CENTER FOR DRUG EVALUATION AND RESEARCH
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`FOOD AND DRUG ADMINISTRATION
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`1
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`FORTY-SEVENTH MEETING
`
`OF THE
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`N
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`0 -
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`DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY C~ITTEE
`
`~
`This transcript has not been edited or corrected,~
`except where relevant for the deletion of materia~
`not releasable under the Freedom of Informatio~
`Act. The Food and Drug Administration makes I?i,g
`representation as to its accuracy.
`::::::
`0
`0
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`8:36 a.rn.
`Thursday, September 4, 1997
`
`Versailles I and II
`Holiday Inn
`8120 Wisconsin Avenue
`Bethesda, Maryland
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`ASSOCIATED REPORTERS OF WASHINGTON
`1523 North Carolina Avenue, N.E.
`Washington, D.C. 20002
`/' .... n .... \ rA.., AOI\(\
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`CFAD VI 1012-0001
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`FOOD AND DRUG ADMINISTRATION
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`1
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`FORTY-SEVENTH MEETING
`
`OF THE
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`N
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`0 -
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`DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY C~ITTEE
`
`~
`This transcript has not been edited or corrected,~
`except where relevant for the deletion of materia~
`not releasable under the Freedom of Informatio~
`Act. The Food and Drug Administration makes I?i,g
`representation as to its accuracy.
`::::::
`0
`0
`
`8:36 a.rn.
`Thursday, September 4, 1997
`
`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
`/' .... n .... \ rA.., AOI\(\
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`CFAD VI 1012-0001
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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
`
`MADELEINE DUVIC, M.D.
`Professor of Dermatology
`University of Texas Medical School
`6431 Fannin, MSB 1-186
`Houston, Texas 77030
`
`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
`
`ASSOCIATED REPORTERS OF WASHINGTON
`1523 North Carolina Avenue, N.E.
`Washington, D.C. 20002
`(202) 543-4809
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`APPEARANCES
`
`(Continued)
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`3
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`COMMITTEE MEMBERS:
`
`(Continued)
`
`MILTON ORKIN, M.D.
`Clinical Professor
`Department of Dermatology
`University of Minnesota
`2733 Huntington Avenue South
`Minneapolis, Minnesota 55416
`
`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 Co~mittee 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
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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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`APPEARANCES
`
`(Continued)
`
`SPECIAL GOVERNMENT EMPLOYEES, CONSULTANTS
`AND GUEST SPEAKERS:
`(Continued)
`
`0. FRED MILLER, III, M.D.
`Geisinger Medical Center
`North Academy Avenue
`Danville, Pennsylvania 17822-1406
`
`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
`
`RANDOLF-ti WARREN
`CEO
`Thalidomide Victims Association of Canada
`P.O. Box 9061 sub 40
`London, Ontario
`Canada N6E
`lVO
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`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
`
`BARBARA HILL, PH.D.
`Pharmacologist
`Division of Dermatologic and Dental Drug Products
`
`ASSOCIATED REPORTERS OF WASHINGTON
`1523 North Carolina Avenue, N.E.
`Washington, D.C. 20002
`(202) 543-4809
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`APPEARANCES
`
`(Continued)
`
`FOOD AND DRUG ADMINISTRATION STAFF:
`
`(Continued)
`
`MURRAY LUMPKIN, M.D.
`Deputy Center Director for Review Management, CDER
`
`LOUIS MORRIS, PH.D.
`Supervisory Psychologist
`Division of Drug Marketing, Advertising and Communications
`
`MARY PENDERGAST, J.D.
`Deputy Commissioner
`
`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
`
`CELGENE REPRESENTATIVES:
`
`WAYNE COLBURN, PH.D.
`DAVID R. CORNBLATH, M.D.
`ROBERT H. GELBER, M.D.
`STEVE THOMAS, PH.D.
`BRUCE WILLIAMS
`LEO YODER, M.D.
