THALIDOMIDE: POTENTIAL BENEFITS AND RISK

OPEN PUBLIC SCIENTIFIC WORKSHOP

Sponsored By

NATIONAL INSTITUTES OF HEALTH

FOOD AND DRUG ADMINISTRATION

CENTERS FOR DISEASE CONTROL AND PREVENTION

Tuesday, September 9, 1997

Auditorium
Natcher Conference Center
National Institutes of Health
9000 Rockville Pike
Bethesda, Maryland

C O N T E N T S
(with hyperlinks to speakers presentations)

OPENING REMARKS AND OVERVIEW

Stephen C. Groft, Pharm.D., Moderator
Director, Office of Rare Diseases, NIH

Opening Remarks and Introductions
Stephen C. Groft Pharm.D. Introduction, 
Stephen C. Groft Pharm.D. Opening Remarks

Welcome
William R. Harlen, M.D.
Associate Director for Disease Prevention, NIH

Historical Perspective
Frances O. Kelsey, M.D.
Deputy for Scientific Affairs
Office of Compliance, FDA

Current Issues and Overview
Janet Woodcock, M.D.
Director, Center for Drug Evaluation and Research, FDA

Experience with Thalidomide in Mexico
Guillermo Bierzwinsky, M.D.
Director, Drug Control Directorate of Mexico

Clinical Pharmacology of Thalidomide
Carol Braun Trapnell, M.D.
Office of Therapeutics Research and Review
Center of Biologics Evaluation and Research, FDA

Ethical Issues in the Use of Thalidomide in Fertile Women
Norman Fost, M.D., M.P.H.
University of Wisconsin-Madison

Report on Meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee
Jonathan Wilkin, M.D.
Director, Division of Dermatological and Dental Drug Products
Center for Drug Evaluation and Research, FDA

Questions

Theresa Toigo, R.Ph., M.B.A., Moderator
Associate Commissioner for Special Health Issues, FDA

Perspectives from the Public -- A Consultation With...
Leo Yoder, M.D.
American Leprosy Mission

Thalidomide: The Survivor's Perspective
Randolph Warren
Thalidomide Victims' Association of Canada

Pharmacist's Perspective
William A. Zellmer, M.P.H.
American Society of Health-System Pharmacists

Physician's Perspective
James Allen, M.D.
American Medical Association

Thoughts About Thalidomide: Are We Now and Can
We Ever be Ready for the Mainstreaming of Thalidomide?
Cynthia Pearson
National Women's Health Network

A Personal Perspective
Nancy Pall 

Questions

Debra Birnkrant, M.D., Moderator
Division of Antiviral Drug Products
Center for Drug Evaluation and Research, FDA

Protection of Human Subjects Involved in Thalidomide
Research: The Role of Institutional Review Boards
Melody Lin
Office for Protection from Research Risks, NIH

Regulatory Consideration in the Clinical Development
of Thalidomide: Safety Monitoring and Investigational
Safety Findings
Debra Birnkrant, M.D. 

Thalidomide Neuropathy
Herbert H. Schaumburg, M.D.,
Albert Einstein College of Medicine

Peripheral Neuropathy and Exposure to Thalidomide
Colin Crawford, M.R.C.P., D.P.M.& H.
Imperial College of Science, Technology and Medicine 164

Neurological Testing of Primates
Tucker A. Patterson, Ph.D.
National Center for Toxicological Research, FDA

Monitoring for Peripheral Neuropathy
Mary K. Floeter, M.D., Ph.D.
National Institute of Neurological Disorders and Stroke, NIH

Questions

PREGNANCY/EMBRYOPATHY

James Mills, M.D., Moderator
National Institute of Child Health and Human Development, NIH

Characterization of Embryopathy Risks
Barbara A. Hill, Ph.D.
Division of Dermatological and Dental Drug Products
Center for Drug Evaluation and Research, FDA

Pregnancy Prevention in Patients Taking Thalidomide
Christine K. Mauck, M.D., M.P.H.
Division of Reproductive and Urologic Drug Products
Center for Drug Evaluation and Research, FDA

How Environmental Effects on Child Health Are Recognized
Robert W. Miller, M.D., Dr.P.H.
National Cancer Institute, NIH

Experience With Accutane
Allen A. Mitchell, M.D.
Boston University

Preventing Birth Defects Due to Thalidomide Exposure
Cynthia Moore, M.D., Ph.D.
Centers for Disease Control and Prevention

Questions

P R O C E E D I N G S (8:35 a.m.)

DR. GROFT: Good morning, everyone. If you'll take your seats, we can get started. We have quite a busy agenda for the next two days, with lots of speakers and some real tight time constraints that we'll be working under, so I would like just to get started.

To give us a welcome from NIH is Dr. William Harlan, the associate director for disease prevention within the NIH.

I'm sorry. My name is Steve Groft, and I've been the coordinator with Terry Toigo for the meeting. There's a little anxiety up here with this, but we're getting it together.

DR. HARLAN: Good morning, and welcome to the conference on "Thalidomide: Potential Benefits and Risks." I want to express my appreciation to those who have collaborated with us in this effort. The Centers for Disease Control and Prevention and the Food and Drug Administration have joined with several of the research institutes here at the National Institutes of Health to put on this program, and we appreciate their active participation in the development of the program, and in the program itself.

The meeting is convened really to look at the novel and potential important actions of thalidomide. It's interesting that we have to look at the unique attributes of this particular drug in order to see it utilized in the future. In essence, the discovery and development process of drugs has been revised somewhat. Ordinarily, a drug is licensed for a potential benefit, and as time unfolds, the full scale of adverse effects of the drug are known, as well as potential new uses. These potential new uses can be elaborated under the protection, if you will, of the licensure of the drug itself.

On the other hand, what's happened with thalidomide, as you know, is the fact that it was not licensed has put a particular onus on it. The very severe adverse effects are very clearly a detriment to some of the investigation that has occurred. It's particularly important, then, that one look at the potential benefits, and that these benefits meet a higher standard, I think, a standard that will remove the onus of the very severe adverse effects that occur.

There are a number of applications under study at the present time. There are about 20 applications. Nine of the institutes and centers at the National Institutes of Health are actively investigating uses for the drug. Twenty of the General Clinical Research Centers also have protocols investigating the potential uses of the drug.

It's a particularly apropos time for the meeting to occur. As you probably know from the reports last week, one of the advisory committees to the Food and Drug Administration has recommended that thalidomide be used for leprosy, and I think that provides an opening for all of us to look at the potential uses that are developed here.

Before we start the meeting, I would like to express a note of appreciation to Dr. Steve Groft, who was the introducer this morning, and will be the moderator. Steve has done a wonderful job of directing the Office of Rare Diseases. As a pharmacologist, he has a long interest in the pharmacologic actions and in looking for new and novel approaches to treatment of disease with pharmacologic agents. He has shepherded this meeting along, has worked with the other federal agencies, with industry, and with others to develop the program, and he is to be congratulated for this effort.

Steve, I'll turn the program over to you.

DR. GROFT: Thank you very much, Bill.

Almost a year ago, we established an interagency working group to look at what was going on with thalidomide. At that time, several of the meetings that have been held were not conducted, were maybe on the planning stages, but we had representatives from the Centers for Disease Control and Prevention, the Food and Drug Administration, and the NIH.

Initially, our plans were to come up with a common research clinical protocol, to guide the research, or perhaps even some research guidelines to have as a direction for the research. It became pretty obvious, after looking at the pharmacological actions of thalidomide and all the uses, that one protocol was not going to suffice for all of the research that was underway or was planned.

So at that point, we decided that perhaps the best thing to do would be to conduct a workshop where we could present the potential benefits and risks associated with thalidomide. So here we are today, almost a year later. I think our first meeting was last October. It has taken some time for us to get the direction that we wanted to go, and arrange the speakers and logistics.

As Dr. Harlan mentioned, it's sort of fortuitous that last week the FDA's advisory committee met and came up with the recommendations. Between Dr. Woodcock and Dr. Jonathan Wilkin, we'll be hearing the results of that, as most of you have already read in the paper.

Since last year, the Centers for Disease Control and Prevention conducted a workshop on preventing birth defects due to thalidomide. Cynthia Moore from CDC will be here to present the results of that meeting, and as I mentioned, Dr. Wilkin. There were also about three other workshops or parts of different scientific meetings that discussed thalidomide during the past year, so we'll be hearing from various people who participated in those workshops and those sessions as the meeting goes along.

I think it's important to realize that this is not by any stretch of the imagination a consensus development conference. It's not a technology assessment conference. We're here really to exchange ideas of where the research is going. What are the opportunities for research? What are the emerging opportunities that we haven't even thought about, but because of the action of thalidomide may prove to be beneficial to a select group of patients?

We also want to discuss risk communication and management of the risks associated with thalidomide. I think everyone here realizes what went on approximately 40 years ago, and none of us want to repeat or even anything close to what occurred at that point. However, there is concern that this is a product that can be very beneficial to a select group of patients, and we really should look at it in great detail.

We also want to discuss the methods of monitoring for safety and adverse effects in both the research environment and the community itself. With perhaps the arrival of the product on the market, plans have to be in place for adequate monitoring of this and prevention of pregnancy.

I think, looking back over 40 years ago, it has been two generations since the product was kept off the market by Dr. Kelsey and her colleagues at FDA here in the United States. In those two generations, it is probably 50 percent of the U.S. population who really don't have a clear understanding of what occurred, and what the effects of thalidomide were on the unborn.

We have quite a task in front of us. All of us -- the health care providers, the researchers, physicians, pharmacists, health educators, the pharmaceutical industry -- I think anyone who has a tendency to get close to thalidomide, adequate warnings have to be made and will be made. We'll be hearing from several of the manufacturers here at this meeting of their plans, how they're going to provide the information to individuals who will be using the drug.

We'll be looking for comments as we go along. Really, the hallmark of the workshop is, there will be time for questions as you go on at the sessions, especially the breakout sessions. We look for your input. We look for your advice as we move along.

Not that we have all of the questions answered with thalidomide. It doesn't boil down just to a safety consideration of trying to avoid pregnancy, or the neurotoxicity associated with thalidomide. We also will be discussing the need for analogs, with less potential for teratogenicity and neurotoxicity. We'll be discussing that in great detail at one of the breakout sessions tomorrow.

The issue of mutagenicity has been raised in several publications, and we will want to hear a little bit about that, if it really is a concern, or if it's something that we should not be really concerned about, or do we need results from additional studies.

The neurotoxicity, is it something that's permanent, or is it transient? Is it dose-dependent? We'll want to talk about that a little bit.

Then another issue is the window of susceptibility as far as teratogenicity. If someone should have the misfortune to take the product while they're pregnant, we know that between days 35 and 50 after a woman's last period of this extreme sensitivity. What happens after that if exposure occurs? We'll want to discuss that as well.

So there are a number of questions that remain unanswered. This gives us an excellent opportunity, I think, if everybody can go a little informal as we go along. The speakers, even though they're up here on the stage and in the various breakout sessions, most of them will be around for the two days. If you have any questions you don't have a chance to ask them here, please just catch them in the hallways and talk with them. I think, from my conversations, they're willing to answer the questions and discuss them with you.

With thalidomide, as with all drugs, we all have to make a benefit/risk decision. I think that the point of the workshop here is that we want to provide a clear understanding of what those potential benefits and associated risks are for thalidomide, and then come up with different methods of communication that will provide that information to the public, all the health care providers and their patients, so that they can make a good decision, and we don't have any unfortunate accidents that have occurred in the past, and in fact have been reported to be occurring now in several other countries in which thalidomide is marketed. We do want to stay away from that as much possible.

