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`TRANSCRIPT
`
`THALIDOMIDE: POTENTIAL BENEFITS AND RlSK
`
`OPEN PUBLIC SCIENTIFIC WORKSHOP
`
`Sponsored By
`
`NATIONAL INSTITUTES OF HEALTH
`
`FOOD AND DRUG AD1\1INISTRATION
`
`CENTERS FOR DISEASE CONTROL AND PREVENTION
`
`Tuesday, September 9, 1997
`
`Auditorium
`
`-,."j'_.._~-~-• Y~- .. ~ ... ~-.i..-- _.rry __ ,_._._
`l'l<UHJ11i:111H::;um~c::l Ul ilt:i11Ul
`9000 Rockville Pike
`Bethesda, Maryland
`
`CONTENTS
`{with hyperlinks to speakers presentations)
`
`
`
`Page 1 of 119
`
`CELGENE EXHIBIT 2023
`Coalition for Affordable Drugs VI LLC (Petitioner) v. Celgene Corporation (Patent Owner)
`Case IPR2015-01103
`
`

`
`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 Phann.D. Opening Remarks
`
`Welcome
`William R. Harlen. M.D.
`Associate Director for Disease Prevention, NIH
`
`Historical Perspective
`Frances 0. Kelsey. M.D.
`Deputy for Scientific Affairs
`Office of Compliance, FDA
`
`,-
`
`Current Issues and Overview
`janeUYQodcock, M.D.
`Director, Center for Drug Evaiuation and Research, FDA
`
`Experience with Thalidomide in Mexico
`Guillermo Bierzwinsky, M.D.
`Director, Drug Control Directorate of Mexico
`
`Clinical Phannacology ofThalidomide
`~<3JQ1Braup_T.r.;w_n_elL M.J)__,
`Office of Therapeutics Research and Review
`Center of Biologics Evaluation and Research, FDA
`
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`Nnrm<>n Pn<::t M n MPH
`...... L.JP.,
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`University of Wisconsin-Madison
`
`....
`
`.&.
`
`Report on Meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee
`Jonatn.l!n~Wilkin.M.D.
`Director, Division of Dermatological and Dental Drug Products
`r.f'ntf':l" fnr· nrno- FvAIIll'ltinn A11rl R P<!P.l'll'r'h J;Tl-A
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`__ _, __ _..,
`
`Questions
`
`PERSPECTIVES FROM THE PUBLIC-- A CONSULTATION WITH~ ..
`
`Theresa Toi!:'!o. R.Ph .. M.B.A., Moderator
`Associate Commissioner for Special Health Issues, FDA
`
`
`
`Page 2 of 119
`
`

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`American Leprosy Mission
`
`Thalidomide: The Survivor's Perspective
`Randolph Warr~l1
`Thalidomide Victims~ Association of Canada
`
`Pharmacist's Perspective
`mHiam 1\__,_Ze~lmer. M.P.H.
`American Society of Health-System Pharmacists
`
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`American Medical Association
`
`.&.,L,._,•
`
`Thoughts About Thalidomide: Are We Now and Can
`We Ever be Ready for the Mainstreaming ofThaJidomide?
`Cynthia Pearson
`Nationa1 Women's Health Network
`
`A Personal Perspective
`Nancy Pall
`
`Questions
`
`MONITORING FOR SAFETY AND MANAGEMENT
`OF ADVERSE EVENTS
`
`~-
`
`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, NJH
`
`Regulatory Considcraiion in the Ciinicai Deveiopment
`of Thalidomide: Safety Monitoring and Investigational
`Safety Findings
`Debra Birokrant, M.D.·
`
`Thaiidomide Neuropathy
`Herbert H. Schaumburg,. M.D.,
`Albert Einstein College of Medicine
`
`
`
`Page 3 of 119
`
`

