~-
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`1
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`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`FOOD AND DRUG ADMINISTRATION
`
`FORTY-SEVENTH MEETING
`
`OF THE
`
`DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY COMMITTEE
`
`~
`This transcript has not been edited or corr~ed,
`except where relevant for the deletion of m~rials
`not releasable under the Freedom of Informat,ion
`Act. The Food and Drug Administration mak'as no
`representation as to its accuracy.
`
`8:37 a.m.
`Friday, September 5, 1997
`
`~ _,.
`cg
`
`Versailles I and II
`Holiday Inn
`8120 Wisconsin Avenue
`Bethesda, Maryland
`
`ASSOCIATED REPORTERS OF WASHINGTON
`1523 North Carolina Avenue, N.E.
`Washington, D.C. 20002
`(202) 543-4809
`
`CFAD VI 1013-0001
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`
`
`1
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`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`FOOD AND DRUG ADMINISTRATION
`
`FORTY-SEVENTH MEETING
`
`OF THE
`
`DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY COMMITTEE
`
`~
`This transcript has not been edited or corr~ed,
`except where relevant for the deletion of m~rials
`not releasable under the Freedom of Informat,ion
`Act. The Food and Drug Administration mak'as no
`representation as to its accuracy.
`
`8:37 a.m.
`Friday, September 5, 1997
`
`~ _,.
`cg
`
`Versailles I and II
`Holiday Inn
`8120 Wisconsin Avenue
`Bethesda, Maryland
`
`ASSOCIATED REPORTERS OF WASHINGTON
`1523 North Carolina Avenue, N.E.
`Washington, D.C. 20002
`(202) 543-4809
`
`CFAD VI 1013-0001
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`
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`2
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`APPEARANCES
`
`COMMITTEE MEMBERS:
`
`JOSEPH McGUIRE, JR., M.D., Chairman
`Carol Herzog Professor of Dermatology
`and Pediatrics
`Stanford University School of Medicine
`Department of Dermatology
`MSLS Building, Room P-204
`Stanford, California 94305
`
`TRACY RILEY, Executive Secretary
`Advisors and Consultants Staff
`Center for Drug Evaluation and Research
`Food and Drug Administration
`Chapman Building, Room 200
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`SUSAN COHEN, B.S., Consumer Representative
`3814 Inglemere Drive
`Bethesda, Maryland 20817
`
`S. JAMES KILPATRICK, PH.D.
`Professor of Biostatistics
`Medical College of Virginia
`Virginia Commonwealth University
`1101 East Marshall Street
`Sanger Hall, Room B-1-039-A
`Richmond, Virginia 23298-0032
`
`JOEL MINDEL, M.D.
`Director, Neuro-Ophthalmology
`Mt. Sinai Medical Center
`Annenburg Building 22-14, Box 1183
`New York, New York 10029-6574
`
`MILTON ORKIN, M.D.
`Clinical Professor
`Department of Dermatology
`University of Minnesota
`2733 Huntington Avenue South
`Minneapolis, Minnesota 55416
`
`ASSOCIATED REPORTERS OF WASHINGTON
`1523 North Carolina Avenue, N.E.
`Washington, D.C. 20002
`(202) 543-4809
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`CFAD VI 1013-0002
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`3
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`APPEARANCES
`
`(Continued)
`
`SPECIAL GOVERNMENT EMPLOYEES, CONSULTANTS
`AND GUEST SPEAKERS:
`
`WILMA BERGFELD, M.D.
`Head, Clinical Research
`Department of Dermatology
`Cleveland Clinic Foundation
`9500 Euclid Avenue
`Cleveland, OH
`44195-5032
`
`COLIN CRAWFORD, M.B., CH.B., MRCP, DTM&H
`Neuromuscular Diseases Department
`Division of Neuroscience and
`Psychological Medicine
`Charing Cross Hospital
`Fulham Palace Road
`London, United Kingdom W6 8RF
`
`KEN HASHIMOTO, M.D.
`Professor and Chair
`Departments of Dermatology and
`Syphilology
`Wayne State University School of Medicine
`4201 St. Antoine
`Detroit, Michigan 48201
`
`W. CHRISTOPHER MATHEWS, M.D., M.S.P.H.
`Antiviral Drugs Advisory Committee Member
`Professor of Clinical Medicine
`University of California at San Diego
`Medical Center
`Mail Code 8681
`200 West Arbor Drive
`San Diego, California 92103-8681
`
`0. FRED MILLER, III, M.D.