I'd just like to go over a couple of things logistically for the meeting. We don't have any floor microphones, but what we will have will be people coming up and down the aisles after each speaker. Some forms have been provided in the package. If you have any questions, please fill them out, and we'll bring them up front, and then try to coordinate them as we go along for each of the sessions. So if you'll do that, that would help out quite a bit.

We prepared a selected bibliography of thalidomide. I culled through, I guess, about 4,500 references from around 1962, and selected around 1,600. So in about a half-hour or so, or after the first break, there should be a copy of the bibliography out over here. My apologies if I've slighted anyone whom I didn't pick as a reference that you may have published, but we tried to get an adequate representation of the literature. That will be available. Karen Patrias from the Library of Medicine helped with that, and I'd like to thank her.

If all of you have got the abstract book, it contains the agenda. I don't know if you've had a chance to look at it, the agenda and the various abstracts from the speakers who were able to get a copy of the abstract to us at the time of printing. There may be others available as the meeting goes on, if they were not included.

In the abstract book, as well, there's an informed consent document that's being used for research purposes. So most of the investigators who are doing research with thalidomide probably are using this, or some form. The template has been accepted by the FDA, and used extensively. Then there is the patient brochure that's being provided to patients as well.

Most of you, I know, did sign up for breakout sessions. Stay in those sessions. Tomorrow, we'll list where they are, which location. Right behind us on top there are three lecture rooms that will be used, the main auditorium, and then Conference Room A will also be used. If you have signed up, stay with it. If you haven't signed up, there will be sheets there in the back at the registration desk for you to sign up, so please do so. It will be helpful for us in planning everything.

The cafeteria is on the main level, upstairs, if you need that. It's open until 2:00, so watch your afternoon coffee levels or caffeine levels. If you need it, then get one before 2:00. The elevators are out to the left here. There are restrooms to the left on this floor, and upstairs, if necessary. As the meeting progresses, if any of you have to leave, there is a telephone that you can summon a taxicab. The registration staff of Prospect Associates with Carol Sadler will be willing to help you with this.

I believe those of you who are eligible for CME credit, there is a form provided. Fill it out and complete it, and turn it in to the registration desk after the meeting, and we'll see that credit is provided to you.

So at this point, I'd just like to thank several people who have been working with us all along. First, Terry Toigo from FDA, who has been the co-chair of this event, trying to put things together, and Dave Banks, who works with Terry. So thank you to both of them, and to my staff -- Anita Pikus, Mary Demory, and Beth Clay -- for sort of giving me the time to devote to this effort.

When we started this, we envisioned a very small workshop, but as things have grown and I've identified more and more uses, the breakout sessions got larger and larger, and it required quite a bit of effort. I thank them for all the help they gave to us.

Thanks to Bill Hall of the Office of Disease Prevention for assisting and putting the meeting together as well, and then finally, to all of those of you who came today, not just the members of the public, but the scientists, the lawyers, the health care providers, the clinicians, and others. Thank you for giving of your time and sharing your experience with thalidomide. We've got quite a way to go, so I think with everyone working together --

We can't get enough publicity for thalidomide, but I think it has to be positive, with the benefits and risks, and the message has to go out that this is a potentially beneficial product, but the risks are so serious that we don't want to have this become another 1957-1962 era.

So thank you. I think we'll get started now, leading into Dr. Kelsey, who back in the 1960s -- if you look at her abstract, we're about three days short, I think it is, of when the application was submitted to the agency, so it's quite a good time to have the meeting.

Dr. Kelsey?

DR. KELSEY: It's a pleasure for me to be here today and recapitulate a bit of the past. I joined the Food and Drug Administration as a medical officer in August of 1960. I spent the first months going around various areas of the Food and Drug Administration getting familiar or getting introduced to the type of work that was done there. On September 1st, I reported to the Bureau of Medicine as a reviewing medical officer.

The thalidomide application was filed shortly after September the 8th. Although it was usual to give applications around more or less in rotation, since I was new, they selected an easy one for me.

Now, at that time, the bureau was, of course, much smaller than it is now. I think, if we could have the first overhead, that would perhaps bring that out. I don't know if you can read it, but in essence, there were seven full-time medical officers and four part-time medical officers. The total applications were about 300 a year. Now, there are over 200 medical offices.

Now, I should explain, however, that the applications really were quite a bit different from what they are today. A lot of them were for fairly ordinary drugs, minor molecular modifications of long-used drugs, or a new mixture of old drugs. It was rare that a really new and exciting drug came in, and it was in those applications that the best clinical and animal studies were performed. In general, at the time, drug testing was not considered a very scholarly pursuit by most people. Many of the studies in support of new drugs were written really more as promotions than as scientific studies.

The ground rules in those days were that after an application had been submitted and filed with the agency, the agency had 60 days in which to decide that the drug was safe for the proposed use or uses. There was no requirement for efficacy, and this of course was one reason why the applications were so much smaller.

In fact, the thalidomide application was four volumes in size, as I recall. That was about standard. I think I remember one that was 11, and one that was one or perhaps two. Now, although I guess they're mostly computerized, it's a matter of 100 or 200 volumes.

The applications were reviewed, as they are now, by a chemist, and a pharmacologist, and a medical officer. The chemists were in the same little prefab building that we were in on the Mall between 7th and Independence, where the Museum of Science and Industry now is. The pharmacologists were in another bureau altogether, in the Department of Agriculture.

The medical officer really had the choice. They could do the pharmacology themselves or they could ask for a consult from the pharmacologist. I chose the latter course.

We had, as I said, 60 days. If we hadn't communicated with the company before that, they could have automatically assumed that it was okay, and marketed it. So very close tabs was always kept on the date.

We did get our letter out on November the 10th, although I said the application was received on the 8th, or some little time before it got logged in. I think the official date of acknowledgement was September the 15th. So we got our letter out on the 10th of November. In this, we declared that the application was incomplete and inadequate, and could not be filed. Then we gave the reasons for our decision.

We all had fairly serious questions. The pharmacologist felt that the chronic toxicity studies had not run for a sufficient length of time. He also felt that there were inadequate absorption and excretion data. The chemist found all sorts of problems or shortcomings with the manufacturing controls. She had concerns about the asymmetrical carbon atom, and wondered what was known about the D and the L forms, and in what proportion they were present, and so on.

She, fortunately, had been educated in German, and a lot of this application consisted of German reprints with an English translation. She of course could read the original German, and did find at least one error in the translation. I, who know no German, or just enough to pass a Ph.D. exam in it, was very impressed by this.

I had some problems. The data to submit safety was very sketchy and anecdotal. The claims were quite fulsome, you might say, almost. It was of course perfectly nontoxic. It lacked hangover effect. It was nonhabituating, or addicting, and so on. But one by one, these claims sort of were modified somewhat.

I was particularly -- and all of us were -- concerned about the fact that you seem to be able to give enormous amounts, both to animals and humans, without any effect of perhaps drowsiness or sedation. In fact, one of the claims or one of the mentions in the brochure included several cases in which persons had tried to commit suicide, and been unable to do so. You've probably heard a later comment that, had thalidomide been on the market, Marilyn Monroe would be alive today.

Well, pretty soon it was acknowledged that, like all other drugs of its class, there was indeed some hangover effect, but we were concerned about this nonabsorption. We felt there might be conditions of the nontoxicity, which we felt was surely due to nonabsorption, and we thought there might be conditions, illness or another drug or something like that, that might change this so much more would be absorbed, and toxic effects might appear.

We did not know, for some years later, that a solution of liquid form of the drug had been marketed in Germany, particularly for use in children. When the British company thought they would market a similar one, their pharmacologist was horrified to find out how very toxic this compound was. I can still remember his anguish when he described experiments he had done. It was a micronized preparation in a sweet solution.

Despite his findings, however, it was marketed for awhile in Britain. As I understand it, the preparation was taken off the market because of some toxicity in humans, but we didn't know this.

The application was resubmitted again on January the 17th, which meant that by mid-March we would have to give them another opinion. We were continually concerned about the lack of data on metabolism, excretion, absorption, and this curious lack of toxicity. Then, at the end of February -- the 23rd, I think it was, actually -- we picked up a number -- it was actually the December 30th number -- of the British Medical Journal, which contained Florence's article posing the question, did thalidomide cause peripheral neuritis?

This was a little late in getting to us, because the mail was on strike. It was actually a shipping strike, I think, and we did not get our British and other foreign publications by air mail in those days. However, this did come in time. When we questioned the company about it, they said they had just seen that, too. They were sort of surprised, and were going over to Europe to find out more, and would let us know when they came back.

Now, what we didn't know, again, was the German company had been questioned about peripheral neuritis as early as the winter of December of 1959, before our application was even submitted. The same person that asked them about it this time gave a paper -- I believe it was in May of 1960 -- describing a number of cases of peripheral neuritis, some of which seemed pretty severe.

The British actually answered the first report by saying that they were aware of it, and had put some reference to it in the material that they distributed with the drug. Our company was not obliged to submit foreign supporting material or material of that type at that time, so we were not aware of this side effect.

They had independently discovered it about May of 1960, and there is good evidence that the German and the British company had a sort of gentleman's agreement to keep the matter rather quiet until the American company had a chance to get the drug on the market. So we were inclined to believe that the American company had not heard of this earlier.

The company did report to us on their trip to Europe. They said that indeed there did seem to be some cases that neither in Germany or in England was it considered of great moment, and that both companies felt a little note on the labeling would suffice.

There were even questions early on whether the drug should continue on an over-the-counter status, as it was in some parts of Germany, and other parts of the world. It was a little time later that the over-the-counter drug status was changed, and the drug became prescription-only.

But it's difficult to exaggerate how popular this drug was at this time. I think it was the third largest-selling drug in Europe. As I mentioned, it was considered so safe that it was over-the-counter in many areas.

We were concerned about the peripheral neuritis, even if the companies did not seem to be. We sought some outside consultations with neurologists, Dr. John Tower at NIH and Dr. Webb Haymaker in the Army Walter Reed Hospital. They both felt the same. They felt that peripheral neuritis could be serious, painful, and often irreversible. The risk of developing this would not be justified in a drug that was used simply as a hypnotic and sedative, since there were other drugs on the market for this purpose.

We continued to feel it might be a serious matter. One of the questions we raised at this time was what would happen if the mother took it through pregnancy, and this drug was taken for quite long periods of time, what would be the effect of the drug on the child?

This was not a shot in the dark, because at that time the Food and Drug Administration and the American Academy of Pediatrics had been concerned about the effects of drugs when taken during pregnancy, and were in the midst of preparing guidelines for the testing of such drugs. There had been a number on the market that had been shown to have disastrous effects -- ananoptrine, chloramphenicol, to name a few.

I'd had a little experience some years previously when I worked on the anti-malarial drug project during World War II. We were given a little time for research, and we were interested in the metabolism of the effective anti-malarials, quinine and Atabrine. We established that the quinine was very rapidly metabolized by the liver of the rabbit, but we found that the fetal liver had no such activity, and it did not appear till shortly after birth. This, of course, was the same situation that causes the chloramphenicol problems. The baby simply doesn't have the enzymes to protect itself against the chloramphenicol as the adult did.

The answer always was, if it had had an ill effect, surely it would have been known by now. That, of course, is a common excuse about any adverse effect. But, interestingly enough, it had. A German in Bonn, Germany, a pediatrician and a geneticist, had been struck by the increase of phocomelia cases in their hospital. They felt it must be due to some recently introduced substance, and they wrote around to a number of other hospitals in Germany. Most of them reported the same thing, that they had had an increase in this very unusual adverse effect.

They then thought they would find out the experience of other countries where thalidomide had been used. Most of them had indeed seen this increase. They were thrown off, ironically, because they were under the impression that the drug was released in the United States. The promotional material said it was widely used in North America, and it had of course been marketed in Canada.