`JERRY ZELDIS, M.D., PH.D.
`
`ALSO PRESENT:
`
`CHRISTOPHER J. DOYLE
`JAMES W. HANSON, M.D.
`LEWIS B. HOLMES, M.D.
`LYNN M. KLEIN
`CYNTHIA PEARSON
`VICKI WALTON
`
`ASSOCIATED REPORTERS OF WASHINGTON
`1523 North Carolina Avenue, N.E.
`Washington, D.C. 20002
`(202) 543-4809
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`C 0 N T E N T S
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`AGENDA ITEM
`
`CONFLICT OF INTEREST STATEMENT
`by Ms. Tracy Riley
`
`COMMISSIONER'S OFFICE STATEMENT -
`A New Chapter for Thalidomide and FDA
`by Ms. Mary Pendergast
`
`OFFICE DIRECTOR'S STATEMENT -
`An overview of the L.A. Data and an
`Overall Chronology of this NOA and
`the Interactions with Celgene Corp.
`by Dr. Michael Weintraub
`
`OPEN PUBLIC HEARING
`American College of Obstetricians and Gynecologists
`by Ms. Tracy Riley
`
`Leonard Wood Memorial American Leprosy Foundation
`by Ms. Tracy Riley
`
`American College of Medical Genetics, the American
`Academy of Pediatrics and the Academy Committee on
`Genetics - by Dr. James Hanson
`
`CELGENE CORPORATION PRESENTATION
`Chronology - Pharmaceutical Development
`By Dr. Steve Thomas
`
`Pharmacokinetics/Metabolism
`by Dr. Wayne Colburn
`
`Leprosy/ENL - Clinical Use
`by Dr. Leo Yoder
`
`Safety and Efficacy
`by Dr. Jerry Zeldis
`
`Neuropathy
`by Dr. David Cornblath
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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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`PAGE
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`C 0 N T E N T S
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`(Continued)
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`AGENDA ITEM
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`CELGENE CORPORATION PRESENTATION
`Fetal Exposure Prevention
`by Mr. Bruce Williams
`
`(Continued)
`
`7
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`PAGE
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`109
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`OPEN PUBLIC HEARING
`
`American Leprosy Missions - by Mr. Christopher Doyle
`
`133
`
`American College of Medical Genetics
`by Dr. Lewis Holmes
`
`The Teratology Society - by Dr. Lewis Holmes
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`National Organization for Rare Disorders
`by Ms. Lynn Klein
`
`National Women's Health Network
`by Ms. Cynthia Pearson
`
`American Behcet's Disease Association
`by Ms. Vicki Walton
`
`FDA PRESENTATION
`Opening Comments/Overview
`by Dr. Jonathan Wilkin
`
`Nonclinical Toxicology
`by Dr. Barbara Hill
`
`Clinical Pharmacology
`by Dr. Dennis Bashaw
`
`Overview on which to Base a Regulatory Action
`by Dr. Michael Weintraub
`
`Various Distribution Options
`by Dr. Murray Lumpkin
`
`Education Plan
`by Dr. Louis Morris
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`C 0 N T E N T S
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`(Continued)
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`AGENDA ITEM
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`BIRTH DEFECTS DUE TO THALIDOMIDE EXPOSURE:
`CDC CONSIDERATIONS - by Dr. Cynthia Moore
`
`THALIDOMIDE NEUROTOXICITY
`by Dr. Colin Crawford
`
`8
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`PAGE
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`234
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`251
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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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`P R 0 C E E D I N G S
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`9
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`(8:36 a.m.)
`
`DR. McGUIRE: This is the 47th convening of the
`
`Dermatologic and Ophthalmic Drugs Advisory Committee
`
`meeting of the Food and Drug Administration.
`
`By the close of business tomorrow afternoon,
`
`this committee should have given the agency some
`
`recommendations on their evaluation of efficacy and safety
`
`of thalidomide. Thalidomide has played a very important
`
`role in the development of standards of the agency, and
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`these should be very interesting discussions.
