Thursday, September 4, 2003
Session 3: Stem Cells:
Moving Research from the Bench Toward the Bedside: The Role of NIH
Part I: Elias A. Zerhouni,
National Institutes of Health
Part II: Mark B. McClellan, M.D.
Commissioner, Food & Drug Administration
CHAIRMAN KASS: I think we should get started, notwithstanding
the fact that a few of our members are delinquent. We'll just
keep them after school.
This session is entitled "Stem Cells—Moving Research from
the Bench Toward the Bedside: The Role of the NIH," and then
in the second of this session, the FDA.
This afternoon we move from the principles of the stem cell policy
to its implementation with a review of the contributions of NIH
and the FDA to efforts aimed at bringing research from the bench
toward the bedside.
Administering government funding of stem cell research is largely
the task of the National Institutes of Health where, as we heard
from Dr. Baldwin over a year ago, vigorous efforts have been made
from the very beginning to make cell lines available to characterize
their properties to support research, training, and infrastructure.
Today we are very pleased, and greatly honored, to have with us
the Director of the NIH, Dr. Elias Zerhouni, who has kindly agreed
to give us a progress report on the developing field of stem cell
research as it looks from the strategic center of federal support
Dr. Zerhouni will make a presentation after which we will have
discussion. He has to leave sharply at 3:00.
Dr. Zerhouni, we are in your debt for taking the time to give
us the benefit of your observations and insights. Thank you very
DR. ZERHOUNI: Thank you, Dr. Kass, and members of the
Council. It's a pleasure for me to be here and to share with
you what NIH is doing in promoting the field of embryonic stem cell
research in particular, and stem cell research in general.
What I'd like to do is really give you an overview of what
has happened since the implementation of President Bush's policy
on August 9, 2001, at NIH, how NIH is tackling the field of stem
cell research, what we are seeing as the major priorities and challenges
that we need to overcome as we speak.
I will not spend too much time on the promise of stem cell research.
I think this Council knows all of the implications of cultured pluripotent
stem cells and the challenges that are needed—that need to be
met to transform these cells in differentiated elements that can
serve in overcoming loss of function and help regenerating lost
You know also the hierarchy of stem cells that go from totipotent
to pluripotent to multipotent stem cells. To this point, we've
never demonstrated a return from a pluripotent to a totipotent stem
cell, but there is one paper that indicates that that may be happening
in mouse stem cells. And we will talk about that a little bit;
we'll touch upon it.
But clearly, there are two known ways currently to make pluripotent
stem cells. One is obviously using the inner cell mass, and one
is using germ cells. This method was promoted by Dr. Gearhart at
Johns Hopkins and Dr. Jamie Thomson at Wisconsin.
So when you then ask yourself, what is so unique about human embryonic
stem cells, clearly two properties come to mind—the fact that
they have an unlimited capacity for self-renewal and culture, and
that potentially they can differentiate into any adult cell type
under the right conditions.
From the standpoint of NIH, as in any field of research that begins
to be funded at the federal level, there is an approach that needs
to be followed in the sense that research is done by people with
resources, with strategies.
And in the area of stem cell research, as soon as I became director,
I convened groups of scientists at NIH, and we tried to define what
the milestones should be and what the pathways should be for this
area of research to grow as rapidly as possible to fulfill its promise.
And when we look at that, there are several phases that need to
be understood, and this is the underlying strategy that supports
our activities at this point. One, clearly, is you need to build
scientific capacity. Remember that prior to the President's
decision there was no federal funding for this kind of research,
and, therefore, the scientific capacity in the country was likely
to be underdeveloped. So the number one priority was to create
career development pathways, training courses, and, more importantly,
establish the infrastructure needed to do the research.
Then, when you look at the field itself, there is a need to prove
the long-term stability of the cells, characterize them very fully
at the molecular level, and understand both theirgenetic stability
and their stability in the host, understanding the differentiation,
the growth factors, the gene regulation—all of the events that
control that specialization.
End cell cycle control—obviously, these cells are pluripotent,
and one of the safety fears that everyone has is that they would
divide uncontrollably in the host. So we need to understand that
mechanism. And, obviously, since we're talking about regaining
lost function in a host, we need to understand cell host interactions.
To do so, one of the first actions that I took as NIH Director
was to create a stem cell task force at NIH. Prior to my arrival,
I think NIH had put together the beginnings of an implementation
But I thought that given the challenge and given the wide-ranging
spectrum of activities that the agency needed to get into, I thought
it was very important to elevate this activity at the level of the
director and to have a specific task force, including both intramural
and extramural researchers, to look at what were the most important
roadblocks to overcome, the most important avenues of research to
stimulate quickly, and where was the—where were the pressure points,
if you will, where we needed to intervene to accelerate the field.
Well, obviously, the task force divided itself into working groups,
as you can see. And, no surprise, career pathways, resources, the
peer review, since obviously NIH is based on peer review and we
needed to have a cadre of competent reviewers. And in a new field
it's always a challenge. Tools and technologies, and obviously
the ability for us to reach out to the research community throughout
This stem cell task force has members who are both active in the
field or have knowledge in the field of developmental biology and
cell cultures and other fields and are advising the director through
the task force, which is chaired by Dr. Jim Battey.
As we looked at the challenges, it was quite obvious that the
immediate challenge for NIH and the human ES cell research community
was first to generate and characterize the distribution quality
human ES cell lines from the NIH.
It's very important to understand what "distribution
quality" means. It is not—a cell line being available is
not enough. A cell line having been derived is not enough. It
needs to be characterized, it needs to be quality controlled, it
needs to be expended, and it needs to be immediately available to
the research laboratories that need it.
The second was the need to stimulate more research on basic biology,
and the third was the training of investigators.
In the basic tools of the field, first and foremost, before the
use of stem cells and the approach of hypothesis-driven research,
we needed to have a cadre of confident and competent investigators
in the field. So those were the action lines that started pretty
much last year, a little bit over a year ago.
Now, when you look at the issue of lines, I know that the public
always tries to understand why is it that the President's policy
talks of 78 lines, and we talk about 12 lines that are available.
And there is always a little bit of confusion, so let me, if you
don't mind, give you the steps that are needed to go from a
derivation to a fully available line. And I think that semantics
sometimes get in the way.
But fundamentally, as you know, derivations occur when you are
collecting the inner cell line—cell mass, and you're developing
your primary colonies. And then, through subcultures, about 1,000
cells per well, you then expend these cell lines with about a 10
percent survival rate.
So as we know today, these cell cultures are not as efficient
or effective as we would like them to be. Then, you have to basically
then multiply these lines through multiple passages.
Well, obviously, because these cells have the potential differentiation,
you need—at each passage you need to characterize through molecular
marker studies and assure yourself that these have remained stem
cell lines. So one flask grows up to 100,000 cells, and one bank
that would be capable of fulfilling distribution needs requires
at least two billion cells. That takes about nine months to a year.
So, and when you distribute these cells, depending on the distributor,
there are about two million cells needed per vial, and that means
ready for distribution.
So when people look at this, they forget that on August 9, 2001,
there were 64, 78 lines, whatever the number of qualified lines
was at the exact time. We end up qualifying 78 sources, but to
make those sources expended and characterized to the point where
you need—you have lines available — takes about 12 months.
So when you look at the schedule, what we have accomplished is
about — last year there was one line that was widely available,
and today there are 12. And that's the reason between the 78
versus 12 numbers that you hear around.
There are other lines that are being expended as we speak. There
are agreements that are being signed. One has to remember that
these lines do not belong to the Federal Government; they belong
to their own derivers, and, therefore, are subject to intellectual
property agreements, which sometimes are easy to negotiate and sometimes
are not so easy to negotiate.