`Geisinger Medical Center
`North Academy Avenue
`Danville, Pennsylvania 17822-1406
`
`~-
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`ASSOCIATED REPORTERS OF WASHINGTON
`1523 North Carolina Avenue, N.E.
`Washington, D.C. 20002
`(202) 543-4809
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`CFAD VI 1013-0003
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`APPEARANCES
`
`(Continued)
`
`SPECIAL GOVERNMENT EMPLOYEES, CONSULTANTS
`AND GUEST SPEAKERS:
`(Continued)
`
`CYNTHIA MOORE, M.D., PH.D.
`Birth Defects & Genetic Disease Branch
`Centers for Disease Control and
`Prevention, MS-F45
`Atlanta, Georgia 30333
`
`EDWARD J. SHANNON, PH.D.
`G.W. Long Hansen's Disease Center
`P.O. Box 20572
`Baton Rouge, Louisiana 70894
`
`EVA SIMMONS-O'BRIEN, M.D.
`Drugs Assistant Professor of
`Dermatology and Internal Medicine
`Johns Hopkins University School of Medicine
`550 North Broadway, Suite 1002
`Baltimore, Maryland 21287-0900
`
`RANDOLPH WARREN
`CEO
`Thalidomide Victims Association of Canada
`P.O. Box 9061 sub 40
`London, Ontario
`Canada N6E lVO
`
`FOOD AND DRUG ADMINISTRATION STAFF:
`
`DENNIS BASHAW, PHARM.D.
`Biopharmaceutist, Division of Pharmaceutical Evaluation III
`
`DEBRA BIRNKRANT, M.D.
`Acting Director, Division of Antiviral Drug Products
`
`MURRAY LUMPKIN, M.D.
`Deputy Center Director for Review Management, CDER
`
`KATHRYN O'CONNELL, M.D.
`Medical Reviewer
`
`ASSOCIATED REPORTERS OF WASHINGTON
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`Washington, D.C. 20002
`(202) 543-4809
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`CFAD VI 1013-0004
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`APPEARANCES
`
`(Continued)
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`FOOD AND DRUG ADMINISTRATION STAFF:
`
`(Continued)
`
`BRENDA VAUGHAN, M.D.
`Medical Reviewer
`
`MICHAEL WEINTRAUB, M.D.
`Director, Office of Drug Evaluation V
`
`JONATHAN WILKIN, M.D.
`Director, Division of Dermatologic and Dental Drug Products
`
`JANET WOODCOCK, M.D.
`Director, Center for Drug Evaluation and Research
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`-
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`CELGENE REPRESENTATIVES:
`
`ROBERT H. GELBER, M.D.
`KAREN KOOK, PH.D.
`THOMAS REA, M.D.
`STEVE THOMAS, PH.D.
`BRUCE WILLIAMS
`LEO YODER, M.D.
`JERRY ZELDIS, M.D., PH.D.
`
`ALSO PRESENT:
`
`ALLEN MITCHELL, M.D.
`
`ASSOCIATED REPORTERS OF WASHINGTON
`1523 North Carolina Avenue, N.E.
`Washington, D.C. 20002
`(202) 543-4809
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`CFAD VI 1013-0005
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`C 0 N T E N T S
`
`AGENDA ITEM
`
`CONFLICT OF INTEREST STATEMENT
`by Tracy Riley
`
`FDA PRESENTATIONS
`by Dr. Brenda Vaughan
`
`by Dr. Kathryn O'Connell
`
`by Dr. Jonathan Wilkin
`
`THALIDOMIDE VICTIMS ASSOCIATION OF CANADA
`PRESENTATION - by Mr. Randolph Warren
`
`COMMITTEE DISCUSSION OF FDA-PRESENTED QUESTIONS
`
`-~
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`6
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`PAGE
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`ASSOCIATED REPORTERS OF WASHINGTON
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`Washington, D.C. 20002
`(202) 543-4809
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`P R 0 C E E D I N G S
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`7
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`(8:37 a.m.)
`
`DR. McGUIRE: Good morning.
`
`If the advisory
`
`committee can be seated, we'll begin our work.
`
`This is the second day of the 47th advisory
`
`committee meeting of the Dermatologic and Ophthalmic Drugs
`
`of the Food and Drug Administration.