`
`I would like to turn the meeting over to Tracy
`
`Riley for the conflict of interest.
`
`MS. RILEY: Good morning. Welcome to the
`
`meeting.
`
`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
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`that all reported interests in firms regulated by the
`
`Center for Drug Evaluation and Research present no
`
`potential for conflict of interest at this meeting.
`
`With respect to FDA's invited guest speaker,
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`Mr. Randolph Warren, he has reported interests which we
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`believe should be made public to allow the participants to
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`objectively evaluate his comments. Mr. Warren would like
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`to disclose that he has, on two occasions, discussed
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`Synovir, thalidomide, with the Celgene Corporation.
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`In the event that the discussions involve any
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`other products or firms not already on the agenda for which
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`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,
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`~ 13
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`in the interest fairness, that they address any current or
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`previous financial involvement with any firm whose products
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`they may wish to comment upon.
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`Also there are four special government
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`employees who are granted temporary voting status today to
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`participate in this meeting: Dr. Wilma Bergfeld, Dr. Ken
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`Hashimoto, Dr. Fred Miller, and Dr. Eva Simmons-O'Brien.
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`And for the people at the table, there are
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`additional review materials in your packet that you had not
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`received before.
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`Thank you.
`
`DR. McGUIRE: There will be introductory
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`remarks from the agency, but before we hear those, I would
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`like to start with the left ~nd of the table and have
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`people sitting at the table introduce yourself, please.
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`MR. WARREN:
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`I am Randy Warren from the
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`Thalidomide Victims Association of Canada.
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`DR. SHANNON: My name is E.J. Shannon, from the
`
`Gillis Long Hansen's Disease Center in Carville, Louisiana.
`
`DR. CRAWFORD:
`
`I am Colin Crawford, from the
`
`London Imperial College, School of Medicine.
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`DR. MOORE: Cynthia Moore for the Centers for
`
`Disease Control and Prevention.
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`DR. MATHEWS: Chris Mathews, University of
`
`California, San Diego, and member of the Antiviral Advisory
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`Committee.
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`DR. DUVIC:
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`I am Madeleine Duvic, from Houston,
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`Texas, M.D. Anderson and UT.
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`I am a dermatologist.
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`DR. MINDEL:
`
`Joel Mindel, Departments of
`
`Ophthalmology and Pharmacology at Mount Sinai Medical
`
`Center, New York.
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`DR. ORKIN: Milton Orkin, from the University
`
`of Minnesota, Minneapolis, Minnesota.
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`DR. BERGFELD:
`
`I am Wilma Bergfeld, a
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`dermatologist from the Cleveland Clinic.
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`DR. McGUIRE:
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`I am Joe McGuire, from Stanford
`
`University, dermatology and pediatrics.
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`MS. RILEY:
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`I am Tracy Riley, the Executive
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`Secretary to the committee.
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`DR. SIMMONS-O'BRIEN:
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`I am Eva Simmons-O'Brien,
`
`from the Departments of Dermatology and Internal Medicine
`
`at Johns Hopkins in Baltimore, Maryland.
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`DR. KILPATRICK:
`
`I am Jim Kilpatrick, School of
`
`Medicine, Medical College of Virginia, Virginia
`
`Commonwealth University, biostatistician.
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`MS. COHEN:
`
`I am Susan Cohen, and I am the
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`consumer member.
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`DR. HASHIMOTO:
`
`I am Ken Hashimoto.
`
`I am a
`
`dermatologist, Wayne State University in Detroit.
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`DR. MILLER: Fred Miller, dermatologist,
`
`Geisinger Medical Center, Danville, Pennsylvania.
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`DR. BIRNKRANT:
`
`I'm Debra Birnkrant, acting
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`Division Director, Division of Antiviral Drug Products, and
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`I chair the Thalidomide Working Group at the FDA.
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`DR. WILKIN:
`
`Jonathan Wilkin, FDA, Dermatologic
`
`and Dental Drug Products.
