going to apply to humans.
20 Non-human primates--we have lots of
21
reagents like cytokines and cell service molecules,
22
and the ability to culture cells that are very
23
analogous to humans. What we
don't have is
24
cardiologists and cardiac surgeons who've worked in
25
these models.
135
1 So as we tried at the NIH to bring some of
2
these cell therapies into the non-human primate to
3
test them, there just isn't very much known, and
4
there's not a lot of comfort with the surgeons and
5
the cardiologists in knowing how these animals
6
react, in terms of arrhythmias and everything else.
7
On the other hand, dogs, where you do know a lot,
8
and pigs where you know a lot, you can't have any
9
idea if the cell populations are correct. So, I
10
either would try to put resources at an extramural
11
level into better defining reagents, antibodies and
12
cytokines for dogs and pigs, or get some
13
cardiologists and cardiac surgeons more comfortable
14
with working in non-human primates.
Because for
15
highly manipulated products, like MSCs, you're
16
going to over-express AKTN, or MAPCs, I really
17
don't think that you would want to put those into
18
humans without having some long-term safety studies
19
in a large animal saying where the cells go, how
20
long they last, do they form tumors?
You know,
21
labeling them with iron or other moieties to try to
22
figure out exactly what's happening to them, both
23
acutely and sub-acutely I think would be pretty
24
important.
25 With non-manipulated cells, and
136
1
mononuclear cells from the bone marrow that you're
2
shooting into coronaries and things that have
3
already been done, maybe that's not necessary, and
4
maybe you can do it in dogs. But
for the
5
manipulated populations, I think you need to try to
6 improve
the primate models--potentially.
7 CHAIRMAN RAO: Go ahead. Just introduce
8
yourself.
9 DR. KELLY: Ralph Kelly. I'm from Genzyme
10
Corporation. And I wanted to
follow up with Dr.
11
Ruskin about the comment regarding arrhythmias.
12 For the MAGIC trial that Phillipe
13
Menaasche is currently running, the protocol
14
specifies that the skeletal myoblasts--autologous
15
skeletal myoblasts--be placed not only in the
16
center of the scar, but also in the border zone
17
surrounding the scar, which obviously brings in
18
issues such as reentry. And you
discussed the
19
canine model, for example, but then just sticking
20
them in a dog and then doing Holter monitor studies
21
and so forth may not be practical, or at least
22
efficient way to do it.
23 Can you comment on optical mapping
24
techniques, for example? Other
measurements that
25
might give us an idea how pro-arrhythmic these
137
1
cells might be?
2 DR. RUSKIN: That's a good question, and a
3
difficult one to answer.
4 The technique of optical mapping is very
5
useful for mechanism and for characterizing the
6
electrophysiologic properties of the tissues, but
7
doesn't tell you very much about arrhythmagenic
8
potential. So I think you would
probably end up
9
doing continuous monitoring with implanted devices,
10
and also electrophysiologic studies.
11 And I suspect that the yield would
12
probably be quite low. And the
concern, obviously,
13
in these models always is that they are
14
insensitive. So if one sees
nothing, you can't
15
take much away from it.
16 If you say a signal--for example, a high
17
sudden-death rate among the animals--that would be
18 a
red flag, obviously, for a major concern.
And
19
that was my only point.
20 I don't think that ;there's a highly
21
specific probe that we can use that's going to
22
answer the question in an animal model as to what's
23
going to happen in the human situation.
24 CHAIRMAN RAO: Dr. Harlan?
25 DR. HARLAN: You started the session
with
138
1
the question: are animal models required before we
2
move to the clinic, or should we do both
3
concurrently. And then Dr. Mule
asked about what
4
question are we asking from the animal models.
5 I think the answer to the latter question,
6
and then to your question, is that we're--in all
7
cases, we're gathering data; that we don't know
8
what we don't know. And, to me,
I don't think
9
there is any ideal animal model.
We learn
10
something from each one. And I
think we learn
11
stuff in the clinic that we can't possibly learn
12
from any animal model, and so that you need to do
13
both, and that then the question is: how do you do
14
the clinical trial in the way that is least likely
15
to do harm. And that will be, I
think, the major
16
topic of discussion.
17 CHAIRMAN RAO: I guess it's you, me and
18
Rumsfeld--right? There are known
knowns and known
19
unknowns, I guess.
20 DR. ITESCU: I'd just like to add a little
21
bit about the small animal models, and disagree
22
with one of the earlier speakers--that, in fact,
23
we've done a lot of work looking at homing and
24
cytokines and chemokines in mice and rats--those
25
immuno-compromised animals. And,
in fact, it looks
139
1 like they're excellent models for being able
to
2
predict the ability of human cells to home and
3
target the myocardium; that many of the chemokines
4
and cytokines produced in these rodent models do,
5
in fact, interact with the receptors on human
6
cells.
7 So I think, in fact, they're very adequate
8
models to study many of these processes. And
9
perhaps the biggest difference between these models
10
and the primate models, obviously, are the immune
11
responses. And we just need to
keep that in mind.
12 But, otherwise, many biological questions
13
can be addressed pretty adequately.
14 DR. BLAZAR: I wasn't saying that the
15
models were inadequate. I was not clear as to what
16
;you all had as a consensus as to the relative use
17
of these xenogeneic system to get where you wanted
18
to go--the way Jim phrased.
19 So if the consensus is that this does
20
provide you the necessary readouts, despite the
21
limitations of a xenogeneic environment, I think
22
that's fine. But it did not come
out in the
23
presentations as to whether that was necessarily
24
the case.
25 DR. ITESCU: Yes, I didn't show yesterday,
140
1
but we've got some pretty convincing data on a
2
variety of cytokines and chemokines made by
3
rodents, and how they interact with the human cells
4
in a similar way to what happens in man.
5 DR. HARLAN: I just want to quickly comment
6
that when you look at your cells and they do home
7
appropriately, what you don't know is what other
8
cells might not work in that model, but would work
9
in a different model. So it's
just the same point:
10
we don't know what we don't know.
11 And so I think it's important to not rule
12
out the possibility that a cell that doesn't work
13
in a non-SKD mouse might work in a different
14
species.
15 DR. ALLAN: Yes, I just wanted to come back
16
to what animal model is appropriate.
Because, I
17
mean, I'm not in this field. So
I sit here and I
18
go, "Gee, you know, I don't hear that much about
19
non-human primates." You
know, because to me it's
20 a
no-brainer. You want to be using
non-human
21
primates.
22 And then--so it was interesting to hear
23
what some of the reasons are why people aren't
24 using
non-human primates. It's a comfort
zone:
25
cardiologists never used--haven't used non-human
141
1
primates very often for this.
Maybe it's also a
2
question of cost, and numbers of animals--things
3
like that--which I can understand.
4 And in this particular case it seems to me
5
that what you're dealing with is basically
6
cost-benefit--or risk-benefit, and that is, well,
7
if you're shooting cells into humans, you probably
8
aren't going to kill them, and therefore you don't
9
have to use non-human primates because you're not
10
sweating as much. Because in
xenotransplantation,
11
they have a bar, and you've got to do
12
pig-to-primate transplants and show that the organ
13
survives for more than, you know, five days or 10
14
days before, you know, they let you go into humans.
15
Whereas here, you know, you shoot a few cells, and
16
you probably are not going to kill the patient.
17
And so therefore maybe you don't need to use
18
non-human primates.
19 But to me, I mean, it's like--I mean, the
20
non-human primates, it's not a perfect
21
model--obviously it's not a perfect model, but it's
22 a
better model than any of the other models, in
23
terms of you've got cytokines that you can use. I
24
mean, this GCSF study, you know, they probably
25
could have done some of that work in non-human
142
1
primates and would have got some ideas.
2 And it doesn't mean that that wouldn't
3
happen anyway because, I mean, you look at gene
4
therapy trials. Some of the
studies in macaques
5
show that if you give them too much virus you kill
6
them, and yet, you know, they still went into
7
humans with the same dosage and there were some
8
adverse reactions there.
9 So I'm just--I'm not trying to promote the
10
use of non-human primates, but I was just sort of
11
like curious as to why people aren't using that
12
more often.
13 DR. BORER: I'd like to get back to the
14
issues raised by Dr. Mule and Dr. Murray, because I
15
think they're very important issues.
And let me
16
try and take a crack at an answer.
17 CHAIRMAN RAO: Dr. Borer, can we hold off,
18
then, on that--
19 DR. BORER: Sure.
20 CHAIRMAN RAO:
--because I want to try and
21
complete this--it's part of the question we want to
22
address which is Question 4, but I want to try and
23
get this whole idea of do we absolutely need
24
models, and which kinds of models, and is there any
25 absolute criteria that we should use first.
143
1 DR. BORER: That is what I was going to
2
respond to, actually. I think
that's the crux of
3
what the question was: do we really need animals if
4
we don't know how to interpret the results?
5 CHAIRMAN RAO: I think Dr. Murray's point
6
was what kind of readouts, and what are you really
7
using the models for? And I want
to wait on that
8
just for a couple more minutes if we can.
9 DR. BORER: Okay.
Maybe I wasn't
10
responding to Dr. Murray's question.
11 CHAIRMAN RAO: Okay, then.
12 DR. SCHNEIDER: So you don't want a
13
response to Dr. Mule's question: why do we use the
14
animal models?
15 CHAIRMAN RAO: Yes--not just yet.
16 DR. SCHNEIDER: Okay.
Let me respond to
17
why cardiologists--
18 [Laughter.]
19 --don't use non-human primates.
20 Apart from the fact of expense, lack of
21
experience in most of the university medical
22
centers, we are also cognizant of the fact that the
23
non-human primate models are, to the public, an
24
abomination.
25 CHAIRMAN RAO: Kathy?
144
1 DR. HIGH: So--maybe I have to wait, too,
2
because I wanted to respond to Dr. Mule's question.
3 [Laughter.]
4 CHAIRMAN RAO: So maybe we can really list
5
these as comments that can be made--give me a
6
minute, then, to try and see if we have some sense
7
of consensus on this minimal first part.
8 From what I heard from everyone here was
9
that nobody thinks you should rush to go and do
10
human trials without doing some sorts of animal
11
studies--right? That seemed to
be pretty clear.
12 And what also seemed to be pretty clear to
13 me
from listening to everyone was that there's no
14
perfect animal model for the disease.
So we're not
15
trying to mimic a particular disease, but you're
16
really trying to look at sort of some kind of
17
critical issues on the cell type that you will use,
18
and the choice really depends on the cell type that
19
you're going to use, and that's why you have to
20
vary between choices of models.
21 And there seems to be clear-cut consensus
22
that for certain things you have to use a
23
large-animal model. So, for
physiology, sort of
24
geometry, imaging issues and so on, it doesn't seem
25
that you can answer those questions with a small
145
1
model.
2 But there are other issues where, maybe
3
because of speed, maybe because the behavior has
4
already been demonstrated, or there's a whole
5
history in terms of sort of bone marrow studies
6
which can be addressed in small-animal models--and
7
there's no reason why they shouldn't be addressed
8
in small-animal models.
9 So, ultimately, you may have to choose
10
which model you use, depending on the type of cell
11 you choose, and what type of readout you're
looking
12
at. And such models exist for
doing that. But
13
clearly there's no perfect model which will clearly
14
answer all of these studies.
15 There still seemed to me a little bit of
16
dissension--and I want to make sure that I haven't
17
missed that--is there seemed to be some argument
18
that safety studies could only be done in a
19
large-animal model. And I wasn't
absolutely
20
sure--maybe some types of safety issues are really
21
critical and can only be done in a large-animal
22
model such as, you know, tachycardia perhaps,
23
geometry and reentries phenomenon.
But other
24
studies may be simply more important in
25
small-animal models--right? You
know, where we
146
1
have--if you're looking at immuno-compromised
2
animals and so on.
3 The last piece that seemed to come through
4
from everybody was that animal cells are animal
5
cells, and there are many, many reasons why they
6
will be different. And we
already know that
7
they're different, so that though you can do
8
syngenic, they're not going to be absolutely
9 predictive of what will happen when you take human
10
cells and put them into human patients, and you
11
have to keep that view in mind.
And if that's the
12
case, then there might be certain times--or
13
depending, at certain stages--where doing either
14
xeno-models, or correlating it with--as Dr. Harlan
15
pointed out--with clinical trials which are
16
happening at the same time might be quite critical.
17 Is that--at least for part of
18
choosing--we've not yet talked about what the Hell
19
are you going to learn from a model--and I
20
apologize for my language, I guess--
21 [Laughter.]
22
23 --but at least it sets up the fact that we
24
need some kind of model. That
seems to be
25
irrespective--that we need something, and we nee to
147
1
get some information, and we need to collect a
2
large amount of data from it.
3 And, Dwaine--
4 DR. RIEVES: But, Dr. Rao, those are
5
excellent points, and it's very difficult to talk
6
in generalities.
7 But if in the discussion the committee
8
members could also consider something Dr. Dunbar
9
touched on, is whether, as witnesses, or reviewers
10
or production of development programs, we should
11
consider flexibility with respect to the nature of
12
the cellular product itself, as to how it's
13
manufactured--these heavily manipulated products,
14
the cultured products.
15 Should the preclinical testing for those
16
type products be different from the many academic
17
investigators across the country who say, "I'm
18
harvesting bone marrow in the operating room suite,
19
and I'm filtering it to get the specules out, and
20
I'm administering it." When
those
21
sponsor-investigators come to us, they're going to
22
ask is there some need for pre-clinical study. Or
23
is it inherently safe because it's autologous and
24
minimally manipulated.
25 If you could consider those type issues in
148
1
the discussion, too.
2 CHAIRMAN RAO: As soon as we start talking
3
now, and hopefully, just next is what do we want to
4
learn from an animal model, and why do you want to
5
put cells in.
6 DR. TAYLOR: [Off mike] When I said the
7
word "safety" I meant arrhythmia. I didn't
8
mean--so there's really not dissension.
When I
9
said "safety" I meant electrical safety.
10 CHAIRMAN RAO: So maybe we can go with Dr.
11
Borer, who was trying to summarize or respond, and
12
then go with Kathy, and then Dr. Schneider, since
13
you wanted to respond, too, sir.
14 DR. BORER: First let me say I agree with
15
everything you said.
16 [Laughter.]
17 I think that where we may be going here,
18
and what seems like a little dissension that I
19
don't think really is dissension, is that what
20
everybody wants is a preclinical construct that
21
would be perfectly predictive so that you really
22
knew what the problems are, and you really knew
23
what the potential benefits were, or what the
24
functional changes in the heart might be so that
25
you could then give your therapy in patients and be
149
1
concerned, really, only about clinical outcome; you
2
know, is there a clinical benefit, is there not, or
3
does the benefit outweigh the risk.
4 There is no such preclinical construct for
5
any disease--in cardiology. I
mean, in other
6
disease there may be. I don't
know. But certainly
7
there isn't in cardiology.
8 So I think what we want from the animal
9
studies is two types of information.
First of all,
10
one would like to have some confidence that there
11
isn't an overwhelming show-stopper lurking out
12
there, safety-wise. Jeremy made
the point: animal
13
studies are not highly sensitive, in general, for
14
cardiac events, but when cardiac events of certain
15
types occur, one should take note of that and be
16
cognizant of that in designing clinical studies if,
17
indeed, it even seems reasonable to do that after
18
you know about the major potential risks that one
19
might have picked up in animals.
20 With regard to the minimally manipulated
21
cells that are taken out of the bone marrow,
22
filtered and put into a person--into the same
23
person from which they came--is there any need for
24
preclinical studies? Well, I
would argue that you
25
would at least want to test the implements that
150
1
you're going to use to take and do, to make sure
2
you haven't changed the cells that you've taken out
3
in such a way that they clump, form emboli and, you
4
know, block arteries, for example.
5 I mean, so some kind of preclinical
6
testing relevant to the specific situation would be
7
appropriate, but here we're talking more about
8
mechanical, I think, than biological
9
problems--although there may be biological
10
problems, too, with the minimal manipulation--I
11
don't know.
12 But, anyway, that's one type of
13 information
one seeks from preclinical studies.
14 The second is some evidence that it's
15
reasonably likely that a benefit might occur if
16
used as therapy. You know, we
can't test animals
17
for clinical benefit, per se. I
mean--or at least
18
it would be very difficult to do it--unless we
19
learned how to talk to the monkeys or, you know,
20
followed the animals for a longer period of time
21
than we usually do to look at outcomes of other
22
sorts. But at least one can look
at surrogates
23
that seem, from a tremendous amount of prior
24
experience, to be at least reasonably predictive of
25
the likelihood that something good clinically may
151
1
result.
2 And for that purpose, I would say you
3
would want to see some consistency among different
4
types of models, properly selected for functional
5
markers of one sort or another.
And I don't want
6
to get very much more specific.
7 Now, at the end of the day you've done all
8
that, and you still may be wrong--as Richard
9
pointed out. I mean, you know,
all the animal
10
studies can look great and you put the product into
11
people and it doesn't work, or it does bad things
12
that you didn't expect. That can
happen.
13 But I think it would be wrong to expose
14
human beings to a putative therapy without at least
15
having done some reasonable screening so that you
16
could--so that a bunch of reasonable people sitting
17
around a table who had experience could say it
18
seems as if we are unlikely to cause great harm,
19
and it seems reasonable to infer that we may cause
20
good.
