CENTER FOR DRUG EVALUATION AND RESEARCH

FOOD AND DRUG ADMINISTRATION

FORTY-SEVENTH MEETING

OF THE

DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY COMMITTEE

8:36 a.m.
Thursday, September 4, 1997

Versailles I and II
Holiday Inn
	8120 Wisconsin Avenue
Bethesda, Maryland

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

APPEARANCES  (Continued)

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 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

APPEARANCES  (Continued)

SPECIAL GOVERNMENT EMPLOYEES, CONSULTANTS 
AND GUEST SPEAKERS:  (Continued)

O. 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

RANDOLPH WARREN
CEO
Thalidomide Victims Association of Canada
P.O. Box 9061 sub 40
London, Ontario
Canada  N6E 1V0

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

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

C O N T E N T S

AGENDA ITEM	PAGE

CONFLICT OF INTEREST STATEMENT
  by Ms. Tracy Riley	9

COMMISSIONER'S OFFICE STATEMENT -
A New Chapter for Thalidomide and FDA
  by Ms. Mary Pendergast	13

OFFICE DIRECTOR'S STATEMENT -
An Overview of the L.A. Data and an
Overall Chronology of this NDA and
the Interactions with Celgene Corp.
  by Dr. Michael Weintraub	17

OPEN PUBLIC HEARING
American College of Obstetricians and Gynecologists
  by Ms. Tracy  Riley	20

Leonard Wood Memorial American Leprosy Foundation
  by Ms. Tracy Riley	20

American College of Medical Genetics, the American 
Academy of Pediatrics and the Academy Committee on 
Genetics - by Dr. James Hanson	24

CELGENE CORPORATION PRESENTATION
Chronology - Pharmaceutical Development
  By Dr. Steve Thomas	28

Pharmacokinetics/Metabolism
  by Dr. Wayne Colburn	33

Leprosy/ENL - Clinical Use
  by Dr. Leo Yoder	45
Safety and Efficacy
  by Dr. Jerry Zeldis	70

Neuropathy
  by Dr. David Cornblath	105

C O N T E N T S  (Continued)

AGENDA ITEM	PAGE

CELGENE CORPORATION PRESENTATION  (Continued)
Fetal Exposure Prevention
  by Mr. Bruce Williams	109

OPEN PUBLIC HEARING

American Leprosy Missions - by Mr. Christopher Doyle	133

American College of Medical Genetics
  by Dr. Lewis Holmes	137

The Teratology Society - by Dr. Lewis Holmes	139

National Organization for Rare Disorders
  by Ms. Lynn Klein	141

National Women's Health Network
  by Ms. Cynthia Pearson	144

American Behcet's Disease Association
  by Ms. Vicki Walton	151

FDA PRESENTATION
Opening Comments/Overview
  by Dr. Jonathan Wilkin	157

Nonclinical Toxicology
  by Dr. Barbara Hill	164

Clinical Pharmacology
  by Dr. Dennis Bashaw	170

Overview on which to Base a Regulatory Action
  by Dr. Michael Weintraub	187

Various Distribution Options
  by Dr. Murray Lumpkin	198

Education Plan
  by Dr. Louis Morris	207

C O N T E N T S  (Continued)