They wrote to three centers in the U.S. where statistics were kept on birth defects. There wasn't really any indication of an increase. This is, sadly enough, what put them off the scent. It wasn't until November of 1961 that Lenz discovered the association.

Now, the first report of phocomelia was announced at the end of November of 1961. The company immediately phoned us, and told us the news, and said they didn't really believe it, but as a precaution they would put a halt to clinical studies going on in this country. But they did want to continue some that they had just started on its possible usefulness in cancer. That seemed no great problem to us, the benefit/risk ratio being entirely different.

In March, early March of 1962, they told us they were withdrawing the application immediately, as they believed there may be some truth to this association. There were some weird differences in wording of their two communications that led us to think it might have been more widely used in this country than we had gathered from the new drug application, so we asked for a complete list of the doctors they had sent the drug to, and were very surprised to find that actually over 1,000 doctors had been given the drug.

Most of these were recruited after the application had been submitted in September, in the expectation that it would be rapidly approved. They were told, in essence, "Don't really worry about recording the results. We just want you to try it out, and see if you want to use it in your patients."

We then visited, or had the company visit, every one of these doctors, and pick up what remaining stocks they had -- and there were indeed quite a lot -- and find out if they had had any phocomelic or abnormal births amongst the patients they had given the drug to. In all, we found about 10 or 11 cases that we thought might be due to the trials in this country. There were an additional seven patients or subjects where it was clear that the drug had been gotten from a foreign source.

Now, the thalidomide tragedy in Europe actually didn't cause a great stir at the time in this country because there really were, except for those few, no victims. The one person who was concerned was Dr. Helen Taussig, who was the professor of cardiology at the Johns Hopkins Hospital. She had heard about the outbreak from an ex-resident of hers who was now in Germany, and he had urged her to come across and see some of the victims, many of whom had cardiac defects.

Before going, she had contacted another ex-president who was working at the Food and Drug Administration, and when she got back she invited both him, Dr. John Nestor, and myself to hear the results. They were essentially published later in the JAMA after she gave a talk to the American Academy of Physicians.

She also spoke before the House committee, but it really wasn't until mid-July when the article in the Post came out, authored by Morton Mintz, that the country realized the enormity of the problem. Almost immediately, the long-awaited Kefauver-Harris bill was passed, in October. This not only required proof of safety, but also proof of efficacy. It also included a last-minute addition that patient consent must be obtained from all subjects in the clinical trials in the future.

Meanwhile, FDA had hastened to strengthen the investigational drug requirements, and essentially published early in July, what was finalized in early March, with the addition of this efficacy and consent requirements.

So these were the two immediate effects of thalidomide, the strengthening of the law and the regulations, both offering greater protection both to subjects of trials and to the public getting drugs later.

It also stimulated other countries to bring new laws. Many of them had laws such as we did back in 1930, before 1930, when a manufacturer could simply put a drug on the market if he felt it was safe when used as labeled. The onus was on the government to remove them. But many of them introduced laws similar to our 1962 ones, and one of the great forward steps has been the harmonization, the efforts being made to bring the requirements of Japan, the European countries, and the United States into harmony. This of course will add to more rapid marketing of good and safe drugs, and protection against unsafe ones.

It also increased greatly the efforts to monitor birth defects. It caused a great increase in the science of teratology, or means of testing drugs for adverse effects in pregnancy. So those were some of the immediate good effects.

I would say, however, that thalidomide never faded away. I mentioned that we permitted certain trials in cancer to proceed. Some years later, when an application was submitted for leprosy, we felt that was a reasonable use, since there was great need for such a drug in this distressing disease, and the patients would be under pretty good control.

I look forward to hearing advances that have been made in the understanding of a pharmacology and the metabolites of the drug, and the many proposed new uses for this fascinating, but rather difficult drug.

Thank you.

(Applause.)

DR. GROFT: Thank you very much, Dr. Kelsey. It almost is a history of FDA regulatory action since the 1960s, so reliving quite a few moments in FDA history.

Our next presentation will come from Dr. Janet Woodcock, who is the director of the Center for Drug Evaluation and Research. It's on her desk that Dr. Jonathan Wilkin will be sending the application to consider for approval.

So, Dr. Woodcock?

DR. WOODCOCK: Thank you, Steve, and good morning to all of you. I also want to join in thanking Steve and Terry Toigo, who I think have really put in a tremendous effort to have this workshop come off in such a timely manner for everyone's consideration of this product.

What I'd like to talk about today -- if I could have the lights down a little bit -- is to bring the history up to date on this, and talk about the challenges in the clinical drug development that thalidomide has presented, and currently presents, because we are seeking everyone's help in dealing with the orderly investigation of thalidomide for various conditions.

Could I have the next one, Steve?

Now, what I want to talk about is, first of all, why is there interest in thalidomide? I mean, some people really asked this with a note of incredulity in their voice. Why would you possibly be interested in such a product with its history? Second, what are these challenges in development? Third, I'd like to really appeal for help from all the sectors that really need to help in this -- patients, academia, industry, media, government, and the public.

First, why the interest in thalidomide now? What has happened? Well, in the midst of the tragedy that Dr. Kelsey described, some leprologists made a serendipitous discovery that some of their patients with a type of reactive syndrome in leprosy had, as they described, a dramatic response when they were given thalidomide for sedation. So in erythema nodosum leprosum, or ENL, they observed a rapid resolution of some of the symptoms in patients who had been put on thalidomide.

Over the years, this kept the drug alive, so to speak, in investigation. I'll go into that a little bit later. But the drug continued to be used. As Dr. Kelsey said, there were investigational applications for clinical investigations.

Today, we have great interest in thalidomide for a wide variety of conditions. We have life-threatening conditions, such as graft-versus-host disease, AIDS wasting, and interest in various malignancies. There are a wide variety of immunologic disorders where there's interest, where it is believed that thalidomide may be helpful, including various types of lupus.

Behcet's disease. We heard from a Behcet patient at our recent advisory committee last week. Sjogren's syndrome, Crohn's disease, and rheumatoid arthritis. Many of these conditions on this particular slide are very prevalent in young women.

In addition, there are a lot of other conditions. A wide variety of serious dermatologic conditions, most of which I cannot pronounce properly, but are very, very serious for those patients who are afflicted; tuberculosis; various types of aphthous ulceration, including ulcerations in patients infected with HIV; and the ocular disorder, macular degeneration. This is a very wide and disparate set of conditions where there is interest in studying thalidomide.

Unfortunately, while there is great interest, there are also serious challenges. What contributes to these are, number one, historical factors, and, number two, the current situation.

Historically, after thalidomide was taken off the market around the world, and failed to be approved in the United States due to the actions of Dr. Kelsey and her colleagues, it was, as I said, investigated for use in leprosy. For over 20 years, it was used in the United States under an investigational new drug application that was held by the Hansen's Disease Center in Carville, Louisiana, and was used there for the treatment of ENL.

Now, this group had extreme difficulty over the years in obtaining a consistent product, obtaining a stable source of product, and obtaining a product that was a consistently defined, pharmacologic, high-quality product.

Now, what happened is, other uses began to be explored over time, extrapolating from what was felt to be the very striking effectiveness in ENL. Other uses began to be explored. What happened in the U.S. was the Hansen's Disease Center was used as a source for other clinical investigators who wanted to hold INDs and perhaps administer the drug to their patient or do a clinical trial. These investigators also were subject to the same whims and problems with drug supply as was the Hansen's Center.

I personally was an investigator who sought to obtain thalidomide for a young woman, a patient of mine who had Behcet's disease. It was at a time of difficulty of supply of obtaining thalidomide. I was unable to obtain it, possibly partly because it was a young woman of childbearing age, but my patient subsequently died of the complications of her treatment.

So this created a lot of problem in the development of thalidomide. There was no real source available. The investigators had single investigator INDs. There was no overall development plan for thalidomide.

HRSA, the Health Research and Services Administration, who ran the Hansen's Center, developed a progressive financial burden of supplying this thalidomide to folks, and of tracking who they had distributed it to. FDA became increasingly concerned about the quality of the drug being distributed. We felt it probably varied in dose significantly. We often were called to participate in testing of the tablets to ensure their quality and uniformity, so the situation was not good for investigation of thalidomide.

Recently, in the last several years, HRSA, because of the current fiscal environment, made a decision to cease supplying the drug outside of the ENL use. At the same time, there became interest in use in AIDS patients for the indications that I mentioned. There began to become access issues of actually being able to get thalidomide for patients who didn't have other alternatives, with AIDS wasting, and severe aphthous ulcerations.

Because of all these issues, buyers clubs sprang up, or began to offer thalidomide illegally through basically mail-order, or going in and obtaining it in various buyers clubs, clinics, or what have you. So distribution of the drug through non-medical channels in the United States began to occur.

At that time, FDA put together the FDA Thalidomide Working Group to try and coordinate regulation. By this time, there were many INDs scattered throughout the various divisions of FDA, where the drug was under study for all these conditions.

The working group was to coordinate access programs to make sure that those who needed access to thalidomide, investigators and patients, would obtain it under controlled conditions, where the possibility of adverse effects could be minimized. To that end, the working group developed a model informed consent for individual investigators to use with their patients, to make sure they would be fully informed, and also a patient brochure that could be given out.

We also, because of the HRSA decision, held discussions with some companies that had begun to develop interest in actually clinically developing thalidomide. We brought those companies in, and had discussions with them, because it appeared that the most prudent path would be to get the drug evaluated and studied in the clinic for these various indications, see whether or not it worked, and at the same time ensure a consistent supply of product that is a high-quality product.

We also either talked the buyers clubs into not distributing thalidomide or, in one case, took legal action against a buyers club to stop illegal distribution of thalidomide. Regardless of this, though, I still hear that thalidomide continues to be available through various channels without having an IND.

Recently, as you heard, there was submission of an NDA for thalidomide in the treatment of ENL. The last step last week in that process was the recommendation of the advisory committee that thalidomide is safe and effective for that condition. Then this conference, I think, is the next step.

The challenges, though, remain. The challenges for all those conditions that I mentioned on the earlier slides, and the other ones that are going to be discussed over the next two days, is getting the drug properly studied.

For sponsors, there are liability risks, of course, involved with thalidomide that have in some extent decreased the interest in this pharmacologically active agent. For investigators, there has been an ongoing challenge -- when we talked to the NIH investigators, they said it was the same for them -- obtaining a stable supply of high-quality clinical supplies, and funding the necessary studies. For patients, it's really balancing needs for access to this drug in these serious conditions against the need to really study the drug in controlled trials, and get the information.

There are additional issues that will be raised at this conference. We need to get to some agreement on what would be required for both safe and respectful inclusion of women of childbearing potential in these clinical trials. There is need for some, if possible, common methods of toxicity evaluation, so we can accumulate safety information across all the trials, and develop a database of safety that will pertain to thalidomide in general. We need to establish reliable sources of product, and we need some public input of where we're going with this.

Where are we going? We've heard repeatedly over the past few years from patients with serious diseases that they need effective treatments that have been shown to be effective, but we've also heard recently from the advocates for children that, of course, as the use of thalidomide would increase, the possibility of fetal exposure rises.

On the other hand, and in addition, we have to consider what I said earlier about buyers clubs and illegal distribution. We understand in this country how difficult it is to absolutely keep drugs out of illegal distribution channels if people want them. That's been well-proven. So severe restrictions on thalidomide availability that are intended to decrease the risk of fetal exposure may, paradoxically, lead to wider availability or use under absolutely uncontrolled conditions.

Some of this buyers club thalidomide just has a label on it. Otherwise, they're just plain tablets in a vial. Somehow we have to balance those issues I just mentioned.