But I think our role was to increase as quickly as possible the
number of widely available lines that the researchers could have
access to to do the research. So the way we did this was by rapidly
awarding to organizations with entries on the NIH-eligible cell
line registry, funds to develop those lines into distribution quality
cell lines, and that's the difference between eligible and distribution
We gave them a two-year period of support. We granted eight awards
for a total of over $6 million, and we have about 12 lines now ready
for shipment, meaning in my criterion for that, which I insisted
be the criterion which is listed on the website, is you can pick
up the phone and get the line delivered to you within a measurable
matter of days.
So the program announcement will be reissued, because we have
now other sources of lines that are interested as they have learned
more about the expendability of the lines, interested in making
their lines commercially available.
In addition to that, I think there are many sources of lines that
have reserved derivations for further expansion as we learn more
in the research. So those are the infrastructure awards that accomplish
Then, NIH has two means, really, of supporting research. One
is obviously training; the second is to fund investigator-initiated
research, which can be either spontaneously generated or can be
stimulated by NIH.
And the way NIH stimulates research is by issuing program announcements
or requests for applications around areas of research that are either
aligned with the mission of the Institute that issues these RFAs
and PAs, or are general announcements that the entire NIH wants
So one of the program announcements we made was to have grantees
develop short-term courses in human embryonic stem cell culture
techniques. We use the T15 mechanism, and it's supported by
11 NIH institutes.
And basically, we have been able to award four of these. These
are courses that can take up to two or three weeks at certain centers,
and investigators can send their own core investigators or personnel
to these centers. And these have been extremely well received by
the research community.
We have also career development awards, career enhancement awards
for stem cell research specifically issued by several institutions,
which allow an investigator to spend up to 24 months with $50,000
of direct cost exploring the field of embryonic stem cell research
as well as have training in the uses of stem cells.
And then, requests for applications are directed towards areas
of scientific priorities that the NIH feels need to be stimulated.
So we have stimulated multi-investigator teams. We have infrastructure,
growth and maintenance, research into biochemical/molecular markers,
and so on.
And we are trying now to establish exploratory center grants that
will lead to, then, formal centers that will have for a primary
mission the development of the applications and the basic science
of human embryonic stem cells.
Then, obviously, as you can imagine, there is a tremendous amount
of interest in rapid application in particular disease areas. So
institutes now have also issued very specific RFAs in avenues of
research that are deemed to be potentially fruitful in the short
So innovative concepts and approaches to developing functional
tissues and organs from NHLBI, plasticity of human stem cells in
the nervous system, and you can obviously imagine what these applications
area—recovery of cardiac function, the recovery of neural function,
recovery of endocrine function in the case of diabetes, and obviously
basic and applied stem cell for arthritis and musculoskeletal disease.
The Institute feels that this is a high priority area, given the
fact that musculoskeletal disease and arthritis is emerging as the
number one cause of disability in an aging population. And then,
development and repair of orofacial structures.
I will just go quickly now in terms of some of the more fundamental
research—for example, NIDDK is promoting comprehensive programs
in beta cell biology, again a diabetic target. And then, obviously
looking at the genome anatomy of the hematopoietic stem cells, given
the genomic techniques that are available to us, and so on. So
I don't want to take too much of your time on details, but this
is the strategy that we have implemented.
In addition, we have also stimulated intramural research. When
this field started, you could basically identify one or two labs
at NIH intramural that had an interest and lead in embryonic stem
cell research. Dr. Ron McKay, through mouse embryonic stem cells,
was probably the most prominent.
Today we have nine laboratories in NIH working aggressively and
publishing in these areas. We have a much expanded interest as
cell line availability becomes more straightforward. So we knew
that that was a roadblock that needed to be overcome before anything
else could happen, and that's what we worked on.
In addition, through the identification of roadblocks by the stem
cell task force, one of the things that became very obvious for
us, for all of us in the field, was that unless we had a formal
way of characterizing and identifying the characteristics of each
cell line, it would be very difficult to compare experiments from
lab A to lab B to lab C.
And when we surveyed the field and we surveyed the level of knowledge
needed for characterization cell markers, molecular characteristics,
and so on, we realized that there wasn't a worldwide agreement,
nor was there a U.S. consensus about how to really make sure that
you're dealing with a stem cell, and how do you know that over
a period of time, and how do you compare line A versus line B.
So we decided to establish an intramural research program dedicated
to the characterization of stem cell lines. We think that this
is an important investment, because it will give us for the first
time the ability to call a stem cell a stem cell in the real scientific
sense of the way—of the word.
So, in summary, what I think you can see between 2002 and 2003
is that we have built the infrastructure, we have accepted investigator-initiated
awards, we had 21 applications in '02. Now remember, in NIH
parlance FY2002 goes from October 1, 2001, which was a month after
the announcement of the policy to September 30, 2002, and 27 applications
We have awarded 25. We have also awarded 66 administrative supplements.
These are scientists who have already accumulated the knowledge
base to work with stem cells, either in adult stem cells or mouse
embryonic stem cells, and we issued a rapid series of supplemental
grants to allow them to work with human embryonic stem cells.
So we have 66 additional grantees, or groups anyway, that are
able to use human stem cells.
We also had a research symposium in June that showcased both the
research conducted and supported by NIH, but integrated this with
the GM cell symposium that occurred here in Washington on June 10th
and 11th, to look at the entire field and try to understand where
the field was at the time.
On the research horizon, I think what came out of those meetings
is that the priorities today are the following. One is to define,
standardize, human ES cell culture conditions that obviate the need
for either mouse or human feeder cells. This is a priority. We
already have grants from investigators that have been funded.
We have several reports from groups that have been funded by NIH
looking at the characteristics of, what is it that gives a mouse
feeder cell the ability to grow human embryonic stem cells? What's
so special about that versus human feeder cells versus feeder-free
And there have been recent papers that indicate that you could—once you understand the molecular drivers of that growth, you
can probably foresee the ability for us to develop, soon I hope,
culture conditions that will obviate the need for any feeder cells.
Then, the second is you can hear many—you can hear through the
scientific community those enabling tools and technologies to further
characterize stem cells as they become specialized cells are needed.
And that goes from specialized antibodies to identify very specific
markers of multiple different lineages.
But it's also a—there is also a requirement from the scientific
community to understand what the genetic events—what the gene
expression patterns are between a multipotent stem cell and the
one that becomes, let's say, a muscle cell or a blood cell.
And that is an area of very, very important research that is ongoing,
and there have been several papers published trying to identify
which genes are really turned on or off as you go from the stem
state to a non-stem state. And that essentially defines the point
number three, which is understanding the molecular pathways that
specify differentiation into these different specialized cells.
And then, obviously, we're not talking about cells just in
culture. They have to survive and function within the host, so
that many, many researchers are now focusing their attention on
the critical factors and conditions that drive the long-term survival
of these cells in the host.
And then, obviously, the one question that requires resolution
before any human clinical trials are even envisioned is the assurance
that we need—and I lwill let my colleague Dr. Mark McClellan talk
about it—to make sure that we can control cell division and prevent
the development of a malignancy or untoward complication.
Now, as we speak about this, you will hear that human feeder layers
are a very important step, and the research already alluded to this.
And the point here is that until recently all human embryonic stem
cells were grown on mouse feeder layers. And new conditions are
being established using human feeder layers.
We know from the Johns Hopkins group there was a recent paper
from the Technion Institute in Israel about developing matrix-like
substances that grow—that can grow without human feeder cells,
these human embryonic stem cells.
There was a publication—not a publication, but at least an announcement
from the Singapore company that you could do that. There are at
least unpublished reports of multiple groups having worked and working
on developing these lines.
Now, this is presented often as a sine qua non of further research.
I'm sure that Dr. McClellan will address the issue of how you
go about qualifying any cell lines that are grown or not grown on
animal or human feeder cells.
Now, but that is still in our mind an issue that requires work,
requires development. It will be much more desirable for us to
have understood the culture conditions without having the variability
associated with either mouse or human feeder cells, even though
that—from the conclusions from FDA and many others — indicate
that it is not a complete obstacle to clinical trials.