AGENDA ITEM	PAGE

BIRTH DEFECTS DUE TO THALIDOMIDE EXPOSURE:
CDC CONSIDERATIONS - by Dr. Cynthia Moore	234

THALIDOMIDE NEUROTOXICITY
  by Dr. Colin Crawford	251

P R O C E E D I N G S
(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 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 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, 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 to disclose that he has, on two occasions, discussed Synovir, 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 participants are aware of the need to exclude themselves from such involvement and their exclusion will be noted for the record.
		With respect to all other participants, we ask, in the interest fairness, that they address any current or previous financial involvement with any firm whose products they may wish to comment upon.
		Also there are four special government employees who are granted temporary voting status today to participate in this meeting:  Dr. Wilma Bergfeld, Dr. Ken Hashimoto, Dr. Fred Miller, and Dr. Eva Simmons‑O'Brien.
		And for the people at the table, there are additional review materials in your packet that you had not received before.
		Thank you.
		DR. McGUIRE:  There will be introductory remarks from the agency, but before we hear those, I would like to start with the left end of the table and have people sitting at the table introduce yourself, please.
		MR. WARREN:  I am Randy Warren from the Thalidomide Victims Association of Canada.
		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.
		DR. MOORE:  Cynthia Moore for the Centers for Disease Control and Prevention.
		DR. MATHEWS:  Chris Mathews, University of California, San Diego, and member of the Antiviral Advisory Committee.
		DR. DUVIC:  I am Madeleine Duvic, from Houston, Texas, M.D. Anderson and UT.  I am a dermatologist.
		DR. MINDEL:  Joel Mindel, Departments of Ophthalmology and Pharmacology at Mount Sinai Medical Center, New York.
		DR. ORKIN:  Milton Orkin, from the University of Minnesota, Minneapolis, Minnesota.
		DR. BERGFELD:  I am Wilma Bergfeld, a dermatologist from the Cleveland Clinic.
		DR. McGUIRE:  I am Joe McGuire, from Stanford University, dermatology and pediatrics.
		MS. RILEY:  I am Tracy Riley, the Executive Secretary to the committee.
		DR. SIMMONS‑O'BRIEN:  I am Eva Simmons‑O'Brien, from the Departments of Dermatology and Internal Medicine at Johns Hopkins in Baltimore, Maryland.
		DR. KILPATRICK:  I am Jim Kilpatrick, School of Medicine, Medical College of Virginia, Virginia Commonwealth University, biostatistician.
		MS. COHEN:  I am Susan Cohen, and I am the consumer member.
		DR. HASHIMOTO:  I am Ken Hashimoto.  I am a dermatologist, Wayne State University in Detroit.
		DR. MILLER:  Fred Miller, dermatologist, Geisinger Medical Center, Danville, Pennsylvania.
		DR. BIRNKRANT:  I'm Debra Birnkrant, acting Division Director, Division of Antiviral Drug Products, and I chair the Thalidomide Working Group at the FDA.
		DR. WILKIN:  Jonathan Wilkin, FDA, Dermatologic and Dental Drug Products.
		DR. WEINTRAUB:  Mike Weintraub, Office of Drug Evaluation V.
		DR. WOODCOCK:  I'm Janet Woodcock, and I'm the head of the Center for Drug Evaluation and Research at the FDA.
		MS. PENDERGAST:  Mary Pendergast, Deputy Commissioner, Food and Drug Administration.
		DR. McGUIRE:  Thank you very much.
		The first remarks will be presented by Mary Pendergast.
		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 so generously of their time and their expertise to the FDA.
		We are here so that our advisory committee can review Celgene's new drug application for the use of thalidomide for the treatment of erythema nodosum leprosum, 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 committee our concept that thalidomide, despite its history and known risks, could be an approvable drug.  We believed, and still believe, that thalidomide may have the capacity to treat as well as to damage.  We also explained why we felt we needed to change the medical landscape when it came to thalidomide.
		Because thalidomide was not approved, patients with Hansen's disease were getting substandard drugs that were not manufactured under good manufacturing practices.  And although thalidomide held out promise for other diseases, there were no well‑planned schemes for studying the drug for other diseases.  
		The Health Resources Service Administration was running out of money to pay for the distribution of the drug under investigational new drug exemptions.  
		And we were concerned about the proliferation of groups that were distributing bootleg, illegal thalidomide to patients with AIDS and cancer, without careful controls that would have prevented birth defects.
		Consequently, we took several steps to change the landscape.  One step was to encourage companies to pursue approval for diseases for which there might be the requisite data.  Celgene took up that challenge and has pulled together an application for the use of thalidomide 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 voluntarily to stop distributing thalidomide.  And we stopped the remaining buyers' clubs' activities through legal proceedings.
		We have also collaborated with the National Institutes of Health and the Centers for Disease Control to design a two‑day public scientific meeting, that will be held next week, to explore whether and how thalidomide could be used for other clinical uses.  We know that thalidomide is being studied as a treatment for many serious diseases, including ENL, chronic graft versus host disease, cancer, and HIV infection.
		This meeting will discuss the advances and research opportunities of thalidomide in the treatment of various disorders.  
		But next week's meeting will have a broader focus as well.  We need to remember that more than half of the population alive today was not yet born when the thalidomide tragedy took place.  There are many in our society, patients and physicians alike, who do not know the thalidomide story.  Thus, as an education to some and as a reminder to others, we will also discuss the past uses of thalidomide, the risks associated with thalidomide and reproduction, the legal, ethical, and other public policy concerns surrounding thalidomide's use, and the management of the adverse effects of thalidomide.
		This will be an important and useful meeting, and the results of that meeting, as well as your expert advice today, will be taken into account before FDA makes any decision on the approvability of thalidomide for ENL or any other disease.
		I know that there are some who wish that next week's meeting could have been held before this meeting.  But scheduling difficulties made that impossible.  In my view, though, it shouldn't matter.  For today, we are attempting to have an ordinary advisory committee meeting.
		What we would like today is for the advisory committee to assist us with their expertise on the particular new drug application that is before them, and help us answer the question of whether thalidomide is effective in the treatment of ENL, and whether the steps that have been proposed to control the distribution and use of the drug will permit thalidomide to be considered safe under that scheme.
		Although these are the normal, straightforward questions we ask of advisory committee members all the time, they will be harder answers to come by today because, as you have seen, this is not a fully conventional data set.  Celgene did not invent thalidomide and then develop the drug through conventional studies.  Rather, thalidomide has been used for ENL for over 30 years without the rigorous collection of data one would expect from real clinical trials.
		Therefore, it is critically important to us that you give a careful and thoughtful look at the data that does exist, and help us decide whether thalidomide should be approved as a treatment for ENL.  This will be challenging, but very important efforts, and we look forward to hearing your deliberations.
		So, I would like to thank you again for being a member of our advisory committee, for helping us out on this very tough question.  Thank you again for your attention.
		DR. McGUIRE:  Thank you, Ms. Pendergast.
		Dr. Weintraub.
		DR. WEINTRAUB:  Thank you, Dr. McGuire.
		Several people have asked, since we've distributed signed reviews, stating the reviewers' conclusions on the approval of thalidomide, why are we having an advisory committee meeting?  And the question of people who oppose it, they said, well, you have already made up your minds; it is a closed issue.  Well, I assure you that it is not.
		Let me tell you a little bit about the procedure at FDA.  We believe that in a science‑based enterprise, which this is, everyone is entitled to their own interpretation of the data ‑‑ particularly people who have worked very closely with the information coming from clinical trials or coming from studies such as these data sets, as Mary just pointed out.  They are not always conventional data sets.
		But we do not demand that everybody has to have an opinion that is totally in concert with other opinions and other points of view.  We believe in the value of ideas and of insights.
		Now, there are many reasons why a particular reviewer can come to a different judgment.  The primary reviews are often completed earlier in the final approval process.  And the reviewer may not have a total picture of the final plans ‑‑ for example, in this case, such as restricting distribution ‑‑ and perhaps, in that sense, altering the risk/benefit relationship.
		Of course, with a controversial drug such as thalidomide, there are bound to be differences of opinion.  The outlook of everybody may be different when the drug is so controversial.  Several people, all acting in good faith, can look at the same numbers, the same dots on a graph, and come to different conclusions.  This is especially true if the numbers and dots come not from clinical trials but from experiences that were never intended to be interpreted as if they came from double‑blind, randomized, carefully controlled experiments ‑‑ for example, things like the information from the clinical care of patients ‑‑ even those who are carefully followed.
		In the FDA, we have a system of supervisory oversight.  That is why we have given you primary and secondary reviews, the Division Director's opinion and the Office Director's view.  In some cases, we have the Director of the Office of Review Management over the Office Director, and the Center Director as well.
		Except for the primary reviewer, we can all write overriding memoranda.  I know that my colleagues ‑‑ the other four office directors ‑‑ and I take overruling our trusted colleagues and coworkers very seriously.  It is not something we do lightly.  Instead, the decision involves delicate balances and inner struggles.
		So, although you have primary and secondary reviews and a Division Director's memo in your packet of materials, I will assure you that our minds are not made up and we are not done yet.  Our analysis has not been locked in one way or the other.
		We invited you here because we respect your judgment.  Even if we do not take your advice, as occasionally occurs, we still learn from your discussions, from your unique points of view, your questioning of the presenters, and your deliberations over the questions.
		Now, I am sure that we will still learn from your deliberations over the next day and a half, and I am certain that we will receive the benefit of your advice.  I appreciate it, and I know actually the entire FDA is really in your debt for doing that.
		Thank you.
		DR. McGUIRE:  Thank you, Dr. Weintraub.
		I conclude from what you have said that this is not a stacked deck.
		DR. WEINTRAUB:  That is correct.
		DR. McGUIRE:  Let's go on to the public hearing.  There are two statements to be read.
		MS. RILEY:  The first statement is from the Office of the Executive Director of the American College of Obstetricians and Gynecologists.
		On behalf of the American College of Obstetricians and Gynecologists, ACOG, an organization representing 38,000 physicians dedicated to improving the health care of women, ACOG does not believe that thalidomide, nor any drug, should be kept from being introduced or withdrawn from the market solely because it may be teratogenic.  We strongly support efforts to prevent exposure of women who are pregnant or contemplating pregnancy from known teratogenic agents.
		Sincerely, Ralph W. Hale, M.D., Fellow of the American College of Obstetricians and Gynecologists.
		The next statement is from the Leonard Wood Memorial American Leprosy Foundation.
		I, Dr. Gerald P. Walsh, Scientific Director of the American Leprosy Foundation, am submitting a written presentation on behalf of my organization in support of the licensing of thalidomide.  I regret that at the time of the meeting it was necessary for me to be at our research facility in the Philippines.
		Founded in 1928, the Foundation conducts, maintains and supports laboratory investigations, clinical studies and related research, with the ultimate goal of eradicating leprosy.  We also disseminate information about the source, diagnosis, treatment, and prevention of the disease, just as we voluntarily aid, establish, maintain, and support clinics, hospitals, and laboratories for diagnosis and treatment of the disease.  The Foundation is headquartered in the United States, and maintains a leprosy research center in Cebu, Philippines.  The Center is staffed by 34 individuals, composed of professional as well as technical and support staff.  It is in Cebu that our scientific research is carried out.  The Foundation is foremost among many American agencies in this field, and we are proud of the many achievements and contributions we have made that we believe will eventually lead to the eradication of this tragic disease.
		Few diseases are as feared and misunderstood as leprosy.  Since pre‑Biblical times, the leprosy patient has been surrounded by myth, superstition, fear, apathy, and rejection.  Some progress has been made toward changing these attitudes, but unfortunately they are still prevalent in many parts of the world, including the United States.
		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 most prevalent in tropical and subtropical climates, but was rampant in temperate climates until the late 19th century.  Of concern to this committee are the approximately 6,000 known cases of leprosy in the United States.  The actual number of cases is undoubtedly higher, and climbing, in light of sustained immigration from Third World countries to the United States.