A lot of it, I think, is information for the public and risk communication. That's where the media are extremely important, and the professional organizations. I did an informal survey, and FDA has done a formal survey, although small. The bottom line is, most people 35 and under have never heard of thalidomide. They have no clue. Most of the reproductively active people in this country have no reaction to the word "thalidomide."

The illegal distribution, as I said, the product isn't well-identified. It might just have "thalidomide" on it, but people have no idea what that means. We have to recognize that among various people with serious conditions, pill-sharing, sharing of medications, is a very common practice. How can we inform the public to make sure the public is protected, even as clinical investigations go on?

In summary, what I believe is that thalidomide needs to have standard clinical drug development, like any other drug, for these conditions. It needs to be evaluated in clinical trials, so we can tell is it effective in these conditions, and what its safety profile might be. The teratogenicity is pretty well understood, although the nuances are not understood, but I think we know enough about that to know it should not be used in pregnant women. But there are many other safety issues pertaining to the drug that need to be explored in the various diseases.

The needs of seriously ill patients for access to treatments must be met, and met safely. We need to have, jointly, a common understanding of where we're going, and public information is vital to the safe use. The public must be made aware.

These are my version of the goals of this workshop. I hope we can accomplish all these goals as we go through the various sessions.

I thank you very much.

(Applause.)

DR. GROFT: Thank you very much, Janet. I think your goals are pretty much consistent with what everyone will be working towards.

I would like to acknowledge Dr. Marlene Haffner, who is here from the Office of Orphan Products Development at FDA, who has taken some actions on giving orphan drug designation to thalidomide for several of the uses, and probably would welcome an application for more uses for thalidomide. So hopefully, the provisions of the act have stimulated the development of thalidomide a little bit.

Our next speaker comes to us from Mexico, sort of the FDA equivalent in Mexico. Dr. Guillermo Bierzwinsky will relate the activities in Mexico related to the use of thalidomide in HIV wasting.

DR. BIERZWINSKY: Thank you, Dr. Groft, for inviting me to this meeting.

This is our volcano, which is about 80 kilometers outside of Mexico City. The name is Popocaqutatal. It's fuming. The issue we are dealing with today is also fuming.

Thalidomide was first synthesized by Kunz in 1956 in Germany. It was initially used as a sedative in various countries. I'm going to repeat information that has already been mentioned. Reports of peripheral neuritis in 1960 delayed approval of thalidomide by the FDA. In late 1961, the possible association between unexplained fetal abnormalities and the use of thalidomide was raised by Lenz at a meeting in Westphalia. The manufacturer withdrew the drug from the market in 1961.

The tragedy of thalidomide is largely responsible for the strict sanitary regulations applied presently for approval of new drugs in several countries. However, positive actions of thalidomide have also been observed. In 1965, Sheskin, in a Jerusalem hospital, serendipitously noted improvement in the inflammatory reaction of leprosy patients known as erythema nodosum leprosum. Since then it has become the drug of choice for its treatment. In Mexico, thalidomide was licensed for this indication in 1988.

It has also been successfully used for the treatment of other difficult ailments, like Behcet's disease, lupus erythematosus, graft-versus-host disease, ulcerative colitis, and esophageal ulcers in AIDS. This has already been mentioned.

More recently, there has been interest in the use of thalidomide in the treatment of certain aspects of the clinical picture in AIDS patients. Mexico has the third place in the number of AIDS cases in the American continent, and the 11th in the world.

It has been shown the thalidomide has no antibacterial effect in cases of erythema nodosum leprosum. These and other observations suggest that its beneficial effects are exerted through a direct action on the immune system, as supported by the suppression of guest-versus-host disease observed in animal experiments and in humans.

It has been reported to selectively inhibit the production of tumor necrosis factor alpha by human peripheral blood mononuclear cells, primarily by accelerating the degradation of TNF alpha messenger RNA transcripts. Also, thalidomide inhibits in vitro both TNF alpha messenger RNA and TNF alpha protein, as well as the expression of HIV-1 in infected cell lines in peripheral blood mononuclear cells of infected patients.

Human immunodeficiency virus disease has detrimental effects on the nutritional status of infected patients. Progressive weight loss is a major clinical feature and a diagnostic criterion of AIDS, and contributes to its morbidity and mortality, independent of the CD4-positive T cell counts. Weight loss in this patient is at the expense of body cell mass, predominantly of muscle protein -- wasting or cachexia -- and may occur in two patterns during the late clinical stages of HIV disease: one, acute, severe, and remitting weight loss, mostly related to opportunistic infections; and two, chronic, progressive weight loss, the wasting syndrome.

At the Instituto Nacional de la Nutricion Salvador Zubiran in Mexico, a randomized, double-blind, placebo-controlled trial was designed to evaluate the efficacy of thalidomide, a selective inhibitor of tumor necrosis factor alpha, in the treatment of wasting syndrome in patients with advanced HIV disease, and to assess the effects of thalidomide on peripheral CD4-positive T cells, plasma levels of tumor necrosis factor alpha, and HIV viral burden in peripheral blood mononuclear cells.

Patients included were adults with an advanced HIV disease who were under antiretroviral therapy without an active opportunistic infection, and with over or equal to 10 percent weight loss in the previous six months. Patients were stratified by severity of weight loss.

Here in the graphic, you can see, most of the patients were in the category three, where the weight loss was between 10 percent and less than 20 percent, with a CD4-positive T cell count of less than 100 for most of the patients in both groups, the placebo and the thalidomide group, 11 patients. There were 14 patients in each group.

>Patients were stratified, as is shown, by severity of weight loss and CD4-positive T cell counts, and assigned in a random and double-blind fashion to receive thalidomide 100 milligrams four times daily or a matching placebo.

Patients were followed for 12 weeks, three months. Weight and anthropometric data were recorded every two weeks. Clinical events were registered. HIV viral burden in peripheral blood mononuclear cells by endpoint dilution cultures, CD4-positive T cells, and tumor necrosis alpha plasma levels were evaluated.

The efficacy of thalidomide was defined as weight gain or no progression of wasting. Between June 1992 and May 1994, 28 patients -- 24 men and two women, non-pregnant -- were randomly allocated to receive thalidomide, 14 patients, with 14 patients on placebo. Both groups were comparable in their baseline status.

Therapeutic failure occurred in 10 of the 14 patients from the placebo group, and in three only of the 14 patients of the thalidomide group. This is the therapeutic failure probability, where it shows that you can have more with placebo than with thalidomide.

Weight gain occurred in one patient on placebo, and in eight on thalidomide. As you can see here, they started within 55 or 56 kilograms, and the patients with thalidomide went up to 68 kilograms, as compared to the patients on placebo, which remain about the same weight.

The Karnofsky index was significantly higher by the end of the study in the thalidomide group. Mild and transient somnolence and erythematous macular skin lesions were significantly more common in the thalidomide group. CD4-positive T cell counts and HIV viral burden in peripheral blood mononuclear cells did not change in either group. Circulating levels of tumor necrosis factor were undetectable throughout the study.

Results suggest that thalidomide not only impeded, but also reverted the wasting syndrome, preserving the Karnofsky index in patients with advanced HIV disease. This is the median of the calculated muscle mass, which also increased from 20 kilograms to about 26, where the patients in the placebo group remained about the same, or decreased.

There was no change in this study. It could not be measured, any change in these parameters.

Based on this study and other similar reports, the Ministry of Health in Mexico approved the use of thalidomide for the treatment of the AIDS wasting syndrome in 1996, considering that at the time there were no better options available.

There is one sole manufacturer of thalidomide in Mexico. The company's name is Serral. Raw material is produced in Mexico by Diorchem, a manufacturing plant managed by investigators of the National University of Mexico and the Polytechnical Institute. The drug is not sold in drugstores. It is directly distributed by Serral, the manufacturing company, to infectologists and dermatologists, and to the Social Security Institute, the largest public health institution in Mexico.

It is supplied in boxes containing 50 100-milligram tablets. The cost of each unit is $38 U.S. The monthly cost of treatment is around $92. This compares favorably to the cost of megestrol acetate or recombinant human growth hormone. It is estimated the total annual sales are in the order of 6,000 units, that's all.

The labeling states that it should not be used in pregnant or fertile women because of the risk of fetal malformations. A pregnancy test must be performed and found negative before treatment is initiated. Contraceptive measures must be used during treatment. Dr. Fost will have something to say about these requirements.

Adverse reactions reported with the use of thalidomide in these high doses have been frequent, but effects have been mild and transient, mostly skin reactions. In the Mexican study, there were two cases of severe skin reaction, requiring discontinuation in one case. Neuropathy developed in one patient, and the drug was also withdrawn.

This is to show you the toxicity. One case was a serious disseminated rash, and two cases were a severe disseminated rash, and neuropathy.

Also, the percentages of efficacy. The placebo was 29 against 79 percent.

In conclusion, it can be said that thalidomide seems to delay and reverse the wasting syndrome in patients with advanced HIV disease. The beneficial effects should be investigated in larger clinical trials. It remains to be determined whether thalidomide alone, or in combination with recombinant human growth hormone, can sustain its effects long enough to significantly alter the clinical course of AIDS, particularly in regard to quality of life and survival in those patients with weight loss. It can perhaps be used in other wasting diseases, as there have been recent reports of accelerated weight gain when it was used in patients with pulmonary tuberculosis.

Thank you.

(Applause.)

DR. GROFT: Thank you very much, Dr. Bierzwinsky.

If there are any questions, I don't know if anyone has passed them over, if anyone has been collecting them, so if some of the staff could come up and down the aisles to see if there are any questions, I would appreciate it if we could bring them up to the stage.

Our next speaker will be Dr. Carol Braun Trapnell from the Food and Drug Administration. Dr. Trapnell is with the Office of Therapeutics Research and Review from the Center for Biologics Evaluation and Research. As I mentioned earlier, she will be talking about the clinical pharmacology of thalidomide and all the potential uses.

DR. TRAPNELL: Good morning. I'd like to first thank the organizers for inviting me to the meeting.

As has been said, I'm going to discuss briefly the clinical pharmacology of thalidomide, and really just hit the high points of some of the major issues with this drug that we know of, or don't know of.

I also would like to say that I noticed in your handout that only one reference is listed for my talk. Obviously, there are more references. If anyone would like a more complete reference list, please see me afterwards. I'd be happy to provide that.

This is the structure of thalidomide. It is a glutamic acid derivative that, as we've heard, seems to have a wide variety of potentially beneficial activities, as well as potentially harmful properties.

The five topics I'm going to just highlight today in my talk are absorption of thalidomide; the issue of enantiomers, and we're all going to have to get the cobwebs out of our chemistry classes from high school to discuss this; issues with metabolism and disposition in vivo; and questions about drug interactions, as well as toxicities of the compound.

First, I want to discuss absorption. This data is from a trial that we did at Georgetown University, looking at the pharmacokinetics of thalidomide and oral contraceptive products, which I'll discuss in more detail in a few minutes. But this is the plasma concentration versus time curve that we generated from 10 healthy women who received this product. They were getting 200 milligrams of thalidomide at bedtime for three weeks.

As you can see, the peak time of absorption of the drug is actually fairly delayed. It's about at two to three, maybe even four, hours. Then it has a first-order elimination that gives it a half-life of between eight and 12 hours.

I think the interesting thing, from my perspective, is that the patients begin feeling quite drowsy within 30 minutes or 45 minutes of swallowing the capsule. So clearly when we're up here at the peak concentrations, we are well above the level that is needed for at least sedation. I think it's fair to say we don't actually know what the concentrations really are that we need for the beneficial effects of this product for really any indication that we are interested in evaluating today.

I think the same is true in reverse. We also don't really understand what levels produce toxicity, although certainly with the teratogenicity, it has been reported that one dose given at the right time in embryogenesis can produce harmful effects.