But in my mind, it's much more desirable not to have that
factor come into play at all if we can avoid it. But it seems to
be doable, and the research is ongoing.
Now, just quickly some important research results. The group
at the University of Wisconsin has been able to report on homologous
recombination in stem cells. For those of you who are not familiar
with that, it's the ability to essentially introduce genetic
material that will modify the genetic makeup of the cell, and so
that you can control—experimentally anyway—some of the characteristics
of these cells. That is an important step, we think, in the field.
In terms of application, you have heard about the work from Dr.
Ron McKay primarily, showing a method that can drive the differentiation
towards dopamine-secreting neurons using these in an animal model
and demonstrating, in fact, recovery of function in a model of Parkinson's
disease—very, very promising avenues of research here.
Then, one of the key areas of research, as I indicated before,
was to identify the key genes, the master genes that control the
state of stemness that we need to understand in terms of being able
to maintain cell cultures in the state that we wish them to be in
over the long- term. And this is a very important advance in the
sense that we are identifying now new genes.
One is nanog—after the mythological Celtic land of eternal youth—which basically maintains the self-renewing properties of mouse
embryonic stem cells, and he has expressed these as inner cell mass.
You couple that with other research ongoing in human embryonic
stem cells—Dr. Rowe at the NIH, Dr. Goldman, I think, is doing
similar research—where gene array studies of these cells are coding
down on a subset of genes which seem to be essential to the stemness
So we are very hopeful that within a short period of time we will
be able to at least identify some of the key master genes that are
really at play in this type of cells.
Then, you see advances in terms of not just looking at the stem
cell state, but looking at a differentiated state and understanding
the pathway going from stem to a specific type of cell, with multiple
papers indicating recipes at this point. They are not well understood.
But clearly, researchers are able to show that through multiple
approaches they can lead a cell to become, for example, a myocyte
that beats, just like a cardiac cell would, an endothelial cell
or a neuron with very specific functional measurements. This is
the most exciting part, if you will, of the research, because it
indicates that there is really proof of concept occurring in multiple
subsystems from the same kind of cells that are being worked on.
Duke University found that you can, in fact, grow a progenitor—from progenitor cells myocytes. The group in Israel also has
shown that they can differentiate human embryonic stem cells into
beating myocytes. Clearly, both in adult stem cells and human embryonic
stem cells you see early results that seem to indicate that cardiac
function recovery can happen with stem cell therapeutic approaches.
That's very interesting.
Obviously, NIH supports research on many types of stem cells.
I'm focusing my comments on human embryonic stem cells, obviously.
But as you know, adult stem cells have been funded for many, many
years, particularly in the field of cancer and hematology malignancies.
Just to give you a sense of the relationship, in FY2002, our investment
in human adult stem cell was over $170 million. In FY2002, which
is the very first year of stem cell research on embryonic human
stem cells, our total investment was about $10 million. This year's
investment is probably going to be $17-, $18-, $20 million in the
human embryonic stem cell research, and will be about the same number,
maybe $180 million, in adult stem cell research.
This is not counting animal stem cell research on mouse embryonic
stem cells or other types of stem cells. So as you can see, the
investment is growing. But, again, we hope for advances in all
fields of stem cell research.
We think that given the very early nature of our knowledge, our
understanding, and the limited nature of our understanding, it is
important to promote both areas of research, we think, at this point
as aggressively as we can.
You know about the multipotent adult progenitor cells that Dr.
Verfaillie has developed. It shows capabilities for self-renewal
and differentiation to many specialized cells. I don't want
to take too much time, but we can see glial stem cells that can
produce neurons in culture—very interesting paper from Nunez.
And satellite cells in muscle that have been identified as adult
stem cells that can divide in response to injury. And, clearly,
some early results that indicate that we can turn on these cells,
particularly in patients with muscle-wasting diseases.
At NIH recently there were stem cells identified in baby teeth
that have also quite a bit of potential. So, clearly, a lot of
things are happening. You can see also bone marrow stem cells that
are redifferentiated towards neural stem cells.
There are a lot of questions on the mechanisms by which these
occur. Some people feel that fusion might be the reason, rather
than just the stem redirection. So we'll see about that as
we go forward.
And we're providing also a large amount of information to
the research community on our websites.
I have material here that I could give you also—I don't
know if I'm okay on time—comments about the stem cell sources
and what is really happening in terms of stem cell sources in the
world right now, to just give the Council an idea of how these things
really develop and what happens in terms of research groups using
So this is the paper that I wanted to mention. By the way, before
I go into that area, there's a paper from Hubner in Science
using mouse embryonic stem cells. They were able to generate what
appeared to be oocyte-like cells in vitro.
This is the very first paper on an animal system that seemed to
indicate that you can revert from the pluripotent state to the totipotent
state. It is not confirmed at this point. We don't really
know that the—what they look at and define as structures resembling
blastocysts in the petri dish are really blastocysts, whether they
have the potential or not.
If these experiments can be repeated in human embryonic stem cells,
there will be important implications for the creation of new cell
lines, generation of tissue, and so on. So this is a paper that
I think the Council should pay attention to, because it is quite
surprising actually to see these events in these oocyte-like—in
these culture conditions.
So in terms of cell sources, the first one that was available
was the H1 line from Wisconsin. It has about 300 vials in inventory.
It has shipped already about 105 orders. About 78 of these were
in U.S. institutions, and the rest was overseas.
And then, the cell characteristics are quite well defined, and
these cells seem to—these are the most healthy it looks like,
from the point of view of passages. These cells are in passage
22 and are available immediately. So this is a very healthy colony
that seems to grow to the right number with a limited number of
H7 is another line. They have just made this one available.
Obviously, it's now commercially available, has slightly different
characteristics. And H9 has—there are about 10 orders that have
been fulfilled with H9. These have all been made available in the
past four or five months, so it's not ? and, again, 10 orders
have been filled in.
The major other source is BresaGen from Athens, Georgia. It has
two lines available. These lines also have interesting characteristics.
You can see they have shipped eight total lines—five in the U.S.,
one to the U.K., Israel, and Australia.
In the world of research in stem cells, the countries that were
just mentioned seem to be the most active, because there is a heterogeneity
in the policies of the different countries as you well know.
From ES Cell International, there are five lines available, and
there were about 33 international shipments and 16 U.S. shipments
from this Australian source. We have a source in Korea. It has
one line. There were 20 shipments made, 17 to Korea, and three
to the U.S., all of which were sent to the NIH for the purpose of
that—of characterization of the lines.
UCSF has now one line commercially available and has 60 vials
in inventory, has shipped 19—15 to the U.S. and four to foreign
sources. And I guess those are the reports I wanted to give you.
And I'd be happy to take questions, Dr. Kass.
CHAIRMAN KASS: Thank you very, very much, for a thorough,
Let me remind the Council that Dr. Zerhouni has a 3:00 departure.
Let's try to keep the questions brief, and no speeches. The
floor is open. Janet Rowley.
DR. ROWLEY: Well, I certainly speak, I'm sure, for
the rest of the Council. We very much appreciate your taking the
time to come and update us on the current status, and certainly
the plans—the present implementation and the plans for the future
I think are ones that many of us would applaud.
I have a series of questions. One of the first is for the cell
lines not established on feeder layers, this implies that there
will be new ES cell lines developed. And so the question is, these
would then not fall within President Bush's August 9th cutoff
date. And I guess, is that really so?
DR. ZERHOUNI: No. Actually, we did an inventory just
prior to a hearing to just make sure that we had all our facts together.
There were several sources—in other words, institutions or companies—that had derived cell lines already by August 9th. They have
not exposed all of their lines to human—to mouse feeder cell lines.
And, in particular, we have specific information on the lines
in Sweden—Gutenberg and the Karolinska—whereby the—as you
saw in the process, there is a process of—where between derivation
and exposure to mouse feeder cell lines you can freeze the lines
and keep them.