21 Yu know, I think that's the basis of doing
22
these studies. There's no
perfect predictor, but
23
without the kinds of evidence that I've been
24
talking about, I don't think we could reasonably go
25 to
humans.
152
1 CHAIRMAN RAO: Kathy?
2 DR. HIGH: So, I just want to make two
3
points, and I think I can be fairly brief because I
4
want to agree with some of the points that Dr.
5
Borer has made.
6 But just that, to me, the point of the
7
preclinical studies--part of the critical goals of
8
those is to define a safe starting dose and at
9
least get a bracket around what would be an
10
efficacious starting dose. And
from everything I
11
heard yesterday, that means work in large animals.
12 And the same point can be made about the
13
deliver system. So that's one
point.
14 The second point I want to make is to
15
respond to Dr. Rieves' point about need for
16
preclinical studies for single-site investigators
17
who are doing small trials. As
far as I'm
18
concerned, they need to be held to the same
19
standard. They need to show that
the way they
20
process the cells, and the way that they deliver
21
the cells has some reasonable expectation in their
22
preclinical studies. And I don't
think that they
23
should be able to avoid that responsibility.
24 CHAIRMAN RAO: Did you have a point, Dr.--
25 DR. CUNNINGHAM: Yes, I just wanted to
153
1
comment that there is a subset of the population
2
who do not like primate studies, but the large
3
segment of the population expects the FDA to
4
ascertain safety. And so there's
a large segment
5
of the population who would also expect everything
6
that was reasonable to be done to ascertain safety
7
be done.
8 CHAIRMAN RAO: We're still trying to focus
9
on the point that: what do we want in the readouts,
10
and it is specific to specific cell types, so that
11
Dr.--you know, that we address some of these
12
issues. So if you can try and--
13 DR. SCHNEIDER: Yes.
With respect to
14
skeletal myoblasts, I think the goal in the
15
preclinical data, along with the safety issues, is
16
more straightforward than for some of the other
17
cell types that we've talked about.
The goal in
18
skeletal muscle therapy is to replace cardiac
19
myocytes with another contractile cell type which,
20
regardless of the presence or absence of electrical
21
coupling, does have strong animal data--as Doris
22
and Phillipe showed yesterday--suggesting that they
23
improve pump function in the regions of the
24
ventricular wall that receive the cells, and also
25
global pump function.
154
1 So, to your point and Jeff's I would say:
2
the skeletal myoblast trials are very simple. What
3
they're trying to treat is heart failure, and it's
4
functional correlates as measured by MVO2, or
5
ejection fraction, or pressure volume loops; and in
6
patients--but not in the animals--symptomatology,
7
and whether or not they also have the other kind of
8
clinical correlates--reduction of hospitalizations,
9
reduction of the need for transplantation,
10
reduction of mortality. That's
one of the things
11
that the animal models just won't answer.
12 For me, the goals in the angiogenesis--or
13
in the pleuripotent cells is more complex. And
14
maybe Steve or Silviu could comment.
Many of those
15
are also being done with pump function as a major
16
endpoint. These studies are done
in a different
17
setting clinically, typically, with treatment
18
within the first days of myocardial infarction, and
19
it's likely that the mechanisms of efficacy include
20
at least some cytoprotective effect on jeopardized
21
myocardium, plus angiogenesis, plus--and this point
22
is highly controversial in the field--the
23
conversion of the bone marrow or circulating cells
24
into cardiac myocytes.
25 Steve, I'm not aware of any cell therapy
155
1
trial that's been aimed at intractable angina as
2
the--
3 VOICE: I think there have been several.
4 DR. EPSTEIN: Yeah.
5 DR. SCHNEIDER: Okay.
So I think what one
6
is asking of the animal models in those cases is
7
different, and not the same as for skeletal
8
myoblasts and chronic heart failure.
9 CHAIRMAN RAO: Dr. Epstein?
10 DR. EPSTEIN: Yes, and I would agree with
11
you--
12 CHAIRMAN RAO: Before you answer, Dr.
13
Epstein--
14 DR. EPSTEIN: Yes--sorry.
15 CHAIRMAN RAO: Dr. Harlan, did you have--
16 DR. HARLAN: Oh, I was just going to
17
respond to Dr. Rieves' question that he asked about
18
should there be different standards of safety and
19
product release for cellular products that just
20
come out of the patient, versus those that get
21
manipulated.
22 And I would simply endorse what the FDA
23
does; that the further you get from what is taken
24
out of the patient, the more rigorous the testing.
25 I
think what you guys do is right.
156
1 CHAIRMAN RAO: Dr. Epstein?
2 DR. EPSTEIN: Yes, there have been, I
3
think, four studies published, including our
4
own--and Dr. Perin's, really--which are not an
5
acute myocardial infarction studies.
They really
6
are angiogenesis trials. Even
Dr. Perin looked at
7
patients with reduced ejection fraction.
8 But I think the goal there was to improve
9
perfusion of that ischemic myocardium.
And our
10
study was in chronic stable angina.
11 So I think there are two approaches for
12
angiogenesis. One is in the
acute myocardial
13
infarction setting, which may be part myogenesis,
14
part angiogenesis. But then
there are
15
many--several centers that are involved in sort of
16
chronic refractory angina.
17 And I completely agree with you. The
18
endpoints that one looks for in the animal models
19
for efficacy would be very different than for
20
myogenesis.
21 DR. KURTZBERG: I have two comments.
22 One, I want to really endorse what Kathy
23
said and just also say that I think if you define
24
all these things going forward, you will save time.
25
You will make progress more quickly.
I think we
157
1
learned that in the bone marrow world after we
2
didn't do that. And it took us
15 years to get
3
together and agree what engraftment meant.
4 But if you have those common definitions
5
ahead of time, you can talk between your studies,
6
and you can compare things. And
so I don't think
7
it matters whether it's a Phase I study at a single
8
institution, or it's a multi-institutional study.
9 I
think having those agreements makes you be able
10
to talk and make progress much more quickly.
11 And I also think, you know, you may be
12
doing skeletal myoblasts now, but who knows what
13
other kind of myoblasts you'll do in a few years.
14
And if you don't agree to have the same common
15
terms and endpoints--even though you'll modify
16
them--you won't be able to compare one to the
17
other.
18 So I think that's really important.
19 And then the second thing I wanted to say
20
was just to clarify my comments about autologous,
21
unmanipulated cells. I think
they should be
22
studied under IND for delivery, but I don't think
23
they should become a product. I
don't think that
24
we should have to pay--the patient should have to
25
pay extra for their own cells that are not
158
1
manipulated in any non-classical sort of standard
2
of care fashion.
3 So once they're proved to be efficacious,
4
and the delivery systems are defined, etcetera,
5
then I just don't want to see them turned into a
6
commercial product.
7 CHAIRMAN RAO: So, you know, there are a
8
couple of things that are still a little bit
9
confusing to me, and I'm going to try and see if we
10
can focus on those as well.
11 So--you know, to me, it's pretty clear
12
that one needs animal models to do some sort of
13
safety study. But, to me, what's
not clear is what
14
kind of safety studies are absolutely critical, in
15
terms of when you put the cells into an animal
16
model?
17 For example, if I were to deliver cells by
18
IV, you know, I don't just want to look at the
19
heart and look at safety studies and look at
20
V-tach. You know, I really would
like to know, for
21
example, what's happened to the cells where we
22
didn't want them to know. You
know, probably a lot
23
of them go to the kidney and the spleen and the
24
lung. And should we be, in
animal studies, be
25
worrying about where they are if that's the method
159
1
of delivery?
2 If we put cells in, you know, with a
3
catheter, and then that's the animal model that
4
you're studying in terms of safety, should we be
5
saying that, you know, you always want to have to
6
look at a leak--right?--because that happens with a
7
certain frequency. Is that a
really specific thing
8
that we need to worry about? And
are there
9
certain, sort of simple, obvious things like this
10
which need to be considered, or should be required
11
in an animal model?
12 I mean, Kathy pointed out one thing and,
13
you know, it came up with Dr. Murray and with
14
several people, is that we need something about
15
dose--right? It doesn't matter
whether they're
16
minimally manipulated or not, or whether they've
17
been grown in culture. We really
need to know
18
what's a safe dose when you deliver them, and we
19
need to know that in that animal model, and we need
20
to know where they are. And that
came up when we
21
talked about it.
22 So are there any such other things that
23
one might want to consider, specifically with
24
taking a particular cell type which has been
25
manipulated in culture, you know, and that has been
160
1
put in by a certain methodology, that you would
2
absolutely want to highlight and say, you know, "If
3
you do this, and you put in an animal model, we
4
really want to worry about this?"
5 For example, in the nervous system, you
6
know, epogen cells which have maintained in
7
culture, I mean we really, really want to know
8
whether they continue dividing for up to six
9
months, and whether they form a proliferating mass.
10 I
mean, we consider that a requirement when you put
11
the cells in--right?-- in terms of doing it.
12 Maybe there are some things like this that
13
should be clear to the whole cardiac community.
14
And maybe there's a consensus.
And maybe the
15
cardiologists can tell us.
16 Who wants to take a first shot at that?
17 [Laughter.]
18 DR. SIMONS: You know, I find it very
19
difficult to speak about these models in such
20
general terms. I think we
haven't gotten into any
21
amount of detail you need to sort of talk about it.
22 And I'm not sure we have enough people
23
around the table, or in the room, who are
24
extensively familiar with these models--of course,
25
we will get into the use of devices, the use of
161
1
cells. And if that's an
important issue--and I
2
believe it is--maybe it should be a subject of a
3
separate discussion by a separate panel. I would
4
really like to suggest that that could be an
5
important step forward.
6 And we're talking about the cells sort of
7
transformed as if this was a single disease. It's
8
not. There are at least two
different
9
circumstances in which this is going to be used
10
clinically, and each of the circumstances will
11
actually dictate a very different model and a very
12
different delivery strategy.
13 And we either have to get into a very
14
profound amount of detail to sort of go over it, or
15
we should maybe sort of postpone this.
16 CHAIRMAN RAO: That's an important
17
perspective and I think, unfortunately, the FDA
18
doesn't have that luxury. And
so--
19 [Laughter.]
20 --we have to see whether--that the
21
conclusion can be that this is all we know, that
22
there's some even generic sort of advice that one
23
can offer.
24 DR. TAYLOR: I'm not a cardiologist, but
25
I've been thinking about this for a long time.
162
1
And, obviously, moving into clinical trials is an
2
important step.
3 I think we're in a very early stage here.
4
When the first myoblast trial was designed, for
5
example, MRI was the surrogate marker that was used
6
as an efficacy endpoint.
Partially through the
7
trials, people discovered that, in fact,
8
ventricular tachycardias were emerging, and that
9
people had to have AICDs implanted.
And all of a
10
sudden the endpoint was no longer useable.
11 And I think it illustrates how dynamic
12
this field is right now, and how flexible we have
13
to be in terms of changing as more knowledge comes
14
forward. And I think that's what
the FDA has to
15
keep in mind; that many of us who have been
16
thinking about this for 15 years haven't yet gotten
17
together and defined all the terms.
We're doing
18
that now, but we don't know.
19 CHAIRMAN RAO: You're right. It's
20
important. You're echoing what
Dr. Simons just
21
said.
22
But let me ask one specific
question
23
before we get to Dr. Harlan.
24 Do you think that one could say that,
25
well, we really, really, absolutely, for safety,
163
1
need to know about cells, so they have to all be
2
labeled so that we can follow them--in a reasonable
3
study.
4 Is that something that should be like a de
5
rigeur requirement--you know, an observation. We
6 don't--
7 DR. TAYLOR: In a clinical study? Or in a
8
preclinical study?
9 CHAIRMAN RAO: In a preclinical--since
10
we're talking about animal models, and--
11 DR. TAYLOR: I think right now it probably
12
depends, to some degree, on the cell type. The
13
short answer would be: I think we need to do
14
bio-distribution studies that we haven't done.
15 There are data that, you know--we know
16
some of these cells track to bone marrow. We know
17
they then get recruited to other places that we
18
don't know anything about yet.
19 On the other hand--and a lack of a label
20
has been a real issue, and that's one of the reason
21
small animals--mice--where you can use genetically
22
labeled cells are an incredibly important model to
23
be able to track these cells in vivo.
That's a
24
situation where safety studies could very easily be
25
done in small-animal models and be important.
164
1 Do I think clinically we need to be able
2
to label and track these cells?
No.
3 CHAIRMAN RAO: Dr. Harland?
4 DR. HARLAN: Well, I just want to respond
5
to your specific question about other potential
6
safety tests to consider, and to follow up on a
7
comment you asked about this morning about
8
karyotype.
9 I wonder if anybody is looking at, say,
10 cells that have been propagated in culture,
11
transplanted into a non-SKD mouse two years later?
12
You know, I think that may be--it may be something
13
that's not being looked at right now: the
14
tumorgenicity of these cells.
And I would suggest
15
that would be a good way to look for that.
16
Karyotype's one way, but an in vivo test would be
17
better.
18 CHAIRMAN RAO: But would you agree--I think
19
it's a very valid point. But
say, for example,
20 that that can't be generalized to all cell
types
21
because there might be a lot of data on, say,
22
minimally manipulated bone marrow cells, for which
23
there's long history of operative reporting, but
24
may not be true for other cell types that are put
25
in.
165
1 I want to ask: do you feel that this sort
2
of addresses some of the issues that you had
3
raised, in terms of the kind of things that one
4
needs in an animal model?
5 DR. MULE: It does.
6 DR. TAYLOR: I slightly disagree with
7
regard to minimally manipulated bone marrow cells,
8
because of some rodent data that haven't fully been
9 explained
yet, which are that GFP
10
transplanted--animals were ablated and green
11
fluorescent protein cells were used to replenish
12
their bone marrow. Tumors were
implanted in those
13
animals, Several weeks later the tumors were
14
explanted and the vessels were green in those
15
tumors.
16 I think we don't know exactly where
17
these--we know these cells go where we want them.
18
We also suspect they go places we don't want them.
19
And until we started--we do need to begin to
20
address that preclinically, I think.
21 At the same time, that's no different than
22
is already being required. I
think people are
23
doing tumorgenicity studies with most of these cell
24
types before they have the ability to implant them.
25 CHAIRMAN RAO: On this note--and I know
166
1
that there still is sort of sense that there's no
2
perfect model, and that we don't have a single
3
model that we can look at, and everything depends;
4
and that "everything depends" is sort of anathema
5
to, you know, the FDA--I guess.
6 But let's add to that just one more issue
7
here so that we can see whether this sort of
8
uncertainty also extends to specific models of
9
ischemia.
10 So--a lot of things that we've looked
11
at--there has been--the data that we've heard has
12
been about transplanting cells in the animal trials
13
and the human trials has been in some sort of
14
either ischemic infarct, or with low ejection
15
fraction where there has been damage.
16 Are there any merits to any specific
17
model, that you would say one is better than the
18
other, in terms of either the cryo model or the
19
banding model, or it's any species?
And, again,
20
maybe I can ask one of the cardiologists who has
21
experience with this to make some general statement
22
and see.
23 DR. RUSKIN: There are a number of canine
24
models that are relevant to the human situation
25
with regard to ischemic left ventricular injury.
167
1
So, certainly, if I were given a choice, I would
2
choose one of those over a cryo model, which is
3
really not a physiologic model.
Cryo produces very
4
uniform scarring, very discrete margins. It
5
doesn't bear any relationship to the architecture
6
of myocardial infarcts.
7 So I think if I had to pick a model--
8 CHAIRMAN RAO: Dr. Ruskin, when you make
9
this, would you also sort of consider this in the
10
light of "predominantly safety" versus efficacy
11
studies, as well, in terms of a bias?
12 DR. RUSKIN: I think that it's relevant
13
with regard to both safety and efficacy.
14 The model that we developed in the late
15
70s, and continue to use, are the transmural
16
myocardial infarction in dogs.
It is highly
17
analogous to some of the questions that are being
18
raised here in humans, in terms of wanting to treat
19
areas of myocardium that are truly dead. This is a
20 model of LAD occlusion with ligation of all
the
21
collaterals, from the right and the left circumflex
22
coronary arteries to produce an aneurism at the
23
left ventricular apex. It
produces a thin
24
transmural scar, with very little in the way of
25
islands of viable myocardium--which would seem to
168
1
me to be an ideal substrate in which to test this
2
kind of question.
3 So, if you asked me to pick a model,
4
that's certainly one of them that I would pick.
5
And, generically, I would certainly pick a true
6
ischemic-induced injury over a cryo or some other
7
synthetic kind of injury, if you will.
8 CHAIRMAN RAO: Dr. Simons?
9 DR. SIMONS: I certainly agree with Dr.
10
Ruskin that the cryo injury model is probably not
11
the way to go, for a number of different reasons.
12 There are two standard ischemia models
13
that's been used as a basis for a lot of the
14
growth-factor trials. One is an
amyloid model,
15
which is the most--which, over the last 10 years
16
became the most common cause of coronary artery
17
disease in pigs. And we know a
lot about this
18
model. We knowhow it works.