		Leprosy is currently treated with a combination of drugs.  Although multi‑drug therapy is the treatment of choice, serious problems still remain.  New drugs are needed and research must continue.
		Up to 30 percent of all people afflicted with leprosy suffer from erythema nodosum leprosum, ENL, an acute reactional phase from leprosy that is very painful and debilitating for patients.  It usually occurs after treatment is started and is characterized by the appearance of tender nodules, accompanied by fever and joint pain.  In severe cases, the patients are bedridden for weeks.  And some of these develop chronic ENL, which incapacitates a patient permanently.  ENL is thought to be immunologically mediated, but the specific factors that precipitate episodes of ENL are not clearly understood.  Recent studies have suggested that cytokines may play a key role in ENL.
		We at the American Leprosy Foundation are proud to have pursued research that addresses the key questions still surrounding the etiology and treatment on leprosy and ENL.  We are very concerned that in our clinics today we can offer patients only a limited number of treatment 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 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 is very effective for controlling ENL.
		Our studies in Cebu, Philippines, that are partially supported by Celgene Corporation, have shown the remarkable effect of thalidomide and represent an important treatment option for patients living with ENL.  We at the American Leprosy Foundation urge you to recommend approval of this drug.
		Thank you.
		Gerald P. Walsh, Ph.D., Scientific Director.
		DR. McGUIRE:  Thank you, Ms. Riley.
		We will have an oral presentation now from Dr. James Hanson.  Dr. James Hanson is representing the American College of Medical Genetics, the American Academy of Pediatrics and the Academy Committee on Genetics.
		DR. HANSON:  Mr. Chairman, members of the committee, I am James Hanson, Professor of Pediatrics at the University of Iowa.  I am here representing the American Academy of Pediatrics, as you have heard.
		It is not without reason that thalidomide has been termed the most notorious human teratogen.  The drug was introduced in 1956 in West Germany, as an effective sedative and hypnotic.  It was also used to treat nausea and vomiting in pregnancy.  By the end of 1961, thalidomide, sold under 51 different brand names, was identified as a human teratogen and removed from the market.  More than 10,000 infants worldwide were born with malformations attributed to the use of thalidomide in pregnancy.  In 7 of the 17 cases reported in the United States, the thalidomide was purchased in another country.
		And I might add parenthetically that the avoidance of a similar tragedy in the United States was largely due to the efforts of Dr. Francis Kelsey, who is sitting over here on my left.
		(Applause.)
		DR. HANSON:  The mechanism for teratogenicity of thalidomide is still not known.  However, the period of greatest sensitivity appears to be between days 21 and 33 of gestation.  It is of great concern that the effects of thalidomide on the fetus do not appear to be dose-related, and teratogenic effects appeared in over 80 percent of the fetuses exposed during the critical period.
		Thalidomide produces major malformations of the upper extremities, ranging from missing thumbs to missing radii to absent ulnas and humeri, including so‑called phocomelia and the micromelia.  It sometimes produces major malformations of the lower extremities as well.  In addition, fetuses exposed to thalidomide can have congenital heart defects, craniofacial anomalies, facial palsies, urogenital anomalies, and a number of other structural birth defects.  Concerns have also been raised about associated developmental disabilities.
		While available research supports thalidomide's effectiveness in the treatment of leprosy, graft versus host disease, aphthous ulcers, wasting in AIDS patients, and several other disorders, use of this drug comes with great risk to the fetus.
		The American Academy of Pediatrics is deeply concerned about the approval of this drug in light of its known teratogenic effect is.  Despite any attempts to educate and monitor patients and to preclude the use of thalidomide during pregnancy, some fetal exposures will occur.  The committee should realize that infants will be born with preventable birth defects if this drug is approved for prescription use.  The experience concerning Accutane use is revealing.  Even with a strong education program, some 40 percent of the women of childbearing potential who took Accutane did not have a pregnancy test before initiating treatment.
		For a drug like thalidomide, that has a high rate of teratogenicity, a 40 percent noncompliance to warnings about use during pregnancy could result in a significant number of affected infants.  This is particularly true if thalidomide is used by women who are infected with HIV, many of whom, because of problems with drug abuse or low education or other risk factors, will be less likely to be compliant with complex regimens.
		It is the opinion of the American Academy of Pediatrics that thalidomide be a restricted drug, available only for indication through a single national resource, subject to public oversight.  At the very least, the American Academy of Pediatrics believes that the use of thalidomide should be restricted to those disorders for which it has been shown to be effective in clinical trials and for which other therapies are not available or have been unsuccessful.  Since thalidomide would rarely be used for emergency medical treatment, documentation of negative pregnancy testing, two means of contraception and educated, informed consent should be required before this drug is given to a premenopausal female.
		We certainly recognize the potential effectiveness of thalidomide in a number of clinical areas, and the benefits of the drug to some patients.  However, even with a massive educational program and adherence to strict guidelines, it is clear that the general licensing of this drug will come with an increase in devastating birth defects, even if effective guidelines are followed.  It cannot be too highly stressed that these birth defects will result in physical, financial, and emotional costs to affected children and their families, and that additional burdens will be incurred by society.
		In closing, the American Academy of Pediatrics urges this committee and the FDA to seek and heed the advice of all organizations whose focus is the health and welfare of America's children before considering the approval of thalidomide.  If the FDA is to approve this dangerous drug, the committee needs to determine appropriate and necessary safeguards to minimize the risks to future children.
		Thank you.
		DR. McGUIRE:  Thank you, Dr. Hanson.  And thanks to the Academy for that well worked out statement.
		We have one more oral presentation from Anne Pasturzak, representing Mother Risk.
		(Pause.)
		DR. McGUIRE:  Absent Ms. Pasturzak, we will go on to the scientific presentations by Celgene.  Dr. Steve Thomas will tell us about the chronology and pharmaceutical development.
		DR. THOMAS:  I'm Steve Thomas.  I welcome you all.
		I think the first thing I should say is that our company is in the debt of the advisory committee and also the FDA in having an opportunity, as of this date, to make some formal presentations to you.  Although this is, and we hope it will be, an ordinary advisory committee, I'm afraid I cannot regard it like that.  I think obviously this is very important from our company's viewpoint.  However, it is of more general import than that.
		I personally am actually 36 years old.  And I actually recognize that it was fate that allows me to be speaking here with one perspective and actually not with another perspective.
		With that in mind, I would just like to lead on to the reason why we are here.  Yes, the reason why we are here is to seek your guidance, to hear your views, to express our views on the efficacy and safety of this interesting, unique compound in the treatment of ENL and leprosy.  
		I would like to ask you, if you have any specific questions that you would like to pass on to representatives of our company, I may be able to help you in actually directing those questions.
		I think it is useful to try and explain how our company has established its interest in ENL and to put that into a time line and a chronology and also in a perspective of what the company is involved with in other areas.  Initially, we became aware of the use of the drug in ENL through an evaluation of the literature, the previous human use of the drug, in support of an AIDS‑wasting IND that was entered into the FDA in January of 1994.
		During that literature overview, it became apparent that there was very extensive previous human use experience of the drug in ENL and leprosy.  Most notably, our company became aware of a substantial database, which spans over 18 years of use, which is held at the Hansen's Hospital in Carville, Louisiana, and continues to acquire data on the use of the drug under an IND that is authorized ‑‑ IND 11,359 ‑‑ actually by the FDA.
		It's also interesting, I think, to note a way in which, the authorization of the IND came into existence.  It was actually based on the substantial earlier clinical experience which identified the potential use of the drug in this ENL indication.  
		I think it is also actually very important that our company points out and agrees with the views which have already been established by Mary Pendergast, that because of the way in which our company has identified data, you will be asked to give your critical opinion on a variety of historical data sets as well as information which is more current from ongoing studies which our company is running in the Philippines.
		These historical data sets are not providing, even from a company's viewpoint, an NDA which is ideal in form or content.  I would ask the members of the committee, when they are making their deliberations, to please actually take in context that ENL is an orphan indication, where access to individuals, patients who are available to enroll in clinical trials in the U.S. is very limited.
		However, with all of the caveats as I have just identified them, our company would like to try to persuade you that it is clear that in the variety of data sets efficacy of the drug has been established, and we believe that the drug can be safely used in this indication.
		I must allude also to the comments of Mary Pendergast again in identifying how our company's interest in this indication intensified.  As the FDA has already told you, they invited interested industry sponsors of INDs to a meeting in November 1995, where it became apparent that the agency had concerns over the potential use of unregulated drug sources, specifically in the AIDS area.
		At that meeting, it was also pointed out that due to the interest in the evaluation of the drug, there was increasing compassionate use needs which were escalating at a very rapid rate and that FDA was keen to try to obtain from sponsors reviewable NDA submissions so that this particular range of circumstances could actually be turned into a more controllable and regulated outcome.
		Coincidentally, at that moment in time, as you have already heard, the availability of drug through the Hansen's Hospital IND for emergency uses other than Hansen's, or other than actually for Hansen's patients, had to come to an end.  Our company interpreted that as providing an urgent need for consistent, high‑quality availability of drug manufactured in compliance with the FDA's own guidelines on good manufacturing practices, and our company at that moment in time actually made a commitment to make our drug supplies available to these other emergency use IND indications.
		I think it is important that I actually put our ENL indication in context.  Our company is committed to the intensive clinical evaluation of this drug in a number of life‑threatening indications.  AIDS wasting, aphthous ulcers and graft versus host disease you have already heard about.  I think it is also worthwhile actually pointing out that as of this date, as a result of our company's efforts, we have, where authorized by the FDA, actually made our drug supplies available in over 500 emergency use INDs, both in the United States and also in Canada, and that this provides very useful information on the exposure of the drug and the safety of the drug.
		Lastly, I would just like to point out that our company recognizes that there are severe problems associated with the use of this drug.  However, there are also unique opportunities of efficacy which have actually been identified previously, will be discussed during this forum, and also at the open meeting next week.  We would like to seek to identify, to understand the mechanisms through which the parent compound is providing efficacy whilst trying to engineer a reduced and changed profile of toxicities.  And this really our company's long‑term goal.
		With that long‑term view in mind, which I think is a laudable and praiseworthy goal, our company is now in the position to take an analog of the parent drug thalidomide into healthy human volunteer studies actually later this month.
		Lastly, I would like to just introduce over the course of the meeting our company's outline and plan overall for speakers and presentations.  It is in a slightly different order to that which you have on your agenda.  The first speaker, who is going to address issues of PK and metabolism is Dr. Wayne Colburn of MDS Labs, which is a clinical research organization, which has undertaken the vast majority of our work in this area.  And I will actually just pass it over to Wayne.
		DR. COLBURN:  Good morning, ladies and gentlemen.  I appreciate the introduction.  And I would like to expand on that a little bit.
		I work for MDS Harris Laboratories, which is a contract research organization, and I have also been working with Celgene over the last two or more years in assisting them with the development program that we are going to talk about today.  MDS Harris has been involved in working with Celgene to design and conduct the clinical studies, as well as to assist in the interpretation and reporting of that data.