Now, the issue of enantiomers is that at this nitrogen in the structure, this ring can either go up out of the screen, or go down into the screen. These are so-called R or S or DNL enantiomers. They are mirror images of each other. The drug is actually administered as a racemic mixture, so half of what someone swallows is the R isomer, and the other half is the S isomer. This is actually very common in drug administration. Usually when there are centers in the molecule that can have either the molecule going up or down, it's given as a racemic mixture. I think most of that is because of the ease of the chemistry. I also think there hasn't been a lot of interest until more recently in what the potential effects of the isomers as individual compounds can be.

Now, what happened is that there was some published information in animals that suggested that one of the isomers could be the toxic isomer, and the other isomer could be the isomer responsible for the activity. I think there was some interest in thinking, well, if we could just give the S isomer alone, could we somehow get away from all the toxicities that we're seeing with the drug?

What happened in response to that was a group in Sweden led by Erikkson did, I think, a very elegant study which was published in the Journal of Chirality in 1995, where they gave to an in vitro experiment, using human blood -- they put the R isomer into the petri dish, if you will, and watched it disappear, and at the same time watched that the S isomer was formed de novo. So somehow in the blood, the R isomer was converted to the S isomer as part of its metabolism. As you can see, out here at about four to six hours, there's really equal amounts of both isomers in the preparation.

A similar thing was observed when the S isomer alone was put into the preparation, and we had increasing levels of the R isomer, so that there were equal amounts seen at about four hours or so.

Now, he did the same thing then in patients to see if the in vitro findings could be proven. Indeed, I think in the subject he reports in the paper, the same paper in Chirality, you can see that administering the R isomer does essentially give you the same concentrations of both isomers, although of course the formation of the S isomer in this time profile is a little bit delayed, because the R isomer has to get into the bloodstream. Again, the same thing is seen when the S isomer is given as the only compound.

Just to get another point about the metabolism here, this is the structure of thalidomide that I showed you earlier. Again, you have to understand that there are two compounds actually being administered, the R and the S. What happens is, this drug is hydrolyzed to a series of metabolites in humans. There is some hydrolysis. There is some metabolism. We actually tried to work with this compound in the lab to do some in vitro drug metabolism studies, and had just a heck of a time keeping this compound as thalidomide because it really loves to break down into all these different products.

Now, the point about this is that we don't actually know what is responsible for both, again, the activity and the side effects of thalidomide. It could very well be that a couple of these compounds would be more active for activity, and a couple may be the ones that really produce the toxicity, but it is very hard to work with this compound, because the breakdown products occur very quickly, and they are hard to measure in the serum. When you're doing a clinical study, actually there has to be very good care taken to how the blood samples are handled, because the breakdown of the parent can occur very rapidly once the drug is pulled out of the blood.

Now, to touch on the drug interactions topic, there was a question about whether thalidomide could affect the pharmacology of concomitant therapies that it was being administered with. In particular, there was a paper published regarding a compound called taglutamide in 1980 by Wiener which implied, really, the taglutamide could induce the metabolism of other compounds in the rat model that he studied. Taglutamide is very structurally similar to thalidomide. So the question was, could thalidomide affect the metabolism of other compounds?

There is no data available that we could find, but we felt that it was important to ask this question, particularly in regard to oral contraceptives, or hormonal contraception, because women of childbearing potential who are receiving thalidomide as parts of clinical trials were being advised to use some kind of hormonal contraception as one of the contraceptive measures to prevent pregnancy.

Of course, if thalidomide was inducing metabolism, what could then happen is that the oral contraceptives would be more rapidly eliminated, and could potentially then not be as effective in preventing pregnancy. Obviously, if the woman is taking thalidomide when that is happening, that is not a good interaction that you want to see, so we performed at Georgetown University a Phase I crossover evaluation in 10 healthy women who had had surgical sterilization, who are between the ages of 21 and 45.

Interestingly, what Dr. Woodcock said -- one of our subjects was young woman who is in her early 20s who had had her children early, and then had undergone a tubal ligation. She told me when she went to the library to ask the librarian to get some information about the drug, the librarian, who I assume was a woman in her 50s, from the study, just about fainted on the spot when she told her she wanted to do thalidomide. My patient could not understand what the big deal was because, again, I think she had never heard of the drug, which is what Dr. Woodcock said.

But these women all were surgically sterilized. Our study design was that, on study days 1 and 22, they received two tablets of the Ortho-Novum 1/35 product, which contained together 70 micrograms of ethinyl estradiol, and 2 milligrams of norethindrone. As you know, Ortho-Novum 135 is a combination tablet of these two drugs.

We obtained blood at regular intervals for 24 hours after each dose, which was then used to determine the pharmacokinetics of these two compounds. Then on days 2 through 21, we administered to the patients 200 milligrams of thalidomide at bedtime every night. The product that we used was supplied to us by Andrulis Pharmaceuticals, so we used two 100-milligram capsules. We did this as outpatients, because it was not really realistic for us to keep our subjects in the clinical research center for three weeks.

We wanted to be sure that we had good compliance with therapy, so we used something that clinical pharmacologists like to talk about, MEMS caps on top of the prescription bottles, to make sure that patients were either taking or not taking the drug, so that we could better understand our data at the end of the study.

This is what a MEMS cap looks like. It's basically a larger top that goes onto a standard prescription bottle. Inside this cap is a little computer chip that records, on the computer chip, when the bottle is opened and when it is closed. It records both the date and the time. The way you use these caps is, you of course have to educate the patients that these are being used, that they are part of the research protocol. Then you obtain from the company that you rent these from software and hardware that can be loaded onto any standard IBM-compatible computer or PC.

It has this reader, that looks a little bit bigger than a mouse, where you invert the cap onto this little part of this device, and you instruct the computer to read it. Within about 10 seconds or so, the data from the cap is actually downloaded into a computer file, and you can then read it on your computer screen.

What you get when you read the caps, you can get the readout in various forms. This is a format from a study that the patient was being asked to take the drug twice a day. You can see, you actually get a very interesting readout of both the date of administration and the times of day that the caps were opened and shut.

In this particular example, this patient had very good compliance. In fact, in our thalidomide study, we had 97 percent compliance with the therapy, which I thought was very good, given that most of my patients were saying they were a little bit sedated from the drug.

What we found in this study when we evaluated the pharmacokinetics is that the baseline ethinyl estradiol area under the concentration time curve compared to the same information after three weeks of thalidomide was essentially unchanged in these 10 subjects. These dots represent the individual patient area under the concentration time curve, and again at baseline, and after three weeks of thalidomide. You'll notice here, there's a fairly large distribution of area under the concentration.

Results within the 10 patients, that actually is very well-reported for ethinyl estradiol. There's a lot of intrasubject variability, but, as you can see, there's no change in the kinetics of this compound with thalidomide. Similarly, we found the same thing with norethindrone. The scale here is in different units because we gave the drugs in different units, but again, no change in the area under the concentration time curve for this compound in the presence of thalidomide.

The toxicities of thalidomide have already been mentioned. Here is just a sum of them. Sedation, I think we could say, is a pharmacologic effect. I was impressed during our trial how well this drug works as a sedative. In fact, one of my patients asked me where she could get more of it because she's never slept so well in her life. So I think that's something that really does need to be taken into account for patients who need this drug for other reasons.

Of course, the teratogenicity has already been discussed by Dr. Kelsey and others, and the peripheral neuropathy will be discussed in more detail as well.

I think, again, it is important to note we do not know the mechanisms for these toxicities. We don't know if it's thalidomide and/or one or more of its metabolites. I think clearly this is an area of research that needs to be done for this drug.

In conclusion, I'd like to just say that I believe there's adequate thalidomide pharmacokinetics available for most purposes regarding the design of larger trials, and to carry out bioequivalence studies in the face of more than one manufacturer of this product.

I think the enantiomer was put to rest by the nice research by Erikkson's group, and that for humans it's really not clinically relevant, that there's no reason to go to the trouble of giving one isomer over the other because the human makes it a racemic mixture anyway, so there's no reason to even ask the question any further.

I think we can also safely say that thalidomide does not affect the pharmacokinetics of either ethinyl estradiol or norethindrone.

Some areas of future research we'll discuss in more detail tomorrow include understanding the pharmacokinetic and dynamic relationships, better understanding of the pharmacologic mechanisms of action, and the impact of the hydrolysis and metabolites in vivo. It clearly, as I said, affects the way samples are handled from clinical studies.

Finally, I just want to acknowledge my collaborators, Jerry Collins from the FDA, Steve Donahue, Darrell Abernethy at Georgetown University, Debbie Birnkrant from the FDA, and Dr. Norman Fost, who worked with us on the design of the Phase I study. Thank you very much.

(Applause.)

DR. GROFT: Thank you very much, Carol.

As she mentioned, tomorrow we will have quite a bit more time available to discuss the pharmacology in The Analogs of Thalidomide. So those of you with an interest, you're welcome to attend and participate in that session.

Our next speaker, Dr. Norman Fost from the University of Wisconsin, Madison, will discuss the ethical issues related to the use of thalidomide in fertile women and the variables that enter into a benefit/risk decision. So we're anxious for your comments.

DR. FOST: Thank you. I'd like to thank Dr. Groft for the opportunity to talk at this really excellent conference.

In the interest of time, I will adopt the method of Hubert Humphrey, who was said to talk at 500 words per minute, with gusts up to 1,000.

No one wants to have a child with phocomelia. All reasonable people will take all reasonable precautions, if properly informed. No one opposes high standards of disclosure and informed consent for patients. No one opposes high standards for education of physicians and pharmacists.

The question is whether coercive measures are warranted to prevent the birth of even a single child with phocomelia; that is, whether it's appropriate to impose restrictions on the liberty of women who have obviously legitimate and understandable interest in access to this drug for the many, and growing, number of conditions.

It's important to remember that a zero risk is not achievable. There is no system that will prevent the single birth of a child with phocomelia. So the goal of my comments will be to try to find some middle ground that properly balances the interests of future children in not being born with this deformity, and second, the interest of women in getting reasonable access to the drug.

I will not today, in the interest of time, be saying anything about the interests of embryos or fetus; that is, an embryo or fetus who might be affected but does not come to term. There are issues there, but we don't have time to get into them.

I'll be discussing solely the interests of children; that is, future possible children who may be born with phocomelia and who obviously have an understandable interest in avoiding this harm. I will make the point that these interests arise, obviously, before the child is born; that is, if these interests are to be protected, they have to be addressed before the child is born.

Balancing these with the interests of women, who have interests not only in access to treatment once the drug is shown to be effective for whatever condition is at issue, but women as a class who have an interest in being included in clinical trials, so that if and when the drug is approved for marketing, there is information available about safety and efficacy.

Gender and pregnancy are obviously not trump cards; that is, while women have very compelling interests in being protected, and in procreative privacy, these are not absolute values. The point, obviously, is that the interests of women and of mothers and the interests of the future child have to be balanced.

I think we can reject extreme positions. On the one hand, the moral claim that a woman, or a man for that matter, should have unrestricted liberty to expose future children to harm I think can be rejected. It's important to mention it because a recent Institute of Medicine report on access to drugs by fertile and pregnant women took that nearly absolutist position; that is, seemed to suggest that there should be no restrictions on women who have a legitimate need for access to drugs during pregnancy that might expose a future child to possible harm.

A more middle-ground position, as illustrated by the recent proposal of the National Bioethics Advisory Commission on the cloning issue, in which they recommended legislation that would restrict the access of women and men to cloning technology for the time being until safety issues are resolved; that is, who thought that legislation was appropriate to protect the interests of future possible children against the possible harms of cloning.

I happen to disagree with the recommendation, but it's an example of a governmental body recommending legislation that imposes some restrictions on the procreative privacy of women, and of men.