19 We also know that the drugs or devices or
20
cells or genes that work in that model don't work
21
in people--which raises an issue of how useful that
22
is. It certainly can be useful for
safety testing,
23
and a lot of other natural history.
But it's clear
24
that if--a pig, and if you have coronary disease,
25
we're going to fix you. And
unfortunately that
169
1
doesn't happen in people. And
this could be the
2
fact that these are young pigs, that are going to
3
grow. They don't have any lipid
disease, and they
4
are not taking drugs. So, it's a
hard one to
5
study.
6
As the other model that I
think is getting
7 a
lot of play now is the hind-limb ischemia in an
8
APE knockout, or an LD with a septal knockout mice,
9
because here you can mimic age, which you cannot do
10
in pigs and dogs. And here you
can mimic a lot of
11
human disease.
12 And it's interesting that the data is sort
13
of emerging now is that none of the growth factors
14
actually work in that model, and that could well
15
explain why they actually don't work in people.
16 So I think you can use pigs or dogs with a
17
chronic ischemia model such as an anaberoid to
18
study how effective your devices are in getting the
19
desired cells in place, and you can use the
20
diseased-mice models to get more of a functional
21
readout of whether the desired therapies will work
22
in the setting of age and disease.
23 CHAIRMAN RAO: Can I ask one more question
24
here, is that even in terms of safety, is it really
25
important to study the effect of these cells in an
170
1
animal model--in some kind of ischemia model?
2
Because the environment has changed; you know, the
3
cytokines have changed, the milieu has changed. So
4
when you look at safety studies, should you be
5
really doing it in some kind of model of ischemia
6
or not?
7 DR. SIMONS: I think the safety study in
8
animals should sort of mimic as close as possible
9
the clinical trial design. So,
if this is going to
10
be a trial of cells injected in-- that's how the
11
testing should be in animals, because of ischemic
12
milieu, and actually it has to work in ischemic
13
milieu, will have a different effect than if you're
14
doing it in healthy animals without it.
15 CHAIRMAN RAO: Dr. Schneider, then Dr.
16
Borer.
17 DR. SCHNEIDER: To follow up on Dr. Simons'
18
comment about using ischemic models to mimic
19
ischemia, the harder part, I think, will be using
20
heart failure models to model heart failure.
21 And if one considers the heart failure
22
population that Dr. Perin was speaking of
23
yesterday, and which is nominally the substrate for
24
many of the skeletal myoblast trials and some of
25
the other therapies, many patients have heart
171
1
failure as the result of prior coronary artery
2
disease and infarction; not all of them do. Many
3
of them have longstanding hypertension as a
4
contributing cause, but not all of them do.
5 And what I would say is that a number of
6
animal models--rather than seeing a limitation of
7
the field being that no one can agree on an animal
8
model which is perfect--specifically, no one can
9
agree on an animal model which is perfect for all
10
clinical situations. I would
also say no one can
11
agree on an animal model which is perfect for
12
either of the clinical situations.
13 You know, you've heard convincing
14
allusions by Dr. Ruskin and Dr. Simons to one of
15
the best ischemic models, in the dog, and one of
16
the ischemic models, in the pig.
And I personally
17
don't think that someone who comes to the FDA with
18
preclinical data should be precluded from using one
19
of those rather than the other.
You know, a number
20
of alternatives are possible, as well.
21 The situation becomes more complex in
22
heart failure, where there is far less agreement on
23
what an adequate large mammal is. Some
24
investigators used rapid ventricular pacing in a
25
dog or some other species. I
would say that the
172
1
smaller mammal models, or the rodent model--Syrian
2
hamster model of cardiomyopathy, which one speaker
3
alluded to yesterday--in fact mimic human heart
4
failure better than the pig or dog models that
5
currently exist.
6 CHAIRMAN RAO: Dr. Borer.
7 DR. BORER: Yes, unless Richard is going to
8
disagree, I think we're all in unanimity
9
here--those who are cardiologists around the
10
table--because I think the point is well made that
11
if the therapy is going to be given to people with
12
ischemic heart disease, then a physical injury
13
model is not appropriate, because the myocardial
14
milieu--the response of the extracellular matrix,
15
etcetera, etcetera--is going to be very different
16
in that setting than in an ischemia setting.
17 Having said that, of course, the animals
18
don't perfectly mimic people. So
what one would
19
like to do would be to look at several models. The
20
dog model is the one that we used to use at the NIH
21
regularly, because it was easy to manipulate and
22
seemed to be predictive. And
there's a god deal of
23
information about the predictive value of the dog
24
and the pig in certain situations.
25 The point I would make here, though, is
173
1
the one that Steve Epstein has mentioned again and
2
again: the selection is going--the selection of
3
model is going to depend, in part, on whether
4
you're thinking about myocardial function alone, or
5
angiogenesis--or arteriogenesis, to be politically
6
correct--because the different species differ, for
7
example, in their collateral development response
8
to coronary occlusion, etcetera, etcetera.
9 So one would like to select the animal
10
depending upon what it is you want to look at.
11 Having said that, the point that mike made
12
is very important. There is no
really--you know,
13
there's no perfect model for heart failure. All of
14
them are deficient in one or another.
And earlier
15
today Dr. Grant said that heart failure is the only
16
cardiac disease that's increasing in incidence over
17
time.
18 There's a subset of that: valvular
19
diseases are also increasing over time.
And the
20
valvular--the valve manipulation models produce
21
heart failure that mimics human disease as well.
22 The point is, there are several types of
23
models one could use. As Mike
said, I think you
24
want to use several, and try to find some degree of
25
consistency of the effect of the therapy in the
174
1
different models, none of which is absolutely
2
perfect.
3 The only thing I think that I would avoid
4
is the physical injury model, which I don't think
5
has much relevance.
6 CHAIRMAN RAO: Would it be fair to say that
7
if you were looking at the behavior of cells which
8
are being transplanted, that it's far better to
9
look at them in an ischemia model--preferably as
10
close to a human disease as possible--and that that
11
would be better than looking at it in a wild-type
12
or a non-injured model?
13
DR. BORER: Absolutely.
14 CHAIRMAN RAO: Because the behavior would
15
be--
16 DR. SCHNEIDER: Absolutely--not only for
17
the reason that you cite--that the milieu in which
18
those cells are required to function would be
19
different, but also for the reason--going back to
20
Dr. Mule's more general question, "What are we
21
looking for in the animal models?"--we're looking
22
for evidence of efficacy.
23 And so to rescue ischemic dysfunction, one
24
needs ischemia.
25 CHAIRMAN RAO: Can I ask one more question
175
1
before--
2 DR. EPSTEIN: Just--directly--just to
3
support what you've said, there was a very recent
4
and very interesting paper in Circulation, where
5
they were looking at adverse events of cells,
6
namely a pro-atherosclerotic effect.
And they were
7
using the ischemic mouse hind-limb model.
8 Cells derived from APLE knockout mouse
9
increased atherosclerosis, but only in the presence
10
of hind-limb ischemia. So that's
another point
11
that substantiates what you and the others have
12
been saying.
13
CHAIRMAN RAO: Did you have
a comment?
14 DR. WEISS: Yes, I'd like to make a
15
comment. My name is Judy
Weissinger, of Weissinger
16
Solutions.
17 I wanted to make more of a philosophical
18
comment in the concept of agreeing on an animal
19
model, or requiring large animals for certain
20
things; requiring small animals for certain areas.
21 I think what I'm hearing today is a lot of
22
people are identifying the question we need to
23
answer, and the considerations that we need to
24
address in developing these products, along with
25
the potential models, the studies, the methods that
176
1
we need to address.
2 And these questions and considerations are
3
really important for the sponsor to propose a plan
4
based on the product--the uniqueness of the product
5
they're developing, and the clinical design of the
6
study.
7 And so I just want to caution again--and
8
go along with the traditional biologics approach of
9
identifying the criteria that are needed to
10
evaluate a new therapy, as opposed to specifying
11
and requiring the exact studies that are needed.
12 Thank you.
13 CHAIRMAN RAO: That's a good point.
14 On that same--I just want some sort of
15
general feeling from people is that, you know,
16
almost all the viral studies we think about, or any
17
other study, we also always have some sort of sense
18
of how long you want to follow--right?
Even in a
19
safety thing--like we talked about tumors.
20 I mean, is there any sense in the
21
cardiology field, for example, that, you know, if
22
we do this animal study and, you know, you want to
23
look at an animal, and we have to look at
24
this--should it be six months?
Should it be one
25
year? Should it be--you know,
"Well, three weeks
177
1
is enough?"
2 DR. BORER: Let me try to answer that in
3
two ways.
4 First of all, you asked a question before
5
that's relevant to this point.
And I don't think
6
it received a specific response.
7 You said given the fact that with some
8
forms of delivery cells will be distributed
9
systemically, leads to questions about whether you
10
should look at other issues besides cardiac issues.
11
And I think the answer is absolutely yes, but there
12
must be--and I don't know what it is--must be a
13
rich experience from hematology studies over the
14
years to tell us about how and what one should be
15
looking for. In that situation,
I think one would
16
want to do that, in cardiac studies as well. And
17
that would drive the duration of follow-up in some
18
animal studies in a certain way.
19 In terms of the duration of follow-up for,
20
specifically, cardiac problems, that depends upon
21
the outcome you're interested in, and it depends
22
upon the model; and, specifically, it depends upon
23
the expected outcome of the animal naturally. You
24 know,
mice don't live very long. I'm not sure
what
25
the duration of follow-up of a mouse would be that
178
1
would be meaningfully extrapolatable to people.
2 But, you know, the average life span of a
3
dog or a rabbit is known, and one would like to
4
follow the animal for a substantial period of that
5
life span that might be relevant to the natural
6
history of the disease, I think.
That doesn't mean
7
that every study has to be done that way, but one
8
might like, for example, in a rabbit to be able to
9
follow it for two years, if you're looking at heart
10
failure issues.
11 I mean, I don't want to give a specific
12
number. But the principle is
that the follow-up,
13
at least in some studies, should be relevant to
14
what you expect the outcome to be in people, I
15
would think.
16 CHAIRMAN RAO: So that seems to be the
17 consensus
from a lot of other stem cell fields,
18
where you expect cells to persist for a long
19
period.
20 I mean, for example, when you think about
21
the nervous system, that seems to be the case;
22
where you say, well, we do it in mice, we want to
23
look at least 50 percent of the life span. They
24
live about two years, so you're going to follow at
25
least--not "at least" in every study, but for
179
1
particular studies, at least follow for a period of
2 a
year--but not in every study.
3 DR. TAYLOR: Talk about a hurdle! I mean,
4
we know that in most of our preclinical studies,
5
the function gets better in a month to two months,
6
and it doesn't get better after that.
It stays
7
pretty level.
8 In patients, the data seem to suggest
9
there's an improvement at three months.
It seems
10
to be maximal about six months, and it stays stable
11
after that.
12 I think requiring two-year follow-up in
13
these animal studies, in light of that, doesn't
14
make a lot of sense--at least from what I can see.
15 CHAIRMAN RAO: Dr. Ruskin.
16
DR. RUSKIN: I was going
to agree with
17
that. I'm not sure--I would say
that it doesn't
18
make sense. I think that it's
very difficult to
19
do, and part of this has to be tempered by the
20
patient populations that are going to be addressed
21
by the studies. And if it's
going to be Class IV
22
heart failure, with ejection fractions less than 20
23
percent, I don't think you need, you know,
24
five-year follow-up unless we're talking about a
25
miracle here--
180
1 [Laughter.]
2 --which would be wonderful.
3 So I suspect that the preclinical
4
requirements will evolve as the therapies evolve,
5 and as we begin to use
them in earlier phases of
6
heart failure, if this pans out, then clearly the
7
preclinical requirements will become much more
8
rigid and demanding with regard to longevity of
9
follow-up.
10 CHAIRMAN RAO: Dr. Borer.
11 DR. BORER: Yes, I mean, I agree with what
12
Jeremy said, and I agree with what Dr. Taylor
13
said--but, to me, the issue isn't whether
14
continuing improvement occurs, but whether
15
deterioration occurs. And you
can't know that
16
unless you study--at least at some point, in some
17
model, and in some way--the natural history of the
18
treatment effect; you know, which may not persist.
19
And I think we ought to know that somehow before we
20
start giving it to people.
21 Jeremy is, of course, quite right. If
22
somebody is expected to live six months and they
23
live two years because of the therapy, that may be
24 a
clinically acceptable benefit and you don't have
25
to know any more. But still, at
the outset, I
181
1
think you'd like to know the natural history of the
2
effect of the treatment.
3 DR. ITESCU: I think that the barrier
4
should be set exactly the same as you would set it
5
for any other pharmaceutical product or biological
6
compound that the FDA requires for testing at the
7
present time.
8 And an example--it depends on which cell
9
you're using, and what type of outcome you're
10
looking for. Some of the
cells--as Dr. Epstein
11
presented yesterday--simply are agents that release
12
preformed effect, and you're looking for an
13
immediate cytoprotective effect that may be fairly
14
short-lived, and the cells themselves may not
15
engraft, may not survive beyond the first couple of
16
days.
17 So I think you've got to keep those things
18
in mind, and not expect a more rigorous approach
19
here than you would with any other type of an
20
approach.
21 DR. BORER: I think that may be correct,
22
but I'd like to point out that the approach to
23
testing with pharmaceuticals is aimed primarily at
24
other issues--at least in cardiac diseases--because
25
we give the drugs every day. So
the issue there is
182
1
development of tolerance, or tactiphylaxis, and
2
there are--you know, we know from trial and error
3
that if an anti-anginal drug continues to work for
4
three months, the patients will continue to
5
benefit, you know, for a long time--who knows how
6
long?--but for a long time.
7 Same thing with drugs for heart failure,
8
etcetera, etcetera, where the follow-up has been
9
even longer. But the drug is
given every day.
10 Here we're giving one treatment, once.
11
And we don't know about its persistence.
12 So I would say that while what Dr. Itescu
13
says is absolutely right, I do think that there is
14 a
slightly different standard here because of the
15
differences in administration, and expectations of
16 the
administration regimen.
17 CHAIRMAN RAO: I'm going to ask the FDA--go
18
head--
19 DR. McFARLAND: I was just going to--from a
20
practical standpoint--I mean, I've really enjoyed
21
the discussion, the way you've been managing it,
22
and the scientific points that have come out.
23 From a practical perspective, what I'm
24
getting--and I want to see if this is the correct
25
consensus--let's say next week when I have a
183
1
pre-IND meeting and they ask what preclinical
2
trials should we do? What
preclinical studies?--it
3
would be reasonable--a degree of flexibility, I
4
mean, on what particular model people choose; that
5
it should be a model that if you're looking at an
6
ischemic disease, it should be a model that
7
clinically monitors ischemia; that there isn't
8
really a consensus on versus cell types, versus a
9
myoblast product versus a hematopoietically-derived
10
product, in terms of what kind of preclinical
11
models people should suggest.
12 And there's not definitive consensus on
13
chronicity of the study, except that it should be
14
long enough to cover the period where we would
15
expect maximal time of safety readouts; and that,
16
you know, given the fact that none of the animal
17
models--particularly double-sided models--a point
18
Dr. Ruskin's made and others have made, is that a
19
positive signal is very important, but a lack of a
20
positive safety signal shouldn't give us over
21
assurance.
22 And--is this sort of the consensus of--
23 CHAIRMAN RAO: I would add two more points,
24
which I thought were emphasized.
And one is that
25
bio-distribution, at least to some extent, in a
184
1
particular model is really quite critical, and that
2 a
dose escalation of any kind is really quite
3
important in terms of being able to do it. And
4
that's irrespective of cell type--that's important.
5 DR. McFARLAND: And one specific question
6
that I don't have an idea of a consensus on: the
7
point was made that large models are important for
8
monitoring delivery systems, and you would expect
9
to see animal models when you're doing innovative
10
catheter delivery systems.
11 There was no comment on, you know,
12
chronicity of the model with respect to that. I
13
mean, we've heard various viewpoints outside of the
14
room about--well, from an hour to six weeks to--and
15 I
would like some discussion on that particular
16
specific point related to the catheter delivery
17
systems.
18 CHAIRMAN RAO: How long to follow?
19 DR. McFARLAND: What sort of a length of
20
time in an animal study of a catheter, in a large
21
model. Is it any different--I
mean--there are
22
problems with acute toxicity with the procedure
23
itself--potentially. And then,
you know, problems
24
with somewhat of chronicity, and I haven't heard
25
discussion about that.
185
1 CHAIRMAN RAO: Should we be considering
2
that point when we talk about devices and delivery
3
in the next question?
4 DR. McFARLAND: Oh, right. Okay.
5 CHAIRMAN RAO: Does the committee feel
6
we've captured some of this discussion in a
7
reasonable summary? That we
really can't be
8
specific, but we need more than one kind of model.
9
It's important that we have models that are run in
10 parallel
when we're doing this, and that they are
11
important for safety, even if you're using
12
minimally manipulated cells--what you require.
13 DR. SCHNEIDER: I wanted to reiterate Dr.
14
Borer's point that a reasonable duration of
15
follow-up is advisable, even for interventions like
16
angiogenic cells, where the expected mechanism of
17
action might be over a short period of time.