`
`This morning we will have an open session, and
`
`rather than charge the committee, I will ask Tracy Riley,
`
`the Executive Secretary for a conflict of interest
`
`statement.
`
`MS. RILEY: Good morning. The following
`
`announcement addresses the issue of conflict of interest
`
`with regard to this meeting and is made a part of the
`
`record to preclude even the appearance of such at this
`
`meeting.
`
`Based on the submitted agenda and information
`
`provided by the participants, the agency has determined
`
`that all reported interests in firms regulated by the
`
`Center for Drug Evaluation and Research present no
`
`potential for a conflict of interest at this meeting.
`
`With respect to FDA's invited guest speaker,
`
`Mr. Randolph Warren, he has reported interests which we
`
`believe should be made public to allow the participants to
`
`objectively evaluate his comments. Mr. Warren would like
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`to disclose that he has on two occasions discussed Synovir,
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`thalidomide, with the Celgene corporation.
`
`In the event that the discussions involve any
`
`other products or firms not already on the agenda for which
`
`an FDA participant has a financial interest, the
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`participants are aware of the need to exclude themselves
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`from such involvement and their exclusion will be noted for
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`the record.
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`With respect to all other participants, we ask
`
`in the interest of fairness that they address any current
`
`or previous financial involvement with any firm whose
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`products they may wish to comment upon.
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`We have on the committee four temporary voting
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`members who are special government employees: Dr. Wilma
`
`Bergfeld, Dr. Ken Hashimoto, Dr. Fred Miller, and Dr. Eva
`
`Simmons-O'Brien.
`
`Thank you.
`
`DR. McGUIRE:
`
`Some of the faces around the
`
`table are different this morning, and I'd like to again
`
`have people introduce themselves, starting with Mr. Warren
`
`on the end.
`
`MR. WARREN:
`
`I'm Randy Warren of the
`
`Thalidomide Victims Association of Canada.
`
`DR. SHANNON: E.J. Shannon, the Gillis W. Long
`
`Hansen's Disease Center in Carville, Louisiana.
`
`ASSOCIATED REPORTERS OF WASHINGTON
`(202) 543-4809
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`DR. CRAWFORD:
`
`I'm Colin Crawford, Imperial
`
`9
`
`College School of Medicine.
`
`DR. MOORE: Cynthia Moore, Centers for Disease
`
`Control and Prevention.
`
`DR. MATHEWS: Chris Mathews, University of
`
`California, San Diego.
`
`DR. MINDEL:
`
`Joel Mindel, Mt. Sinai Medical
`
`Center, New York.
`
`DR. ORKIN: Milton Orkin, dermatology,
`
`University of Minnesota.
`
`DR. BERGFELD: Wilma Bergfeld, dermatologist,
`
`the Cleveland Clinic.
`
`DR. McGUIRE:
`
`Joe McGuire, dermatology,
`
`pediatrics, Stanford.
`
`MS. RILEY: Tracy Riley, Executive Secretary to
`
`the committee.
`
`DR. SIMMONS-O'BRIEN: Eva Simmons-O'Brien,
`
`dermatology and internal medicine, Johns Hopkins.
`
`DR. KILPATRICK:
`
`I'm Jim Kilpatrick, School of
`
`Medicine, Medical College of Virginia, Richmond, Virginia.
`
`MS. COHEN: Susan Cohen, consumer member.
`
`DR. HASHIMOTO: Ken Hashimoto, dermatologist,
`
`Wayne State University in Detroit.
`
`DR. MILLER: Fred Miller, dermatologist,
`
`Geisinger Medical Center, Danville, Pennsylvania.
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`DR. BIRNKRANT: Debra Birnkrant, Division of
`
`Antiviral Drug Products, FDA.
`
`DR. WILKIN:
`
`Jonathan Wilkin, Division of
`
`Dermatological and Dental Drug Products.
`
`DR. WEINTRAUB: Mike Weintraub, Office of Drug
`
`Evaluation V.
`
`DR. WOODCOCK:
`
`Janet Woodcock.
`
`I'm head of the
`
`Center for Drug Evaluation and Research at FDA.
`
`DR. LUMPKIN: And I'm Murray Lumpkin, the
`
`Deputy 9enter Director at the Center for Drug Evaluation
`
`and Research, FDA.
`
`DR. McGUIRE: Welcome to all of you.