Similarly, the absolutist position that the child's interests should always take precedence -- that is, that the goal here should be a zero-risk environment, that the goal here should be to ensure that no child is ever born with this deformity -- I don't think can be sustained. Just one Supreme Court decision that takes the view that interests of future children cannot be absolute is the Johnson Controls case in which a company in Milwaukee that prohibited women from working in a work place where batteries were made on the grounds that future children would be exposed to established dangers from exposure to lead -- that this was an unreasonable restriction on the liberty of women; that is, the interests of children were not the only factor, that women's access to jobs, and so on, had to be balanced in.

As Judith Ahren, an attorney at George Washington, has said, "A woman has no legal or moral duty to be a procreative saint."

Let's first discuss, then, the interests of children. Children obviously have an interest in not being disabled and being severely disabled. Postnatal phocomelia, if it were to occur, would constitute child abuse. That is just to imagine the hypothetical example that if a woman or a man took a drug, and if suddenly their child's arms and legs would fall off, we would consider that an unreasonable risk to expose the child to.

Even if there were a compelling argument for the woman to take the drug, there would at least be a claim that the child has an interest here to be protected, and there should be some regulation or perhaps some restrictions on it. Maybe not an absolute restriction; it would depend on the reason. But we would take measures to try to reduce the interests of this, even restricting the liberties of people who had access to such drug.

The purpose of such laws in the postnatal setting is not punishment, but prevention; that is, the purpose of child abuse laws is to prevent children from risk of harm, although in some severe cases, even criminal penalties might be warranted.

Well, if postnatal children have an interest in having their arms and legs intact, these interests obviously exist for future possible children as well. This is reflected in many aspects of our laws; that is, damage that occurs while a fetus is in utero can result in liability in some jurisdictions if the child is born alive. Preconception damage can result in liability; that is, if DES were to cause damage in a second generation, there might still be liability if it were prescribed under negligent circumstances; that is, the fact that the child had not even been conceived at the time of prescription would not be an argument legally against a claim.

The interval between when the agent is administered and when the injury occurs is morally and legally irrelevant. Just to make the analogy, someone who puts a bomb in a school yard, even if it's timed to go off in 100 years, we would still say there's a strong moral argument for restricting this activity and there would be legal prohibitions against the activity. The fact that children had not been conceived yet would not be an argument for saying that there are no interests here to be protected.

The cloning example, again, is an illustration of a proposal to restrict a technology for the time being, while safety is unknown, to protect children who are not yet even conceived. So the point I want to make is that children have interests which can be legally protected, not only before they're born, but before they're conceived.

Women's interests, on the other hand, as I said, include access to treatment for effective drugs for life-threatening and disabling diseases such as the ones that we'll hear about. They have an interest as a class in being included in clinical trials; that is, even women who might not presently benefit from access to thalidomide have an interest as women as a class being included in trials, so that if the drug is shown to be effective for a clinical condition, down the road physicians can intelligently and safely prescribe it.

Women also have an interest in procreative privacy, apart from their interest in access to the drug for treatment; that is, they have an understandable legal and moral interest in being left alone with regard to procreative decisions, and even exposure of future possible children to risks.

Let me first just say a few words about the procreative privacy issue. The procreative privacy issue arose legally in full force with Roe vs. Wade, which, it's important to remember, had to do with the right not to procreate; that is, the claim in Roe vs. Wade and most of its progeny to protect the interests of the woman not to have children -- not a positive right to procreate, but a negative right to, if you will, avoid procreation, to be left alone.

This is not the same as an affirmative right to create a child under any conditions of harm. We do have other legal trends, which we'll probably hear more about tomorrow, on ways in which the law has restricted the liberty of women when harm to a future possible child was at issue. In some jurisdictions, for example, women have been forced, compelled by court order, to undergo a Caesarian section medically indicated to protect a child from harm of being born vaginally.

There is also a federal case which refused to acknowledge that; that is, which overruled a court which did that. But there are cases that have gone both ways, including two state supreme courts. In contrast, the Johnson Controls case, as I mentioned, set some limits on how far the state can go in restricting the liberty of women.

But I think the point is that morally it would be wrong -- I think we would all agree -- to knowingly bring a child into the world under conditions of probable misery such as that associated with phocomelia, or at least extreme disability. At least it would require some compelling reason to justify doing that; that is, there would be a moral responsibility to take reasonable steps to avoid that.

Now, with regard to the woman's interest in treatment, which is the central issue here I think, I would suggest that it's important to distinguish the following variables, and this is the heart of my comments. What degree of restrictions are appropriate, and what kind of access women are entitled to have to thalidomide is not one question. It's many questions, depending on a number of variables. I've tried to identify them here.

First, whether or not the disease for which treatment is being sought is serious or trivial. Now, at the moment, all the disorders for which treatment are being sought are serious, life-threatening, seriously disabling, associated with extreme suffering, such as AIDS, cancer, Kaposi's sarcoma, and so on.

It's important to point out, though, that the drug will almost surely turn out to be -- will probably turn out to have efficacy for diseases which may not be life-threatening. Rheumatoid arthritis is one example. Rheumatoid arthritis, of course, can be associated with severe suffering, but there can be milder forms of rheumatoid arthritis.

So the first point I'm trying to make is how compelling the woman's interest is in having access and how weighty that claim should be against the interests of the future child will depend on the severity of the illness and the amount of suffering involved. We would not think, for example, there were a compelling reason if thalidomide were shown to be effective for acne or mild asthma.

Second, the likelihood of benefit would be morally relevant. If the drug has been shown to be proven effective, a woman has a much stronger claim for access to it than if it's in a Phase I trial where efficacy is statistically unlikely. The vast majority of Phase I trials never show efficacy and never wind up going to market. So the claim for access during that phase of testing would be less compelling.

Third, it would depend on the alternatives. If, just hypothetically, asthma turned out to be a disease that was responsive to thalidomide, the claim for access to it for that, even if proven effective, would be less compelling if there were other effective drugs that the woman had not yet used. That is, obviously when it's a last resort, the claim is much more powerful.

Two other variables that are relevant but I think perhaps not as important are obviously the probability and severity of harm to the child. I'm not going to dwell on that because I think everyone would agree that the embryopathy, the phocomelia, everyone would agree, is a severe degree of harm and warrants strict scrutiny.

The importance of the pregnancy might be a relevant variable; that is, there might be a more compelling argument for a woman who is trying to have her first child than one who -- maybe third is not a clear enough example, but a woman who is trying to have her 10th or 12th child. The argument could be made that her claim for procreative freedom in that circumstance would be less compelling than a woman who is seeking to have her first child.

So I've tried to identify some of the morally relevant variables that might guide us in deciding how strong the claim is.

Now, other variables would have to do with the amount of intrusion on the woman's liberty to protect the child. That is, there are different remedies for promoting the safety of the future child. I've just listed four of the common ones here just for points of discussion. The drug could be restricted to just infertile women; that is, women who were surgically sterilized. That would obviously be too severe a restriction. It would be too severe an incursion on procreative privacy and would force too many women to be denied access.

One could require abortion for affected fetuses. I won't dwell on it because it's morally complicated and legally untenable in our country, but it's a method of protecting children that would almost surely be rejected.

Everyone would require strict informing and consent standards; no one is against that. The question is whether that's a sufficient amount of protection, whether that's too loose of a standard to protect the interests of the children.

The most controversial, and I think where most of the discussion needs to occur, is over the question of possible, for example, weekly pregnancy testing, which would be an almost fail-safe mechanism; that is, restricting the supply of drug in exchange for a negative weekly pregnancy test. I think comments of Dr. Woodcock were very appropriate on this point; that is, the trade-off here, if you required something as strict as weekly pregnancy testing, which would be a near fail-safe mechanism, the problem there is if it's perceived as too restrictive by a majority of women, it will drive them underground. It will drive them to buyers clubs.

So the question is, what kind of restrictions here in terms of frequency of pregnancy testing will attract a sufficient number of women -- that is, make it acceptable -- without driving them outside of the system?

Let me just close by trying to apply these principles to two specific examples. For a Phase I study, such as the thalidomide/birth control pill study that Dr. Trapnell mentioned, I think there was a conclusion that obviously there was no benefit to patients. Even in other Phase I trials for therapeutic intent -- that is, for diseases -- since most Phase I trials fail, I think the point could be made that there's no clear benefit, and therefore the claim of women to have access in this would not be compelling. They are not being denied anything which involves a likely benefit.

If gender is important to assess biologic variables in dosing and so on, then it would be reasonable in a Phase I trial under this kind of analysis to require very strict standards, namely infertile women at that stage of testing.

In contrast, if efficacy were established -- that is, if Phase III testing had been completed and the drug were shown to be effective for any of the conditions we're talking about -- if there were no alternatives, no alternative therapy, there was now a high likelihood of benefit and obviously a severe risk of harm and disability for the child, if pregnancy were avoidable through not just contraception but through some kind of periodic pregnancy testing, there would obviously be an obligation to take reasonable measures not to bring a child into the world under conditions in which he or she, presumably, would rather avoid.

The question is mainly, I think, a political one, as Dr. Woodcock phrased it, or a sociologic one, of what degree of pregnancy testing, what frequency would attract or be acceptable to a sufficient number of women?

In summary, balancing is clearly required. We cannot take a position that women should just have unrestricted access to this; no one has suggested that. But, on the other hand, we cannot take the position that a zero-risk environment is what is being sought here. It's impossible anyway. Even if you had daily pregnancy testing and restricted access to the drug, the drug would still find its way into the open market, as Dr. Woodcock made clear. We will never have a world in which there is zero risk of exposure of fetuses or of future possible children. So the goal here is to find some reasonable middle ground that will get that incidence as close to zero as we reasonably can.

Thank you.

(Applause.)

DR. GROFT: Thank you very much, Dr. Fost. You've really given us something to think about in further discussions as the meeting progresses.

Dr. Wilkin has arrived. Last week, as many of you read in the newspapers and probably saw on TV, one of the FDA's advisory committees looked at thalidomide for the second time, and Dr. Jonathan Wilkin from the division will present the summary of that meeting.

DR. WILKIN: Thank you very much, Steve. I appreciate the invitation to this important meeting that you and Terry Toigo have crafted. I think we'll look back on this meeting in the future as an important exchange of information at the beginning of a new era in therapeutics and clinical pharmacology.

We did have a meeting just down the street five days ago. It was a meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee, which hereafter I'll refer to as DODAC. That will shorten this presentation by five minutes. We considered Celgene's NDA new drug application, thalidomide for ENL.

The Federal Advisory Committee Act establishes the legal framework for all of the FDA advisory committees. They provide scientific and technical expertise. They advise and make recommendations. They do not decide finally on regulatory decisions. That goes to the people who work at the agency. But the real asset is that they do provide this independent expert scientific advice.

The DODAC group has approximately three to four meetings per year. There's a fixed membership, with three-year rotations. There are nine dermatologists who serve on the committee, four ophthalmologists, one biostatistician, one consumer representative, and for the particular meeting that we had last week, we did invite obstetrician/gynecologists from other committees, and neurologists from other committees. But the only person from another committee who came was a member of the Antiviral Drugs Advisory Committee. In addition, we often have special government employees who are previous members of committees who come and sit in on the deliberations.

Approximately two to three weeks before the meeting, the committee will receive a briefing package which will consist of the sponsor's summary of safety and efficacy, the FDA's summary of safety and efficacy, data from the clinical trials, the FDA reviewer's reviews, and often articles from the literature.

The types of issues that will come before an advisory committee are many and varied. There have to be at least 25 really great reasons. Some of the ones that we thought about when thalidomide was coming to the advisory committee are it's the first product in a class, it's a new molecular entity, it's never been approved at the agency. Products that have attracted significant public interest and controversy were all here today. Any product under review with significant safety or effectiveness issues -- and again, we thought it was important to have outside advice on these points.