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`DR. WEINTRAUB: Mike Weintraub, Office of Drug
`Evaluation v.
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`DR. WOODCOCK:
`
`I'm Janet Woodcock, and I'm the
`
`head of the Center for Drug Evaluation and Research at the
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`FDA.
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`MS. PENDERGAST: Mary Pendergast, Deputy
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`Commissioner, Food and Drug Administration.
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`DR. McGUIRE: Thank you very much.
`
`The first remarks will be presented by Mary
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`13
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`Pendergast.
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`MS. PENDERGAST: Good morning. And thank you
`
`for coming to our Dermatologic and Ophthalmic Drugs
`
`Advisory Committee meeting.
`
`I would like to especially thank the Chairman
`
`and the other members of our advisory committee, who give
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`so generously of their time and their expertise to the FDA.
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`We are here so that our advisory committee can
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`review Celgene's new drug application for the use of
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`thalidomide for the treatment of erythema nodosum leprosum,
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`abbreviated as ENL, a complication which occurs in a subset
`
`of patients with Hansen's disease, also known as leprosy.
`
`Last November we brought to this advisory
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`committee our concept that thalidomide, despite its history
`
`and known risks, could be an approvable drug. We believed,
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`and still believe, that thalidomide may have the capacity
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`to treat as well as to damage. We also explained why we
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`felt we needed to change the medical landscape when it came
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`to thalidomide.
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`Because thalidomide was not approved, patients
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`with Hansen's disease were getting substandard drugs that
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`were not manufactured under good manufacturing practices.
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`And although thalidomide held out promise for other
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`diseases, there were no well-planned schemes for studying
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`the drug for other diseases.
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`The Health Resources Service Administration was
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`running out of money to pay for the distribution of the
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`drug under investigational new drug exemptions.
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`And we were concerned about the proliferation
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`of groups that were distributing bootleg, illegal
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`thalidomide to patients with AIDS and cancer, without
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`careful controls that would have prevented birth defects.
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`Consequently, we took several steps to change
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`the landscape. One step was to encourage companies to
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`pursue approval for diseases for which there might be the
`
`requisite data. Celgene took up that challenge and has
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`pulled together an application for the use of thalidomide
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`for ENL, an indication for which the drug has been used for
`
`over 30 years.
`
`We also stopped the illegal distribution of
`
`thalidomide through buyers' clubs. Several clubs agreed
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`voluntarily to stop distributing thalidomide. And we
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`stopped the remaining buyers' clubs' activities through
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`legal proceedings.
`
`We have also collaborated with the National
`
`Institutes of Health and the Centers for Disease Control to
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`design a two-day public scientific meeting, that will be
`
`held next week, to explore whether and how thalidomide
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`could be used for other clinical uses. We know that
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`thalidomide is being studied as a treatment for many
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`serious diseases, including ENL, chronic graft versus host
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`disease, cancer, and HIV infection.
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`This meeting will discuss the advances and
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`research opportunities of thalidomide in the treatment of
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`various disorders.
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`But next week's meeting will have a broader
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`focus as well. We need to remember that more than half of
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`the population alive today was not yet born when the
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`thalidomide tragedy took place. There are many in our
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`society, patients and physicians alike, who do not know the
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`thalidomide story. Thus, as an education to some and as a
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`reminder to others, we will also discuss the past uses of
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`thalidomide, the risks associated with thalidomide and
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`reproduction, the legal, ethical, and other public policy
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`concerns surrounding thalidomide's use, and the management
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`of the adverse effects of thalidomide.
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`This will be an important and useful meeting,
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`and the results of that meeting, as well as your expert
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`advice today, will be taken into account before FDA makes
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`any decision on the approvability of thalidomide for ENL or
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`any other disease.
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`I know that there are some who wish that next
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`week's meeting could have been held before this meeting.
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`But scheduling difficulties made that impossible.