`
`The major work of the day is to answer
`
`questions that were generated by the agency, and before I
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`do that, because of mailing issues and various problems,
`
`the briefing books were not received by all the members of
`
`the advisory committee in a timely way. So, I'm afraid
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`that the reviews of the primary and secondary medical
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`officers may have been overlooked, and I would like to ask
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`either one of them, Dr. Vaughan or Dr. O'Connell, to go
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`over their conclusions and a little bit of the background
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`material, if they would, and then we could have some
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`discussion of that.
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`DR. VAUGHAN: Good morning.
`
`Just bear with me.
`
`I'm a little nervous.
`
`I wasn't quite prepared to give a
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`__ --......
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`11
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`presentation this morning.
`
`I was prepared to possibly
`
`answer questions.
`
`The application was unique in that, as
`
`presented by the sponsor, Celgene, there was a
`
`retrospective review of a published controlled clinical
`
`trial conducted by Hastings, et al. at the Carville U.S.
`
`Public Health Service site in Louisiana. The study is
`
`called L-001.
`
`In my review, I approached it -- I
`
`looked at
`
`the published report.
`
`I looked at the results that were
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`given, the data -- well, not at the data.
`
`I
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`looked at the
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`results of the published report, and then I
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`looked at the
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`data as extracted and presented by the company.
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`There were several problems with the study as
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`presented. There was no protocol provided and the
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`randomization code was lost, but we were informed that
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`Hastings had provided Celgene with information for patients
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`that were identified between 1967 through 1969, were
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`identified as the original study group.
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`However, there were difficulties with the
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`information as presented, and some of the results had to be
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`inf erred and some of the randomizations had to be inf erred.
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`There were problems with the verbatim
`
`transcriptions that were provided in assessing success or
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`failure.
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`12
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`There were problems with the results as
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`reported in the published paper and those that were
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`presented by the sponsor.
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`There were incomplete data sets and there was
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`difficulty with the data validation.
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`I don't know how many of you were able to read
`
`the review.
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`However, I have as one example some of the
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`problems that I did have with the review and why I
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`reassigned some of the patients.
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`This patient had been deemed a success in the
`
`review. However, this illustrates the difficulties and why
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`I excluded this patient. This patient did not have on-
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`study evaluation.
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`I did not know if the patient had
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`actually qualified for study entry as written. The
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`temperature chart was provided, but there were not the
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`required temperature elevations above 99.6 at entry.
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`However, the patient did spike temperatures on day 1.
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`This patient also presents a problem with the
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`assignment of which group, whether the patient was in the
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`active or the placebo group. One of the main difficulties
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`is that assignment was made from bottle A, and bottle A
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`could contain either the active drug thalidomide or
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`placebo. So, therefore, without the code, it would have to
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`be inferred.
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`Now, some of the trials did show evidence of
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`well, you could glean evidence of blinding.
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`Some did not.
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`So, this patient was excluded from my reassessment of the
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`-- was not included in the efficacy analysis.
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`Additionally, there were problems with data
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`validation. This patient 1707 was assumed to have been on
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`thalidomide and successfully completed because the progress
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`notes said two courses A. However, when the actual record
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`was provided by the company, this assignment could not be
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`gathered. It's very diffisult to read but the assignment
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`was from the 6/15/68, and the note continued to the second
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`page, could not say that this patient had received two
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`courses A.
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`It was not there.
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`For some of those patients that I could see
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`that blinding was evident was patient 2643, and tLis
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`patient illustrates some of the difficulties I had with
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`validation of the published results.
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`The published studies gave the results of
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`single and double-blinded studies. We were to look at the
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`double-blind studies only. The results of the published
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`study, although this is not a critique of the study -- I'm
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`just giving what was presented. The published study stated
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`that there were no placebo successes. However, this
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`demonstrates that under the date of 1/22/68, it did give
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`the impression that this had been a double-blinded study.
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`Just found out patient was not receiving thalidomide, but
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`rather placebo. His improvement is doubly astounding.
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`The published report gave O successes and
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`clearly there were 3 successes as provided by Celgene.
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`There was a problem with the verbatim
`
`transcriptions since we have to infer which group that the
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`patients belonged to. Patient on thalidomide once more.
`
`Has been afebrile times 2 days. This made a difference in
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`the patient assignment. That was from the actual record.
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`The date was 3/18 -- 3/15 -- 3/18.