Now, the advisory committee meeting has identifiably separate portions. There is an open public hearing, where anyone can sign up. There is a format for this, but one can sign up and get 5 to 10, sometimes 15 minutes and present their own opinions on the issues that are before the committee, or perhaps issues that might be related to that particular area of the FDA but are not really being discussed that day. It's truly open.

Then there is the part where the committee will listen to the FDA presentations, the sponsor's presentations, invited speakers. That's the open committee discussion. There was no closed session for the thalidomide meeting. In our particular committee, the usual reason for a closed session is where we are updating them on the drugs that are in-house at the FDA that we're considering.

So the meeting began on September 4th with an open public hearing. We heard statements from the American College of Obstetricians and Gynecologists, the American Leprosy Foundation, the American Academy of Pediatrics. Then there were brief introductions by the agency, and then we moved to the sponsor presentations.

After lunch, we came back and had a second open public hearing. American Leprosy Missions presented a statement, as did American College of Medical Geneticists, the Teratology Society, National Organization for Rare Disorders, National Women's Health Network, and American Behcet's Disease Association.

This was followed by the FDA reviewer presentation. Then after that we had two invited speakers. Dr. Cynthia Moore from the CDC discussed elements of strategy to prevent birth defects due to thalidomide exposure, and Dr. Colin Crawford presented information on thalidomide neurotoxicity in ENL.

On September 5th, we opened the morning with a committee discussion. Then there was a statement by the Thalidomide Victims' Association of Canada. Then the committee received the questions and deliberated on them.

One of the aspects of the questions as presented to the committee was that we knew that the term "erythema nodosum leprosum" is actually used ambiguously in the literature. It can refer to the entire systemic syndrome of ENL or just to the cutaneous lesions. So the questions were originally crafted in a way that the chair could go either way on this. For question one, the chair exercised his prerogative of altering the question. He limited it to: Has the efficacy of thalidomide in the treatment of cutaneous ENL been demonstrated?

I should tell you that this is still in draft format. The chair needs to sign off on this, but this is the initial draft from advisors and consultants -- nine yes votes, one no vote.

Question two: Has the safety of thalidomide been adequately described in the treatment of the systemic ENL syndrome, or any subset of ENL, such as cutaneous ENL? The vote was three yeas and seven nays.

Then, really, the pivotal question three: Do the benefits outweigh the risks? The interpretation of this is, does the committee recommend that Celgene's thalidomide be approved for the systemic ENL syndrome, or any subset of ENL, such as cutaneous ENL? The response to this was eight yes, one no, one abstention.

Everyone, I think, outside of the agency focuses a lot on the outcome of the questions. I think there's a tendency to under-value the rich insights that emerge in the discussion. We at the agency spend a lot of time going over all of the discussion points that were raised by the committee.

The discussions seem to begin among the committee members with restricting the distribution of erythema nodosum leprosum, but it evolved. They discussed that the distribution system might be a better, safer system than the IND mechanism, actually, and in the end they came up with not restricting distribution to ENL. That's an example. I'm not trying to be exhaustive and encyclopedic in all the comments that I thought were important. I'm just trying to give you an idea of some of the types of comments they made.

The comment emerged to use the actual photo of an infant in the package insert or the packaging for thalidomide, and that there needs to be a really good monitoring for neuropathy.

They thought that there were a few other things at the end that were still needed. There's a study ongoing by the sponsor in the Philippines, E003/P, and they would like to have those results, when that study is completed, presented to DODAC. Also, they would like to have some information on studies that are performed to learn more about neurotoxicity. They are encouraging sponsors to develop safer congeners. For thalidomide, they would like more pharmacokinetic information, specifically information on metabolites, elimination, and storage.

So, what is next in the regulatory process? Well, after we have an advisory committee meeting, we then have an internal meeting at the FDA, a debriefing meeting to go over the responses to the questions, and also all of the insights and discussion points that emerged at the meeting. That will be done this week.

This is a new molecular entity, and you may know the system is that the office director, the Director of the Office of Drug Evaluation V, will be signing off on this particular application. He'll be taking everything that he has on his desk into consideration -- all the reviews, the information that emerged at the advisory committee meeting, discussions with others in the agency. I'm sure he'll be looking for ideas that come from this meeting as well.

Thank you.

(Applause.)

DR. GROFT: Thank you very much, Jonathan.

Are there any questions? I don't know if the people have collected questions. We have a couple of minutes for questions before we break. If there are any, if you could stand up and identify yourself and project as well as possible, we'll try to pick you up.

PARTICIPANT: (Inaudible.)

DR. GROFT: Jonathan, did you get the last part? Oh, I'm sorry.

PARTICIPANT: Do you want me to say it again?

DR. GROFT: Would you, please? Yes. Why don't you come up here to the microphone, and I think by the afternoon session we'll try to get a floor microphone.

PARTICIPANT: The first question. It was mentioned in passing that there is some ongoing cases of phocomelia in countries from thalidomide currently. I wondered what some of them were.

The second question was, is erythema nodosum in leprosy patients the same as it is in ordinary erythema nodosum, in that the nodular manifestations occur primarily, or at least initially, on the legs?

DR. WILKIN: Well, I'm a dermatologist and not a leprologist. There are leprologists here, and I'm sure later in this meeting you might be able to get some more definitive information on the distinction of erythema nodosum leprosum.

Erythema nodosum is different from erythema nodosum leprosum. They are two different inflammatory types of reactions. I think it might be possible to have erythema nodosum and erythema nodosum leprosum occur in a patient with leprosy, and perhaps they well could make the distinction between the two entities. The old-timey name for erythema nodosum was actually erythema contusaformi, because, as these lesions resolve, they leave what looks like a bruise. I'm not sure if that's the way the lesions of erythema nodosum resolve.

But we have Dr. Yoder and Dr. Ray and others here who might be able to speak to that.

DR. GROFT: I think the second part of the question, with the occurrence of phocomelia in other countries -- Dr. Bierzwinsky?

DR. BIERZWINSKY: Well, thalidomide is being used in Mexico for the treatment of erythema nodosum leprosum. We have had no reports of phocomelia, which means that people are being careful about which people are taking it.

DR. GROFT: I don't know if anyone has any other comments.

Dr. Trapnell?

DR. TRAPNELL: We actually had information sent to us when we were starting our study that there are cases apparently occurring in Brazil, but I have no scientific data at all. This was just mailed to us, really, at random.

DR. GROFT: For Dr. Trapnell: What are the inter-species differences in metabolism, pharmacokinetics, pharmacological effects, toxicity of thalidomide?

DR. TRAPNELL: Frankly, I don't think it's really been studied well enough to be able to delineate that with total certainty. A lot of the metabolism studies in animals were done after the teratogenicity issues were discovered in humans. There is a lot of different metabolites in animals that are found; many of them are found in developing embryos and fetuses.

But I would have to say that, at this point, that's probably one area of research that we need to do so that we can develop better animal models to be used to assess the human toxicity.

DR. GROFT: Dr. Bierzwinsky, is thalidomide going to be approved for other indications in Mexico?

DR. BIERZWINSKY: If there is enough scientific support, and clinical trials are conducted in Mexico which show benefit, then it would be approved for new indications, yes.

DR. GROFT: Dr. Fost, would you comment on the advisory committee's decision in the context of risk versus benefit for a condition as rare as ENL?

DR. FOST: I don't know enough about what, if any, prescribing or distribution restrictions were put on it. Obviously, the condition is a serious one, and serious enough to warrant some access. The question is, under what degree of restrictions? I'm not clear on whether the advisory committee -- what distribution mechanism you recommended.

DR. GROFT: We've got several others that I don't know if we'll have enough time to get through.

DR. WILKIN: Would you like a comment on the distribution?

DR. GROFT: Go ahead, sure.

DR. WILKIN: There was a presentation by Dr. Lumpkin at the advisory committee meeting on the different possible types of distribution schemes. The one that is most rigorous can be found in 21 CFR, the Code of Federal Regulations, 314.520. It's a mandatory restricted distribution.

I have to say, though, that while these were discussed, nothing was concluded at that meeting. It was merely just presented to the committee as different choices.

DR. GROFT: Dr. Wilkin, please clarify your comment on the photo of the infant. Do you mean an infant with phocomelia?

DR. WILKIN: We may hear more about this from Cynthia Moore or others. I think the committee had the notion that if there were a photo in the informational package that went to patients who would be taking thalidomide, that that might be more compelling, more educational than just simply a line drawing.

DR. GROFT: Then again, why are there no teratologists or neurologists on the committee?

DR. WILKIN: The neurologists on the -- there is an advisory committee. Our advisors and consultants staff person contacted that committee, attempted to obtain neurologists to attend and vote, but no one agreed to come.

We did have Dr. Crawford, a neurologist, and of course the sponsor had Dr. Cornblath at the meeting. So they provided expert advice to the committee.

DR. GROFT: Dr. Fost?

DR. FOST: At the risk of seeming self-serving, I think it would be desirable to have qualified ethicists on some of the advisory committees when there are obviously major ethical issues.

DR. GROFT: Dr. Kelsey, was the January 1961 NDA denied because of neurotoxicity? This is a multiple-part question.

DR. KELSEY: Could you repeat the question?

DR. GROFT: Was the 1961 NDA denied because of neurotoxicity?

DR. KELSEY: We delayed approving it, not that we ever did. The neurotoxicity was certainly our first concern, and it increased. We had an advisory committee, too, in September. They actually didn't think it was too serious; it could be dealt with by labeling. They also felt the teratology would have been disclosed. As I mentioned, it had been suspected before this.

Then after that meeting, we got much more reports on the severity of this peripheral neuritis. My opinion is that we would probably have never approved it on that basis alone, but we didn't have to make that decision once the word of the teratology got around. So I say, yes, it concerned us very much.

Remember, the proposed uses were as a sedative and a hypnotic.

DR. GROFT: We're going to have to cut the questions off now in order to keep the meeting moving. So if you did submit a question, please gather one of the panelists with you and present the question to them. Or, if we have time, as the meeting progresses, perhaps we can bring these questions back in tomorrow.

One other bit of housekeeping. If any of you would like to make a presentation at the open public session tomorrow, please sign up out back. I think we referred to it earlier. It's important for us to know what the time constraints will be, if necessary, for tomorrow afternoon.

We also have received the bibliography that was put together by the National Library of Medicine, and that is available outside as well.

So if we could reconvene in about 10 minutes, at five of.

(Recess.)

MS. TOIGO: I guess we'll get started, if everybody is ready. My name is Terry Toigo, and I'm with FDA's Office of Special Health Issues.

This meeting is described as an open scientific workshop. Given the meeting's scientific focus, some have asked what's the purpose of this panel? A public perspective? After all, like NIH and CDC, FDA is a science-based agency, where scientific facts and not opinions must prevail, and where scientific facts represent the impartial arbiter of conflicting views and our best protection from human error.

As a consumer protection agency, FDA must make certain that the public's interest is protected as those scientific facts are being discovered. In that regard, we must constantly be mindful of the impact of our actions on the people we serve, people from all walks of life who often have differing views about what FDA can and should do.

Although our constituencies are diverse, we nevertheless strive to be responsive to all citizens. One of the most effective ways in which we can live up to this principle is by inviting the public to actively participate in our deliberative process.

Thus, the purpose of this panel is to give all of us an opportunity to hear from you, the public. We'll hear from health care practitioners, an advocate for women's health, a thalidomider, and a patient advocate.

What might we learn from this panel? I think we will learn that each participant has a unique point of view. Some may be personal, some may be legal, and some may be societal. I think we will also learn that although individuals and the groups they represent may differ in their perspective, they are each working towards the same public health goal. In this case, that is to maximize the benefits and minimize the risks associated with this potentially therapeutic but dangerous drug.