So there are at least those, which is about 16 lines, I believe,
that have not been exposed to either mouse or human cell—human
feeder cell lines.
And the reason given to us by the investigator is very simple.
They thought that the field was not mature enough, and the understanding
of the culture conditions was not there. So I think what they're
doing is they are basically doing experiments on non-approved U.S.
cell lines, non-approved by—for federal funding, and they have
reported, for example, experiments where they are trying to use
methods that will require neither human or mouse feeder cell lines.
And they stated very clearly that once they master those techniques,
they will then apply them to the federally fundable cell lines.
DR. ROWLEY: Okay. The next question is: what kind of
restrictions on intellectual property are attached to the lines?
For example, those from the University of Wisconsin, because I understood
that there were certain very important restrictions. And I know
also that NIH was trying to get some of those modified, and I wondered
what the current status was.
DR. ZERHOUNI: Right. Basically, the restrictions are,
one, the recipients cannot implant the provider cells in the uterus,
mix the cells with an intact embryo, or attempt to make a whole
embryo. The recipients and recipient institutions are free to publish
their research results as they wish. The providers retain ownership
of the original material. So WiCell retains ownership of the original
materials and any unmodified derivatives.
However, the recipient institutions own any new materials and
inventions its researchers create.
DR. ROWLEY: Okay.
DR. ZERHOUNI: Those are the agreements that NIH negotiated
with WiCell, and made those agreements transferrable to NIH-funded
The provider of the cells can request a sample of any new materials
for internal research users. So WiCell could request samples from
the university to develop something new for their own research,
and is free to use that for its own internal programs—any newly
patented invention. So WiCell essentially is saying that if somebody
discovers something, they can use that for their own needs internally.
Other restrictions—basically, the main restriction is that WiCell,
for example, granted any PHS-funded nonprofit investigators the
right to use its patented technology, and granted a royalty-free
non-commercial research license to PHS-funded researchers as long—and this is the real important statement—as long as the agreements
with such third parties were no more onerous than those in the WiCell
And WiCell specifically excludes sponsored research where the
research sponsor gives commercial rights to a third party. In other
words, let's say, you know, Dr. Foster receives cells at UT
Southwestern, and then using those cells and whatever discovery
he or she makes, goes to a third party and conveys commercial rights
without WiCell being—having its right respected.
So those are the interesting issues I think that govern that.
DR. ROWLEY: Can I ask you just one more question, which
there is—in Britain, the MRC is trying to develop a cell bank,
and I just—presumably, it would be parallel with the cell bank
that's being developed at NIH. And is there any collaboration
or coordination of efforts?
DR. ZERHOUNI: Okay. Let's be careful. NIH is not
developing a cell bank. It's developing a cell characterization
unit. In other words, we will develop the reagents, we will have
the lines that we will compare, and we will do a full catalog of
all of the characteristics that researchers tell us are very important.
Make the reagents available, make the antibodies available. We're
not going to be distributors of cell lines as we speak.
The British model is a little different. They have a commission,
obviously, that approves or disapproves requests, and all lines
developed under that policy have to be deposited in the cell bank.
To my knowledge, to this—I think last week there was an announcement
that the first line had been successfully derived. And, therefore,
those derivers have the obligation to deposit that in the British
bank for wider distribution. So they're assuming, if you will,
the infrastructure role that we granted to the sources here, they're
assuming it within the cell bank.
Any collaborations we communicate constantly. The most important
areas of collaboration, from my standpoint, are we need to understand
the characteristics of cell lines. We need to exchange information.
We need to have a more formal way of understanding what the field
is doing worldwide. And those are the things that we're doing
with the MRC and others.
DR. ROWLEY: Thank you.
CHAIRMAN KASS: Michael Gazzaniga.
DR. GAZZANIGA: I just think it's important to get
the scale down here. So in terms of current embryonic stem cell
research, the investment at NIH is .1 percent of your budget. It's
extremely small. Would you—what would be your guess that—should
more cell lines be made available through a change in the current
policy? How fast do you think that would scale up to be more in
line with adult stem cell vessels?
DR. ZERHOUNI: I don't think the limiting factor is
the cell lines. I really don't. I really think the limiting
factor is human capital and trained human capital that can quickly
evaluate a wide range of research avenues in stem cells.
So I am not of the opinion that the number of stem cells—you
can see the shipments, how many have been requested, and there are
many more available. So I think it's more important to stimulate
the field at the human capital level in my mind, and it will take—as you know, it takes time. You have to have fellowships. You
have to have centers.
You have to have young post-docs that really get involved in the
field and have new publications and ideas and grants of their own
for that to grow. It's not something you can, you know, drive
top-down, I don't think.
DR. ROWLEY: And just in that vein, your slides showed
that there were three post-doctoral fellowships awarded in FY02,
and out of four applicants. So this highlights, I think, the problem
of human capital.
DR. ZERHOUNI: I think you're right. But we see a
lot of is in the applications that are granted, R01 types or program,
what you see is that post-docs tend to be funded through those grants
directly, without going through a fellowship route. But I think
you're making a good point, and we want to stimulate that.
CHAIRMAN KASS: Bill Hurlbut.
DR. HURLBUT: I want to clarify something. The 16 cell
lines—I think that's what you said that were not grown on
mouse feeder cells—are those part of the original 70 designations?
DR. ZERHOUNI: That's correct. I don't know if
it's 16 or 12. I mean, I can give you the exact information,
but it's about that number.
DR. HURLBUT: These were essentially disaggregated and
DR. ZERHOUNI: Right.
DR. HURLBUT: Doesn't it stand to reason that given
the months preceding this policy there might be thousands of such
disaggregated embryos out there?
DR. ZERHOUNI: Do you mean between August—prior to August
DR. HURLBUT: Everybody saw it coming, right?
DR. ZERHOUNI: I'm sorry?
DR. HURLBUT: Everybody saw it coming, that there might
be such a policy that would say, "No further derivations."
Isn't it possible that there are quite a few cell lines out
DR. ZERHOUNI: I wasn't at NIH at the time. But I
can tell you that the NIH staff that worked on that truly canvassed
the world and made sure that whatever lines there was documentation,
there was informed consent, there are some—so it may be that there
are lines out there that have been derived before August 9th, but
they may not fit all of the other characteristics—informed consent,
no inducement, and so on.
I don't know the answer to your question, but I don't
think there are thousands out there that were waiting for the policy
to come out.
DR. HURLBUT: I shouldn't have said thousands. It
was a hyperbole.
But let me ask you two other specific questions. As you characterize
these cells and understand the molecular signals, and so forth,
obviously the hope is that you can derive them without creating
embryos somehow back—pull them down or something. Is there any
special program that NIH is looking at in an effort to bypass the
moral problem? And would it be reasonable to fund such a specialized
DR. ZERHOUNI: I thought you were the program to do that
I think Dr. Kass is in charge of that program.
No. I don't think there is a particular program that scientifically
could look at the moral or ethical issues. There is no question
that we have in every one of our human subjects and animal subjects
a—you know, a very strong moral and ethical review based on institutional
review boards or the—you know, the typical ethical considerations
that you attach to research.
But I think this one is not something that NIH is looking into,
feeling, and I said that in jest, but I think it's serious.
I think all of the institutions that have looked at this issue would
be the National Academy of Sciences, the Institute of Medicine.
The administration feels that this is a debate that really needs
to happen in forums like this one.
I don't know if I'm answering your question.
DR. HURLBUT: Well, I didn't really mean debate it.
I mean, I think everybody agrees if you could de-differentiate an
adult cell down to an ES cell, a pluripotent cell, without making
it totipotent, that you would have a moral solution to the derivation
of ES cells. And I just wondered if there's—if the science
might be ripe for a special program to seek those avenues and what
you might call morally derived ES cells.