18 I think it's logical to insist, before
19
going into a clinical trial, to ascertain, in a
20
relevant animal, that the benefit of induced
21
angiogenesis is persistent rather than transient.
22 CHAIRMAN RAO: Did you have a comment?
23 DR. SERABIAN: My name is Mercedes
24
Serabian. I'm the branch chief
for the Pharm-Tox
25
Branch, and also Soft Tissue and Gene Therapy.
186
1 I just have a couple of comments, real
2
quick. I mean, the more I'm
hearing with respect
3
to all the animal models that are potentially
4
possible is I stress early communication with
5
FDA--pre-IND; what we call "pre-pre-IND" even;
6
connect with us early. You're
deciding you're
7
going into preclinical studies, because these are
8
very resource intensive studies, and we want to
9
make sure that we're in agreement with what you're
10
planning on doing. I think
that's really, really
11
important, the more I hear the conversation.
12 And just one more general comment. Again,
13
with all these models that we're talking
14
about--these disease models, specifically. I
15
always question the potential validity of the
16
model. I mean, whose--is it a
lab that's doing it?
17
Is it a--you know, a model that's been used before?
18
Is it published in the literature?
19 Even more important than the number of
20
animals that are used, the controls that are used;
21
the potential blinding for the study.
Again, just
22
because if this is your efficacy as well as your
23
safety study, that's really, really important for
24
us.
25 CHAIRMAN RAO: On that note, I think we can
187
1
break for lunch. And the
committee has some lunch
2
for it already ready.
3 [Off the record.]
4 CHAIRMAN RAO: Back on the record.
5 So now that everybody's well fed, I think
6
we're going to have a much shorter discussion.
7 [Laughter.]
8 We'll see. No,
I think it will be shorter
9
just because many of the points have been discussed
10
throughout--from yesterday and today.
11 Before we start, Dr. Cunningham wanted to
12
make a statement, and I think this might be a good
13
time to make it.
14 DR. CUNNINGHAM: Thank you.
15 I just wanted to make a comment that
16
doesn't fit any of the questions that we've been
17
asked today, and yet I think it's important to
18
include. And that is the
importance of looking at
19
both genders when we study this issue; that I think
20
that Dr. Taylor has indicated--her data indicated
21
that there's a signal that there may be a
22
significant difference between the genders.
23 There may be more differences than that,
24
and I think that, overall, in the long term, we
25
want the populations to be studied to be
188
1
representative of the populations that we wanted to
2
treat. But if we're talking even
just a Phase I, I
3
think at least we should begin with being sure that
4
the safety data includes both men and women, and
5
then from there on we'd like to have more diversity
6
as possible.
7 CHAIRMAN RAO: So, I'm going to set up two
8
extreme positions for this next question, and
9
that's in terms of devices.
10 And you heard one relatively extreme
11
position, I guess, which was that if you've got a
12
device and it's already approved, and it's been
13
approved for use, and there's a lot of studies and
14
data on the safety of that particular device, then
15
you don't need to worry, as long as you have some
16
simple tests on saying that you can use those--give
17
cells, and that the cells are viable, then that's
18
fine.
19 And then the other extreme is that, you
20
know, there are many, many things we don't know,
21
and we'll never know about how they interact, and
22
so we can't really make sure that we understand
23
this in any simplistic way, and so we need lots of
24
detailed studies; and that lots of detailed studies
25
often is a red flag.
189
1 And perhaps there is a happy medium. But
2
let's maybe sort of think about it, and try and set
3
this up and whether it all makes sense to the
4
committee as well.
5 To me it seems that catheters can be used
6
to deliver in a variety of ways.
And whether
7
you're doing it through the venous end, or you're
8
doing it through the arterial end, there are going
9
to be differences. And so can't
generalize from
10
one site of delivery to another.
11 There's another thing that I felt that one
12 can't
generalize at all--and which, I think, Doris
13
Taylor raised in her talk, too--is that a lot of
14
the data in delivering cells has been using a
15
needle which is at right-angles to the orientation
16
of the fibers. And that's important. Orientation
17
is really important. While a lot
of catheters,
18
when they deliver it with a needle, may be
19
delivering it at right-angles to the epicardium, or
20
delivering at a different angle than what we have
21
studies on.
22 So, keeping those sort of thoughts in
23
mind, maybe we can have people think about what
24
should be studied, if somebody came to the FDA and
25
said, you know, here is a device.
It's already
190
1
approved, or we know how to use it and we've used
2
it for hundreds of years. And,
you know, here are
3
cells. And we've already got a
lot of data on
4
cells.
5 What would be sort of really important in
6
consideration that we'd have to worry about?
7 And one obvious thing has already been
8
talked about, and that's pressure effects, and size
9
and gauge of the needle; and, you know, how you're
10 going to give it; and issues of vessel wall and
11
pressure on the catheter.
12 So those are all straightforward things
13
which are obvious. But there are
also particular
14
interactions between cells and reagents, and the
15
FDA already raised them when they talked about
16
things like the lubricants which coat, and so on.
17 So there are probably things that we who
18
are not familiar with the field don't understand.
19
And maybe some of the cardiologists can enlighten
20
us, or raise red flags on this as well.
21 DR. KURTZBERG: I have a real simplistic
22
question for the interventional cardiologists.
23 As I think about it, you're in there with
24 a
catheter, in a beating heart, trying to be
25
precise about delivering whatever many cells in a
191
1
very small volume to an exact perimeter. I mean,
2
how realistic is that, to think that you really can
3
do that?
4 DR. SIMONS: I actually think that's the
5
easiest part. There are lots of
systems for doing
6
this with any degree of sort of precision that you
7
want. And I'm not sure that you
want an extreme
8
degree of, you know, precision.
You can do it
9
with, you know, a millimeter accuracy.
If that's
10
not good enough with a biosense system, you can do
11
it with 100 micron accuracy. If
that's not good
12
enough, with--you can probably do it even better
13
than that.
14 I think that really is the easy part.
15 DR. KURTZBERG: Even if you're moving a
16
needle--
17 DR. SIMONS:
Oh, yes. Absolutely.
18 DR. KURTZBERG:
--through, that's causing
19
trauma as it's going--
20 DR. SIMONS: Yes.
Mm-hmm.
21 [Laughter.]
22 CHAIRMAN RAO: Dr. Borer?
23 DR. BORER: I think there are two sets of
24
questions--maybe--
25 CHAIRMAN RAO: Will you hit the button?
192
1 DR. BORER:
--or maybe six sets of
2
questions here. But let me
dispense with one that
3 I
think is important, first, and then move on to
4
the second.
5 The issue of the safety of the catheter
6
does depend, obviously, on the prior--the issue of
7
how much testing you have to do about safety,
8
placement, etcetera, depends upon prior experience.
9
And I think, you know, there's a lot that can be
10
done with catheters. And I
should tell you I speak
11
from the point of view of someone who did several
12
thousand, first at the NIH, and then when I was
13
running the cath lab at Cornell.
There are a lot
14
of things you can do with catheters.
15 The issue I would think, however, with a
16
device that's already been approved for something
17
else is, first, where are you going to put it? Are
18
you going to put it in the same place that you've
19
put it in for a hundred years, or are you putting
20
it someplace new?
21 Manipulating the catheter can be
22
relatively simple, but if you're putting it into a
23
new location, you have to be reasonably certain you
24
can do that safely; and not nine times out of 10.
25
It probably has to be 99 times out of 100, or maybe
193
1
better than that. I don't
know. And so some
2
experience might be necessary there.
3 And then I would say, too, for the
4
applications we're talking about, there probably
5
will be multiple new devices with potential and
6
putative advantages developed as better delivery
7
systems than the already available delivery
8
systems. And there, I would say
that it is not--I
9
don't think it's actually right to believe--and you
10
said this yesterday, Dr. Rao--to believe that
11
testing at the bench a few mechanical parameters is
12
quite enough. You actually have
to feel the
13
implement, and to know how easily it turns, and
14
torques, and da-da-da-da-da. And
in gaining that
15
experience, you have to keep count of the serious
16
and non-serious adverse events.
17 So I think one has to have some experience
18
with a new product, just in terms of the mechanical
19
viability and ease of handling, and safety of
20
putting a device into a body--as opposed to an old
21
device that's being dealt with with new use. And
22
there, I think the issue is a little simpler, but
23
you do have to be sure that putting it in the new
24
place is viable.
25 Now, once you get past that set of issues,
194
1
there is the major issue, it seems to me, of the
2
viability of the product after it's extruded
3
through the catheter. I was
surprised--I tell you,
4
honestly, I was surprised to hear about the
5
27-gauge needle. And you already
made the point,
6
Dr. Kurtzberg. You know, you do
have to know that
7
the product, once it's extruded through the
8
delivery system, is not fragmented; that it is
9
viable; that there are cells there, and not, you
10
know, junk.
11 And, of course, there's the whole issue of
12
the interaction of the--chemical, as well as
13 physical interaction, of the product with the
14
substance from which the device is made. You know,
15 I
mean, you've said it already. I don't
want to
16
belabor the point. But, you
know, there are so
17
many examples--not just with biological materials,
18
but with simple drugs--where the drug is adsorbed
19
to catheter materials. If some
key component of
20
the diluent, or the excipient, or something was
21
adsorbed to the catheter, who knows what would
22
happen when the product is delivered into the
23
myocardium?
24 So, there are several different levels of
25
questions, beginning with the safety of the device
195
1
mechanically, through the effectiveness of
2
mechanically delivering a viable product, through
3
the issue of chemically or biologically delivering
4 a
viable product.
5 And I separate the mechanical and the
6
biological or chemical--or biochemical, or
7
whatever--because the fragmentation of the product
8
can raise safety issues by itself.
And it would be
9
naive to believe, in this latter context--that is,
10
the interaction of the product with the
11 device--again,
that bench testing can tell you
12
about safety issues beyond the viability of the
13
product. I'm thinking
specifically of
14
thrombogenesis, for example. I
mean, there are two
15
different heart valves that, you know, meet the
16
mechanical--valve prostheses that meet all the
17
specifications. Both are
approved, made by
18
different companies. And it
wasn't know until
19
multiple years of experience that one of them
20
turned out to be more thrombogenic than the
21
other--importantly so, changing the recommendations
22
for anticoagulation of one versus the other. It
23
wasn't known until clinical testing.
24 Now, how much clinical testing you need so
25
that you can be reasonably safe in a population as
196
1
sick as the population we're talking about is a
2
different set of issues, and we can't solve that
3
here. But that some information
is necessary from
4
direct testing--to some extent in animals, to some
5
extent in patients--about the mechanical safety,
6
the safety of manipulating the device in the heart
7
and in the patient; the mechanical--the physical
8
viability of the product, and the chemical and
9
biological viability of the product, I think must
10
be defined before you can approve the device.
11 CHAIRMAN RAO: Before Dr. Ruskin, I just
12
want o make a statement and ask you to comment on
13
it as well.
14 So, from what you said--or what I heard
15
from this--was that it almost seemed that you would
16
want to test this in an animal model.
Is that what
17
it seemed like?
18 DR. BORER: Absolutely. And before
19
approval, I would think you'd want a certain amount
20
of patient experience.
But--sure.
21 CHAIRMAN RAO: Dr. Ruskin.
22 DR. RUSKIN: First, I'd like to just second
23
Dr. Borer's comments about the need for getting
24
hands on experience with any catheter design.
25
Bench testing tells you a great deal, but it
197
1
doesn't tell you how it's going to perform in the
2
body. And that can only be
answered in large
3
animal models, and in early clinical trials.
4 I want to come back to Dr. Kurtzberg's
5
first question, though--or previous question--and
6
expand a little bit on the answer that Jeff gave,
7
and also Mike Simons. I think he
was kidding, by
8
the way, when he told you we could do this with 100
9
micron accuracy.
10 [Laughter.]
11 I think there are couple of components to
12 the question as I heard it. One is mapping
13
substrate, which we can do pretty well.
We can
14
delineate, by voltage mapping and other criteria
15
the presence of what we believe to be scar, and we
16
can do it with a reasonable precision, and we can
17
do it reproducibly.
18 Getting the catheter where you want it to
19
go is also achievable with current mapping systems,
20
but I must emphasize something that Nick Jensen
21
brought up yesterday, which is that catheters are
22
inherently unstable in terms of holding a position
23
in the left ventricle, and that problem has not
24
been overcome yet. The mapping
systems do help you
25
mark spots and get back to them, but it doesn't
198
1
ensure that your catheter will stay there.
2 The other is the deliver, which is a
3
needle of some sort. And I think
that is a huge
4
challenge, and one which is not yet solved. And I
5
don't think we know where we're putting materials
6
when we inject through needles via catheters. And
7
we've done some of this with gene delivery, and I'm
8
not at all convinced that much of the time we get
9 anything into the tissue; or, if we do, I
suspect
10
it's a small amount.
11 So I view that, right now, as an area of
12
enormous challenge, and not a problem that is
13
solved, from a technological standpoint.
14 CHAIRMAN RAO: Dr. Lederman, you had a
15
statement?
16 DR. LEDERMAN: I think I agree with most of
17
the points made, except in the execution. So,
18
sure, we'd probably need to know most of the
19
information mentioned before deploying
20
drug-delivery devices in early clinical studies.
21 But let's take the example of cells.
22
Let's say than in animal models we have proof of
23
principle for a given cell preparation that we'd
24
like to deliver by direct myocardial injection.
25
And let's say that those data come from small
199
1
mammals, and that there's no satisfactory
2
large-mammal model of that cell.
3
What is it that we need to
know about the
4
catheter device before we can declare it adequate
5
to deliver cells into humans?
Would it not be
6
satisfactory to measure a simple index, like tripan
7
blue exclusion after passage, or after some dwell
8
time? Do we really need to push
cells through and
9
then show preserved biological activity by some
10
more complex in vivo measure?
Doesn't that seem
11
excessive?
12 CHAIRMAN RAO: So--before Dr. Simons--I
13
think that's a point we want to try and really get
14
to here is that are there certain minimum things?
15
Is there a consensus on what's excessive or not?
16 And I think from the earlier part of what
17
we looked at, we said that cells themselves need to
18
be characterized in quite a lot of detail, and that
19
we need to characterize them when they get there,
20
in the heart. And that's why you
needed to do them
21
in animal studies.
22 So we have to keep that in mind and say:
23
that's absolutely true, that what we need to study
24
about catheters in general is true, and that those
25
are simple things, and maybe we can look at them
200
1
and you can also get an answer to how you deliver.
2
But then subsequently we really need to know, once
3
they've been delivered from the catheter, what are
4
the characteristics of the cell.
5
And--Dr. Simons?
6 DR. SIMONS: Well, you just said what I was
7
going to say. Because you can
damage cells at
8
several different points when you use a catheter to
9
put them in. One is in a
physical contact with the
10 catheter polymers; second when it goes through the
11
27-gauge needle. And, actually,
most cell types
12
will not get damaged by passage through the
13
27-gauge needle.
14 But a lot of damage occurs when the cells
15
contact tissue at high sort of pressure, and you
16
are not going to model that in vitro.
You really
17
have to model this in vivo, and you need to know
18
what happened to the cells once they're in the
19
tissues.
20 CHAIRMAN RAO: Perhaps even that could be
21
modeled, say, in an animal prep, you know, where
22
you--you have a heart prep, and you can look at
23
those sorts of pressure--maybe.
24 So, I'm not arguing that we have to
25
absolutely make it specific. I
just want people to
201
1
keep in mind that there are certain criteria that
2
you'd really want to worry about in terms of
3
characteristics of cells.
4
Dr. Harlan, and then Dr.--
5 DR. HARLAN: Well, my only comment with
6
regard to Dr. Lederman's question was: implicit in
7
your scenario as you presented it was that here was
8
no animal model to test the viability of these
9
cells in. So I think what the
FDA continually--my
10
read of it is that they say, "Do all the testing
11
that's reasonable to expect."
If there is no way
12
to test the hypothetical cell that you're talking
13
about, then I think the FDA would be reasonable, if
14
you identified the patient population
15
appropriately.
16 DR. KURTZBERG: I was going to just comment
17
on the tripan blue question.
18 I don't think tripan blue is enough of a
19
measure to tell you that your cells will preserve
20
function and viability later. If
you see a lot of
21
cell death that's important. But
you can have
22
cells that will not exclude tripan blue five
23
minutes later, but who will still die, you know,
24
several days later.
25 So if you have a functional assay like a
202
1
colony assay or something like that, that would be
2 a
better measure.
3 CHAIRMAN RAO: Dr. Borer.
4 DR. BORER: Yes, I would like to agree with
5
what Dr. Simons said, that you do need--I think you
6
need an in vivo assay. I don't
think it's a heart
7
prep, because there is a difference--an important
8
physical difference, I think--or there may
9
be--between the outcome, in terms of the adequacy
10
of delivery and the state of what's delivered, if
11
you place the delivery device within turbulent
12
flowing blood and a beating heart, than in a
13
preparation that's external to the body, that's not
14
subjected to those same mechanical stresses--even
15
if it were a beating heart on a Langendorf
16
apparatus or something--or something analogous to
17
that.
18 So I think you do need some in vivo
19
experience. I don't want to say
how much, what
20
model, how much in people. Those
are degrees of
21
specificity that I don't think we can get to here.