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`In my
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`view, though, it shouldn't matter. For today, we are
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`attempting to have an ordinary advisory committee meeting.
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`What we would like today is for the advisory
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`committee to assist us with their expertise on the
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`particular new drug application that is before them, and
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`help us answer the question of whether thalidomide is
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`effective in the treatment of ENL, and whether the steps
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`that have been proposed to control the distribution and use
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`of the drug will permit thalidomide to be considered safe
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`under that scheme.
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`Although these are the normal, straightforward
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`questions we ask of advisory committee members all the
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`time, they will be harder answers to come by today because,
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`as you have seen, this is not a fully conventional data
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`set. Celgene did not invent thalidomide and then develop
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`the drug through conventional studies. Rather, thalidomide
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`has been used for ENL for over 30 years without the
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`rigorous collection of data one would expect from real
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`clinical trials.
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`Therefore, it is critically important to us
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`that you give a careful and thoughtful look at the data
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`that does exist, and help us decide whether thalidomide
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`should be approved as a treatment for ENL. This will be
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`challenging, but very important efforts, and we look
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`forward to hearing your deliberations.
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`So, I would like to thank you again for being a
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`member of our advisory committee, for helping us out on
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`this very tough question. Thank you again for your
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`attention.
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`DR. McGUIRE: Thank you, Ms. Pendergast.
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`Dr. Weintraub.
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`DR. WEINTRAUB: Thank you, Dr. McGuire.
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`Several people have asked, since we've
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`distributed signed reviews, stating the reviewers'
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`conclusions on the approval of thalidomide, why are we
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`having an advisory committee meeting? And the question of
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`people who oppose it, they said, well, you have already
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`made up your minds; it is a closed issue. Well, I assure
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`you that it is not.
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`Let me tell you a little bit about the
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`procedure at FDA. We believe that in a science-based
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`enterprise, which this is, everyone is entitled to their
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`own interpretation of the data -- particularly people who
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`have worked very closely with the information coming from
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`clinical trials or coming from studies such as these data
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`sets, as Mary just pointed out. They are not always
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`conventional data sets.
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`But we do not demand that everybody has to have
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`an opinion that is totally in concert with other opinions
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`and other points of view. We believe in the value of ideas
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`and of insights.
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`Now, there are many reasons why a particular
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`reviewer can come to a different judgment. The primary
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`reviews are often completed earlier in the final approval
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`process. And the reviewer may not have a total picture of
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`the final plans -- for example, in this case, such as
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`restricting distribution -- and perhaps, in that sense,
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`altering the risk/benefit relationship.
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`Of course, with a controversial drug such as
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`thalidomide, there are bound to be differences of opinion.
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`The outlook of everybody may be different when the drug is
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`so controversial. Several people, all acting in good
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`faith, can look at the same numbers, the same dots on a
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`graph, and come to different conclusions. This is
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`especially true if the numbers and dots come not from
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`clinical trials but from experiences that were never
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`intended to be interpreted as if they came from
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`double-blind, randomized, carefully controlled
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`experiments -- for example, things like the information
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`from the clinical care of patients -- even those who are
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`carefully followed.
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`In the FDA, we have a system of supervisory
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`oversight. That is why we have given you primary and
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`secondary reviews, the Division Director's opinion and the
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`Office Director's view.
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`In ;ome cases, we have the
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`Director of the Office of Review Management over the Office
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`Director, and the Center Director as well.
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`Except for the primary reviewer, we can all
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`write overriding memoranda.
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`I know that my colleagues --
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`the other four off ice directors -- and I take overruling
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`our trusted colleagues and coworkers very seriously.
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`It is
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`not something we do lightly.
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`Instead, the decision
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`involves delicate balances and inner struggles.
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`So, although you have primary and secondary
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`reviews and a Division Director's memo in your packet of
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`materials, I will assure you that our minds are not made up
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`and we are not done yet. Our analysis has not been locked
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`in one way or the other.