DR. ZERHOUNI: Well, that's the adult stem cell program
in some ways. That's what Dr. Verfaillie is trying to do by
using adult stem cells. And then, going back in history and trying
to de-differentiate them, that's really the—now that I understand
your question, I mean, that is the hope of those investigators.
Cord blood was another source that is used that does not have the
same moral connotation as human embryonic stem cells derived from
So yes, actually, if that's—I'm sorry. I didn't
quite understand your question. But absolutely, there are—as
you can see, there is a tremendous amount of activity in adult stem
cells and understanding the differentiation pathways.
CHAIRMAN KASS: I have a couple of questions as well.
In part, you give the impression that we're still at a very
early stage in the road from the bench to the bedside. And you've
indicated at least some of the obstacles that—some of the steps
that would have to be taken and some of the obstacles in the way.
One of the things that you didn't speak about was research
addressed to the immunoprotection problem. And I wonder whether
there are special efforts in that area with respect to stem cell
And, second, notwithstanding the fact that we seem to be at a
very, very early stage in this research, you do indicate that there
is some work going on to look for fairly immediate clinical payoffs,
say in the area of cardiac disease.
I wasn't absolutely clear that that was with human ES cell—with cells derived from human sources or not. But how do you
square the sense that on the one hand we are at a very, very early
stage, and on the other hand the field might be ripe already for
certain kinds of clinical trials. What message should we take away
on that particular point?
DR. ZERHOUNI: I think I may not have—I may not have
been clear, but what I refer to as "host cell interactions"
imply immunological responses. We need to understand those. We
need to clearly make sure that either the transplant is not destroyed,
nor is the transplant left to grow in an uncontrolled fashion.
So I didn't mean to ignore those issues. They are there,
and they need to be addressed.
Now, science, as you can imagine, advances by leaps and bounds,
and investigators have passion and sometimes believe there is a
shortcut or not a shortcut. So that the two areas of research that
I think are driven to applications are those that, through what
I call, you know, recipes or lucky strikes or understanding of pathways,
whatever it is, try to find an application, a path to application,
in a proof of concept fashion, usually in animal systems.
And that's really what researchers tend to do. In other words,
you try to build from the solid ground you're at, and then you
go out and build an island, and then you fill in the blanks.
The fill in the blanks are still in the basic region that I described.
Even if you showed today that there was a recovery of cardiac function
through some pathway, you still will have to do the demonstration
that you understand the host cell interaction, you understand immune
response, you understand all of the safety considerations, and so
So I don't mean—in my view, they are not incompatible with
each other. At least the characterizations I gave are very compatible.
What happens typically in biomedical research, you have multiple
avenues, and that's the strength I think is to let people demonstrate
that. Your question about, is it in humans—adult stem cells have
been reported to have been used in humans in Italy, in Brazil, from
bone marrow sources. So adult sources that have then been implanted
in the heart, it is not clear, really, that it is the implantation
of those adult stem cells that has accomplished the result.
We've had embryonic stem cells injected in rat hearts that
have been infarcted that showed recovery. But those are proof of
CHAIRMAN KASS: Thank you.
DR. MAY: At one point you talked about arcing back from
pluripotent to totipotent. Is a reversal from pluripotent to totipotent
in effect the creation of a new cell line?
DR. ZERHOUNI: That's a very, very difficult question
for me to answer, because there's one experiment that showed
that, at least on the surface in a mouse model, that you had structures
that seemed to form not only a totipotent cell but an oocyte-like
structure. So that—a blastocyst-like structure.
So the question is: are you creating a new cell line, or are
you creating a new organism—is not clear in that. But this is
a very early area of research at this point.
DR. MAY: It does bear on the August 11th cutoff date I
guess, doesn't it?
DR. ZERHOUNI: It could.
CHAIRMAN KASS: Michael, and then Janet.
DR. GAZZANIGA: Just a followup, because I think your point
on the human capital is important. Sort of in the labs in various
biomedical institutions, there's an unwillingness on the part
of many young investigators to go into this field because of the
uncertainty of its political scientific status.
And so there's an interaction here where if it was clear that
this program is going to move forward, it was clear that there are
going to be more lines developed, because certainly more lines are
going to be needed for a variety of biomedical issues, that the
human capital aspect of it might be solved very quickly.
Certainly, that is what happens in all other fields which are
not constrained by the sort of—these sort of political moral issues.
But if there's a new technique, gene expression work—as you
know, overnight it remade the field, the DNA chips, and so forth.
So if it was clear what the policy would be in the future, wouldn't
your guess be that the human capital part would be solved rather
DR. ZERHOUNI: Again, that's a question that goes from
a premise that there is an issue. Clearly, when you look at the
increase in publications and names on publications, you see a lot
of new entrants. I wasn't at the first meeting at NIH two years
ago about these issues, but the symposium that we had in June, 600
people all supported in some fashion or another. How you compare
that to another field, I don't know.
The other anecdotal piece of information is I visited a few sites,
and they don't report a dearth of post-doc candidates for their
programs. Once they're established, you see—if you go to
Jamie Thomson, he has a tremendous amount of required—or demand
for trainees to come into his program as post-docs.
And so once you have an established program, it seems like you
are able to attract people. If you go to an institution where there's
no leader, no established program—I knew from my experience at
Hopkins, John Gearhart, he had his pick. I mean, he could choose
whoever wanted to come. So I think it's the program that drives
the young investigators to enter the field—program with funding,
with available resources.
Is the fact that cell lines are under the policy a driver of going
and not going into the field? I don't have the answer to that.
But obviously, since this is an issue of federal funding, private
funding is also available, an avenue that is not prohibited, as
you know. And the biotech industry—there was a recent report
that shows that there is still quite a bit of activity in the biotech—and growing activity in the biotech industry for stem cell research.
So I'm not sure that from the standpoint of human capital
that there is a monofactor here that you can identify, saying, "Well,
this will prevent for sure the growth of human capital." I
can't answer that question in the affirmative.
CHAIRMAN KASS: Last question before we let Dr. Zerhouni
go. Jim Wilson.
PROF. WILSON: Do you have any estimate—it would have
to be crude, I assume—as to how much money private sources are
putting into stem cell research?
DR. ZERHOUNI: Actually, there's a paper that was published
just recently, and I can give you a copy of it. And this is not
an NIH study, but I understand that there is spending of $200 million
per year in stem cell research, embryonic stem cell research, and
1,000 FTEs, full-time equivalents doing research worldwide.
About 60 percent of those are in the United States, about 15 in
Europe, and 27 percent in the rest of the world, primarily Australia,
Singapore, Korea, Japan. I have that reference if you want it.
PROF. WILSON: Thank you.
CHAIRMAN KASS: Actually, if you can take one more, Janet
had been on the list—if you'll make it brief.
DR. ROWLEY: I just want to make a question and a comment.
The comment is actually related to Kay Hubner's paper in Science,
and I think that it is important to recognize that this is work
that was done in the mouse. And we've had a great deal of difficulty
in terms of translating success in the mouse and other animals into
humans, so this is going to take some time.
The question is you mentioned that there is a program at NIH now
for characterizing these cells, and I wondered what institute it
was housed in.
DR. ZERHOUNI: The Institute—NINDS, neurological diseases,
under—actually, it's associated with Ron McKay's laboratory,
because we feel he has the best expertise in that area.
DR. ROWLEY: Thank you.
CHAIRMAN KASS: Dr. Zerhouni, thank you very, very much
for a wonderful presentation and very frank discussion. We really
appreciate your presence. Thank you.
CHAIRMAN KASS: As we learned from Dr. Zerhouni, we are
at a relatively early stage in our journey from basic stem cell
research to therapeutic benefits. And as one looks ahead down this
road, we see in advance the important role that the FDA is going
to play in verifying the efficacy and the safety of any eventual
stem-based—stem cell based therapies.
In recent months, the FDA issued its guidance regarding xenotransplantation,
the introduction into human beings of materials of animal origin
or derived from materials having contact with animal tissues.