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`Patient on thalidomide once more. Has been
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`afebrile plus 2 days. No more ENL. This is different from
`
`the transcription, although the words are the same. The
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`reason I reassigned this patient to the thalidomide group
`
`was because of the patient on thalidomide once more, which
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`then with the period here, it refers to the thalidomide and
`
`not to the febrile episode.
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`I was able to count back and
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`reassign the patient.
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`The other problem with the verbatim
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`transcription was what was provided. One instance that I
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`noted was that the nurse's note was provided in the safety
`
`assessment as opposed to the doctor's note which provided
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`vital signs, and this particularly would have been useful
`
`information given the systemic nature of the ENL.
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`Additional problems that I had with this
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`submission was the validation of the data. There was a
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`patient that was listed as having expired prior to entry
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`until the double-blind study. It's patient 2253. However,
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`when a request for the actual records, the patient did
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`receive thalidomide, four doses, -- the dates are up here
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`-- on January 29th.
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`The listing that was used to identify the
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`patients was later identified -- Dr. Yoder informed us that
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`this listing could not be used as an official listing
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`because it was kept by a non-medical person.
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`With the reassessment of the patient outcomes
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`of the patients that I did include in the review, I could
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`not find that the evidence as presented demonstrated
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`efficacy.
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`Safety assessments.
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`I was not able to glean a
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`successful -- an adequate safety profile because I was not
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`sure of what information had been transcribed and which had
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`not.
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`I did not have time to review the primary patient
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`records.
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`this?
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`DR. WOODCOCK: Could I clarify something about
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`DR. VAUGHAN: Yes.
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`DR. WOODCOCK:
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`Just to make sure that everyone
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`is clarified. My understanding of what happened here is
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`there was a published report of the experience. The
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`clinician had used courses of either placebo or treatment,
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`and that was historically collected over quite a while.
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`Is
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`that correct? And that the primary record keeping that was
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`done for this study was not obtainable at the time that the
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`firm went back to obtain the records. So, what you had to
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`do and the firm had to do was try and reconstruct the
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`course of the study from the primary patient records.
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`Is
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`that an accurate description?
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`DR. VAUGHAN:
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`I'm not understanding.
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`DR. WOODCOCK: WAre the actual case report
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`forms of the study obtainable for you?
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`DR. VAUGHAN: The actual case report forms?
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`DR. WOODCOCK: Yes.
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`DR. VAUGHAN:
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`From the study.
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`DR. WOODCOCK: Yes, from the study itself.
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`DR. VAUGHAN:
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`I'm not sure what Celgene had
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`access to.
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`I was not presented with that.
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`DR. WOODCOCK: My understanding from the review
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`is that those records were
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`yes, maybe the firm could --
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`I think we need to clarify what was done here. There was a
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`published report and there was an attempt to verify the
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`data in the published report.
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`DR. KOOK:
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`I'll just give a few words on
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`basically how the data collection went.
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`I'm Karen Kook.
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`DR. McGUIRE: Could you identify yourself for
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`the transcriptionist?
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`DR. KOOK: Yes. Karen Kook, regulatory advisor
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`to Celgene.
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`When we became involved with Dr. Hastings, we
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`were interested in collecting supportive documentation to
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`support this particular published clinical trial. It was a
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`placebo-controlled trial that was conducted in 1968 and
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`1969, published in the beginning of 1970.
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`Dr. Hastings, who was involved in the initial
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`setup of the data collection, indicated that all of his
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`records pertaining to this trial, such as his original case
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`report forms, his original protocol, his original
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`randomization, were lost.
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`In assisting us to identify the patients
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`involved from the Carville medical records -- these are
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`medical records for patients who were hospitalized or who
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`resided at Carville at that time.
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`I believe there are
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`probably 3,000 medical charts there.
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`I'm not quite sure.
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`But to assist us in identifying those patients who may have
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`participated in that trial, what we were given was a multi-
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`page typed listing that had patient numbers, that also had
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`patient dates when they received thalidomide. There were
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`certainly discrepancies between those dates and the dates,
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`once you looked in the medical records, whether it was
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`nursing notes or doctor's orders, from when they received
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`thalidomide.
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`But nonetheless, we went through all of those
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`charts to attempt to identify patients that participated in
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`this double-blind trial.