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`We invited you here because we respect your
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`judgment. Even if we do not take your advice, as
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`occasionally occurs, we still learn from your discussions,
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`from your unique points of view, your questioning of the
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`presenters, and your deliberations over the questions.
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`Now,
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`I am sure that we will still learn from
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`your deliberations over the next day and a half, and I am
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`certain that we will receive the benefit of your advice.
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`I
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`appreciate it, and I know actually the entire FDA is really
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`in your debt for doing that.
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`Thank you.
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`DR. McGUIRE: Thank you, Dr. Weintraub.
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`I conclude from what you have said that this is
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`not a stacked deck.
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`DR. WEINTRAUB: That is correct.
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`DR. McGUIRE: Let's go on to the public
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`hearing. There are two statements to be read.
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`MS. RILEY: The first statement is from the
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`Off ice of the Executive Director of the American College of
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`Obstetricians and Gynecologists.
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`On behalf of the American College of
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`Obstetricians and Gynecologists, ACOG, an organization
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`representing 38,000 physicians dedicated to improving the
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`health care of women, ACOG does not believe that
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`thalidomide, nor any drug, should be kept from being
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`introduced or withdrawn from the market solely because it
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`may be teratogenic. We strongly support efforts to prevent
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`exposure of women who are pregnant or contemplating
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`pregnancy from known teratogenic agents.
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`Sincerely, Ralph W. Hale, M.D., Fellow of the
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`American College of Obstetricians and Gynecologists.
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`The next statement is from the Leonard Wood
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`Memorial American Leprosy Foundation.
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`I, Dr. Gerald P. Walsh, Scientific Director of
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`the American Leprosy Foundation, am submitting a written
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`presentation on behalf of my organization in support of the
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`licensing of thalidomide.
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`I regret that at the time of the
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`meeting it was necessary for me to be at our research
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`facility in the Philippines.
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`Founded in 1928, the Foundation conducts,
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`maintains and supports laboratory investigations, clinical
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`studies and related research, with the ultimate goal of
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`eradicating leprosy. We also disseminate information about
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`the source, diagnosis, treatment, and prevention of the
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`disease, just as we voluntarily aid, establish, maintain,
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`and support clinics, hospitals, and laboratories for
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`diagnosis and treatment of the disease. The Foundation is
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`headquartered in the United States, and maintains a leprosy
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`research center in Cebu, Philippines. The Center is
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`staffed by 34 individuals, composed of professional as well
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`as technical and support staff. It is in Cebu that our
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`scientific research is carried out. The Foundation is
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`foremost among many American agencies in this field, and we
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`are proud of the many achievements and contributions we
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`have made that we believe will eventually lead to the
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`eradication of this tragic disease.
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`Few diseases are as feared and misunderstood as
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`leprosy. Since pre-Biblical times, the leprosy patient has
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`been surrounded by myth, superstition, fear, apathy, and
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`rejection. Some progress has been made toward changing
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`these attitudes, but unfortunately they are still prevalent
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`in many parts of the world, including the United States.
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`Contrary to popular thought, leprosy remains a
`
`major health problem in many developing countries, with
`
`more than 600,000 new cases detected annually. Today it is
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`most prevalent in tropical and subtropical climates, but
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`was rampant in temperate climates until the late 19th
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`century. Of concern to this committee are the
`
`approximately 6,000 known cases of leprosy in the United
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`States. The actual number of cases is undoubtedly higher,
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`and climbing, in light of sustained immigration from Third
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`World countries to the United States.
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`Leprosy is currently treated with a combination
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`of drugs. Although multi-drug therapy is the treatment of
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`choice, serious problems still remain. New drugs are
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`needed and research must continue.
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`Up to 30 percent of all people afflicted with
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`leprosy suffer from erythema nodosum leprosum, ENL, an
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`acute reactional phase from leprosy that is very painful
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`and debilitating for patients. It usually occurs after
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`treatment is started and is characterized by the appearance
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`of tender nodules, accompanied by fever and joint pain.