Almost immediately, there were press reports, many of them grossly
off the mark, about what this guidance might mean for the possibility
of future clinical trials using material derived from the Presidential
To help us separate fact from fiction, and, more importantly,
to help us understand how the oversight and regulatory activities
of the FDA might eventually figure in the area of stem cell based
therapies, we're very fortunate to have with us Dr. Mark McClellan,
who is the Commissioner of the Food and Drug Administration.
Dr. McClellan, many thanks to you for taking the time to help
us understand this important aspect of the road that we are on that
will take us from the bench to the bedside. Welcome.
DR. McCLELLAN: Thank you, Dr. Kass. And all of you on
this distinguished Council, thank you for inviting me here today
to discuss the role of the FDA in helping to make new safe and effective
xenotransplantation treatments available, including potentially
valuable stem cell treatments.
FDA's job is to protect and advance the public health, and
one of our primary responsibilities involves helping safe and effective
products reach patients and consumers quickly.
Our Center for Biologics Evaluation and Research, which I'm
sure many of you are familiar with—goes by the acronym CBER—has the lead in FDA for regulating xenotransplantation, including
emerging cellular therapies. FDA regulates cellular therapies under
broad authority from the Public Health Service Act and the Federal
Food, Drug, and Cosmetic Act.
Under this authority, FDA has taken many steps to foster the development
of safe and effective stem cell therapies, while assuring appropriate
protections for human subjects involved in the research.
As you know, xenotransplantation is a set of procedures that includes
the transplantation or implantation into a person of live cells
from non-human animal sources, including human cells that have had
ex vivo contact with live non-human animal cells or tissues.
And as you just heard from Dr. Zerhouni, recent evidence suggests
that transplantation of cells and tissues may one day provide many
important therapeutic benefits for diseases such as neurodegenerative
disorders, diabetes, many other conditions involving organ dysfunctions
and cellular dysfunctions. Because the potential health benefits
may be considerable, it's appropriate that there are many clinical
research and development studies going on now to better characterize
the risk and benefits of these potentially important treatments.
Xenotransplantation products, under the Food, Drug, and Cosmetic
Act are treated in accordance with our statutory provisions governing
premarket development. And so they are subject to FDA review and
approval. Investigators of such products should obtain FDA review
of proposed xenotransplantation clinical trials before proceeding.
In addition to providing necessary assurances of protection for
human research subjects, FDA takes many steps in its regulatory
oversight to help researchers and product developers avoid mistakes
and translate good research ideas into safe and effective treatments
as efficiently as possible.
And in an area as complex and with as many practical uncertainties
as stem cell research, this regulatory guidance can be extremely
helpful for obtaining the most public health benefit from basic
science insights. For example, applied research conducted at CBER
has been instrumental in improving our understanding of safety issues
associated with xenotransplantation.
CBER is engaged in a range of scientific investigation of safety
issues, including on known and emerging infectious agents, immunological
issues, transfer and differentiation issues, and others that will
need to be overcome for the safe and effective use of xenotransplantation
The results of these studies have helped CBER in its safety assessment,
including assessment of risk and the development of better diagnostic
methods and standards to assess risks. CBER researchers are continuing
to develop assays appropriate for safety monitoring and are working
with sponsors and collaborating with other government scientists
in the development of these assays.
In addition, to improve our regulatory policies related to xenotransplantation,
CBER working groups are analyzing data and events and developing
and proposing strategies for appropriate studies, for risk assessment,
for prevention, for communication, and agency response or regulatory
action, such as requests for more data from sponsors or for particular
product assays and the course of clinical investigation, or, when
necessary, the placement of clinical holds on clinical investigations.
We discuss all of these proposals and strategies with our advisory
committees when needed or at public meetings as appropriate to make
sure we've got full opportunities for public comment on the
most effective way to regulate these important but complex new areas
of medical technology.
CBER has also developed a mechanism for the systematic and regular
evaluation of the scientific and clinical literature relevant to
xenotransplantation as well as careful scientific evaluation of
the submissions that we get in our xenotransplantation product files.
If you put all of that together, that not only the research studies
but what we see in terms of the studies, the details of the studies
that are ongoing now, not just the published studies but the ongoing
work, this amounts to the most extensive data available on the practical
application of stem cell technologies.
We have a xenotransplantation product review or working group,
which consists of the review staff responsible for the review of
xenotransplantation submissions, the clinical product and pharmacology
and toxicology reviewers, as well as our veterinary staff.
They all meet regularly to discuss application of the principles
that are in our relevant regulations and guidances to review and
discuss current scientific and medical data and literature relevant
to xenotransplantation, to review and discuss the current status
of xenotransplantation applications that are before the agency,
to discuss, the unique issues that these products may present and
to highlight areas of concern where further expert advice and solicitation
of public opinion, and outside expertise may be needed.
This working group structure gives us an approach—gives us a
consistent and up-to-date review approach for xenotransplantation
applications, and it helps us recognize patterns or trends or common
problems that may be associated with xenotransplantation products,
and, again, a highly—a new and high emerging research area. And
it should be communicated to xenotransplantation product developers
and other interested parties in a timely way.
Our data evaluation and management process is linked to this regulatory
process, and it's applied during regulatory decisionmaking and
product and policy design at the agency. We have augmented our
own experience with cell therapies by sponsoring and participating
in a large number of open public meeting and workshops, both domestic
and international, that focus in whole or in part on cellular therapies.
These activities are essential for both sharing information and
receiving public input on relevant issues. To make sure that our
insights and our assistance reach those involved in planning stem
cell trials effectively, FDA has also been proactive in educational
partnerships, workshops, and guidance development.
And this work collectively includes discussing preclinical pharmacology
and toxicology studies, and good clinical practices, and product
characterization studies—all difficult issues that need to be
addressed effectively in these emerging sciences.
All of this work is intended to support our goal of helping clinical
research and development of stem cell therapies proceed as efficiently
as possible. And our extensive experience with cell therapy clinical
trials, and the processes for obtaining effective outside expertise,
has helped a wide variety of clinical studies involving xenotransplantation
of stem cells proceed with public confidence about safety and without
avoidable costs or complications for the subjects involved.
With respect to the details of our oversight of clinical xenotransplantation
studies, as in other areas, FDA allows INDs—investigational new
drug applications—for these trials to proceed as long as they
don't pose unreasonable risks to the human subjects.
Reflecting both the flexibility of our risk-based regulatory framework
and the energy of this important new research area, well over 1,000
separate INDs for all forms of cell therapies have been implemented
over the past decade. Hundreds of subjects, hundreds of human subjects,
have received experimental products comprised of animal cells or
human cells that have had contact with animal cells since the early
1990s under FDA oversight.
Hundreds of additional human subjects have been treated with a
human skin cell product called Epicell that was grown on mouse feeder
cell layers. FDA discussed this Epicell product at a public advisory
meeting in January 2000, and we agreed with the advisory committee's
conclusion that the safety data concerning the use of the well characterized
mouse feeder cells in this case was sufficient to allow clinical
trials to proceed generally.
And that is, the lesson here is that when murine cells can be
characterized as in this Epicell product, then as a general regulatory
matter there is no overarching need for monitoring and surveillance
with respect to this particular safety concern.
FDA is continuing to support the development of safe and effective
cellular therapies, and we work directly with sponsors to help ensure
that all promising therapies can be clinically evaluated in an ethically
sound, scientifically rigorous, and efficient manner.
The agency evaluates each individual product on its own merits.
FDA's regulations, our guidances, and our policies, provide
useful information on safety and product development issues to help
sponsors interested in development of cellular products.
CBER's regulatory guidance and regulations are continuing
to evolve, and this is appropriate to ensure that the continued
advancement of a very dynamic and growing field is matched by continuing
advancement in our regulatory guidances to support it.