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`Peripheral Neuropathy and Exposure to Thalidomide
`Coli-n Crawford, M.R.C.P., D.P.M.& H.
`Imperial College of Science, Technology and Medicine 164
`
`Neurological Testing ofPrimates
`Tuck_~r A. Patterson. Ph.D.
`National Center for Toxicological Research, FDA
`
`Monitoring for Peripheral Neuropathy
`Manr._KJJoet~r,__M..J)____,_,_Eb.D.
`Nationallnstitute ofNeurological 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. Hiii, 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 Reproduciive and Uroiogic Drug Products
`Center for Drug Evaluation and Research, FDA
`
`How Environmental Effects on Child Health Arj~ Recognized
`Robert W. Miller, M.D_,_J)r.P.H,
`
`Experience With Accutane
`Allen A. Mitchell, M.D.
`Boston University
`
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`£;yn_thi'!}100!~._M.n .. Ph.D.
`Centers for Disease Control and Prevention
`
`Questions
`
`P R 0 C E R 0 IN G S (8:35a.m.)
`
`DR. GROFT: Good moming1 everyone. If you'll take your seats, we can get started. We
`
`
`
`Page 4 of 119
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`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. fn 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 fuli 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
`iicensed has pui: a particular onus on it. The very severe adverse effects are very cieariy a
`detriment to some of the investigation i:hat has occurred.It's particuiariy important, then, thai
`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 centeis at the National Institutes of Health are
`actively investigating uses for the drug. T\<venty ofth.e 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
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`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 pha.rmaco!ogic actions a.11d Ln looking for new a.TJ.d nove! approaches to
`treatment of disease with phannacologic agents. He has shepherded this meeting along, has
`
`
`
`Page 5 of 119
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`worked with the other federal agencies, with industry, and with others to develop the
`program, and he is to be congratuiated for this effon.
`
`Steve, 1'11 tum the program over to you.
`
`DR. GROFT: Thank you very much, BilL
`
`Aimost a year ago, w~ eslablished 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
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`the uses, that one prot9col 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
`\~vorkshop v·.rhere ~ ... .re could present the potential benefits and risks associated \vith
`thalidomide. So here \l.le are today, almost a year later. I think our first meeting ·v.ras 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 ::~nd came un with the recommendations_ Hetween Or_ Woodcock and Or Jonathan
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`Wilkin, we'll he hearing the results of that, as most of you have already read in the papec
`
`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 tl\ink 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.
`
`
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`Page 6 of 119
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`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 FDf ... here in the United States~ In
`those ~...\'0 generations, it is probably 50 percent of the U.S. population \Vho really don't ha\re
`a clear understanding of what occurred, and what the effects ofthalidomide were on the
`unborn.
`
`We have quite a task in front of us. All of us-- the health care providers, the researchers,
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`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 a1ong.
`
`Not that we have all of the questions answered with thalidomide. It doesn't boiJ 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 pennanent, or is it transient? Is it dose-dependent?
`We'll want to talk about that a litt1e 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 wiU
`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.
`
`
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`Page 7 of 119
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`With thalidomide, as with all drugs, we all have to make a benefit/risk decision. [think that
`the point ofthe 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. lf you have any
`questions, please fil1 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 ofthalidomide.l culled through, I guess, about 4,500
`references from around-1962, and selected around l ,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 sessjons. 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 until2:00, 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 car± summou a taxicab. The registration staff of Prospect Associates with Carol Sadler
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`Page 8 of 119
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`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, tl)'ing to put
`things together, and Dave Banks, who works with Terry. So thank you to hoth of them, and
`to my staff-- A_nita Pikus, Mmy 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
`reonired ouite a bit of effort I thank them for all the heln thev 12ave to u~.
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`Thanks to Bill Ha11 of the Office ofDisease Prevention for assisting and putting the meeting
`together as well, and then finally, to all of those ofyou 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, sol 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 ·(cid:173)
`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 p]easure for me to be here today and recapitu]ate a bit of the past. I
`joined the Food and Drug Administration as a medicai officer in August of i 960. 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
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`Now, at that time, the bureau was, of course, much smaller than it is now. I think, ifwe
`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 applicatior.s were about 300 a year. l'lo\v, there are over 200 medical
`offices.
`
`
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`Page 9 of 119
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`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 ami exciting drug came in, and it was in those applications that the best clinical and
`animal studies were perfonned. In general, at the time, drug testing was not considered a
`very scholarly pursuit by most people. Many ofthe 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 whieh 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.Hwe hadn't communicated with the company before that, they
`could have automaticaiiy assumed that it was okay, and marketed it. So very dose tabs was
`always kept on the date.
`
`We did get our letter out on November the lOth, 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
`ac~towledgement was Septembei the 15th. So we got oui lettei out on the 1Oth of
`~.Jovember. In 'Lltis, we declared that the application \Vas incomplete and inadequate, atid
`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 oftime. He also felt that there were inadequate absorption
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`present, and so on. .
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`She, fortunately, had been educated in German, and a lot ofthis application consisted of
`German reprints with an English tra.TJs!ation. She of course could read t.lJ.e original Genna.Tt,
`~ttd did find at least one error in the tra..11slation. I, who k110\V no Genna..'l, or just enough to
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`Page 10 of 119
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`na~!': a Ph.D. exam in it. was verv imnressed bv this_
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`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.
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`T was narticularlv -- and all of us were -- concerned about the fact that vou seem to be able
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`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 unabJe to do
`so. You've probably heard a later comment that, had thaJidomide 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 ofthe 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 cm::npany 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 t1ndings, 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 wouid have to give them another opinion. We were continuaiiy concerned about the iack
`of data on metaboiism, excretion, absorption, and this curious iack 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 Uiink, and we did not get our British and other foreign publicaiions 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.
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`Page 11 of 119
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`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 materia) that they distributed with the drug. Our company was
`not obliged to submit foreign supporting material or material ofthat type at that time, so we
`were not aware of this side effect.
`
`They had independ