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`Dr. Hastings initially conducted a single-blind
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`trial using thalidomide with a product that was provided by
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`Merrell Dow. There were probably a half a dozen patients
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`whose orders for thalidomide referred to MRD730, or
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`whatever the code name of the drug was. We kept a listing
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`of those numbers of patients but did not attempt to collect
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`any information from them.
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`It is clear also that he did in a single-blind
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`fashion treat some patients with what he identified as
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`thalidomide. But there were 27 patients who had in their
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`medical charts in the doctor's orders section a one-page,
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`typed-up study sheet that contained all of the instructions
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`for how the patients were to be treated in this particular
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`trial, and that included withdrawing whatever medications
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`they were on to control their ENL, whether it included
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`prednisone in some patients, analgesics, antipyretics, what
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`have you. Patients were observed for a 4-day period of
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`time off of anti-ENL treatment.
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`He had his criteria for initiating double-blind
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`treatment and patients did begin on bottle A.
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`Unfortunately, bottle A either contained, as Dr. Vaughan
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`indicated, thalidomide or placebo capsules. So, it was not
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`very easy to decide what these patients were receiving.
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`They received double-blind medication for 4 days and then
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`were either crossed over to bottle B, which again contained
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`the alternate treatment, but it was not that -- one had to
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`extrapolate, and then continued some on single-blind
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`treatment. And there were periods when they ran out of
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`medication, so they were on single-blind placebo, what have
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`you.
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`What we did was transcribed progress notes, and
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`what Dr. Vaughan was the electronic version of our
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`transcription of those records beginning on day minus 4,
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`which was when their treatment was discontinued, on through
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`the double-blind period and for varying lengths of time,
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`either until open-label thalidomide was discontinued or up
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`until about the time of publication.
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`A lot of these patients actually continued to
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`receive thalidomide for many years and we did not attempt
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`to collect that entire experience. What we really were
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`trying to focus on was the double-blind phase.
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`We created a series of listings. Dr. Vaughan
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`showed the listing for patient 1707, and it illustrates how
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`we approached doing this. There are many ways that you can
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`do it. The intent was not to extrapolate based on looking
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`at the data and coming to our own decision. What we were
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`looking for were words of Dr. Hastings that indicated what
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`his judgment at that time had been.
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`So, patient 1707, you could see that there were
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`not progress notes for every day, but on day 6, or whatever
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`day that was, he had in his note written, success on
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`thalidomide, or whatever it was. When we saw that, we
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`would have categorized that as a success. We did not sit
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`down and make our own independent judgment, and created
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`listings that gave what the basis for that judgment was.
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`One can certainly debate the treatment attribution for
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`every patient.
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`We created similar listings -- and Dr. Vaughan
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`showed an example of that -- where because we were
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`extrapolating from records to attempt to decide what
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`patients were receiving, again we created listings so that
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`one can, to the extent possible, independently decide
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`whether one disagrees or not.
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`And then there was a third listing for text
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`taken from the notes that could have represented adverse
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`events.
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`I have looked at Dr. Vaughan's review quickly,
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`and while I haven't had a chance to go through all of the
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`cases, but there are 18 patients for whom her assessment of
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`treatment response and our assessment does overlap.
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`Basically this is what it looks like, that roughly two-
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`thirds of the patients on thalidomide by this approach
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`would have been considered responders as compared to one-
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`third of the placebo patients.
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`Dr. Vaughan did show an example of one of the
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`patients that was a placebo responder. That is in the
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`medical record. That is how we reported that patient. Why
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`Dr. Hastings did not include that patient in his
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`publication I have no idea. It's not surprising to me that
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`the numbers do not match up.
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`our intent was to validate that these patients
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`existed, that yes, this was a double-blind trial. This is
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`fairly representative of what we believe the outcome of
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`this particular study was.
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`DR. McGUIRE: Thank you.
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`Yes, Dr. Miller.
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`DR. MILLER: Could I ask one question? When
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`you said that 18 were responders, what do you think the
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`criteria were for response for a positive response. Did
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`you look at Dr. Hastings' note which said patient improved?
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`But what were the criteria that you could glean from there
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`that would indicate a response?
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`DR. KOOK: The publication stated that patients
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`had to be af ebrile after 4 days of treatment and to have no
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`acutely inflamed lesions. He did not address the other
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`systemic manifestations of ENL.
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`And I don't have an overhead of this.
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`If you
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`look at the mean temperatures during the 4 days prior to
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`initiation of double-blind treatment, you can see that the
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`temperature is steadily increasing, and following the
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`implementation of double-blind treatment, it basically is
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`sort of an inverted U-plot.