22
But I agree with the point that Dr. Simons made
23
that you do need in vivo experience.
24 CHAIRMAN RAO: Phillip?
25 DR. NOGUCHI: Not to comment specifically
203
1 on these particular catheters, but I will point
2
out, since our device colleague is not here right
3
at the moment, that under the device law you have
4
something like this--this happens to be a
5
blackberry. But as a
manufacturer makes it, they
6
are not restricted to always manufacturing
7
everything themselves. So, for
example, they may
8
have several suppliers for the steel that's being
9
used, or several suppliers for any of the
10
lubricants, or for the tubing.
11 And so, from a real practical point of
12
view, while rare, we do have experience where
13
substitutions that are made by the manufacturer on
14 a
reasonable basis, based on their specifications
15
and qualifications, can sometimes lead to fairly
16
distinctive changes in the same device--let alone a
17
comparable device--that can have severe adverse
18
reactions.
19 And, again, we won't be talking about
20
specifics, but let's just say that on a rare
21
occasion, the fact that a device is made through
22
multiple suppliers can lead to the question, and
23
the realization, that sometimes we find it hardest
24
to, off the shelf, just say: "This catheter is
25
equivalent to this catheter," or "This device is
204
1
equivalent to this device," because it's not always
2
quite the same supplied material.
3 CHAIRMAN RAO: We've had all of these
4
experiences with tissue-culture plastic, and the
5
same manufacturer changing the manufacturing
6
protocol, and then the cells wouldn't grow. So, I
7
mean, I completely agree with you that that's an
8
issue to worry about.
9 Dr. Neylan?
10 DR. NEYLAN: I would love to take the
11
opportunity to segue your comments to, I think, a
12
closely related but perhaps still sidebar issue.
13
And that is that just as the conversations here
14
have demonstrated the importance of the interaction
15
between the device and the constituents being
16
delivered, I think there's another analogy that can
17
be made within VDA about the importance that this
18
instance brings up--and others like the
19
drug-eluting stints--about perhaps finding new ways
20
of working so that the different divisions can work
21
more synchronously--CBER, and the devices
22
division--so that it doesn't fall into some more
23
prolonged review process, or step-wise review
24
process, but perhaps could be done in a more
25
consultative fashion.
205
1 DR. NOGUCHI: Just to quickly respond,
2
that's exactly why we had Dr. Jensen throughout all
3
the preparation for this, and he's been involved in
4
all the reviews of all the products.
5 So--that point is well taken ,and we
6
strongly endorse it.
7 CHAIRMAN RAO: Here's another question for
8
the cardiologists, related to device--and I think
9
Dr. Borer alluded to this already--is: though we
10
can be accurate, we're not a hundred percent
11
perfect in terms of delivering things.
And with
12
cells, then, that means if you deliver it into the
13
cavity, or you deliver it into the epicardium, or
14
you do that, then there's going to be a whole
15
different effect of what you've delivered.
16 And should there be, when one does some
17
sort of study like this, some way of monitoring
18
that so that, you know--you're assessing a device
19
and the cell, and should one be looking at
20
bio-distribution after this has been done to worry
21
about it? Or hopefully those
things are
22
discovered, because you've already looked at cells.
23 DR. BORER: Yes, I'll take the first crack
24
at that.
25 At some point I was going to make the
206
1
suggestion that we should do just that.
You know,
2
nobody knows how much difference it makes.
3
Jeremy's point is, of course, very well taken. We
4
don't absolutely know where these things are being
5
delivered with the best of implements.
You know,
6
there's reasonable accuracy but not total accuracy.
7 But we also don't know where they should
8
be delivered. We don't know
whether there is a
9
difference in outcome if you deliver to the
10
mid-wall, or whether you deliver to the endocardium
11
or the epicardium. We don't know
whether one part
12
of the ventricle is more important than another; we
13
don't whether the border zone or the center of an
14
infarct--of a scar is important.
We don't know any
15
of those things. And information
needs to be
16
obtained.
17 Now, does that mean that all the
18
information has to be available by the time a
19
product may be ready for clinical use?
I think
20
perhaps not. It depends on the
outcome from
21
clinical studies. But
information that would allow
22
one to know these things would be very important
23
if, for nothing else, for improvement of a
24 product--even if a product were approved.
25 And I think that, therefore--getting back
207
1
to the point we all made earlier--there must be a
2
data collection protocol set up that will allow
3
data to be used from all the studies that are done,
4
to allow us to answer questions like that. And I
5
do believe that bio-distribution is very
6
important-- knowing about it--not only throughout
7 the
whole body, but throughout the heart, so that
8
we can somehow retrospectively relate the outcome
9
to the location of what's been delivered. So I
10
think it's very important.
11 CHAIRMAN RAO: Go ahead Joanne.
12
DR. KURTZBERG: I agree with
everything you
13
said. But I don't know, right
now, of any safe way
14
to label human cell and see them--on whatever you
15
want to look at them with.
16 I mean, you can do things with iron and
17
fluorescent dyes in animals, but those things are
18
not safe for the cells, and there is no material
19
that allows us to track human cells yet. We need
20
one. It would be terrific. But I don't think it's
21
there yet.
22
CHAIRMAN RAO: So would you
say, Joanne,
23
that this is true for animal studies when you're
24
looking at them, or in preclinical studies, that
25
there should be a way, but we can't necessarily
208
1
expect that that be done?
2 DR. KURTZBERG: I mean, it's just not ready
3
for prime time in humans.
4 DR. BORER: Yes, I think that's a critical
5
point. I think studies should be
done in animals.
6
But, I don't know whether the methods I'm going to
7
describe are appropriate for the purpose.
8 But radio-nucleide based molecular imaging
9
is becoming a reality. And it
may be possible to
10
monitor the presence and location of cells with
11
label that can be administered after the fact to
12
localize cells with certain characteristics. I
13
mean, there would need to be enabling research to
14
allow this to happen, but the imaging techniques
15
have developed to the point where I think this may
16
be a viable issue.
17 I think it's an important issue, so some
18
time should be spent at some point looking at the
19
various methods that can be used to identify cell
20
types within the myocardium. But
it may be that
21
newer techniques for imaging could be used.
22 CHAIRMAN RAO: Dr. Simons, and then--
23 DR. SIMONS: I would like to come back to
24
the safety issues of the needle-based material
25
delivery.
209
1 Essentially, with all the needle devices
2
now, there will be some loss--there will be some
3
loss of the material. And, you
know, depending on
4
what the material is and what the catheter is, that
5
it could be up to 50 or 70 percent of the dose.
6
And it could be lost either in the left ventricular
7
chamber, or it can be lost then through the
8 coronary--into the myocardial vasculature and
will
9
immediately get washed out. And
that happens to
10
cells, too.
11 So I think it's something to sort of
12
consider, because depending on the cell type used,
13
you would clearly have a number of cells injected
14
essentially in the left ventricular cavity.
15
Whether that's a risk, I think, needs to be
16
assessed. And this would be
assessed, and it
17
should be assessed, I think, in an animal model.
18 CHAIRMAN RAO: Here are a couple more
19
questions for the cardiologists.
20 We heard that when you infuse cells in a
21
long vessel--whether it's venous or arterial--that
22
there are some specific complications of putting
23
cells in; one was this idea of micro-emboli, and
24
the other one was that you have ventricular changes
25
in the echocardiogram.
210
1 Is this something that's of sufficient
2
concern from experience, or that's something that
3
one can learning by doing the experiment in an
4
animal model? Or it's something
that should be
5
required or, you know, considered of urgent
6
criteria? In any of things, in
general?
7 DR. TAYLOR: Can I directly speak to that?
8 We know for years of our preclinical
9
studies with surgical delivery, that we lose a
10
relatively large percentage of the cells after we
11
deliver them. And we may very
well lose those both
12
epicardially and into the left ventricular cavity.
13
So I don't think it's that different for catheters
14
than it is for surgical deliver in terms of the
15
loss of cells.
16 More recently we have begun to
develop
17
some radio-nucleide labeling that lets us start to
18
follow the bio-distribution of these cells. And I
19
think what we're finding is size matters. The
20
larger the cell, the more likely it is to be in the
21
lungs; the smaller the cell, the more likely it is
22
to be in the spleen or the liver--and that's not
23
particularly surprising.
24 So I think--there probably is a whole lot
25
of data already out there from surgical delivery of
211
1
these cells, and also from the delivery of bone
2
marrow cells for other situations, that would
3
directly feed into this, and we don't have to
4
re-create that wheel.
5 CHAIRMAN RAO: Specifically, though,
6
related to catheter delivery, though, one can't
7
assume that it's going to be the same--right?--in
8
terms of distribution.
9 DR. TAYLOR: No, but we do know that we've
10
lost--we lose a significant number surgically into
11
the ventricle as well.
12 DR. EPSTEIN: I'd like to just recall Bob
13
Lederman's comments yesterday: we know that we're
14
going to lose cells into the general circulation.
15
So you could take an animal model and just inject
16
the cells into the left atrium.
You don't need a
17
catheter. I mean, you know that
cells are going to
18
be lost into the circulation.
And then, by
19
whatever technique you may have, you could track
20
them. But then what?
21 So, you know that the cells will be in the
22
brain, in the spleen. But are
you going to follow
23
those animals for a year or two to see if there's
24
an oncogenic--I mean, you know, that that's going
25
to happen, and then you have to ask yourself, "What
212
1
do you do with that information?"
2 And I would have real questions as to how
3
important that information is.
Because you know
4
what the answer is going to be.
5 Your other question is a very important
6
one, and that is: the intra-coronary injection of
7
cells--and I've forgotten the name of the gentleman
8
who presented yesterday, with the dogs, showing
9
small areas--
10 CHAIRMAN RAO: Mule.
11 DR. EPSTEIN: Yes--and we did a study like
12
that--Dr. Unger of the FDA many years ago--where we
13
injected endothelial cells that were harvested from
14
the carotid arteries of dogs.
These were
15
autologous cells. And these were
dogs with an
16
amyloid constrictor around the circumflex coronary
17
artery. We genetically altered
those cells and we
18
thought that we were going--it was really a smart
19
experiment, injecting the genetically altered cells
20
into the LAD to enhance collateral development.
21
And all we did was kill dogs.
22 Because if you think about the situation,
23
the LAD--the circumflex is totally occluded, and
24
the LAD is feeding the entire left ventricle,
25
essentially. And these cells
embolize. I mean
213
1
they're too big to go through the capillaries.
2 So you probably wouldn't see any
3
hemodynamic perturbations if
you gave those cells to
4
an animal with normal coronary arteries. But if
5
you have a collateral dependent--if you inject them
6
into a feeder vessel, then you'll see what, you
7
know, you saw yesterday.
8 So the clinical studies that have been
9
done to date--acute myocardial infarction, total
10
occlusion of an artery, opening up the artery, and
11
then several days later injecting cells--in that
12
situation, I think you're okay, because you'll
13
never be worse off than with the situation you were
14
in five days before, with a totally occluded
15
artery.
16 But now if you extend that and say, okay,
17
let's take patients with chronic coronary disease,
18
where you're injecting cells into a vessel that may
19
feed collaterals to the rest of the heart--you
20
know, I think you really need animal studies for
21
that, for safety, but you have to model it very
22
carefully.
23 And my prediction is that it would be very
24
dangerous. So, you know, once
again it depends on
25
the clinical situation.
214
1 CHAIRMAN RAO: Go ahead, Dr. Lederman.
2 DR. LEDERMAN: I think that's a very good
3
point. Alternatively, you could
model this--since
4
we have very sensitive biomarkers--of myonecrosis,
5
both imaging-based or biochemical.
And these can
6
be testing in healthy animals.
7 And if we--as I say, again, there are
8
fairly high-sensitive biomarkers.
We could
9
administer whatever cell prep we're interested in
10
by intra-coronary infusion under different
11
conditions, and if there is no myonecrosis, I think
12
that's probably a satisfactory test.
13 Do other members of the committee agree,
14
or do they disagree?
15 You gave us a much more
16
difficult-to-achieve test.
17 VOICE: [Off mike] But those are the
18
patients [inaudible].
19 DR. LEDERMAN: I'm not disagreeing. I'm
20
wondering if others have other opinions. It's not
21
self-evident to me that your system, which is much
22
more harder to accomplish, has more
23
predictive--necessarily have more predictive value.
24
And I just wonder what other
opinions
25
might be?
215
1 CHAIRMAN RAO: Dr. Harlan, did you have a
2
comment to make? Okay.
3 Let me see if I have a sense here--and
4
nobody mentioned anything about monitoring, in
5
terms of looking at arrhythmias of any sort. Is
6
that something that one would consider as an
7
important thing to do? And would
that be something
8
one would consider as a routine thing to do when
9
one is testing?
10 DR. RUSKIN: Actually, I had mentioned
11
something in response to one of the questions that
12
was raised. And I would think if
you were to
13
pursue any of this work in a canine
14
model--hopefully a relevant infarct model--that
15
chronic monitoring with implanted telemetric
16
devices would be appropriate, as would
17
electrophysiologic testing--invasive testing--and
18
just routine clinical monitoring for the kinds of
19
adverse events that Jeff Borer described.
20 And I think those would be important to
21
do, based on concerns about creating what may be a
22
highly arrhythmagenic substrate.
I'm not convinced
23 that we know that happens, because of the
kinds of
24
patients in whom these procedures have been done.
25
But at least the potential for doing that certainly
216
1
seems to be there, and it would have to be pursued,
2 I
think, pretty aggressively--including monitoring.
3 CHAIRMAN RAO: So--go ahead, Dr. Simons.
4 DR. SIMONS: If I can just amplify this
5
point, because the concern of an arrhythmic even
6
has been raised with skeletal myoblasts.
7 To my knowledge, this has not been raised
8
with different cell types. So,
do people around
9
the table feel that this kind of monitoring is
10
required for all cell types, or just for skeletal
11
myoblasts?
12 CHAIRMAN RAO: I think we're just looking
13
at delivery through a catheter, either through
14
venous--or putting it in, not like a long-term
15
thing--one week later monitoring, or--I'm just
16
wondering about whether it's important, when you do
17
the procedure--just like you would with dye or
18
something--
19 DR. SIMONS: Oh, if you're talking about
20
acute settings, it's standard to monitor. I mean,
21
that's a standard of practice.
22 CHAIRMAN RAO: It would be something one
23
would consider really important, you said.
24 DR. RUSKIN: I'd just like to respond to
25
Dr. Simons' question.
217
1 My own bias would be in the beginning to
2
be rather conservative and cautious with regard to
3
monitoring in any of these models; my answer being,
4
to his question: yes, I would be inclined to, even
5
with other cell types--only because I think the
6
potential exists for creating a substrate that is
7
very dangerous.
8 I'm not at all convinced that happens.
9
But introducing cells that morph into myofibers of
10
any sort, in a situation in which we don't know how
11
they line up, how they communicate, what the
12
intracellular substrate looks like, what their
13
action potential characteristics are, what their
14
ion channel properties are--is one of the ways that
15 I
would, if you asked me to invent an
16
arrhythmagenic substrate, that's one of the things
17 I
would think--one of the ways I would think of
18
doing it.
19 So I think that the bar ought to be pretty
20
high early on for some form of careful vigilance.
21
The problem is that the sensitivity of these models
22
is going to be low. And I would
take no
23
reassurance from the fact that nothing adverse was
24
observed.
25 But, on the other hand, if adverse
218
1
outcomes are observed, it raises a very important
2
issue, in terms of how one proceeds.
3 CHAIRMAN RAO: Go head, Dr. Schneider.
4 DR. SCHNEIDER: I'd like to follow up on
5
Dr. Ruskin's cautionary note, and ask him how best
6
might the FDA, or should the FDA take into account
7
the established safety as demonstrated in Phase I
8
trials elsewhere? I think that
the nightmare
9
scenario is appropriate, if it hasn't been done or
10
60 or 100 patients already. But
once its been done
11
in 60 or 100 patients already, it seems to me that,
12
without cutting corners, and without jeopardizing
13
safety, the information has an applicability.
14 DR. RUSKIN: I think that's a very
15
important point. And
electrophysiologists have
16
sledgehammer answer for all of that, and it's
17
called an ICD.
18 And my own bias is that, yes, I think
19
there is information that's quite reassuring
20
already, and that given the nature of the patient
21
population being studied, it would be relatively
22
easy, I would think, to do your Phase I studies in
23
patients who are already recipients of implantable
24
defibrillators--because of the primary prophylaxis
25
trials that have recently been completed and that
219
1
point out, I think, quite clearly that most of the
2
patients we're talking about here are already ICD
3
candidates.
4 So that's the ultimate protection. And I
5
think given the data that's already available, it's
6
quite reasonable to move ahead--with appropriate
7
caution, and the protection of a defibrillator.
8 CHAIRMAN RAO: So this maybe gets back to
9
what Dr. Lederman raised, then, that if that's the
10
case, and that's how you're going to do your Phase
11 I
clinical trials, why is it necessary to worry
12
about it in the animal model?
13 DR. RUSKIN: Because I think we can learn a
14
great deal from animal models, and if we--my
15
sense--and, again, I'm naive about this, but I get
16
the sense that we don't know exactly what the right
17
cell type is, how to deliver it, in what kind of
18
media. There are all sorts of
unanswered
19
questions. Are the cells going
to be genetically
20
modified, and so on, and are there going to be ways
21
of ensuring that they lay down appropriately and
22
form connections?