The panel reminds us of the various constituencies who may be affected by our actions and that it is very important for researchers, industry, and the government to be mindful of these varied needs when making policy decisions or designing a clinical trial or recruiting patients to a clinical trial, or developing an educational program for a drug targeted at multiple audiences. The public's views must be included.

I'd like to thank the panel members for taking their time to share with us their perspectives. I'd also like to thank my co-chair, Steve Groft, for his flexibility in working with his sister agencies and others to accommodate the various agenda needs of this meeting.

Finally, I'd like to thank the staff in the Office of Special Health Issues, and particularly David Banks for his dedication to the many unanticipated tasks that accompanied this meeting.

That being said, I'd like to introduce the panel members of the public perspective.

Dr. Leo Yoder represents health care providers for leprosy patients, and he was formerly the chief of the Medical Department at the Hansen's Disease Center in Carville, Louisiana. Dr. Yoder has extensive experience treating leprosy in the United States and Africa.

Mr. Randolph Warren represents the Thalidomide Victims' Association of Canada, an association created to empower and enhance the quality of life of Canadian thalidomiders.

Mr. William Zellmer represents the American Society of Health System Pharmacists, where he serves as the vice president for professional and public affairs.

Dr. James Allen represents the American Medical Association, where he serves as the vice president for science and technology.

Ms. Cynthia Pearson represents the National Women's Health Network, where she serves as executive director and oversees all program and policy projects.

Finally, Mrs. Nancy Paller, who represents herself in her role as the mother of an HIV-infected young man with aphthous ulcers.

That being said, I'd like to start with Dr. Yoder. We're going to try to keep these to 10 minutes, so you'll have the light. At nine minutes, the yellow will go on.

DR. YODER: Thank you, and good morning. I come to you, as has already been stated, as a physician who has been involved with Hansen's disease, or leprosy, for about 20 years. The last 15 years of those were at the Hansen's Disease Center at Carville, Louisiana.

In that situation, we are the referral center for the United States, and we tend to see many of the more complicated and difficult cases of ENL. In that role, I have lived through this difficult experience, these ill patients, sometimes for a number of years, and have experienced not only the physical pain but also the psychological distress, and even depression, that goes with this illness, especially in some of the more ill forms.

When I was asked to give this talk, I was asked to talk about what I would say to a patient for whom I was prescribing thalidomide. Basically, that's what I intend to do for just a few minutes. At least I will try to touch on the areas that I would discuss with a patient who would have come to Carville or to me and I was considering putting that patient on thalidomide for the first time.

Just a few facts about the disease itself. Leprosy is a disease with a spectrum. You can have very mild disease, very few bacteria, limited disease, and it may not even be of major consequence; to the other end of the spectrum, where patients have generalized disease, they have a lot of bacteria, they have many nerves involved, and it can be a devastating illness.

This disease is caused by bacteria, Mycobacterium lepri. Part of the problem with this disease is not only that it's a bacterial infection which persists for a long period of time, but it's an immunological problem as well, and especially also the fact that it has a predilection for certain specific cooler parts of the body, namely the nerves of the hands and feet. Also, some other organs are affected in the lepromatous type, the type which I indicated has the diffuse type of disease -- namely, the eyes, the testicles, and sometimes joints and other areas can be affected as well.

A group of these patients who have the generalized former disease get what we have talked about here this morning as ENL. We don't have time, obviously, to go into a lot of the things that we could talk about.

But primarily I would point out to you as a patient who has this problem that this is an immunological problem. It's a problem with the immune system. It is not a treatment failure. It's not a drug reaction. Incidentally, this often occurs sometime after a patient has been on treatment for a period of time, sometimes maybe a year or two. He cannot be present at the time the patient is diagnosed.

But often the patient is started on treatment. We have good antibacterial drugs. We can kill the bacteria actually fairly rapidly with some of the drugs, but the bacteria do not clear from the patient rapidly. They stay around for a long time. The dead bacteria stay around even for several years at times. It is this immune response of the body to these dead bacteria that are around that cause this problem that we know as ENL.

These patients not only have a skin eruption, but I would note in response to a question that was asked earlier that it is quite different than simple erythema nodosum of the lower extremities, which you've seen in other disorders.

The skin lesions can look very similar, but these can occur in any part of the body -- the face, the extremities, all over the trunk. It is associated often with fever, pain. You can get swelling of the glands. These patients often are rather acutely ill. These skin lesions not only are painful, but they may ulcerate. So it is a generalized severe illness in many patients. It can be in a mild form, but we're primarily talking about patients who are fairly ill.

I want to show just a few slides of what it looks like. I hope the slides are on. I think we went one too far.

This is a typical skin eruption. These look like the erythema nodosum you may have seen in other disorders, but they are tender and painful. Usually an individual nodule will stay for a week or so, and then they do resolve with a slight darkening pigmentation of the skin as they go away. But untreated, you will get new crops of these.

A second patient with a similar type of problem, and the same patient with these lesions on the face. These look like they might be almost ulcerating. A little different type of lesion -- this young lady had typical eruption of the upper part of the body in the extremities, but also had these blistering type lesions at the lower extremities.

This is another patient with sterile pustules which may ulcerate. Finally, a young lady who I remember so well some years ago was referred to us and was actually in our institution for several years. Because she had persistent and chronic ENL, she suffered all the side effects of prednisone, which I will mention again in a moment. She even ulcerated on her face.

That's the end of the slides.

The treatment options for this disorder in leprosy patients are quite limited. There are only a few that are useful, other than in the mildest cases. The mildest cases can be treated with simple analgesics, but that is basically a drug called clofazimine, number one, which is a drug that is of some benefit. However, it is slow-acting and benefits patients primarily if it is given at large doses for four to six weeks, and importantly causes significant pigmentation of the skin, which persists for a long time and is therefore unacceptable to some patients, especially young women.

The second drug that is very effective is prednisone, or what is commonly known as cortisone-type drugs. These drugs will work and have been used for many years to treat this disorder, but the problem is that you have to give them in fairly large doses, often in this country 60 to 80 milligrams a day. This disease tends to be chronic, and therefore you have to give it a long time. You need to give it in fairly large doses, which produces significant side effects such as thinning of the bones, diabetes, cataracts, glaucoma, and other things.

So one of the main reasons I would give thalidomide to you is to avoid these side effects from prednisone, which is really the only good alternative.

Thalidomide, in our experience, works. It allows people to return to work. It allows them to get off of their prednisone, or at least in much-reduced doses, and therefore is a god-send to many of these people who really have no other alternative.

It has been recognized by the treatment of choice by many leprologists for many years. There is a rather extensive body of literature. In our experience, it has been found to be very effective.

We do not, however, ignore or forget the serious disadvantages and side effects of this drug. If I were going to give this drug to you, I would certainly start out by telling you the serious birth defects that can be caused if it is given to women of childbearing age. Therefore, pregnancy is an absolute contraindication, and under the present program -- I am not giving you this as necessarily my opinion of how it should be done. Under the present program, under the IND that we have, it cannot be given to women of childbearing age anywhere in the United States, except at Carville.

Therefore, we can give it as outpatients only to men or to women who have been surgically sterilized or women who are postmenopausal. This does limit access of the drug to some women who would certainly benefit from it.

There are a number of other side effects that every patient would need to know about. One, of course, is sedation, particularly in the larger doses. Patients would need to be warned about the fact that they should not drive or engage in other hazardous activities which would endanger them if they were sedated.

Neuritis, which has been mentioned, which will be talked about some more, we would talk about at some length. We're also dealing with a neurologic problem with leprosy as well. So patients are very much warned about the possibility of new numbness, tingling, any change which might indicate a problem with the nerves, and that we need to be advised so we can do appropriate testing and evaluation to see if indeed this is due to the Hansen disease or leprosy itself, or whether there might be any reason that it might be connected to the use of thalidomide.

There are less common, less serious side effects associated with it -- sometimes dizziness, constipation, swelling of the extremities -- which are usually mild and do not necessitate discontinuing a drug.

So I would say in conclusion, with many years of experience and the experience of other people who have used this drug, we have found it to be very effective in use in these patients which would allow them to avoid the serious side effects of prednisone and allow them to continue their reasonably normal activities of work or whatever they might be. If properly monitored and given according to instructions and used only by the patients for which it is indicated, I think the risk can be minimized to an acceptable level.

Thank you.

(Applause.)

MS. TOIGO: Thank you, Dr. Yoder. I can say I've learned far more about thalidomide in the last two years than I did as a pharmacist in the outpatient pharmacy in the Staten Island Clinic, where once a month we had a Hansen's disease clinic.

Our next presenter is Randy Warren.

One more thing. If you have questions after the speakers, Carol is going around collecting. So if you flag her, she will get them.

MR. WARREN: My name is Randy. I'm 36. During her pregnancy, my mother was prescribed thalidomide to alleviate severe morning sickness symptoms. My mother took thalidomide twice, two teaspoons total. Thalidomide caused my birth disabilities, necessitating 32 operations over my life and eight years accumulated time spent in the hospital before I was 16, in a different city from where my parents lived.

When I was 12 years old, I looked at my chart on my hospital bed and I read the words, "congenital anomalies as a result of the drug thalidomide." I learned, and I continued to learn what happened to me and to my friends 40 years ago.

Today, I describe myself far more professionally, as a founder and CEO of the Thalidomide Victims' Association of Canada. I represent the 125 Canadian survivors of the drug that violated our mothers and betrayed their doctors. Many of our mothers and fathers were doctors and pharmacists.

I speak for thousands of unborn babies, murdered as they were to grow. I speak for the 50 to 60 percent of us born who died young. There are 5,000 of us alive today.

I came here today to dazzle you with my eloquence and the triumph-over-tragedy stories of my brother and sister thalidomiders. That's what we call ourselves, thalidomiders, lest we forget. But I kind of feel somber and resolute. I grieve, yet I feel conviction and a sense of purpose. It's been a really, really tough week for us.

In 10 minutes, I want to say so much. I want to tell you of brave women raising children expected to live to be only 10 years old, and then 20 years old, and now we're told 55 years. But I know these children, now adults, and I am one. We want to enjoy our grandchildren and great-grandchildren, those of us who can have children. Some of us, I know, will live longer. But nobody can really say what can happen to us until we're all gone.

We thalidomiders, we're a family. We were all born together in the same few years, whether we're from Japan, Australia, Germany, Great Britain, Sweden, Brazil, or Canada. We even look alike. We know each other, and we understand each other without words. We want you to understand us. After all, today is yesterday's tomorrow. We are you. We're your brothers, we're your sisters, we're your mothers, we're your fathers. We're the people that you marry; we're the people that you broke up with before you intended to get married.

We feel. We laugh. We cry. We love, and we are loved. Yes, we suffer. We're degenerating. We're deteriorating in ways we were never warned of by doctors or scientists or persons who develop artificial limbs to make us look like everybody else. But these things should have been easy to predict.

We who know pain and uncertain futures extend ourselves, our empathy, to those who suffer from other unjust diseases and conditions where thalidomide might help.

Thalidomide, I have heard, takes people out of wheelchairs, and so much more. But please respect and remember the fact that thalidomide put me in my wheelchair. Thalidomide gave many of us shortened arms, or no arms, meaning we can't hug back. We can't comb our own hair. We can't even touch our own backs.

We of the Thalidomide Victims' Association of Canada will never accept a world with thalidomide in it. We cannot. But we cannot fight thalidomide. It wins every time.

We're forced to prefer regulated thalidomide over illegal thalidomide available on street corners, without warnings. We who know suffering cannot deny quality of life or longer life to others who suffer. We demand mandatory compliance with strict distri