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`Again, because we were focusing on his
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`publication, we did not address any of the other symptoms
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`that the patients may have had, but you can see from the
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`notes that they were relatively brief.
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`DR. McGUIRE: Dr. Wilkin?
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`DR. WILKIN: Well, I think the sponsor is
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`correct in that you can go back through and look at where
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`you can assign individual patients.
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`But the continual reference to this being a
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`double-blind study I think the committee needs to
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`interpret. The placebo was not a sedative and the amount
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`of thalidomide being given likely would break the blind in
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`this particular study.
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`Then Dr. Vaughan also was the reviewer for
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`E-002.
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`DR. VAUGHAN: This was my reassessment of the
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`patients from the data that I was presented and my findings
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`were different from the sponsor's findings with my
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`reanalysis of the patients.
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`DR. McGUIRE: Dr. Kilpatrick?
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`DR. KILPATRICK:
`
`I have to say that I find this
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`23
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`discussion moot, and I'd like to say why and ask the FDA
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`whether I'm wrong on this.
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`I'm coming to the Philippine study where we
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`were told by the sponsor that FDA had agreed that this
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`should not be a placebo-controlled trial which implies to
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`me that the FDA had accepted that thalidomide was
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`effective, perhaps not Synovir, but thalidomide in other
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`formulations.
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`DR. WILKIN: Yes.
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`I can say that from the
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`discussions with the group from Celgene over the last two
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`years, that we were given the strong impression from them
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`and from their consultants.
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`I believe that the
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`leprologists who are their consultants sincerely believe
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`that thalidomide does indeed work, and I believe that
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`Celgene believed that when they looked into the database,
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`looked into the Hastings study, looked into the vast amount
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`of data that was at Carville, that they would indeed find
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`that this was the case.
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`On that basis, yes, we did request that they do
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`placebo, but they could not find leprologists who were
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`comfortable with placebo.
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`I think you heard their argument
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`for no placebo yesterday. It was on an ethical basis.
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`They believed they had convincing information that they
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`were not prepared at that time to actually convey to us.
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`It wasn't in that particular form. Frankly, we didn't see
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`data on this until the NDA submission.
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`DR. McGUIRE:
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`I'd like to hold other questions
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`for just a moment.
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`Dr. O'Connell, did you want to respond to any
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`of this or did you want to give your conclusion of your
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`review of the submission?
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`DR. WILKIN: Could she speak to E-002 just
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`briefly?
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`DR. McGUIRE:
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`I can't hear you, John.
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`DR. WILKIN: Dr. Vaughan reviewed E-002 and she
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`said a couple of words about E-002. That was that really
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`vast database that the sponsor was referring to.
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`DR. VAUGHAN: Study L-002 was a retrospective
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`look at a 16-year experience under IND 11,359 sponsored by
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`the U.S. Public Health Service. The sponsor collected
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`data, as I understand it, as entered into a database at
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`Carville. My understanding is that the company did not
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`have access to the case report forms in this instance.
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`The problems that I found with the review of
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`L-002 was that there is not a known current protocol that
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`is being followed, and maybe one of the major problems was
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`the way in which the data were collected and entered into
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`the electronic database.
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`This is a sample of the annual case report form
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`that was revised in 1978, and the difficulty with the
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`reporting is that the dose of thalidomide is the mean dose
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`of thalidomide taken during the year.
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`It was difficult for
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`us to make an assessment using mean dose on an annual
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`basis.
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`Additionally, the safety profile of thalidomide
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`was collected in a way that we usually don't collect for
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`clinical trials. However, this was not intended initially,
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`I
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`imagine, to be reviewed as a clinical trial. But the
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`side effects due to thalidomide only were reported and the
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`reported.
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`The response to thalidomide was collected, but
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`without a protocol, it was unknown exactly what criteria
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`were being used.
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`Again, it was difficult to determine whether
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`there was adjunctive therapy or monotherapy from the
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`database because previous therapy for ENL was listed, but
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`not necessarily adjunctive. Even if adjunctive therapy had
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`been listed, as I understand it, if the drug were not
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`considered experimental, they were not necessarily entered
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`into the database.
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`During the 16-year period, the source of
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`--
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`ASSOCIATED REPORTERS OF WASHINGTON
`(202) 5
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