23 These are all unanswered questions. And I
24
think until they're answered, the more information
25
you get from preclinical models, the smarter you'll
220
1
be.
2 CHAIRMAN RAO: Dr. Cannon, you had a point
3
you want to make?
4
DR. CANNON: I was just thinking,
listening
5
to Steve's comments, I would take exception, Steve,
6
to your lack of concern about cells--large cells,
7
now, not the peripheral blood mononuclear cells, by
8
the myoblasts, the larger cells--about whether they
9
go to the brain or not, and will that matter,
10 I think it might matter--after looking at
11
what happens in the coronary circulation of dogs
12
when these cells are injected, if a similar
13
phenomenon were to occur in the brain, I would be
14
worried that the patient may be different
15
cognitively after the procedure than before the
16
procedure, even though there may be benefit to the
17
pump function of the heart.
18 So I think it would be important to know,
19
in an animal model, injecting cells into the left
20
ventricle, the left atrium, if they do lodge in the
21
brain, and for how long. And, if
so, certainly
22
that would raise concerns for cognitive monitoring
23
in this kind of application.
24 CHAIRMAN RAO: Joanne?
25 DR. KURTZBERG: You know, if you had been
221
1
here for the neural stem-cell meeting, they would
2
be so happy if you could put cells into the left
3
ventricle and get them into the brain.
4 [Laughter.]
5 I mean, that's very hard to do unless you
6
have some kind of connection you're not supposed to
7
have.
8 So, I mean, realistically, that probably
9
is the one thing you don't have to worry about.
10
They'll go all over the place, but to go into the
11
brain at the time you inject them into the blood is
12
not a worry, I don't think. It's
actually a
13
challenge for the people who want to get cells into
14
the brain.
15 CHAIRMAN RAO: But it's a general problem,
16
right? Anything which is in
artery circulation
17
essentially--where they might be distributed might
18
be something to worry about, right?
19 DR. TAYLOR: I actually wanted to address
20
the point of whether--Dr, Ruskin's point about
21
whether or not we need to deal with--when 60 or 100
22
patients have already been treated, whether or not
23
we need to still demand preclinical information.
24
And I guess what we have to get back to is whether
25
or not the cells are identical.
222
1 If the cells are not identical--just
2
because one group can grow appropriate endothelial
3
progenitor cells for three days in a dish doesn't
4
mean if somebody else tries it they're going to get
5 the same cells. So I think the data have to be
6
fairly convincing that you're working with the same
7
cell population, or it's not appropriate to base
8
that on previous data.
9 And just calling it the same thing doesn't
10
mean it is the same thing. The
markers have to be
11
the same.
12 CHAIRMAN RAO: Do you have a comment? Go
13
ahead, Dr. Lederman.
14 DR. LEDERMAN: I also want to comment on
15
Dr. Ruskin's point.
16
Certainly, it's
defensible to advocate a
17
strategy--in fact, European investigators have
18
already sometimes applied a strategy of
19
prophylactic defibrillator implantation before
20
testing cell therapies for various applications.
21
But to mandate that I think is a bit extreme in a
22
way that would hurt the field, and patients in
23
that, our most sensitive, surrogate markers of
24
myocardial performance would then be unavailable
25
for our patients. And that means
MRI endpoint
223
1
assessment.
2 So, unfortunately, that's a very high
3
price. And I think to mandate it is--
4 CHAIRMAN RAO: Remember, the committee
5
doesn't mandate, and the committee's only advisory,
6
and it's not looking at any specific applications.
7 DR. LEDERMAN: But, unfortunately--this is
8
not a compromise.
9 DR. RUSKIN: Yes, your point's very well
10
taken, and Mike Sunn has made the same point with
11
regard to how it compromises imaging.
12 I didn't mean to suggest that anybody even
13
think about mandating a population in whom this is
14
done, or mandating the use of a prophylactic ICD.
15
What I was suggesting was that there's a very large
16
patient population that already exists that have
17
ICDs implanted for appropriate clinical
18
indications, who have severe congestive heart
19 failure, and are at the end of the road, and have
20
had CRT therapy, and might provide an appropriate
21
population in which to begin to do some of these
22
studies--if the question of arrhythmagenesis
23
remains high on the list.
24 I understand that that involves
25
compromises in terms of imaging.
Nor do I mean to
224
1
suggest at all that that be the only group in whom
2
one ought to consider appropriate trials.
3 DR. BORER: I think that several important
4
points have been made, and I'd like to comment on
5
three of them.
6 First of all, I agree with what Jeremy
7
said about conservativism in doing these studies,
8
and would just amplify by saying that
9
arrhythmias--potentially lethal arrhythmias--could
10
occur at several points after the administration of
11
cell therapy, and the mechanism in each case could
12
be different. So you have to
watch at many points
13
in time. I don't know when the
watching needs to
14
end. Again, it may be beyond the
scope of this
15
meeting, and maybe in the too-hard box.
16 But the important point is that there is
17
the potential for problems with the initial
18
mechanical perturbation, with the initial physical
19
injury of the myocardium. Then,
subsequently,
20
there are problems when the cells begin to grow
21
before they have fully defined their
22
interconnections with the surrounding tissue. And
23
then there are other problems that could occur when
24
they have made those connections.
25 So one has to monitor. And I would
225
1
suggest that we do need that information.
2 I think that Jeremy was absolutely right
3
in indicating that the availability of ICDs reduces
4
the risk compared to what it might be, but there a
5
couple of points that we have to keep in
6
mind--without negating in any way what he said. I
7
think Dr. Lederman's point is a good one. If you
8
use that population, you can minimize the capacity
9
to make certain measurements you want to make.
10 But, more importantly, the fact that an
11
ICD is in place doesn't mean that someone has been
12
made immortal. [Laughs.] So, if you create
13
arrhythmias and they are sufficiently severe, they
14
may override the ICD, and we wouldn't want to do
15
that. So we'd want to know if
that was a potential
16
problem--number one.
17 Number two, even if the ICD was
18
successful, people don't like to be shocked. I
19
mean, it hurts--they tell me.
So, you know, one
20
would like to know about that problem.
And, you
21
know, I'm not saying anything different from what
22
Jeremy said--and he could say it better than I.
23
But I think you have to keep that in mind.
24 So we'd still like to know about
the
25
arrhythmias, their likelihood, etcetera.
226
1 Now, how much do we know because 60 to 100
2
patients have been studied? I
have a statistician
3
sitting two seats to my right, and he should answer
4
this. But I think--and you'll
correct me if I'm
5
wrong Dr. Tsiatis--that the power we have from zero
6
out of 100 doesn't rule out a heck of a lot. There
7
could still be a lot of events.
And so we should
8
have, I think, some preclinical data to help us in
9
this situation.
10 So I think those are just three
11
observations on the important points that have been
12 made.
13 CHAIRMAN RAO: Dr. Schneider.
14 DR. SCHNEIDER: In part, to follow up with
15
Jeff's cautionary note in terms of the numbers--I
16
think it's either naive or disingenuous for someone
17
to suggest, as Dr. Lederman did, that it would harm
18
patients for any of the conservative precautions
19
being imposed as they're being discussed here.
20 Since Phase I trials haven't been done
21
there's no proof yet of safety in humans in the
22
U.S., much less of efficacy in humans.
So to wrap
23
yourself in the mantle of protecting patients by
24
speeding the trials along is preposterous.
25 CHAIRMAN RAO: Let's see if I can try and
227
1
summarize and see whether we have some consensus on
2
some basic statements here.
3 So, it seemed to me from just listening to
4
everyone was that everybody thought that one needs
5
animal studies. And since this
is with the device,
6
it seemed very clear that one needed animal studies
7
in a large animal--of some kind, right?
8 And that you couldn't extrapolate from one
9
type of delivery to another, because there were
10
issues with it. And you couldn't
extrapolate from
11
one type of catheter to another, because there are
12
issues with doing that, or if you're using it in a
13
different way than what it was supposed to be used.
14
And that if people in
different centers
15
used one device, they should have some sort of
16
hands-on experience, because things change when
17
you're using it in a different fashion--if I have
18
paraphrased that right.
19
And that once you deliver
cells, you
20
really need to look at the function of the cells as
21
they've been delivered, and so that they need to be
22
delivered in vivo in some fashion because simple
23
models will not be adequate in terms of doing it.
24 And you have to look at their behavior
25
where they've been delivered; and that monitoring
228
1
has to be of a reasonable length of time, in terms
2
of that behavior in terms of safety of what you'd
3
look at.
4 And that during that process--especially
5
if you're doing it into arteries and veins, that
6
there are issues of monitoring because of what's
7
known about micro-emboli and what's known about
8
that; that you need studies to look at whether
9
that's going to cause ischemia or an infarct, or
10
it's going to cause arrhythmias, and that that
11
needs to be monitored for at least some period of
12
time in a critical way; and those would be unique
13
or specific to delivery via the cardiac route.
14 Does that seem like a--have we missed
15
something? I mean, there was
some issue that we
16
did not really look at in terms of long-term
17
follow-up, and that wasn't absolutely clear. Dr.
18
Borer seemed to point that you might need to worry
19
about it on a longer basis, and one might need to.
20 DR. BORER: Can I just come back to the
21
point Richard Cannon made? And
I'm asking a
22
question here. I don't know
anything about cell
23
delivery to the brain, or whatever.
24 But I think there may be an important
25
difference between delivery of functional
229
1
progenitor cells to the brain that might cause a
2
benefit, and delivering a bolus of something that
3
might obstruct an artery, even though it couldn't
4
grow into a new part of the brain.
5 So I would continue to have Richard's
6
concern about the embolization--the importance of
7
potential embolization to the brain, despite the
8
fact that, apparently, the neurologists have a hard
9
time developing a therapy by delivering cells that
10
way.
11 Am I wrong about that? Is that--
12 DR. KURTZBERG: It can't cross the
13
blood-brain barrier--okay?
14 DR. BORER: But you don't have to. All you
15
have to do is block an artery.
16 DR. CANNON: I'm worried about plugging the
17
microcirculation, much as the microcirculation of
18
the dog heart was plugged by these cells. And
19
these are large cells. They're
not like stem cells
20
that are small and deformable and that circulate
21
very easily. These are
large--I'm talking about
22
the myoblasts, now, not the stem cells.
23 And, certainly, we send patients to
24
surgery, and even to the cath lab, and they
25
sometimes come back differently because of things
230
1
that are dislodged during the course of the
2
procedure that make their way to the brain. So,
3
certainly, the circulation can carry debris to the
4
brain.
5 It's just a concern.
And I would think an
6
animal model, perhaps--just injecting the cells
7
into the cavity of the left ventricle to see if
8
they do, indeed, lodge in the brain for a period of
9
time that might be anticipated to cause some damage
10
would be a worthwhile thing to look at--for the
11
large cells, not the mononuclear--the stem cells or
12
the peripheral blood mononuclear cells.
I don't
13
think that's a concern. It's the
large cells.
14 CHAIRMAN RAO: Dr. Grant, you had a
15
comment?
16 DR. GRANT: Yes, I just want to just speak
17
to this third point, the injection of cells into
18
systemic circulation.
19 And the question that would be consequent
20
to your discussion is: do you think that an animal
21
study--that an additional animal study needs to be
22
done in which the cells are specifically injected
23
into the systemic circulation to see about the
24
systemic effects? Or do you
think that these kinds
25
of effects that you're worried about would be
231
1
picked up in the other animal model--in other
2
animal studies?
3 Because there would be enough systemic
4
distribution we'd need to do additional studies?
5
That's, I think, what that third question was
6
about.
7
CHAIRMAN RAO: Let me see if
this was
8
summarized from what people said: is it depended on
9
the cell type; that bone marrow cells, we have a
10
lot of experience with in terms of putting them in
11
systemic circulation, but that's not true for, say
12
myoblasts, or for some of the other cells.
13 And for myoblasts, maybe we have some
14
experience because that's been done in some of the
15
animal models already, but that's not true for some
16
of the other sorted cells or the passage cells.
17 DR. SCHNEIDER: Michael Schneider--but to
18
deal with Dr. Grant's question specifically, it
19
would be my expectation that the kinds of
20
information that would be useful to address this
21
point about embolic risk would come about as part
22
of the natural dose-ranging studies that would
23
occur. I don't envision that it
would
24
scientifically advance a protocol to inject
25
non-physiological numbers, or non-therapeutic
232
1
numbers of those cells into the systemic
2
circulation to see what happens.
3 And I share Dr. Cannon's cardiologists's
4
view of the nervous system as a sponge that vessels
5
go to.
6 [Laughter.]
7 DR. TAYLOR: I just want to make two quick
8
comments--oh, I'm sorry.
9 One is that myoblasts are not the only
10
large cells we're talking about here.
Some of the
11
mazenchymal cells are as large or larger than
12
myoblasts, and we need to keep that in mind.
13 VOICE: [Off mike] What's--
14 DR. TAYLOR: 10 microns. Yes. Rounded.
15 But the other issue is that we did studies
16
for different reasons, where we injected many of
17
these different bone marrow-derived cell
18
populations intravenously to try to treat vascular
19
injury. And we found that there
were some negative
20
effects of some of those cells, and positive
21
effects of other of those cells.
And we didn't
22
expect that.
23 And I think what we have to say is if
24
intravenous is going to be your preferred route of
25
administration, then obviously you have to do that.
233
1
But, otherwise, I think it's a waste.
2 CHAIRMAN RAO: Dr. Borer.
3 DR. BORER: In response to Dr. Grant's
4
specific question, I do think it may be worth doing
5 a
specific animal study. I think Mike is
right,
6
that the information may well fall out of the
7
studies that are done with dose-ranging in the
8
normal course of development.
9
But the problem I see
here is that we
10
don't actually know how many cells are escaping
11
into the systemic circulation with the various of
12
routes of delivery we've been talking about. And,
13
therefore, we may miss the information that we
14
want.
15 Doing what Steve said, which is to inject
16
some cells into the left atrium and, you know, see
17
what happens, seems to me to be a good idea because
18
ultimately what you wind up with is the lower bound
19
at which problems might be begin to develop. And
20
if, in fact, the lower bound of injectate size at
21
which problems would develop is above the size of
22
anything you're injecting, then it's a non-problem
23
and you don't have to worry about it anymore. If
24
it's not, then you have to worry about it a little
25
bit more, and maybe the strategy would change.
234
1 So I think it may be worth doing a
2
specific study to determine what happens to these
3
large cells.
4 DR. CUNNINGHAM: I also want to comment
5
that for when we do this in patients, that it's
6
going to be a risk they would at least want to know
7
about; that there was going to be a cognitive
8
change. That's something people
tend to care a lot
9
about; either whether it's in themselves or it's in
10 a
family member, that it's not a simple thing, and
11
you at least would want to know that was a risk,
12
and you might not choose to have the therapy if
13
that were going to be something you had to endure.
14 CHAIRMAN RAO: Quick comment, Dr. Lederman.
15 DR. LEDERMAN: Unfortunately, yet another
16
question.
17 If we are administering locally cells
18
derived from a patient by leukopheresis, for
19
example, how important are the questions we've been
20
discussing about systemic distribution, or
21
mal-distribution of cells themselves recovered from
22
the circulation?
23 CHAIRMAN RAO: I mean, I thought we tried
24
to cover that, because we did try to point out that
25
there might be different criteria--you can have a
235
1
standard criteria on the cell type.
But even if
2
it's a cell which is endogenous, you know, if you
3
put RBCs back, there is an issue of the
4
concentration at which you're putting it relative
5
to the concentration at which they're circulating.
6
And that's always been an issue.
7 And so I don't know if it would change
8
specifically for leukopheresis versus any other
9
method, but I would still want to know what
10
happened when we put in cell by a particular
11
method, and how they went, and what they did.
12 DR. KURTZBERG: I mean, there is data about
13
the upper limit of safe cell dosing when you give
14
leukopheresed cells. I mean,
it's way, way, way
15
above--it's logs above the doses that you're
16
talking about for these injections--even if the
17
whole injection escaped into the circulation. I
18
mean, we're talking 5 x 10
10 to 10 x
1010. And there
19
are rates per kilogram to infuse them to not have
20
leuko-agglutination. But you're
two to thee logs
21
below that in the numbers that you're talking
22
about.
23 The other thing is that, I mean, in
24
leukemia, people have circulating blasts that are
25
large cells. They may be 20, 25,
30 microns in
236
1
diameter if they're certain kinds of blasts. And,
2
in general, they have high numbers of those cells,
3
and they're not clogging things--until the white
4
count gets very high, and then they do clog--you
5
know, decrease CNS perfusion.
6 But, I mean, you can learn some lessons
7
from those kinds of cells that may help sort some
8
of this out.
9 CHAIRMAN RAO: To me, the sense is that the
10
committee's telling people that one should be
11
cautious, and that testing is required.
12 Does that seem like a short summary?
13 And I'm going to ask the FDA--did they
14
feel that they had a sense for the kind of issues
15
that one needs to worry about?
16
DR. GRANT: Yes, we're ready
to move on to
17
the next questions. But Richard
had something he
18
wanted to say.
