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Thursday, September 4, 2003

Session 3: Stem Cells: Moving Research from the Bench Toward the Bedside: The Role of NIH and FDA

Part I: Elias A. Zerhouni, M.D.
Director, 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 and direction.

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 much.

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 function.

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 policy. 

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 the country.

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 quality.

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 that.

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 to support.

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 term. 

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 in '03.

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 cells? 

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 state. 

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 them.

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 passages.

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, illuminating presentation. 

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 investigators.

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 agreement.

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 then frozen.


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 1—August 2001?

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 there?

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 effort?

DR. ZERHOUNI:  I thought you were the program to do that here.


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 embryos.

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 research.

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 on.

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 concept experiments.

CHAIRMAN KASS:  Thank you.

Bill May.

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 quickly?

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 cell lines.

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 products.

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 for industry.

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 infectious agents.

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 the—

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 concerns.

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 emerging science.

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 it carefully. 

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 work.

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 p.m.)


  - The President's Council on Bioethics -  
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