		What I want to talk with you about this morning are some of those outputs.  In addition to the initial three clinical studies that were presented in the data package, there are four additional studies which we'll also briefly take a look at this morning.
		Could I have the first slide, please?
		The first three studies listed on this slide were presented in the original data package.  And essentially, this is a summary that gives the study number or protocol number, the population studied, the number of participants, broken down by number of male subjects and number of female subjects.  It also provides a very brief overview of the design and what dose or doses were used.
		In the first study, PK‑001, we looked at healthy volunteers to assess the bioequivalence of two Celgene lots, as well as a Tortuga lot, to determine whether the proposed commercial dosage form was bioequivalent with the dosage forms that were used in clinical trials, as well as to look at a lot that had been evaluated in ENL in previous years.
		The next study looks at healthy volunteers, again, single dose, to evaluate dose proportionality of subjects, looking at doses up at 200 milligrams.  
		Then the other study that was in the original package was actually a study conducted in a small group, two men and four women, with Hansen's disease.  This was a single‑dose study, which was intended to look at the pharmacokinetics in that patient population as well as to look at the metabolism of thalidomide.
		Now, subsequent to that submission, we have conducted additional studies.  And those I will go over briefly here.  PK‑006 is also a study in healthy volunteers.  There were 13 study participants, of which 5 were male and 8 were female.  This was a single‑dose bioequivalency study to look at the effect of food on the bioavailability of the Celgene product, as well as to look at another lot of material manufactured outside of the United States.
		Another study, PK‑UK001, was conducted in HIV‑positive subjects.  16 participants, all male, participated in a dose‑proportionality study which looked at doses of 100 and 200 milligrams.
		I might mention back here that this study, in fact, has doses that range from 50 to 400.
		Two additional studies which are put into another category ‑‑ all of the previous studies were single‑dose in nature ‑‑ looks at multiple dosing.  There were two studies in that that have those characteristics, the first one being PK‑003, conducted in healthy female volunteers ‑‑ 12 females ‑‑ which received single doses.  
		This is somewhat of a misnomer.  It really looks at the single‑dose and multiple‑dose thalidomide pharmacokinetics.  In addition, a single dose of Ortho Novum, a commonly used oral contraceptive was administered after thalidomide had been brought to steady state, or on day 21.  And essentially, we looked both at the accumulation of thalidomide, or the effect of repeated dosing on thalidomide, as well as the effect of thalidomide on an oral contraceptive in this study.
		Then, finally, we did a multiple‑dose study in Hansen's disease patients ‑‑ 4 ‑‑ due to the small numbers of patients available ‑‑ 3 of which were male, 1 of which was female.  And here we looked at the steady state pharmacokinetics in doses that was what these people were receiving during their normal therapy, which ranged from a single, daily 50‑milligram dose, up to 300 milligrams given in a t.i.d. regimen.
		Now, let's evaluate, or take a quick overview of, some of the data that resulted from these studies.
		First, one study that was not listed on the previous slides is we also looked at the in vitro human metabolism of thalidomide.  And this was done in human liver microsomes.  It's shown here.  And what it showed was that, in fact, the human liver microsomes did not metabolize thalidomide to any appreciable extent.  What this would suggest, then, is that the predominant change or apparent metabolism of thalidomide is a function of simple hydrolysis.
		In addition to this, one of the concerns was that thalidomide could either be induced or inhibited itself by other drugs or could cause the induction or inhibition of other drugs.  In support of that question, we provide the following information.
		We looked at a series of cytochrome P450 isozymes, and in no case was there any evidence of inhibition or induction for CYP 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4.  And these are the enzymes that are most commonly associated with drug metabolism.  So, we don't anticipate that there will be any impact of thalidomide on other drugs or any effect of other drugs on the metabolism of thalidomide.
		Now, to go through the studies that we talked about briefly before, or gave the outlines for.  The basic take‑away messages for these single oral‑dose studies was for a 200‑milligram dose, the oral absorption, or apparent absorption, half‑life is 1 hour, based on this data as well as others.  In reality, this is probably the elimination half‑life.
		The apparent elimination half‑life is approximately 5 and a half hours.  And as we will see from other data that I'll show later on, in fact, this is probably the absorption half‑life in what kineticists would call a flip‑flop model.  And this is true not only in healthy volunteers but in HIV‑positive subjects that we studied.
		Looking in healthy volunteers at the 50‑ to 400‑milligram dose range, there is dose proportionality with respect to the area under the curve.  In fact, the extent of absorption is the same from 50 to 400 milligrams.  However, Cmax does not increase proportionally due to delayed absorption or prolonged absorption between the 200‑ and 400‑milligram dose.  How that evidences itself is, again, the apparent elimination half‑life, which we believe is truly the absorption half‑life, changes from 5.5 to 7.3 hours between 200 and 400 milligrams.
		Again, back to the 400‑milligram dose level, but, in this case, looking at patients with Hansen's disease, the pharmacokinetics are similar when dose-adjusted back to the 200 milligrams, and also compared to the 400 milligrams here, to all of the pharmacokinetic profiles that we observed in healthy volunteers.  So, the overall message there is that the pharmacokinetics in Hansen's patients is similar to that which we see in healthies.  
		The other observation was that absorption and elimination half‑lives were somewhat longer at this 400‑milligram dose.
		Taking this to the next step, they are similar, as we stated before.  And the absorption half‑lives were somewhat longer, but the metabolism that we observed in vivo is essentially confirmed in this 400‑milligram dose study in Hansen's disease patients.  In fact, the three metabolites that would be anticipated to be formed were not observed in the plasma of these subjects.  Less than 1 percent of the dose was excreted intact in urine, and even a lesser extent, less than .1 percent of the dose, was excreted by one of the hydroxy metabolites, 4‑hydroxy‑thalidomide.
		Finally, to get back to the bioequivalency issues from the single‑dose studies, Celgene's proposed commercial formulation is bioequivalent to their formulation that was used in their clinical studies.
		However, the Tortuga lot, a lot of material, or a manufacture of material, that has been used extensively in the treatment of Hansen's patients having ENL, was not bioequivalent to either of the Celgene formulations.
		The extent of availability was identical.  The areas under the curve were identical for the two products.  However, the Cmax for the Tortuga lot was about one‑half that for the Celgene lots.
		I think this is the final single‑dose overview slide, and it looks at the effect of food on the pharmacokinetics of thalidomide.  And, in fact, there is no change in the area or the extent of availability, but there is a slight delay in the absorption, and this results in a delay in Tmax, or the time of the peak concentration after a single dose.
		Now, we'll move on to the multiple‑dose pharmacokinetic information.  Again, the first set of data has to do with Hansen's disease patients.  We see, using the multiple‑dose data, that, again, the pharmacokinetics in Hansen's disease patients is similar to that observed in healthy subjects.
		Also, supporting the single‑dose study at the 400‑milligram dose, the purported metabolites, again, were not measurable in plasma, and only less than 1 percent of the daily dose was excreted in urine.  And only approximately 0.2 percent of the dose was found in urine as the 4‑hydroxy metabolite.  Neither of the other two metabolites that we looked for were observed.
		The final multiple‑dose study is shown here.  The results from that study.  When thalidomide was administered to women over 18 days, the pharmacokinetics were similar between day 1 and day 18, indicating only a slight accumulation of drug during that period.  That's consistent with repeat‑dose studies in male healthy volunteers as well.
		In addition, when a single two‑tablet dose of Ortho Novum oral contraceptive was administered, the pharmacokinetics of the ethinyl estradiol and the norethindrone from that product was not altered by the 21‑day administration of thalidomide.  
		The other observation was that, during the 18 days of dosing, the pharmacokinetics of thalidomide did not change in premenopausal women.
		Now, just to come back to the take‑home messages from this significant amount of data that I have tried to present in a short period of time, I'll try to briefly summarize what I think the take‑home messages are.
		One of the things that has been a concern is the lack of equivalence between the Tortuga lot and the Celgene lot, because some of the data that will be presented later today, the Tortuga lot was used.  
		If, however, we take the data that was generated from that pharmacokinetic study and simulate what steady state conditions would be -- the concern had been that Cmax was lower by about one‑half that of Celgene -- on repeated dosing, because of the difference in the apparent elimination half‑life, in fact, Cmax, in the areas under the curve, will be very similar at steady state.
		Secondarily, gender.  Female subjects composed 26 of the 83 subjects that were studied during these clinical trials.  Both females and males exhibited very similar pharmacokinetic profiles.  So, gender is not an issue, and this was true not only on single doses, but at steady state.
		Looking at the patient populations, the patient population of interest here, obviously, is ENL.  And we have shown that although there are slight differences on single dosing in ENL patients, that in fact on both single dosing and multiple dosing, the pharmacokinetics are similar to those observed in healthy volunteers.
		Then, finally, to close, with the in vitro and in vivo metabolism that was conducted here, we have shown that there should be no concern for potential interaction of thalidomide with rifampin, dapsone, or any other treatments that are commonly used in Hansen's disease patients based on the data that we have provided today.  And we have shown conclusively that there is no interaction with oral contraceptives.
		I'd like to thank you for your attention, and then our next speaker.  Thank you very much.
		DR. McGUIRE:  Let me question the sponsor.  Would you like for the committee to ask questions during the presentations?  Or we can hold questions until the end.
		DR. THOMAS:  If you would feel more comfortable asking the questions when they are fresh, maybe that is how it should happen.  But our company is in your hands.  We will do it either way.
		DR. McGUIRE:  Does the committee have any questions at this point?
		Dr. Bergfeld.
		DR. BERGFELD:  I have a question.  In my background is as a dermatologist and a dermatopathologist, not a chemist.  I fail to see how the drug is eliminated if you are unable to measure it in the urine.  And if you say it is by hydrolysis, your metabolites that are hydrolysized are not present in the urine even.  So, how is it eliminated?
		DR. COLBURN:  Unfortunately, I cannot give you a definitive answer on that, but I can give you a little bit of information, and hopefully document what I would anticipate is happening.  The hydrolysis products are formed, but my belief is that they are quickly converted downstream to other products that we were unable to measure.  And we only account for 1 percent of the thalidomide in urine.  So, it obviously is not a major route of excretion.  We anticipate that it is hydrolysis, but to products that we were not able to measure.
		DR. BERGFELD:  Is there any problem with this drug being stored in fat?
		DR. COLBURN:  Stored in fat?  There is no evidence of that.
		DR. BERGFELD:  You have not measured the fat?
		DR. COLBURN:  No.  We have not done any distribution studies of that nature.  However, the characteristics of the compound would suggest that it is not going to be taken up in lipid material.
		DR. McGUIRE:  Dr. Shannon?
		DR. SHANNON:  Yes, sir, I found your comment about the using of the liver microsomes to study metabolites was not affected with Celgene's formulation.  I wonder if you would comment on that, because that is a rather common protocol to generate metabolites of thalidomide, established in several laboratories.
		DR. COLBURN:  There's literature data that shows essentially what we've concluded here ‑‑ that hydrolysis, in fact, does occur.  It occurs more quickly in liver homogenates, for example.  But our data, based on the three metabolites that we measured, as well as parent compound, indicate that it is not through the cytochrome P450 system.
		DR. SHANNON:  How did you control for hydrolysis in that experiment, in the liver microsomes?
		DR. COLBURN:  You can't.
		DR. THOMAS:  I wonder if I could just add a point there, Dr. Shannon, and that is that even in the paper which I think you are alluding to, which is the Knoche and Blaschke paper, they were only able to identify very, very low levels of these metabolites.  And I think that is actually borne out in our data.
		DR. McGUIRE:  I think that is all for the committee right now.
		DR. THOMAS:  Okay.  Thanks again, Wayne.
		I would now like actually to pass the microphone over to Leo Yoder, M.D., recently retired from over 30 years of handling ENL and leprosy patients on behalf of the U.S. Public Health Service.