19 DR. McFARLAND: I don't want to spend a lot
20
of time on this, but one specific question--just as
21 a
ballpark--for the studies that are to test safety
22
of catheter administration of a cell--I don't--at
23
this point it doesn't matter which cell--how long
24
would one expect the studies to go out?
Three
25
hours? Weeks? Four weeks?
Three weeks?--not
237
1
dealing with, necessarily, the biological
2
properties of the cells, but just the safety
3
related to administration.
4 CHAIRMAN RAO: Let me take a stab at this,
5
and then see if the committee aggress.
6 So, there are a whole set of studies that
7
we talked about which are related specifically to
8
cells--right? And those are
really in terms of the
9
safety of the cells and the long-term effect after
10
they incorporate and what happens with them. So,
11
really, when you're thinking of a combination of
12
cells with a device, you're looking at the
13
short-term effect of delivering those cells, and
14
the complications if they go to an inappropriate
15
place.
16 My feeling would be that that's the issue
17
that you would want to look at, which is relatively
18
short term rather than long term, in terms of
19 looking
at it.
20 Does that seem like a reasonable--
21 DR. BORER: I think that's reasonable, but
22 I
would just--you know, you're talking specifically
23
about device-related injury, I believe.
24 DR. McFARLAND: Correct.
25 DR. BORER: You know, my understanding of
238
1
this situation--and you'll correct me if I'm
2
wrong--is that if you create a physical injury, it
3 takes a couple of weeks
for the necrosis to be
4
maximal, and the scar to begin to form; and, you
5
know, a little bit longer until the scar is fully
6
mature.
7 It seems that those kinetics would define
8
the time--the duration of the observation period,
9
because we are talking here about creating a
10
physically-mediated injury.
11 So, you know, just as a stab, if you
12
looked at some set of animals, or some experimental
13
preparation--whatever it is--for a month, I think
14
you would encompass all the device-related
15
problems. Probably you could do
it in less time,
16
but I would be thinking about the kinetics of
17
injury, tissue necrosis and scar formation as the
18
basis for making that decision.
19 DR. SIMONS: I think I would be looking at
20 a
much shorter time frame. I think the
injury from
21
the needle-based devices is minimal.
We have
22
pretty extensive experience with the devices in
23
animals. They're really benign,
all of them.
24 And after what we did--you know, to hearts
25
with lasers, what we can do with a 27-gauge needle
239
1
does not even come close. I
would not really be
2
worried about the acute safety of a needle-based
3
device.
4 DR. NEYLAN: And I'd just like to revisit
5
my sidebar issue of the need for close
6
communication between the divisions at FDA, because
7
this is an example where I think we would not like
8
to see one set of experiments go forward that
9
describe device-related safety, and another about
10
the delivery of the cells.
11 So I think it would be much better if we
12
create one set of experiments that answer both
13
questions.
14 DR. McFARLAND: No, I agree, and that was
15
part of the impetus for asking the question, so
16
that TDRH and CEBR can have a basis for discussion.
17 CHAIRMAN RAO: Now that we've talked this
18
one through, shall we move on to the--I guess the
19
clinicians have been waiting for this, I guess--in
20
terms of the clinical aspects of these questions.
21 So I'm going to read out that question,
22
and then I'm going to just let people make
23
individual comments, and then see whether we can
24
put that together.
25 So the question was: Please discuss the
240
1
appropriate frequency and duration of follow-up.
2
In addition to any other events, please consider
3
the following potential adverse pathological and
4
clinical events in your discussion items: scar
5
formation, left ventricular dysfunction,
6
ventricular arrhythmias and neoplasia.
7 And I guess, here, I just want to make
8
sure that we are clear on this, is that we're
9
thinking about early clinical studies that will be
10
done, rather than looking at animal models here.
11
So this would be some kind of clinical study where
12
you've done it, and you want to worry about whether
13
this makes appropriate sense, and what kind of
14
follow-up should one consider, and what are the
15
issues related to this?
16 VOICE: [Off mike] [inaudible].
17 CHAIRMAN RAO: Yes, I think that's an
18
important point, given what we've already heard.
19
That's another important issue to worry about.
20 DR. CUNNINGHAM: How about cognitive
21
function, since we just discussed that; and also
22
stenosis.
23 CHAIRMAN RAO: Okay.
24 Go ahead, Dr. Borer.
25
DR. BORER: I'd like to focus on
left
241
1
ventricular function or dysfunction here. I mean,
2
we've talked about arrhythmias and the duration of
3
observation that might be necessary for those. But
4 I
want to point out something that has an impact
5
here.
6 If you replace an aortic valve in a person
7
with aortic regurgitation, it takes three years
8
until left ventricular function has maximized. If
9
you replace a mitral valve in someone with mitral
10
regurgitation, it takes three years for left
11
ventricular function to maximize--systolic function
12
to maximize.
13 Now, forgetting about the whys and
14
wherefors, there are lot of processes--and as Steve
15
said yesterday, we don't understand them all, but
16
the cells do. The fact is that a
great deal of
17
remodeling goes on after you change the milieu; the
18
exogenous hemodynamic milieu and, I would suggest,
19
perhaps the cellular milieu in the scar, because
20
what you do in the scar is going to impact--if it's
21
effective, it's going to impact on what's happening
22
in the non-scarred areas.
23 So, with that as a preamble, I would say
24
that at some point in some studies, you've got to
25
look for a long time to know everything that may
242
1
happen. Is it necessary to look
that long before
2
you approve a product? No, of
course not--at least
3 I
don't think so, not if there are sufficient
4
animal studies and early clinical experience that
5
suggest you don't get deterioration.
If you get
6 some
improvement that's clinically relevant, you
7
know, at six months or whatever the time point
8
you're looking at is, one might approve a product.
9 But in terms of the duration that we
10
should make observations, ultimately, at some
11
point, either before or after approval of a
12
specific product, you have to look for a long time
13
if you're going to see the effects.
And we don't
14
know the process that's going on here.
We're
15
injecting cells. The cells may
be
16
re-differentiating, transdifferentiating. They may
17
be doing all kinds of stuff. We
don't know the
18
kinetics of those changes. We
don't know what that
19
means. We know that--I have to
infer from the data
20 I
saw yesterday that important changes in the
21
interaction between myocytes and extracellular
22
matrix is going on during this period; the kinetics
23
of extracellular remodeling is much slower than the
24
remodeling of myocytes--on and on and on and on.
25 In order for us to fully understand the
243
1
biology here, if we're just talking about
2
mechanical function, it's necessary to look for a
3 long time.
Again, that may not be necessarily in
4
order for a product to be approved--there are other
5
issues there--but to know the biology, monitoring
6
has to go on for a while. And
although it's not my
7
field--and Steve and others may want to comment on
8
this--I think the same thing is probably true of
9
the angiogenesis-arteriogenesis issue.
10 CHAIRMAN RAO: Before you cede the mike can
11
you say, well, what kind of monitoring?
I mean it
12 should
be Holter monitoring for one month or, you
13
know--
14 DR. BORER: Well, in terms of left
15
ventricular performance, you know, there are a
16
number of non-invasive techniques that easily can
17
be applied periodically over time; you know,
18
echocardiography, radio nuclide angiography, MRI if
19
you happen to have it available and the patient can
20
undergo MRI. There are a lot of
techniques.
21 But there are global, left ventricular
22
function assessment techniques, and that's what we
23
really care most about. If we
see improved wall
24
thickening someplace but the heart's not putting
25
out more blood and not pumping better, who cares?
244
1 So I would say that there are a variety of
2
standard, non-invasive techniques that can be used
3
to evaluate mechanical performance of the heart.
4 In terms of electrical performance, as
5
long as you're looking at the mechanical
6
performance, you may as well look at the
7
electrophysiologic aspects of what's going on--and
8
there, yes, I think a Holter and a standard 12-lead
9
electrocardiogram would be the minimum.
10 In earlier studies--as Jeremy pointed out
11
before--during the first few months after an
12
intervention--now I'm talking about animals,
13
because you wouldn't re-do this in people--I think
14
standard electrophysiologic testing--invasive
15
electrophysiologic testing--would be very
16
important. In people, I can't
imagine that you
17
would want to do that very often.
People don't
18
like to have that done to them.
19 I don't think you'd want to do standard
20
electrophysiologic testing very often.
There might
21
be some subset--and, you know, Jeremy should
22
comment on this--in whom a pair of standard
23
electrophysiologic studies might be done, separated
24 by
an interval of, you know--whatever the interval
25
is; whatever the preclinical data and the 24-hour
245
1
ambulatory electrocardiogram suggest is correct;
2
maybe a month, maybe two months--I don't know.
3 But I think you do have to look at certain
4
aspects of the electrical function of the heart.
5
It's simple to do that with electrocardiography,
6
because if the electrocardiogram's okay, if you're
7
not seeing arrhythmias, then, again, who cares
8
about what's going on in the substrate?
And as
9
long as I was looking at mechanical function, I'd
10
look at electrical function by these simple means.
11 CHAIRMAN RAO: Joanne?
12 DR. KURTZBERG: I would think it would be
13
important also to, if possible, require or strongly
14
suggest an autopsy for any patients who die--given
15
that you're saying this is such a high-risk
16
population. Because you may
learn something about
17
the anatomic and histologic things you find in the
18
heart, even three years later, that will help you
19
optimize this.
20 DR. RUSKIN: I think, with regard to
21
follow-up, the issue of safety with regard to
22
ventricular arrhythmias is a very difficult
23
challenge. I think if we've
learned one thing in
24
the last 20 years it's that you don't follow
25
ventricular arrhythmias. You
either stay out in
246
1
front of them, or people die.
2 And Holter monitoring, I think, in this
3
population is a waste of time because the
4
prevalence of spontaneous arrhythmias in this
5
patient group is somewhere between 60 and 80
6
percent--talking about non-sustained ventricular
7
tachycardia. And the question
then arises as to
8
what you would do about it if you saw it, because
9
anti-arrhythmic drugs--talk about Dr. Epstein's
10
Janus effect--you know, we might just as easily
11
kill people with the drugs that we use to try to
12
suppress these things as help them.
And that's why
13
it brings me back, I think, to the issue of having
14 a
group as protected as possible at the time that
15
they get the therapy, with an implantable
16
device--at least early on; not that it's perfect,
17
but at least it offers a high level of protection
18
against anything other than an incessant VT or VF.
19 And I think that's really what the
20
follow-up is. It's having a
protected patient with
21 a
monitoring device that records events 24 hours a
22
day, seven days a week, 365 days a year. But the
23
real lessons will be learned from outcomes and, I
24
think, from the preclinical work that gets done.
25
And it's not going to get answered by ECGs and
247
1
Holter monitoring and other simple forms of
2
observation.
3 There are host of other risk
4
stratifiers--like T-wave alternans, signal average
5
DCGs, and a number of other things--all of which
6
would be of interest. The
problem, again, will be
7 that the positivity rate is so high in this
8
population, even without the therapy, that I think
9
it's going to be very hard to distinguish the
10
treatment groups from the non-treatment
11
groups--even if there's a pro-arrhythmic effect.
12 CHAIRMAN RAO: I'll ask this in a more
13
particular way, and it's really part of Question 7,
14
which sort of segues into this, and you've already
15
raised that as a point.
16 So, once you've chosen a patient
17
population--and there's a caveat on how you choose
18
the population from the points of the worries that
19
one has with any kind of new therapy--you have to
20
worry about monitoring them, and there's going to
21
be a certain basis of monitoring which is dependent
22
on the disease or the underlying process that they
23
have.
24 And then you want to have some kind of
25
additional monitoring--maybe--which is specific to
248
1
the therapy that you've now introduced.
In this
2
case is there anything which is new or unique that
3
has to be added on, or can one simply say that,
4
well, you've chosen this patient population.
5 You're going to have to
really be doing massive
6
monitoring anyway. Do you need
anything else.
7 And, you know, Joanne pointed out that
8
even if you do all of this, one important thing one
9
should suggest is that they also do an autopsy,
10
which is not really monitoring on side effects but
11
is learning after the fact; and that one should be
12
looking at closely monitoring improvement in some
13
fashion, or at least it's function of the cells, by
14
looking at left ventricular ejection fraction in
15
some fashion, or left ventricular function in some
16
fashion.
17 Are there other sort of additional things
18
that one can use, and which would distinguish
19
between, say, the therapy--like you pointed
20
out--versus the underlying disease?
21 DR. SIMONS: If I can attempt to begin to
22
sort of address these issues--and it really takes
23
us into, I think, Question 7.
24 As Dr. Ruskin points out, there is a very
25
high frequency of all sorts of events in these
249
1
people, given what these patients are.
I really
2
think the only way you can find out how safe these
3
kinds of therapies are, if you do double-blind
4
randomized trials, and you have control group--not
5
to assess efficacy but to actually assess safety,
6
because there will be a number of adverse events in
7
this patient group, and we will not be able to say
8
whether that is because of therapy or because of
9
natural history of disease if we don't have a
10
control group.
11 CHAIRMAN RAO: Dr. Perin.
12 DR. PERIN: In talking about monitoring LV
13
dysfunction, I think we probably should start from
14
the beginning, which is really--obviously, we need
15
to see these people pretty often, in terms of
16
clinic visits because I think symptoms, even though
17 are
not completely objective are an important thing
18
to assess in these people.
19 And in our limited clinical experience we
20
noticed that people really had a change in
21
improvement--we presented this at ACC--around the
22 seventh and eighth week.
So that's something that
23
you might want to know.
24 Also, I think that echocardiographic
25
evaluation is simple--because there is a problem of
250
1
doing MRI, because a lot of these people are going
2
to have a problem with having MRIs.
3 One other thing I would like to take note
4
is the issue of global versus regional improvement.
5 I
think that--I don't agree with what was said.
6
You don't have to have--the meaning of global
7
improvement, it's great to have LV global
8
improvement, but we've seen patients that have
9
regional improvement and this may translate in a
10
function way into a very significant improvement.
11 And so another way of looking at LV
12
function is really--and I had said this before--is
13
exercise capacity. And I think
we need to be
14
evaluating these patients functionally as they go
15
along--and this is a translation.
So maybe if we
16
injected part of the heart we don't see a global
17
improvement in LV, but that patient may be able to
18
walk a lot further on a treadmill, be able to
19
exercise more, and that's important, as well.
20 DR. BORER: Yes, I think Dr. Perin's points
21
are very well taken. I didn't
mean, in what I said
22
before, that in any way a clinical evaluation
23
should not be done, or should be precluded.
24 Obviously, that's the name of the game. The
25
patient has to feel better and/or live longer, or
251
1
you haven't done anything useful--no matter what
2
the ejection fraction turns out to be.
3 So I would absolutely agree that clinical
4
evaluation has to be the key, and it's a given in
5
the follow-up of patients getting these kinds of
6
treatments.
7 I would also agree that there could be
8
clinically meaningful regional improvement without
9
much change in global left ventricular function.
10
I'd sort of doubt that it would be very meaningful
11
if there wasn't any change, but I was thinking more
12
in terms of the kinds of echo studies that show
13
that with sonomicrography--the ultrasonography, you
14
can see thickening in one small region.
That
15
doesn't mean much to me.
16 But the point is well taken that you made,
17
and I don't disagree with it at all.
18 There's a sort of a more overarching issue
19
here about the various modalities that we might use
20
to evaluate patients. And, you
know, Jeremy, of
21
course, is an expert in this area, and he's
22
undoubtedly absolutely right that the yield from
23
simple rhythm-monitoring studies would be pretty
24
low in people who are as sick as these people are,
25
and maybe that's the wrong example for me to take
252
1
here.
2 But, you know, in general if you don't
3
look you don't find something.
There are simple
4
means of following patients, and I like Dr. Perin's
5
suggestion--which I think should be part of any
6
follow-up--clinical follow-up of people with heart
7
failure--that is to assess exercise tolerance
8
formally.
9 There are lot of simple things that you
10
can do that are sort of part of a standard
11
armamentarium of researchers and clinicians who
12
follow patients who are very sick that I think
13
should be done. They may not
show much, but unless
14
you look, you don't know.
15 So I just offer that.
If, you know, it
16
gets back to we-know-what-we-know,
17
we-don't-know-what-we-don't-know, as Dr. Harlan
18
said before. Better to look with
a wide compass
19
when our knowledge base is relatively small, then
20
we can eliminate things as we go along.
21 CHAIRMAN RAO: Dr. Ruskin.
22 DR. RUSKIN: Just a quick comment.
23 Jeff, I agree completely, and I didn't
24
mean to suggest that we shouldn't do the Holtering
25
or the routine ECGs. We would certainly
do those,
253
1
and it's possible one might see things that were
2
very surprising.
3 The issue that I raised really related to
4
safety; and that is that doing Holter monitoring as
5 a
safety maneuver is not productive in this patient
6
population because, clearly, it's an icepick in
7
time, and you may see absolutely nothing and have a
8
dead patient 12 hours later, or see florid
9 arrhythmias that
purport nothing ill with regard to
10
long-term outcome.
11 So the data would, I think, be necessarily
12
obtained, but it couldn't be used to ensure safety.
13
And that's really the reason for making the plea
14
that early on one consider populations that have
15
protective devices. They're not
perfect, but
16
they're a lot better than not having them.