The hundreds of patients that have been treated in clinical trials
in which non-human animal cells have been implanted or infused directly,
or in which human cells that have had ex vivo contact with animal
cells have been administered, have been treated using protocols
that meet FDA safety standards.
For Phase I or early clinical trials, the most important aspect
of safety is the demonstration of the products not contaminated
with adventitious infectious agents, including viruses, bacteria,
fungi, and so forth. This safety criterion needs to be met, and
it has been met by most FDA-regulated products, including biological
products, before they can be used in the clinic.
For all cellular products, including human cells, non-human cells,
animal cells, or human cells that have been exposed to such cells,
which often can't be tested for sterility prior to administration
because they can't always be stored, FDA has pursued a flexible
approach that does not compromise patient safety. In particular,
FDA has allowed sponsors to administer the cells based on the results
of interim, in-process, bacterial and fungal sterility testing in
which the absence of infectious agents is demonstrated.
The sponsors then perform sterility tests on the final product,
though results are frequently not available until after the products
have been administered. A positive sterility test on the final
product is quite rare if the interim tests have been negative.
But if the result is positive on the final test, the results of
these sterility tests are used to inform subsequent patient treatment.
To address potential viral contaminants, FDA requests that prescreening
of components that could introduce viral infections occur. For
example, before using porcine tests in humans, sponsors have been
asked to demonstrate that the pig tissue that they use doesn't
produce infectious porcine endogenous retrovirus.
In the case of Epicell that I mentioned a few minutes ago, the
manufacturer was able to use standard techniques to show that the
transmission of murine viruses to the co-cultured human cells shouldn't
be a problem. As a safety net, the recipients of animal cells or
human cells exposed to non-human animal cells are monitored for
unexpected infectious diseases.
When human cells are transferred from one human to other humans,
whether or not animal cells enter the equation, FDA asks that the
human cells, and, if possible, the donors of those cells be thoroughly
tested for known viruses. So we've overseen treatment of thousands
of patients with human cells or with animal cells, or with human
cells that have been exposed to animal cells, in which the transmission
of infection has been tightly controlled.
Human embryonic stem cells are just one type of living human cells
among the many somatic cellular therapies that FDA regulates. Most
of the issues that will be involved in the production of human embryonic
stem cells for clinical use are shared with these other cell therapies.
Of course, there has been a high level of interest, as I've
heard in my time here today, in the research involving particular
human embryonic stem cell lines that are listed in the NIH registry.
Just about all of these cell lines—all of these cell lines have
been in ex vivo contact with live, non-human animal cells or tissues.
And the exposure of such human cells to animal cells, though, represents
only one of a large number of issues to be considered in evaluating
the development and use of human embryonic stem cells.
Among the many further technical challenges to be addressed are
the manufacture and testing of the human embryonic stem cell products,
preclinical testing of human embryonic stem cells in animals to
show potential clinical benefit as well as potential toxicities,
appropriate clinical trial design issues, and appropriate followup
of human subjects treated with human embryonic stem cells.
And our regulations and our guidance has to address that whole
panoply of issues. Recognizing the potential importance of new
cellular therapies that may be derived from these cells, FDA extended
an invitation to each of the derivers of the NIH registry cell lines
to meet and discuss critical issues pertaining to the derivation
of these lines to help us assure safety in the clinical studies.
We discussed FDA expectations of safety, and we gained insights
from the derivers on how they can best meet those expectations.
We also gathered information from the derivers of the HES cell lines
regarding specific methods of preparation and propagation of the
cells to add to our understanding of the manufacturing of these
novel cell lines.
FDA is in the process of publishing a series of guidance documents
through a notice and comment process to assist sponsors and investigators
interested in conducting clinical trials in the field of xenotransplantation.
These documents are providing reasonably detailed and timely pragmatic
guidance to sponsors regarding xenotransplantation product safety
and clinical trial development, including specific recommendations
for how FDA believes that studies can be conducted efficiently and
with adequate safety assurances.
The guidances that we published so far include a guidance for
industry for human somatic cell therapy and gene therapy published
in 1998, a guidance for reviewers on instructions and templates
for chemistry, manufacturing, and control of human somatic stem
cell investigational therapies, published in the past year.
And, in addition, earlier this year we published a new xenotransplantation
guidance for industry entitled "Source Animal Product Preclinical
and Clinical Issues Concerning the Use of Xenotransplantation Products
in Humans." All of these guidances are available online at
FDA. We also recently just this past month published a draft guidance
for our reviewers to go along with this xenotransplantation guidance
These guidances provide information to sponsors interested in
developing products that include animal cells or exposure to animal
cells. All of the human stem cell lines, as I mentioned earlier,
are subject to this guidance.
And the goal here is to provide a comprehensive approach for the
regulation of xenotransplantation that efficiently addresses the
potential public health and safety issues associated with xenotransplantation,
and at the same time to provide guidance to sponsors, manufacturers,
and investigators regarding xenotransplantation product safety and
how to conduct clinical trial design and monitoring.
One of the many issues that's addressed in the guidance is
the development of human embryonic stem cells that have had ex vivo
contact with mouse cells in clinical trials. In our guidance, we
note that this guidance is relevant to all of the stem cell lines,
all of the human embryonic stem cell lines that have used mouse
feeder cell layers, and so fit into—this fits into the definition
of xenotransplantation used in our guidance and in our broader public
health service guidances.
FDA has had a number of meetings, as I said, with the derivers
of these stem cell lines, and what the guidance focuses on is that
certain precautions are required to maintain the safe use of any
xenotransplantation product. In the case of the existing embryonic
stem cell lines, the precautions include appropriate testing of
cells in mice if the mouse feeder cell layers continue to be used
for adventitious agents.
This testing is manageable and is readily available and achievable
using current technologies. So our xenotransplantation guidance
provides some specific, useful steps that sponsors can and should
take to address safety concerns. A sponsor who wishes to investigate
a stem cell product derived from existing human embryonic stem cell
lines in a clinical trial may need to demonstrate to FDA that the
stem cell line is free from infectious agents, including the murine
Given the current technologies available as described in the guidance,
this should be feasible without undue burden. The same recommendations
apply to other xenotransplantation products that contain human cells
with a history of co-culture with non-human animal cells.
So overall we are very committed at FDA to evaluating each specific
product that comes into us on a case-by-case basis. We try to augment
this with guidance to make it as straightforward as possible. And
this is important, because in a world where most clinical trials
and most products that enter clinical development fail to show benefit,
each new individual proposed clinical study might still provide
a crucial step forward.
There are multitudes of patients who have yet to benefit from
the biotechnology revolution, and as a public health agency we are
committed to making sure that every experimental product to be tested
in humans is as safe as possible, with the ultimate goal of getting
safe and effective products as quickly as possible.
I want to thank you all for listening to me today, giving an overview
of FDA's regulatory and guidance activities in this important
area of emerging science, and I'd be pleased to answer any questions
that you all might have.
CHAIRMAN KASS: Thank you very much.
Dan Foster, are you on the way to—no, I'm sorry.
Let me start and, first of all, thank you, really, for a very
comprehensive and helpful account. And I emphasize that because
I'm going to ask a sort of flat-footed and dumb couple of questions.
If I wanted to say, Dr. McClellan, the take-home lesson, if I wanted
to sort of put it in a nutshell, would be xenotransplantation involving
stem cells in contact with murine cells, we have experience with
that, and we are careful.
We know what to do, and it's—while it's something to
be paid attention to, it's not an insurmountable obstacle or
one that deserves extra special attention.
DR. McCLELLAN: We've certainly had experience, successful
experience, in thousands of patients in documenting the safety of
cells that have been exposed to animal feeder cells, mouse feeder
cells, and the like.
The other take-home lesson that I think is important is that while
this is a very important emerging area of technology, this is a
quite complex cellular therapy that presents many new safety issues
as well as effectiveness issues that have to be evaluated.