		DR. YODER:  Good morning.  I am Leo Yoder.  I recently retired from the Public Health Service after 15 years of working almost exclusively with leprosy, or Hansen's disease.  Prior to that, I spent a number of years in Africa and also as a consultant in some other countries.  So, I am talking to you briefly from the perspective of a person who has done hands‑on care of patients, leprosy patients, and particularly patients with ENL, and lived through some of these difficult illnesses and experiences with them.
		I will give you just a brief overview of leprosy, the syndrome itself, and then focus especially on ENL and its treatment, and my own experience and impressions in the management of this problem.
		Leprosy is an infectious disease primarily of man caused by Mycobacterium leprae.  It is an unusual organism.  It has never been cultured in a laboratory as of this date.  It has a special affinity for skin and nerves, which are the cooler parts of the body, primarily the peripheral nerves, involving the hands and feet, and some other organs, particularly the anterior part of the eye.  Testicles are often involved, as well.  Especially also the respiratory tract, the nose especially.
		Just a word about the problem worldwide as it still exists today.  The World Health Organization uses the figure of 1 million to 2 million cases under treatment, which is the way they define prevalence currently.  There certainly are an additional other 2 million or 3 million, at least, who have significant deformities and disabilities from this disease, who require care.
		In the United States, we estimate approximately 7,000 or so cases that have been diagnosed and treated for the disease.  Not all of these are now currently under treatment or have active disease, but these are on registers.
		However, probably the more important numbers to look at what's ahead for this disease is to look at the new case rates, or incidence rates.  In the U.S., approximately 200 new cases occur per year, or are reported per year.  This has been fairly consistent.  It is down slightly, but this is not very much different from what it has been for quite a number of years, excepting for the mid‑1980s when there were more immigrants from Southeast Asia.
		Worldwide, as somebody has already mentioned, the current figure is about 600,000 new cases per year.  And the significance of that number that I would make is that that number is not changing or decreasing very much.  There are some notable exceptions to that in a few countries, but, in general, the number is going down very slowly.
		So, in spite of the fact that WHO is talking about elimination as a public health problem by the year 2000, they are not reflecting the real new cases numbers, which are staying almost constant or decreasing very slightly.  So, this disease is going to be with us for many years to come.
		Leprosy is a spectrum of disease.  From the simplest type of disease, tuberculoid disease on one side of the spectrum, patients in that category have a fairly intact cell‑mediated immune response to this bacteria.  These patients actually have very few bacteria.  They have possibly one or two skins lesions or a few nerves involved.  But the pathology is in excess of the number of bacteria.  There is primarily an immunologic process that takes place and causes the nerve, or other, damages.
		On the other end of the spectrum is lepromatous disease.  These patients have diffuse, generalized disease, especially of the skin and nerves.  They have a lot of bacteria in the skin and nerves.  They have involvement of other organs, as I have already mentioned.  They have a specific cell‑mediated immune defect to this organism, Mycobacterium leprae.  It is very specific for this organism.  They handle other infections quite normally.
		The other item of note is that there are antibody levels in these patients.  In lepromatous patients, there are fairly high antibody levels.  They do not do anything apparently to kill or clear these bacteria, but they do have some significance as far as ENL is concerned, which we will mention again later.
		I am not going to talk about chemotherapy.  There is antibacterial therapy which is quite effective, although it may take a number of years, but chemotherapy is effective.  And I want to focus primarily on this problem of reactions.
		This does not occur in all patients.  The figures that one sees is anywhere from 10 to 50 percent, depending on when and what time frame you were talking about.  But a significant number of these number of these patients do have reactions.  There are basically two types of reactions.  
		One occurs in the tuberculoid end of the spectrum.  And I should also say, in that spectrum, from tuberculoid to lepromatous, obviously there are a lot of patients who fall in the middle somewhere ‑‑ a big proportion of them ‑‑ and those are, in our lingo, known as borderline patients.  And so patients near the tuberculoid end of the spectrum get something called reversal reaction, which is a cell‑mediated reaction, quite different from ENL, usually treated with prednisone.  And I will say nothing more about that.
		On the other end of the spectrum, the lepromatous patients with high antibody levels and borderline lepromatous, the near‑lepromatous patients, get erythema nodosum leprosum.  These are not treatment failures.  In fact, they can occur before treatment even is initiated, although usually they occur after a period of treatment.  They are not drug reactions or drug allergies.  They are, in fact, an immunologic problem.
		There is a lot we don't know about that syndrome as yet.  However, it is generally accepted that it is an immune complex disorder, antigen/antibody complement.  Immune complex is deposited in the tissues, sometimes found in the circulation, although not always.  And this produces an acute inflammatory response in the tissue, in the skin, a vasculitis, panniculitis.  There is neutrophil infiltration in these lesions, and these patients also have usually a rather significant leukocytosis in the peripheral blood, as well.
		In recent years, it has also been noted that tumor necrosis factor-alpha is elevated in these patients, which decreases as the syndrome subsides.  The significance of that is certainly not entirely clear at this point.
		Now, turning to what this looks like clinically, the obvious visible thing is the skin lesions classically are erythematous nodules which look like erythema nodosum on the lower extremities from other etiologies.  But these nodules can occur anywhere on the body, including the face, trunk, limbs.  They can vary from mild, a few nodules, to extensive nodules.  They are usually painful.  They are easily palpable in the skin.  I will show you just a few photographs of those.  In the more severe cases, they can ulcerate and eventually produce scars as they heal.
		This disease, to some degree, waxes and wanes.  Even untreated, it will eventually end, but may take years, and the patient will experience a lot of pain and illness before that occurs.
		But it is not only a skin problem.  These patients, excepting for the very mildest ones, are acutely ill, with fever.  Neuritis is common, although not always present.  As I said, they have a leukocytosis.  They may be anemic.  Other organs may be involved.  They may have an orchitis, iritis in the eye.  Nephritis used to occur.  It's not so common these days since we treat it much more effectively and earlier.  Lymphadenitis can occur.
		The other part of the story is that this may go on and on and recur over a long period of time.  It is rare, especially for the type of ENL that we see in this country, for it to last for only a short period of time.  It usually, more typically, lasts for at least several years.
		The diagnosis generally is not difficult.  It occurs typically in a patient who is already on chemotherapy, sometimes for a year or two, and they think everything is going well, and then they flare up with these new skin lesions that may be associated with painful and tender nerves.  They maybe have edema of the hands and feet.  And usually there is acute febrile illness, where they have generalized aching and pain and malaise, and they are just generally ill.
		These are just a few photographs of typical lesions.  These lesions are on the chest on a gentleman, which is the classic type of lesion.  Now, they don't look terribly striking as you look at them on a photograph, but if you palpate them, they are actually deep infiltrations and generally are tender.
		This is another patient who had been treated for approximately a year, doing well, and then developed these lesions on his chest.  The same patient has these very painful lesions, which potentially are ulcerating, on his face.
		Another young lady who had the typical erythematous nodules in the upper portion of her body and extremities, but she also had associated lesions, like this, on her lower extremities, with ulcerations and blisters.
		A patient with actually sterile pustules, painful lesions on the arms.
		Finally, this is a young lady who I lived through.  I worked with her for a number of years, managing this reaction.  You may not appreciate it in the photograph, but she is quite cushingoid from long‑term use of steroids.  In spite of that, with our best efforts, she still had ulceration of her face.  And that is typical of some of these very difficult young ladies that we see occasionally, where this disease process continues for several years.
		The treatment options for this problem, other than for the very mildest ones, really are very few.  For the mildest ones, which we rarely see in this country ‑‑ I used to see these in Africa occasionally ‑‑ you could simply treat them with analgesics.  But much more commonly in this country, they are more severe than that.  And we really only have, for the acute situation, only two options.  The standard of treatment in our field now is thalidomide as the drug of first choice if it is in a situation where it is available and not contraindicated, as we will mention, especially women of childbearing age.
		Prednisone and clofazimine are the other alternatives, and I will briefly address those.
		First of all, clofazimine is used and can be used in some cases, but it's slow acting.  It has a number of disadvantages.  It is not useful in the acute stage because it takes a month to 6 weeks at large doses ‑‑ 200 to 300 milligrams a day ‑‑ to get an effective therapeutic effect.  At that point, it does have a steroid‑ or thalidomide‑sparing effect, and it is useful in patients who have severe problems.  
		But there are other disadvantages to it.  One is skin pigmentation, which occurs in virtually 100 percent of cases, which is unacceptable in many patients, particularly in light‑skinned persons, and especially in young women.
		There are also gastrointestinal symptoms in patients who take large doses.  And most patients will not tolerate 300 milligrams a day for more than 6 weeks or so.  The dosage then has to be reduced.  And occasionally I have seen patients who have had severe gastrointestinal symptoms, and even bowel obstructions have occasionally been reported at large doses.
		This is a photograph of a person who has taken clofazimine for a considerable period of time, and you can see the skin pigmentation over his face and arms.  Typically, this pigmentation occurs where the bacterial load is large and inflammation is taking place.
		Corticosteroids, or commonly what we use is prednisone orally, is effective.  There is no question about the efficacy if you use large enough doses.  The doses do need to be large.  Many times in the U.S. we generally will have to start with 60 to 80 milligrams a day.  We have often used even larger doses than that.  And these need to be given for long periods of time.  As I mentioned, this continues for extended periods ‑‑ often years ‑‑ and so you will require these large doses for a considerable period of time.
		If you attempt to withdraw the steroids, the reaction will tend to occur.  And, for the most part, short courses of prednisone do not work.  If you withdraw them, they will simply recur again.  I am talking about 2 weeks or so, and stop them.  It is not an efficacious or a good way to manage these patients.
		Consequently, many of these patients who do not have access to thalidomide, or it is contraindicated, develop serious side effects from the prednisone.  These are well known to you physicians who treat patients with cortical steroids ‑‑ osteoporosis, collapsed vertebrae, weight gain, diabetes, cataracts.  We've seen all of those in some of these patients who had to, for various reasons, take steroids for long periods of time.
		And one of the benefits of thalidomide is the avoidance of these significant side effects and, occasionally, even life‑threatening situations that can develop from patients who take steroids for long periods of time.
		Thalidomide is effective in the acute state, often as monotherapy, or in combination with steroids and clofazimine, as I mentioned.  But the other important use of it is in maintenance therapy.  Once the acute stage is controlled, to maintain these people on thalidomide for extended periods of time will prevent the recurrence of these episodes.  So that further steroids or only very low doses of steroids are required for the period of time that it takes for this patient to clear the bacterial load.
		The potential for these reactions to occur is as long as the bacterial load or the antigens of the bacteria remain in the body.  And the antigen, incidentally, in leprosy clear very slowly.  It takes years to clear these bacteria out.  Even though the antibacterial therapy is effective, the dead bacteria remain for years ‑‑ 5, 6, 7 years, sometimes longer -- before they actually are completely cleared.
		As was mentioned already, thalidomide has been the standard of therapy, recommended therapy, for ENL for many years, including the World Health Organization.  There has been a large experience with it in many parts of the world.
		At Carville, there has been an IND for the use of this drug since 1975, which will be mentioned and will be discussed in some further detail later by another speaker.