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`In
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`severe cases, the patients are bedridden for weeks. And
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`some of these develop chronic ENL, which incapacitates a
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`patient permanently. ENL is thought to be immunologically
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`mediated, but the specific factors that precipitate
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`episodes of ENL are not clearly understood. Recent studies
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`have suggested that cytokines may play a key role in ENL.
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`We at the American Leprosy Foundation are proud
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`to have pursued research that addresses the key questions
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`still surrounding the etiology and treatment on leprosy and
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`ENL. We are very concerned that in our clinics today we
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`can offer patients only a limited number of treatment
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`options appropriate to their medical needs. This, of
`
`course, includes thalidomide, which the World Health
`
`Organization has determined is standard of care for the
`
`treatment of ENL.
`
`We recognize that thalidomide is restricted in
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`that it cannot be used to treat pregnant women or, for that
`
`matter, women of childbearing age. But for the appropriate
`
`groups, it has the potential for enormous good in leprosy
`
`patients who develop ENL.
`
`In the words of the
`
`International Federation of Anti-Leprosy Associations, it
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`is very effective for controlling ENL.
`
`Our studies in Cebu, Philippines, that are
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`partially supported by Celgene Corporation, have shown the
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`remarkable effect of thalidomide and represent an important
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`treatment option for patients living with ENL. We at the
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`American Leprosy Foundation urge you to recommend approval
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`of this drug.
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`Thank you.
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`----
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`~
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`Gerald P. Walsh, Ph.D., Scientific Director.
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`DR. McGUIRE: Thank you, Ms. Riley.
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`We will have an oral presentation now from
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`24
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`Dr. James Hanson. Dr. James Hanson is representing the
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`American College of Medical Genetics, the American Academy
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`of Pediatrics and the Academy Committee on Genetics.
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`DR. HANSON: Mr. Chairman, members of the
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`committee, I am James Hanson, Professor of Pediatrics at
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`the University of Iowa.
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`I am here representing the
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`American Academy of Pediatrics, as you have heard.
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`It is not without reason that thalidomide has
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`been termed the most notorious human teratogen. The drug
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`was introduced in 1956 in West Germany, as an effective
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`sedative and hypnotic.
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`It was also used to treat nausea
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`and vomiting in pregnancy. By the end of 1961,
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`thalidomide, sold under Sl different brand names, was
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`identified as a human teratogen and removed from the
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`market. More than 10,000 infants worldwide were born with
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`malformations attributed to the use of thalidomide in
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`pregnancy.
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`In 7 of the 17 cases reported in the United
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`States, the thalidomide was purchased in another country.
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`And I might add parenthetically that the
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`avoidance of a similar tragedy in the United States was
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`largely due to the efforts of Dr. Francis Kelsey, who is
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`sitting over here on my left.
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`ASSOCIATED REPORTERS OF WASIIINGTON
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`(Applause.)
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`DR. HANSON: The mechanism for teratogenicity
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`of thalidomide is still not known. However, the period of
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`greatest sensitivity appears to be between days 21 and 33
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`of gestation. It is of great concern that the effects of
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`thalidomide on the fetus do not appear to be dose-related,
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`and teratogenic effects appeared in over 80 percent of the
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`fetuses exposed during the critical period.
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`Thalidomide produces major malformations of the
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`upper extremities, ranging from missing thumbs to missing
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`radii to absent ulnas and humeri, including so-called
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`phocomelia and the micromelia.
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`It sometimes produces major
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`malformations of the lower extremities as well.
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`In
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`addition, fetuses exposed to thalidomide can have
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`congenital heart defects, craniofacial anomalies, facial
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`palsies, urogenital anomalies, and a number of other
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`structural birth defects. Concerns have also been raised
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`about associated developmental disabilities.
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`While available research supports thalidomide's
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`effectiveness in the treatment of leprosy, graft versus
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`host disease, aphthous ulcers, wasting
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