And we've got multiple parallel efforts to try to assess and
help manage and address the different risks that are involved in
stem cell therapy treatments, so that we can hopefully as a result
get more rapid development of stem cell therapies that really work,
and that can be used widely.
But as is the case with all of the biologicals, especially complex
new technologies like this, ultimately it's nature that determines
whether the products are really going to benefit the needy if we
can—and we need to unlock, through a whole—evaluation of a whole
host of complex safety and effectiveness issues, whether they can—whether those benefits can be demonstrably given to patients.
And we're still very early on in that process.
And the mouse feeder cell issues are one area where we have a
regulatory process in place to address it, but there are many other
safety and effectiveness concerns that remain to be addressed, and
that we're working hard to help product developers address effectively.
CHAIRMAN KASS: Thank you. And let me just very quickly—am I right in thinking that cells grown on human feeder cell layers
would be subjected to—have to be subjected to the same kinds of—
DR. McCLELLAN: Yes, they do. They are incorporated in
our same xenotransplantation guidance, and they are subject to the
same kind of evaluation of potential exposure to adventitious infectious
agents. They need to go through the same kind of testing procedures
and the like.
CHAIRMAN KASS: Thank you.
Questions or comments? Dr. Gómez-Lobo.
DR. GÓMEZ-LOBO: This is a question out of total
ignorance. I have great confidence in FDA. In fact, I think it's
a great institution and—
DR. McCLELLAN: I do, too.
DR. GÓMEZ-LOBO: Well, I'm glad you do. But
here's my question. I'm also convinced that human knowledge
is very limited, and you speak with great confidence about identifying
bacteria and viruses, etcetera. Could it be the case that at a
nano level there might be problems, say, with some of these products
that we cannot yet detect?
In other words, what I'm thinking about is, what's the
next step when we go into, say, gene therapy and that kind of thing?
Is FDA going to be able to detect any problems with that? Should
we be cautious, or should we just trust FDA and just rush forward?
In other words, it's a very general, sort of prudential question
that I'm raising.
DR. McCLELLAN: Yes, that is a good general question.
FDA is not usually accused of making people rush forward, but glad
to hear that's -
—the perception in at least some corridors.
These are very challenging new technologies, and there's a
great scientific concept out there and a great potential. And that's
something that generates a lot of media interest, and the like,
and holds out a lot of hope. I think, you know, with some reason
that we are going to be able to bring new benefits, important new
benefits, to many millions of patients that don't have effective
treatments available today.
But as with so many other areas of emerging technologies, moving
from ideas that seem to work well even at the proof of concept stage,
to treatments that demonstrably can be shown reliably to be safe
and effective in patients is very difficult. And we are early in
that process now for these complex biological treatments.
I have talked a lot about some of the issues related to transmission
of infectious diseases related to feeder cells, because that's
gotten a lot of the attention. But you're absolutely right
that there are a host of other important safety issues and effectiveness
issues that also need to be much better understood before these
treatments can be used reliably and confidently by the public to
improve the health of the public.
And that's what this investigational process is really all
about. That's why we have a comprehensive guidance for the
INDs involving stem cell therapies and many other types of therapies
as well, so that we can conduct those studies in a way that's—that relies on the best-available knowledge as to whether we're
presenting patients with unreasonable risk.
We can do it in a controlled setting, so that we can learn from
the latest studies and add to the state of knowledge that exists
from what goes before. And then we can modify our research protocols
and guidances and research activities accordingly.
But this is a difficult process. You know, a lot of people talk
about the fact that it takes over a decade for going from—for
something as simple as a small molecule drug, just a simple chemical,
from the time that it's first identified and people first suspect
that it's going to have a benefit in patients. It can take
well over a decade to go from that proof of concept to a product
being commercially available to the public.
It's a long, complicated process. And these complex biological
treatments and cellular therapies are far more complex and have
far more potential interactions and consequences that are not well
understood than a simple small molecule drug.
So this is an ongoing process, a careful one, and I don't
think we're rushing headlong into this. But at the same time,
I want to make sure that our regulatory staff is apprised of all
of the latest science, is working closely with researchers and others
involved in product development, to make sure that we're making
the most of the available knowledge, both for the sake of the patients
that are involved in these clinical studies and for the sake of
creating the knowledge base we need to get safe and effective treatments
to patients as quickly as possible.
CHAIRMAN KASS: Rebecca Dresser.
PROF. DRESSER: Thank you very much for your overview.
I guess a comment and a question. I do think it's interesting
there has been so much in the press about this particular issue
as a potential safety issue as I think you've observed, compared
to other safety issues that this technology might present such as
tumor risk and, you know, the ability to channel the cells into
DR. McCLELLAN: Pluripotency.
PROF. DRESSER: —appropriate tissue, and all of those
things. So it seems that in some ways you and your colleagues are
being forced to address this issue, at least publicly, with more
attention than these other issues. And I'm glad to hear that
you're thinking about these other issues.
But I guess just to play devil's advocate, isn't there
a risk with xenotransplants that there is an undetected animal virus,
an undetectable virus we don't even know about, that could be
present and transmitted if the cells are grown on animal feeder
layer, that wouldn't be a risk if you had, you know, the absence
of a feeder layer or a human feeder layer? And so wouldn't
it be nice if you could avoid that risk?
DR. McCLELLAN: It's certainly possible that there
are completely unknown, you know, animal viruses that could potentially
be transmitted to humans.
We just haven't ever seen them observed, and that's why
an important part of our guidances here is followup on the patients
who are involved in these studies, so that as we learn more over
time we'll be able to identify any problems that might subsequently
emerge in the patients that have been brave enough to participate
in these early studies, and to make sure that we can let the patients
know if there is new technology that becomes available that ought
to influence their subsequent treatment.
But there are—you know, those kinds of hypotheticals exist in
each and every one of these many complicated aspects of stem cell
therapy. There are the potential for human cells to harbor completely
unknown illnesses that might also be transmitted.
It might even be easier to transmit to humans than in animals,
and even for cells that are harvested and used in treatment without
the use of any kind of feeder layers. There are still a host of
other issues, as you identified, that could present important safety
We do have to make our regulatory decisions and allow studies
to go forward under uncertainty. You know, these issues are never
going to be fully resolved, and I think that the best job we can
do is try to make sure we're apprised of all of the latest science,
all of the, you know, concerns that might impact on potential risks
and benefits for patients involved in the studies, and then do as
careful of a job as possible in making sure that the best and latest
knowledge is applied as we move forward in this important area of
CHAIRMAN KASS: Thank you. Permit me one very quick question.
You've indicated how your experience with xenotransplantation
in other areas gives you some confidence that you might not have
received with this aspect of it.
Is there any precedent and experience for dealing with the specific
kind of risk of teratoma or tumors that are associated with—well,
possibly it could be associated with, say, residual, undifferentiated
stem cells that might accompany a population that have been differentiated?
DR. McCLELLAN: That's certainly something that we're
monitoring for here. And some of the—and in many of the earlier
human stem cell—I mean, human cellular studies that—or cellular
studies more generally, they were differentiated cells involved.
And so it raised different kinds of issues than a pluripotent
or an undifferentiated stem cell might. It's definitely something
that's on people's minds, and we're watching carefully.
We don't know of any specific evidence of important problems
there yet that we haven't accounted for, but we are monitoring
I think that's one reason we pay so much attention in these
protocols to understanding and tracking the exact conditions under
which the cells were derived, because that can potentially have
an impact on how they might differentiate and act in—after implantation
subsequently. It's just an area where we have to watch closely,
because it's not very well understood.
CHAIRMAN KASS: Well, Dr. McClellan, thank you very much
for being with us, for your presentation, and for your very good
DR. McCLELLAN: Thank you.
CHAIRMAN KASS: We're adjourned for 15 minutes.
(Whereupon, the proceedings in the foregoing matter went
off the record at 3:35 p.m. and went back on the record at 3:55