17 CHAIRMAN RAO: How about, you know,
18
monitoring for potential complications.
I mean,
19
should people be worried about "We are putting in
20
cells. There might be an
inflammatory response
21
because of all the necrotic material." Should one
22
be looking at C-reactive peptide?
Is that
23
something which should be over and above what one
24
would normally be doing in a sick patient?
25 Are there any other such tests that you'd
254
1
want to do, you know, to look at--?
2 DR. BORER: I think you'd do whatever you
3
can think of. It may not be
worth anything. But,
4
again, if you don't look you don't find out.
5 I wouldn't particularly have picked
6
C-reactive protein, but it's fine.
You know--sure.
7
Why not look at systemic inflammatory markers?
8 Steve Epstein made the point yesterday--I
9
have to backtrack for a moment.
I've referred to
10
Steve at least 20 times here--and as you look
11
around the table--well, one of them just left, but
12
there are three generations of Steve Epstein
13
trainees or underlings sitting at this table. So
14
it shouldn't be--and, unfortunately, I am now the
15
most senior of those three.
16 [Laughter.]
17 Which, as Steve would say, what does that
18
make him? But--what was I
originally talking
19
about? [Laughs.]
20 [Laughter.]
21 There was a point here. Oh, yes--about
22
atherosclerosis. You know, the
inflammatory
23
milieu--this is important because, remember--I
24
mean, your point is very well taken.
Steve pointed
25
out that some of these treatments we give could be
255
1
good for the myocardium but, depending upon how we
2
give them, they could be atherogenic.
That's very
3
important.
4 You know, undoubtedly, that the event
5
rate--coronary event rate--is substantially
6
higher--two- to threefold higher among patients
7
with rheumatoid arthritis than among patients
8
without rheumatoid arthritis;
that is, among
9
patients with rheumatoid
arthritis with positive
10
markers of inflammation.
11 So there's some evidence that a systemic
12
inflammatory milieu somehow potentiates the
13
development of coronary disease.
14 Now, I don't want to talk about mechanisms
15
because we don't know them--or at least I don't.
16
But I think, therefore, if we believe that there is
17 a
likelihood that we're going to stimulate an
18
inflammatory response with what we're doing, we
19
should be looking for evidence of that so that we
20
can relate that--even if retrospectively--to other
21
events that occur in this population.
So I think
22
the point is very well taken and we should be doing
23
that.
24 CHAIRMAN RAO: Given that this is a sick
25
population that would be the first sort of
256
1
candidates for this, irrespective of how you select
2
them, would be anything you'd suggest which will
3
change the frequency of monitoring from what you'd
4
normally do for a sick population of this sort? Or
5
would it be more frequent? Or
would it be longer,
6
in terms of the anticipated complications? Or
7
anything that one might imagine?
8 DR. SIMONS: I actually don't know what
9
patients--or the population that we're talking
10
about. Because as we discussed
several times,
11
there are really two different patient groups here.
12
One is an acute myocardial infarction patient, and
13
one is a patient who is chronic heart failure. And
14 I
think you would monitor differently in these two
15
different groups because in acute MI, the
16
patients--the risk is early. And
once it's been
17
successfully treated, that's a pretty low-risk
18
group, with a very low mortality rate.
19 While, you know, Class IV heart failure
20
patient, who has a 20 percent ejection fraction has
21 a
pretty high mortality rate. I think you
would
22
sort of treat those things in a very different
23
manner.
24 CHAIRMAN RAO: Either of those groups--so,
25
you know, you take acute MI, and you're trying to
257
1
treat it with, say, bone marrow cells, and you
2
would monitor acute MI in a particular way.
3 Would it change now that you've added
4
cells to the therapy?
5 DR. SIMONS: Probably would--you'd probably
6
want some sort of non-invasive imaging such as
7
echo. During the first two weeks you'd probably
8
want it several times to see there's no pericardial
9
effusion, and there's--if the left ventricular
10
function is not changing in sort of adverse
11
ways--there's some adverse left ventricular sort of
12
remodeling.
13 But after two weeks I would go back to
14
pretty normal schedule; three months, six months.
15 CHAIRMAN RAO: If something changed, it
16
would change acutely.
17 And in a chronic disease model, would
18
there be anything that you'd change?
19 DR. SIMONS: Once again, if this is a
20
catheter-based delivery, I think you need to
21
monitor more intensively within the first couple of
22
weeks.
23 CHAIRMAN RAO: Dr. Borer?
24 DR. BORER: Yes, I agree with what Dr.
25
Simons says. But I think you
have to be aware--you
258
1
say, "Should there be a difference compared with
2
what we usually do?" There
is no "we." You know,
3
what someone who is working in an academic
4
institution, collecting data in a research milieu
5
might do is very different from what one might do
6
in private practice, or in primary care, or what
7
have you.
8 So what I would say is that we should
9
pre--that people who set up these protocols should
10
pre-specify regular evaluation--by objective
11 techniques
that we've all talked about here, at
12
some appropriate frequency, be it, you know, every
13
month for a few months, every six months after
14
that, every year after that--whatever it is. I
15
don't know how the patients will live.
16 But I think that that kind of monitoring
17
probably should be continued for many years--again,
18
given the fact that remodeling takes a long time.
19 CHAIRMAN RAO: Dr. Cannon, and then Kathy.
20 DR. CANNON: I would second Dr. Borer's
21
comments about long-term follow-up because,
22
particularly in thinking of this approach for the
23
chronic, intractable anginas, sort of an
24
angiogenesis or neovascularization approach. It's
25
conceivable to me that you could have a short-term
259
1
benefit, but not just a late failure, but maybe
2
even a worsening of the situation over time.
3 So perhaps putting cells in, either
4
directly or indirectly, stimulates new vessel
5
growth. But that may not be
permanent in that
6
those cells will have to be replaced in time. They
7
don't live forever. And if that
person's own
8
progenitor cells are very poor in function and few
9
in number, then the growth that was stimulated by
10
putting in a large number of perhaps activated or
11
genetically modified cells, or what have you, that
12
effect may go away in time, and the patient doesn't
13
have a way of replenishing or replacing the cells
14
that compose the new vessels.
They could fail
15
fairly quickly, perhaps.
16 It's conceivable--it's like the movie
17
Charlie. You know, there's
short-term great
18
benefit, but then a deterioration that actually
19
makes the individual worse off than were had
20
nothing been done at all.
21 CHAIRMAN RAO: do you feel we have enough
22
information to point out how long?
23 DR. CANNON: No.
No. I just raise that as
24 a
possible concern, or a justification for
25
following them longer and perhaps more closely than
260
1
you ordinarily would someone with chronic stable
2
angina.
3 DR. HIGH: I just wanted to raise a
4
question to the cardiologists about one other
5
method of data capture, and just get your response
6
to this.
7 But, how often are these people
8
re-instrumented, or re-angio'ed, or whatever? And
9
how much risk is it to do an endomyocardial biopsy
10
if they are?
11 CHAIRMAN RAO: Dr. Epstein, do you want to
12
take that?
13
DR. EPSTEIN: Well, my question
was going
14
to be directly related to that.
15 I would like to raise a difficult
16
question, because it's very expensive.
Given the
17
Lancet article of two weeks ago that was called--it
18 was
a very small number of patients, and I don't
19
know how much credibility to give it, but it raises
20
the interesting question that infusion of cells
21
into the coronary artery that had been harvested
22
after GCSF stimulation seemed to be associated with
23 a
much higher incidence of re-stenosis than would
24
have been expected.
25 Should patients receiving cell therapy at
261
1
the time or shortly after angioplasty--should they
2
have a repeat coronary angiogram in six months to
3
rule out this very important possible adverse
4
effect?
5 What do you think, Richard?
6 DR. CANNON: You know, with the new
7
drug-eluting stents, it may be that that will not
8
be an issue in sort of the current environment now
9
that it was with the bare metal stents used in
10
that. So perhaps following more
for
11
ischemia--non-invasively, perhaps--would be more
12
acceptable.
13 Doing repeat cardiac catheterizations
14
serially--
15 DR. EPSTEIN: It's expensive--
16 DR. CANNON:
--it would obviously add to
17
the expense--
18 DR. EPSTEIN:
--and it's--but that is, you
19
know it's a good question. And,
you know, given
20
that recent study, you know, it's a very relevant
21
one.
22 CHAIRMAN RAO: Is biopsy dangerous, though?
23 DR. EPSTEIN: Oh, yes, I wouldn't think
24
about biopsy. And, also, I think
you'd have a
25
sampling. You couldn't be
confident that you were
262
1
getting tissue in the area where you think you've
2
done some.
3 DR. HIGH: [Off mike] Well, no, he said he
4
could do it within one micron--
5 [Laughter.]
6 DR. EPSTEIN: Well, but Mike he was just
7
joking.
8 [Laughter.]
9 DR. RUSKIN: You know, about the--if there
10
were a credible scientific question to ask from
11
repeat catheterization, I think the primary
12
question you're asking is: does the risk preclude
13
doing it?
14 The risk of a cardiac catheterization for
15 a
major event, among all comers, is one in 500.
16
Now, it may be a little higher in a very sick
17
population, but, you know, I think that that risk
18
is--not death, but some major event, stroke, MI,
19
death, bleeding, infection--one in 500.
20 I think that if we had a credible
21
scientific question that was very important to
22
answer--and I'm not sure that we do.
I think
23
Richard's point about doing non-invasive assessment
24
might suffice for the question about re-stenosis.
25
But if we had a question, I think that the risk
263
1
would be supportable, or could be supportable,
2
given what I've just said.
3 In terms of biopsy, in fact the biopsy
4
data suggests that, in experienced hands, that's
5
reasonably safe, too. The big
concern I would have
6
is exactly what Richard said--you know, the
7
sampling error. I mean, a
catheter-based biopsy is
8 a
right ventricular biopsy. It's not
anywhere near
9
where we're looking--where the problem is, where
10
the cells were put in. To do it
on the left side
11
would be very dangerous, I think.
12 So I would be concerned that we wouldn't
13
be able to get the information that we want to get.
14
And I would be interested in--just with regard to
15
your question, which I think is a very good
16
one--applying non-invasive methods, like MRI if it
17
were possible, or perhaps PET scanning to ask some
18
of the questions that you might have wanted to ask
19
with a biopsy.
20 CHAIRMAN RAO: Dr. Perin?
21 DR. PERIN: If we look at the population of
22
patients that are the chronic ischemic end-stage
23
patients, the reason they got there is they've got
24
horrific coronary disease, have very aggressive
25
coronary disease. Their
coronaries are already all
264
1
stopped up.
2 So I think it's really hard--and we've
3
done this--but to re-angiogram these patients, it's
4
really hard to differentiate what's progression of
5
disease that they were going to have anyway; what's
6
do to the stem cell injection.
So it's very
7
difficult to evaluate--and which is completely
8
different in the acute MI population, where that
9
may actually be something that's important to look
10
at, because you have a target vessel, and a lot
11
different coronary situation.
12 DR. BORER: I think that that's a very good
13
point that leads to the point Dr. Simons made a few
14
minutes ago, and that Jeremy made yesterday, which
15
is Question 7, about controlled studies.
16 I think, Jeremy, what you said was that
17
from the earliest studies they should be
18
controlled. And I agree with
that.
19 I think there's absolutely no way to
20
interpret the data in a very disparate, very sick
21
population--very heterogeneous population. I don't
22
think that it's possible to interpret most of the
23
data that are of interest to us without some
24 comparator.
25 And I would go back to Dr. Murray's
265
1
earlier point. You know, you can
not ethically
2
justify studying human subjects unless you can
3
interpret the data.
4 So I would say that Jeremy's point is a
5
very important one. I think
controls have to be
6
built into these trials, even from the earliest
7
studies, and that probably it's not worth a heck of
8 a
lot to do observational studies with no
9
comparator in most situations.
10 You know, the type of control could vary.
11
There are active controls, there are placebo
12
controls--if you want to call it that.
There are
13
dose--different doses, in a dose-response design,
14
that could be used. But I think
you do have to
15
have comparators.
16 CHAIRMAN RAO: That's an important point,
17
and I think it came up a couple of times before in
18
the past, too, and I'll just try and summarize
19
those few comments and then turn it over to you.
20 So, there seemed to be consensus in the
21
field--in fact, almost everybody who talked about
22
it said that controls are important, or that
23
placebo controls are quite important.
24 And then I asked this question yesterday
25
was that is it possible to get controls. Will it
266
1
be possible to recruit them? And
the answer was
2
yes--as long as there was some kind of cross-over
3
option. And that seemed to be a
possibility, so
4
that that wasn't an absolute limiting factor that
5
was there.
6 And you've reiterated that point, that it
7
would be very hard to interpret these in small
8
studies without any kind of controls.
So it seems
9
that that's one important thing that one should
10
keep in mind in any kind of clinical study that's
11 going
to be done--right?
12 Go ahead.
13 DR. MURRAY: From the point of view of
14
ethics--and science, here--there's one absolute
15
requirement: namely, the study would have to offer
16
interpretable results--right?
We've talked about
17
that. You cannot justify doing
trivial things to
18
human subjects if the design is basically never
19
going to yield anything of any value and you know
20
that going in.
21 The other thing you want to do--and as I'm
22
understanding the situation, is it's going to be
23
very difficult to get a good signal-to-noise ratio
24
so that you can actually pick out what the actual
25
effects of the intervention are.
So there's a need
267
1
to maximize sensitivity to be able to pick those
2
out, and the discussion that's gone on about, you
3
know, what to look for here has been very helpful
4
for that.
5
Even in small numbers
you'd want to have
6
some sense--we don't usually do power calculations
7
on small sizes, but we probably--we ought to do the
8
best calculations we can in these so, again, so
9
that we have some assurance that we will have
10
interpretable results.
11 I don't think it will be easy to design
12
studies that will be ethically clearly acceptable
13
with the placebo design Phase I studies here. But
14 I
suspect it's the way we have to try to go.
And
15
I'm going to count on the creativity of the
16
investigators and the courage of the subjects.
17 CHAIRMAN RAO: Go ahead, Dr. Borer. I
18
thought--did you want to make a comment?
19 DR. BORER: About placebo, I did.
20 The issue of doing a placebo-controlled
21
study and then offering, as the benefit, a
22
crossover--or I would--it's not a crossover, it's a
23
dropout--at the end of a certain period of time, if
24 the
treated group actually shows benefit is very
25
attractive, but we may not have information that
268
1
would support doing that from early small trials,
2
or early small studies. So I'm
not sure that that
3
would be the out.
4 I think that one has to think creatively
5
about some other types of controls.
And I do like
6
the multi-dose design, because that does allow you
7
to know, if you see a dose response, that, in fact,
8
there is, by definition, an effect.
In that
9
situation, you know, everybody gets something.
10
And, of course, we don't know going in what's
11
better and what's worse; whether there is a dose
12 relation, whether there's a maximal dose
that's
13
effective and above that you have safety problems.
14
You don't know that.
15 So I think that that might be some--a
16
creative approach to dealing with this need for
17
comparators. And maybe a
placebo-controlled
18
approach would be the appropriate way.
I don't
19
know.
20 I'm just suggesting that we have to be
21
more creative about the thinking about study design
22
to provide appropriate comparators.
And then I'd
23
get back to what we all discussed before, which is
24
that since multiple small studies will be done with
25
these agents, the designs and data collection
269
1
strategies should be compatible--sufficient
2
compatible--with one another so that you can pool
3
some data and eventually come up with some
4
information that might be more interpretable than
5
the data from any single study alone.
6 So, just sort of overarching thoughts.
7 CHAIRMAN RAO: In some ways we've been
8
trying to answer this question but it's been a
9
little bit different from the way it's been set up
10
there.
11 I mean, it seems to me that,
listening to
12
all the experts in the field, is that they seem to
13
feel that selection of patients, and the design of
14
the experiment, in terms of the controls, or the
15
placebo used, was really as critical as sort of the
16
readouts. And, in fact, nobody
seemed to feel that
17
there weren't enough adequate readouts which were
18
non-invasive and that it would not be possible to
19
design them. It was just simply
that you will have
20
to design them adequately, depending on the type of
21
patient you chose and the kind of, you know,
22
disease you were treating.
23 And I think the two points that were made
24
to me which were really important was that you're
25
going to have to follow up for certain things for a
270
1
long time. It's not an
aggressive follow-up, but
2
you need to follow them up because you have to
3 learn
something from these things. And that
the
4
other was that in this trial itself there should be
5
some urgency, or some selection so that you could
6
have the option of performing an autopsy because
7
that might work really well, given that the choice
8
of patients is such that they are relatively sick,
9
and that that might be a really important thing to
10
keep in mind.
11 Does that seem to capture? Does the FDA
12
think that that addresses some of the issues on the
13
clinical trial?
14 DR. GRANT: Yes.
15 CHAIRMAN RAO:
In that case, it's amazing.
16
We actually finished on time.
17 [Laughter.]
18 Well, thank you for all the people who
19
stuck out here to the bitter end.
That was useful
20
And I thank all the experts who gave the time to
21
come to this. It couldn't have
been done without
22
them.
23 [Whereupon, at 3:00 p.m. the meeting was
24
adjourned.]
25 - - -