		This IND has made it possible to use thalidomide in leprosy patients, but it is restrictive, in that every physician who desires to use the drug has to obtain approval from his own institutional review board, wherever he is located.  He has to go through a considerable process to get that done and then to obtain it.  Under this protocol, it can be given to males and post‑menopausal females as an outpatient.
		For childbearing age females, the requirement is that they must either be surgically sterilized, which has been done on some occasions because of the chronicity and the severity of the illness, or they would have to be hospitalized at Carville, in the hospital for the duration of the time that they take the thalidomide ‑‑ which, during that time, they would be on contraception and weekly pregnancy tests.
		Finally, just a word from my own experience and the experience with that IND for the last 20 years or so as far as adverse events are concerned.  In our experience, we have not seen any congenital deformities that have ever been reported to us under these conditions.
		Sedation is very common.  However, this is generally not a significant problem when it's given in the hospital, of course, or, in general, as outpatients, it is given as an evening dose, and most people develop a tolerance to this and manage this quite well.
		Peripheral neuropathy has always been a concern.  We have known about this.  Even before this IND was initiated, it was reported.  In addition, we are dealing with a neurologic disease, so people who treat leprosy patients are sensitized to the fact that we have a neurologic problem.
		Patients who develop reactions and are treated appropriately with thalidomide or prednisone generally do not develop further deterioration in their neurologic status.  These patients are all evaluated at baseline, with various methods and, on occasion, not all, but some, with nerve conduction studies.  There are also other ways that we do sensory testing.  And so these patients do get looked at for neurologic problems.  
		Our experience has been that we rarely, if ever, see any significant deterioration in the neurologic status after we start treatment.  Now, we are aware that there is the possibility that we could be missing occasional thalidomide neuropathy which presents as a tingling and a paresthesia primarily.  But the experience is that we do not see any significant deterioration in neurologic status with these patients on treatment.
		We have seen it on occasion, and we have, on occasion, seen situations where the time frame of the neurologic symptoms suggested that it could possibly be thalidomide, and it would be discontinued in that situation.  But overall, our impression is, as in many others, that thalidomide neuropathy either is very mild in leprosy patients or occurs very rarely.
		The other items on there ‑‑ peripheral edema, constipation, leukopenia, rash ‑‑ are occasionally seen or reported, but they are almost always of very mild nature and manageable and almost never require the discontinuation of the drug.
		So, in conclusion, I would say that, in our experience this has been a very useful and efficacious drug in management of these patients with a very difficult chronic problem.  And I think that we have been able to show that, under properly controlled and monitored situations, it can be used safely.
		DR. McGUIRE:  Thank you, Dr. Yoder.
		Are there questions from the committee?  Yes.
		DR. KILPATRICK:  Dr. Yoder, I missed something in the write‑up, perhaps.  As a statistician, I'd like to know, in your own experience, what percent of ENL patients are women of childbearing age, let's say, in the United States and/or in Africa?
		DR. YODER:  Well, the proportion of males to females with leprosy overall is something in the order 60/40.  You know, there are more males than females.
		As far as proportion of those that get ENL, I am not aware of any sex differences there.  And the proportion that get ENL ranges widely.  In the literature, you see reports as high as 50 percent.  I don't think, certainly, it's that high in the United States.  But I am not aware of any specific sex differences in the ratio.
		DR. McGUIRE:  Dr. Hashimoto.
		DR. HASHIMOTO:  Apparently you did not have any pregnancies in your institution, so the teratogenicity is zero.
		DR. YODER:  Yes.
		DR. HASHIMOTO:  How many reproductive‑age patients have you treated since 1975?  And you mentioned sterilization, but that is not very practical outside of an institution.  What would you recommend?  What would you be comfortable with, other than the method of sterilization?  Is the contraceptive pill enough, or what do you think?
		DR. YODER:  Well, I think if you were going to use it as an outpatient, it would be important that you would use at least two methods of contraception.  Certainly an ideal would be if you would use some method that does not apply to compliance.  But I think it would require a very stringent program, and I think we will hear more about that, later today, what Celgene's proposal is to do that.  But I think it would require a very stringent one, with at least two methods of contraception, regular pregnancy testing.
		At Carville, we did weekly pregnancy testing ‑‑ that may have been a little excessive ‑‑ along with very stringent requirements for mandatory education and consent forms and so on.  So, I think it would take a very stringent program.
		DR. McGUIRE:  Dr. Orkin.
		DR. ORKIN:  Is the pigmentation with clofazimine persistent, continuous, permanent?
		DR. YODER:  No, it will fade.  It takes 6 to 12 months, or sometimes even longer, for it to go away.  But generally it does go away after you stop the drug.
		DR. McGUIRE:  Dr. Crawford.
		DR. CRAWFORD:  Do you warn the patients that they might develop neuropathy from thalidomide?
		DR. YODER:  Yes.  It is included in the consent form.  All patients sign a consent form, and the neuropathy is in there, and of course, it is always discussed with the patient.  Of course, we are dealing with leprosy, which is a neurologic disease, so we are discussing neuropathy which may occur from leprosy as well.
		DR. CRAWFORD:  Have you any clinical data on the state of the peripheral nervous system before thalidomide is started?  Because, in my experience, patients with ENL may not have involvement of the peripheral nervous system because it's lepromatous leprosy, which is treated.  The viable count or the morphological index falls to normal in many of these patients.  Clinically, anyway, they have a normal examination of the peripheral nervous system.  Have you any data of that before you start thalidomide?
		DR. YODER:  All our patients do have a neurologic evaluation before they are started on treatment.  Is that what you were asking?
		DR. CRAWFORD:  Yes.
		DR. YODER:  Yes.
		DR. McGUIRE:  Dr. Shannon?
		DR. SHANNON:  Yes, Leo, I ask this question in the context of we are here to meet, and maybe one of the things that is thought that thalidomide does is suppress tumor necrosis factor-alpha, and clearly it does in the conditions.  I'm asking this question to draw from your experience as a clinician, particularly in Africa, and to address the comment on reversal reactions, where immunologically there is a lot of indication that TNF‑alpha message and protein is in reversal reaction lesions, yet I hear anecdotally from a lot of clinicians that thalidomide does not work in reversal reactions.  So I have to ask you your opinion, your observation, if that is correct.
		And then, the other question is, have you had any experience with pentoxifylline, which is classified as an anti‑TNF‑alpha drug in the treatment of ENL?
		DR. YODER:  The first question, it is my impression that thalidomide does not work in reversal reaction.  And we occasionally have patients in the borderline group, where it is clinically sometimes difficult to be sure of whether they are having ENL reversal reaction and, on occasion, we find no response from thalidomide.  So, it is my opinion that thalidomide does not work in reversal reaction.
		The other question, regarding Trental, is that we have used it in a few cases ‑‑ simply on patients at Carville ‑‑ not a formal clinical trial.  Our impression was it is not dramatic.  It may be a mild benefit in several cases that we have used it on, but I am not impressed that it is ‑‑ it certainly is not a miracle drug in this disorder.
		DR. McGUIRE:  Dr. Simmons‑O'Brien.
		DR. SIMMONS‑O'BRIEN:  Dr. Yoder, I'd like to know what actually comprised your neurologic evaluation and how often was it repeated.  What were the intervals of evaluation for all of the patients?
		DR. YODER:  Well, you will see some data later.  This data is collected from a number of different centers around the country.  And actually the report forms that came in -- there were a large number of centers that report here.  And so I am sure there will be considerable variation as to the type of evaluation.  
		If I can respond to specifically what we do at Carville.  At Carville, of course, the physician does a neurologic examination.  Then all of our patients are seen in the occupational therapy department, who do a sensory testing and motor testing of the upper extremities, using monofilaments, graded monofilaments.  Similar evaluations are done in the physical therapy department for the lower extremities.
		Nerve conduction studies are not done in all cases.  If it appears that they will be useful or if we have difficult problems to sort out, they will be done also.
		The frequency with which they will be done will vary.  If we had somebody in the hospital who had evidence of a neuritis and possibly changing neurologic status, they could be done as often as every 1 to 2 weeks.  There is not a standard protocol.
		Beyond that, if there is no change or evidence of neuritis, then clinically they would probably generally be done.  The first few years, we would do them as often as twice a year on their visits.  Standard procedure was that if they come for a routine follow‑up, they would have one done at least once a year.  So, it would vary considerably on the actual clinical situation.
		DR. McGUIRE:  Dr. Duvic has the next question.
		DR. CRAWFORD:  Could I just add a word about your figures?  Can I bring you up to date?
		The WHO, at the moment, has 900,000 patients on treatment.  According to the mortality and morbidity, July the 18th, there were 53 new cases of leprosy reported.  And last year, 112, which are considerably lower.  I think this is important, in view of Celgene's use of the drug ‑‑ that the numbers may be quite small.  And of course, only a proportion of those will have ENL.
		DR. YODER:  I missed your last numbers.
		DR. CRAWFORD:  Fifty‑three.
		DR. YODER:  Of what?
		DR. CRAWFORD:  New cases of leprosy.  That is the mortality and morbidity report for July the 18th.  That is the latest figure we have in the U.K.  And last year, 112 new cases.
		Now, those are all cases of leprosy.  And of course, only a proportion of those will be lepromatous leprosy, and only a proportion of those will have ENL, depending on ‑‑ 5 to 20 percent.
		DR. YODER:  Are you giving those numbers for the United States?
		DR. CRAWFORD:  Yes.
		DR. YODER:  Well, I would disagree with those numbers.  I'm giving you numbers from our registry at Carville.
		DR. McGUIRE:  I think these are U.K. numbers you are offering.
		DR. CRAWFORD:  No, no.  These are the USA mortality and morbidity published by the CDC.
		DR. McGUIRE:  Okay.
		Yes.
		DR. DUVIC:  Dr. Yoder, from your experience, what percentage of patients who get ENL would you use thalidomide in?  And of those, what percent would benefit from it, having improvement that was clinically significant?
		DR. YODER:  I would use it in virtually all of them if it was available, or if it was not a female of childbearing age.  Those you might, because obviously most of them would not want to be sterilized or be hospitalized at Carville.  You would use something else.
		But if it was a male or a surgically sterilized female already, or post‑menopausal female, thalidomide would be the drug of choice in virtually all of them.
		DR. DUVIC:  And of those, how many would it help?  What percentage?
		DR. YODER:  The vast majority.  I would say better than 90 percent.
		DR. DUVIC:  Okay.  
		Why is it assumed that women are so stupid that they can't use birth control for a drug that causes this kind of birth defects?  Why do you assume that someone has to be sterilized surgically?  Give us a break here.
		(Applause.)
		DR. YODER:  This is not my assumption.  But let me tell you why the situation exists.  This is the way the IND was set up in 1975.  And actually, the original protocol did not exclude women of childbearing age.
		However, that protocol had to be approved by the Tulane University Institutional Review Board, which is standard for any kind of investigation program.  And they came back and told Dr. Hastings in 1975 that they felt that the liability for Dr. Hastings and the Public Health Service, et cetera, were too great and that they should prohibit women of childbearing age from receiving the drug.  And, therefore, they complied with that.  And that is the way it was submitted to the FDA.  And that is the historical reason for it.
		DR. McGUIRE:  Dr. Moore.
		DR. MOORE:  Yes, I have one question, and a follow‑up actually, to Dr. Crawford's question.
		In your experience, Dr. Yoder, how successful have U.S. clinicians been in getting the thalidomide they need to treat their patients with ENL?
		And my follow‑up to Dr. Crawford's question is, you said the figures that you gave us for incidence and prevalence came from Carville, but can you tell us exactly what the sources are from those data?  Because, again, they are higher than estimates we have received from our infectious disease ‑‑
		DR. YODER:  You are from?
		DR. MOORE:  The CDC.
		DR. YODER:  Okay.  There are several ways that we get our data.  And this has a fairly long history that the figures from CDC are fewer than ours.  I am not sure how CDC gets their figures, but ours, some come directly from physicians.  We get a lot of biopsies sent to us from all over the country.  In addition, we have eight contract centers around the country.  If we get a biopsy at Carville that's positive, our medical records people will contact that physician and get the appropriate information.  So, there are various sources that we collect information from that probably does not get to CDC.  
		I know there have been discussions about exchanging data, and apparently that has not taken place.
		You had another question I think.
		DR. MOORE:  The first question was, in your experience, how successful have U.S. physicians been in getting the thalidomide they need to treat their patients who have ENL?
		DR. YODER:  You are questioning the availability of thalidomide?
		DR. MOORE:  Have there been problems getting the thalidomide?
		DR. YODER:  There was at one time, yes.  A number of years ago, we used to get it from Germany, Chemie Gruenenthal.  They eventually refused to sell it to us anymore for various reasons.  So, at one time, there was no source.  And there was an agency that compounded this for us, and we actually put it in capsules at Carville, and partly manufactured it ourselves.  Then we eventually went to foreign sources, and there was some problem with the quality of some of those.
		In more recent years, we had been able to get somewhat better‑quality thalidomide from Brazil, actually.  So, in recent years, we have not had a shortage of product.  But there have been problems.
		DR. McGUIRE:  Dr. Yoder, we are going to let you finish, but I did want to ask one brief question.  What is the total number of ENL in the United States per year, including repeat?  These are not necessarily new ENL, but you could include the repeat.
		DR. YODER:  Yes, the annual report usually has been in the range of 200 to 225, and maybe a little more than that.  That is the approximate number of cases that we report on that IND annually that goes to the FDA.
		DR. McGUIRE:  This is ENL, not new cases of leprosy.
		DR. YODER:  This is patients that are on thalidomide for ENL, yes.  That's right.  That is exactly right.
		DR. McGUIRE:  Thank you.
		Dr. Thomas, do you want to take over again?
		DR. THOMAS:  Thank you very much, Dr. Yoder.
		I'd just like to alert everybody in the room that as well as having Dr. Yoder here as a learned expert, we also have available in the room actually Dr. Tom Rea and Dr. Bob Gelber, who also have extremely extensive experience in actually dealing with this indication.  And if, at a later date, or as a result of other discussions, you think it would be useful to get their perspective, then please just let me know.
		I'd now like to pass you over Dr. Jerry Zeldis of the Celgene Corporation.  He will actually present information on the safety and efficacy of the drug as it pertains to that information which is in the NDA package.
		DR. ZELDIS:  Thanks, Steve.
		First of all, good morning.  My name is Jerry Zeldis, and I'm Vice President for Medical Affairs at Celgene.  I am very privileged today to be able to present to you both the efficacy and safety data that was presented in our application.
		The first aspect of our application I would like to discuss is efficacy.  And it is quite remarkable that since this drug was discovered in Israel around 1965 to be effective or potentially effective for treating ENL, there has been extensive literature on the use of this drug for treating this condition, and there has not been a single article that ever questions the efficacy of using thalidomide for treating ENL.
		I want to harken back to some words that Mary Pendergast said in the beginning of this session today.  This is orphan indication.  And by hearing Dr. Yoder talk about the numbers of cases, and Dr. Crawford backing him up with even lower numbers, this is an orphan indication.  You have to look at both the historical published literature and the experts who are actually in the field, arm deep in the syndrome, and trust their judgment, besides looking at randomized, controlled clinical trials.
		And I hope the committee keeps an open mind as I present to you this, admittedly, by 1990 standard, flawed data set.  But it isn't as flawed as perhaps I imagine or perhaps that others would purport.
		Let me get to the first slide.
		There are basically four elements to our application which I'll discuss today.  Basically, the literature, which composes experiences of over 1,800 patients.  In addition, there was a survey conducted among Hansen's disease treatment centers, which provides information ‑‑ at least a global overview ‑‑ of how over 4,700 patients have fared with the drug.
		This literature, as Mary Pendergast mentioned earlier, there were over 50 ‑‑ actually, I think it was the pediatrician who mentioned it earlier ‑‑ there were over 50 brand names for the drug.  This represented various lots from many different companies.  Even within the same companies, there was lot‑to‑lot variation.  With the exception of a few manufacturers, most of this drug was not made by the standards that we would consider good manufacturing practices and controls.  Despite that, the literature is uniform in praising the effectiveness of this drug.
		In addition, Celgene was able to obtain an electronic data set which contained 19 years of data from Carville's experience.  The case report forms from which this data set was derived was not completely audited, but we did audit 2 years' worth of data and found very good congruence between what was in the case report forms and what made up the data set.
		We also went back to Carville and audited the medical records of patients who underwent a study at Carville by Dr. Hastings, which was a double‑blind, placebo‑controlled trial, although not done under the rigorous good clinical practices protocols that is required by 1990's standards, which also demonstrated that the drug is effective in treating ENL.
		And, finally ‑‑ and actually, to begin with ‑‑ but, finally, I am going to talk about a Celgene study which is currently being performed in the Philippines.  At this juncture, 21 subjects have entered the study.  It is a double‑blind, dose‑comparison trial.  And I will present a blinded interim analysis of the results on this study.
		If you look at these four lines of evidence, the only evidence which is being done, which was collected under good clinical practices, under the types of, I'd say, clean data sets and assurances that the FDA normally requires for a larger drug application for a more prevalent indication is this ongoing study.  But, despite that, I think you will see that the weight of evidence will show that this drug is effective and also safe for treating ENL.
		I would like to first give you my overall impression of this data set, and then I'll go into specifics.
		Despite how response was defined in these various studies and data sets, we have found that greater than 90 percent of patients will respond, if they have moderate to severe ENL, to thalidomide treatment.
		Furthermore, their response rate is similar regardless of the type of anti‑lepromatous regime used ‑‑ whether they are given the intermittent WHO regimen or the more continuous regimen which is being used in the United States.
		Furthermore, as Dr. Yoder said earlier, the drug is steroid‑sparing.  It prevents steroid rebound.  It has been used as an effective single agent even in patients who were deemed to be steroid dependent ‑‑ meaning that you could not get them off steroids without getting a severe steroid rebound ‑‑ and is effective both in the acute treatment of ENL as well as in maintaining remissions.
		Furthermore, in some individuals, a complete response ‑‑ that is, the absence of not only the skin lesions or new skin lesions being formed and healing of the old ones, but also the systemic problems as well, can disappear within 1 to 2 weeks of initiating therapy.  In others, it takes longer.  However, in virtually every patient who will respond to the drug, a response becomes evident in as short a time as 48 hours after initiating therapy.
		The response rate does not appear to be affected by the age, the sex, and the race.  And this is supported especially in both the literature and the Carville experience.
		While the painful skin lesions and the fever respond first, the other symptoms that make up the syndrome will respond with time.  And, furthermore, it is the observation in both the literature and Carville that steroid‑dependent subjects resolve more slowly.
		I would like to now turn our attention to the Celgene study, E-0O3/P, which is currently being performed in the Philippines.
		The rationale for the study was to perform a study that showed that Celgene's formulation was effective in treating ENL.  While Celgene wanted to do a placebo‑controlled clinical trial, it simply cannot be done in the late 1990s, period.  We talked to our advisors.  We went to IRBs, ethics committees and other similar institutions around the world, and we could not find an expert.  We actually went also to the leprosy foundations.  We could not find anybody who has experience with this disease who felt that it was conscionable or ethical to do such a study.
		So, therefore, we were left with the fact that we need to do either a drug comparison trial or a dose comparison trial.  When we looked at the alternatives for therapy, it was felt by our experts that there really wasn't a good drug to compare it to.  These had been done in the older literature, and that it was not felt ‑‑ the trouble with steroids was such that it was not a good dose comparison trial to try to do.  So, after an extensive dialogue with the FDA, it was agreed that we would do a dose comparison trial.
		Why did we pick the Philippines to do the trial?  Well, in the United States, as you have heard, there are just not enough patients, and most patients who are diagnosed with ENL go on to thalidomide as fast as they can jump through the regulatory hoops.
		The Philippines, however, presents a different situation.  There is enough of a population of people who have leprosy and who are thalidomide naive or are not being treated with thalidomide that we could actually perform a trial in a reasonable period of time.
		The purpose of the study was to compare two doses, either 100 milligrams a day or 300 milligrams a day, a 7‑day treatment, for treating mild to severe ENL.  After, if the patients responded to the drug, we then looked at what happened if you tapered the patients off the drug, and the time to relapse after successful treatment.
		Design of the trial was straightforward.  Patients were, in a double‑blind manner, randomized to receive either 100 milligrams per day or 300 milligrams a day of thalidomide.  Patients to be entered had to have moderate to severe ENL confirmed histologically.  Furthermore, patients who were deemed to have mild disease or life‑threatening disease were excluded from this protocol.
		Even though patient status was judged on a daily basis, at 7 days, the subjects were classified as either a complete responder, a partial responder, or a treatment failure.  Those patients who were partial or complete responders then entered into a tapering phase.  And at the end of the taper, the extent of their disease was then reassessed.
		The rating scale was based on two aspects:  the presence of fever and the presence of skin lesions.  A complete responder had to have, at the end of the 7 days, the absence of fever and no acute or active skin lesions occurring.  If they had one or the other, but not both, they were considered a partial responder.  If they had fever and they had active lesions, they were considered a treatment failure.
		There was a clause built into the protocol that if after 72 hours the patient received an analgesic, by definition, they were a treatment failure, period.  Furthermore, if they received steroids at any time, they also automatically were deemed a treatment failure.
		I would like to get back to this point in about two minutes.
		What we submitted in our initial NDA package in December was a blinded database consisting of nine completed subjects.  Now, every subject either received 100 milligrams or 300 milligrams of thalidomide.  
		I just want to make one point which Dr. Yoder mentioned, but I want to emphasize this.  While the lesions of ENL do wax and wane, it is extraordinary and probably beyond anyone's clinical experience to see a patient who has many lesions on their body to have none 7 days later.  When ENL burns out, it is a slow burn.  It is a slow resolution, which often takes months.  In fact, I doubt you can find a diagnosed patient with ENL today who is not receiving therapy.  You just don't find the natural history of this disease which is not treated anymore.
		Anyway, what we have done in the last few weeks is go back to the Philippines and collect another blinded data set.  We have efficacy data on 16, and now it is up to 17, patients.  We added a patient last night, although the data set, I believe, was delivered to the FDA last week.  The reason why we have more safety data than efficacy data is that 1 patient was admitted into the study who had neuritis due to ENL, but did not have skin lesions and, therefore, we cannot assess efficacy in that patient.  You can't analyze that patient.
		The target is to bring 30 patients into this study, and then we will un‑blind the study.
		At baseline, all subjects had fever and all subjects, except for the one patient who we exclude from our efficacy analysis, had greater than 40 skin lesions on their body.  Some people had more than 80.
		Systemic complaints included fatigue, chills, anorexia, mild arthralgias, neuritis, painful lesions, and nasal congestion.
		This is the results which we have determined.  And they are similar to what was in your package, although now we have more patients.  
		I just want to make one point about this.  These patients were classified based on the treating physicians in the Philippines.  Here is the data on the 16 patients.
		At the end of 7 days, 9 were deemed to be complete responders; 5 were partial responders; and there were 2 treatment failures.  Now, we do not know the doses that they received.
		The acutely inflamed nodules healed in everybody between 2 to 5 days.  The patients who had ulcerations on their skin, the ulcers healed within 2 days; the pustules resolved within 5 days.  Both treatment failures were then placed on open-label thalidomide at 300 milligrams per day, and both responded to therapy.
		Now, I have been told ‑‑ I was told this last night, I think around 12:30 in the evening, when we looked at the data set one last time ‑‑ that both these patients, after they responded, went off thalidomide.  They relapsed, and they were then re‑randomized and put back into the study.  And so, when the FDA is looking at the data set, they will notice that we actually sent them more patient information, but we identified these as repeat patients in this study.  It doesn't change the conclusion.
		But, furthermore, when you look at shift tables at 7 days, what you found was that the following ENL symptoms improved in these patients:  Anorexia disappeared, arthralgias, chills, shortness of breath, fever, malaise, nerve enlargement and tenderness, neuritis, orchitis pain, rhinitis, and vasodilatation.
		In the patients who were treatment failures, these symptoms worsened, but it was only in these patients:  One person had epistaxis, and epistaxis is a complication of lepromatous leprosy and ENL ‑‑ chills, edema, fever, malaise, neuritis, and pain.
		Now, what happened after what happened after tapering ‑‑ and let me walk you through this semi‑complicated slide.  These are the 9 patients who initially were deemed as complete responders, and at the end of their taper, only a few remained complete responders.  The rest either became partial responders or treatment failures.  These are the 5 patients who, at the end of 7 days, were diagnosed as being partial responders.  It turns out, at the end of the taper, 4 of the 5 were now deemed complete responders and the fifth was now a treatment failure.  That is a "TF," not a "TR."
		Our conclusions from the study are that thalidomide is capable of inducing a complete response and partial response in patients with moderate to severe ENL.  Furthermore, withdrawal of thalidomide may result in disease recrudescence.
		Now, I would like to just briefly bring up the overhead.
		As I said, around 12:30 last night, we were rummaging through the database and looking at concomitant medications.  And what we discovered was that there was a protocol violation.  5 subjects continued to take acetaminophen, or paracetamol ‑‑ the same drug ‑‑ for 4 days.  And, therefore, by definition, these 5 automatically had to be reclassified as treatment failures.  It does not change the overall conclusions of this study.
		When we reclassified these patients, we still find that 10 of 17 people responded to therapy.
		What happened to these 5 people who were, quote, treatment failures, because they took acetaminophen 4 days into the protocol.  Now, at this point, they were off paracetamol or acetaminophen.  And as you can see, it breaks down now.  Again, this person here, who is a treatment failure, was not deemed a treatment failure by the physicians, based on skin lesions and the absence of fever.  He now is definitely ‑‑ we have one partial responder.
		Okay.  I'd like to now go on to the Carville experience.
		As Dr. Yoder explained, since 1975, the Public Health Service has maintained an IND with the FDA to allow the treatment of people with ENL with thalidomide.  And in many respects, Carville became the conduit for thalidomide therapy in the United States, not only actually for leprosy but for other conditions as well.
		Now, I am going to tell you what was in the protocol, and I will also tell you what happened ‑‑ at least my interpretation of this, and I am going to rely also heavily on Dr. Yoder to help clarify any interpretations or questions that I may have.
		Patients were admitted into this IND if they had biopsy‑confirmed severe borderline leprosy or lepromatous leprosy.  They were allowed to take various anti‑leprosy medications while on therapy with thalidomide, and they were evaluated every 2 months.
		On an annual basis, the treating physicians would complete a case report form and send it to Carville.  This included demographic data, dosing data; the physicians were asked to write down any adverse event or side effect that they believed was drug-related.  So this is different.  In a normal GCP, or good clinical practices, you write down any adverse event that occurred, not whether it is drug-related or not.  And they were asked to give a global assessment of how the patients were doing.
		I will just say parenthetically, again ‑‑ and I would like to reiterate what Dr. Yoder said earlier ‑‑ since the early 1960's, everyone using thalidomide has been aware of the peripheral neuropathy caused by thalidomide.  And this was in the informed consent.  And every patient who received the drug and every physician who used it was aware of this and was looking for this.
		Subjects were rated on a yearly basis as being good, in good control ‑‑ and this is a global assessment.  So, if they had partial control, they were fair; if they had no response or they were treatment failures, it was poor, unknown, or lost to follow‑up.
		By protocol, subjects were supposed to take 100 milligrams four times a day of thalidomide.  The reality is that, as more experience with the drug was accrued, most physicians gave the drug at bedtime and at lower doses, but it also depended on the type of drug that they were receiving.  Certain batches of drugs from certain manufacturers appeared to be so ineffective that subjects were told to chew the tablets to try to increase the availability so they could respond.  There was tremendous lot‑to‑lot variation.
		If they got their ENL under control, a taper would begin.  And the actual dosage used really depended on the judgment of the clinician.  If the clinician saw what they considered a very severe case, they would tend to start at a higher dose.  If it was moderate, they would get a lower dose.
		Also, the response.  If initially the patient was started on a lower dose and they did not respond as well, they would go to a higher dose.  
		Also, on drug availability, there were a few crises, where it looked as if the U.S. was going to run out of drug, and there was some rationing going on.
		Every 6 months, physicians were encouraged to try to wean patients off the drug.  If they had an ENL relapse, the patients could be re‑treated again with thalidomide, and the maintenance dose suggested was anywhere from 100 milligrams every other day to 50 milligrams twice a day.
		Basically, each year Carville collected between 227 to 341 case report forms, for a total of 4,767 case report forms collected between 1978 and 1994.  In the beginning of the program, you had the most case report forms collected, because you had the largest pool of people who were getting thalidomide for the first time.
		This translated into 33 to 234 new patients initiated each year, for a total in this experience, over 17 years, of 1,367 patients who received the drug.
		The age range was mostly between 18 to 64, but there still was a significant number of people above and below that range.  About 20 percent of the patients were women, although as Dr. Yoder explained, the women who we have records on were either surgically sterilized or hospitalized in Carville for the duration of their thalidomide treatment.
		The ethnic makeup of this group was consistent with the ethnic makeup of leprosy that we see in the United States:  mostly Hispanic, Asian and white.
		85 percent of the patients had lepromatous leprosy.  About 15 had borderline leprosy.  And the average patient had the Hansen's disease for at least 5 years.
		The average mean dose during the initial course of therapy was about 132 milligrams per day, although there was a wide variation.  And, again, you have to understand that many different manufacturers' drugs were used, and there was tremendous lot‑to‑lot variation even within the same manufacturer.
		The average duration of treatment was 3.3 years.  Even though the dose went down with subsequent years of therapy, at year 3 it was virtually the same as in year 1.  The longest treatment duration of any patients in this 17‑year database was 14 years.
		How did these patients do?
		At the end of the first year, when we looked at the case report forms, 79 percent of the people were complete responders; 17 were partial responders.  That means 96 percent of the people responded.  The rest either were treatment failures, very few lost to follow‑up, or it was not rated.  It's not known.
		When we looked at the response to continued treatment, we found there were three things that were readily apparent.  Complete responders tended to remain in complete response.  Greater than 90 percent of people who, at the end of year 1, were rated as complete responders remained in complete response over the next 10 years.  Partial responders also improved with prolonged therapy.  Year by year, a higher percentage of the partial responders became complete responders.
		This is important, because patients on steroids respond more slowly, and it may take them over a year to go into a complete response.
		Furthermore, some treatment failures ‑‑ about half ‑‑ with continued therapy, became responders.  
		When we did subset analyses, we found that the initial response was unrelated to the dose of the drug used, to the age, the gender, the race, and the type of concomitant medication they were being given.  And I can tell you that the drug was being given as monotherapy, as co‑therapy, and as adjunctive therapy in these patients.
		So, our conclusion from this large experience is that thalidomide is effective for treating ENL as monotherapy, co‑therapy, and adjunctive therapy, and that continued use of the drug is associated with increased response rates.
		The next leg of data on this table ‑‑ it is a four‑legged table ‑‑ is the Hastings study, performed in the late 1960s and published in 1970.  
		Now, what Celgene did was go back to Carville, find the medical records, and actually abstract the medical records as if this was a brand‑new study, and put together a data set, which we then analyzed.
		Because this was not a GCP‑conducted study by the standards in the 1990s, it is not surprising that there were patients in that we identified who were not in the final publication by Dr. Hastings.  When there was a doubt about what happened, we excluded the patient from our database.  We feel very confident about the way that we abstracted the data.
		Basically, this was a double‑blind, placebo‑controlled trial.  And to enter the study, patients were taken off all their therapy for ENL.  Many of these patients were on steroids.  And after 4 days, if the patients developed new skin lesions and fever, they were allowed to enter the study.  Many of these patients had steroid rebound and therefore had a severe response.
		They were then, in a double‑blind manner, randomized either to receive 100 milligrams a day of thalidomide four times a day or placebo.  A response was defined as, at the end of 4 days' treatment, the patients had to have the absence of fever and no more skin lesions.  A failure was defined as having either both new lesions and fever or one or the other.  So, this is a very stringent study.  You have 4 days to respond or you're out.
		At the end of 4 days, patients were crossed over to the other regimen or entered open label.
		Celgene identified 25 patients who were treated during this period when Dr. Hastings ran the study, who were treated in a manner consistent with being in the Hastings study.  Again, this is not as if we went and pulled the case report forms.
		About half of them were on dapsone.  88 percent of them were male.  The ethnic mix is consistent with what Carville sees.  And the results are absolutely straightforward:  The drug, thalidomide, was superior to placebo in healing acute ENL, based on loss of fever and loss of new skin lesions and at the p less than 0.005 level.  10 of 12 thalidomide‑treated subjects responded as opposed to only 3 of 13.
		Now, if you go back to the original Hastings paper, he states that none of his placebos actually responded.  Because we were being conservative, we believe that there were 3 who actually did, based on his criteria.
		Equally important, 8 placebo‑treated patients who failed therapy were subsequently treated with thalidomide, and all of them, 100 percent, responded within 4 to 11 days.  Furthermore, when patients had relapses off thalidomide and they were placed on thalidomide, the majority of these episodes did respond to repeat therapy.
		Our conclusion is that thalidomide is more effective than placebo for alleviating fever and preventing new lesion formation in ENL.
		The last leg on this table of efficacy is the published literature.  And it is quite extensive and quite varied, and it also involves different lots from the same manufacturer, with different availability, as well as many different manufacturers.  But the results are absolutely consistent throughout the literature:  The drug works.
		There were five controlled trials published in addition to Dr. Hastings' ‑‑ 168 treated patients.  The response rate was greater than 90 percent.  And these responses included studies which looked at responses for skin lesion healing, absence of fever, resolution of neuritis, orchitis, arthralgias, headaches, anorexia, uveitis, lymphadenitis, and fatigue.  In one study, which was a double‑blind comparison trial between aspirin and thalidomide, thalidomide was superior.
		Thalidomide also was deemed to be steroid-sparing.
		When you look at the open label trials ‑‑ there were three of them, involving 313 patients ‑‑ all three are unanimous:  Improvement occurred within days of starting the drug.  
		Furthermore, thalidomide was superior to standard therapy, which at that time did not include thalidomide.  
		Thalidomide also was superior to chloramphenicol.  
		And when you add clofazimine to thalidomide, the results were actually superior than when you used thalidomide by itself.
		And 27 studies, involving 1,378 patients, were open-label, non‑comparator studies.  Again, what we found by reading this literature was progressive clinical improvement in 48 to 72 hours, including the loss of fever and painful skin lesions.  All studies found greater than 90 percent response.  This is very repetitious.  I'm sorry, but that is the literature.
		Thalidomide allowed continued anti‑leprosy treatment.  It is steroid-sparing, and if you rebound after you are off the drug, or you react after the drug, you can control it by going back onto the drug.
		The survey which I alluded to earlier of Hansen's disease research centers around the world showed that 95 percent of 4,769 patients who were evaluated by their doctors had a satisfactory or excellent response to being treated with thalidomide.  So, the world out there feels that this drug works.  The clinicians in the trenches feel this drug works.
		As far as case reports, there are 20.  In 19 of these cases, the patients responded.  1 patient was discontinued from the drug shortly after beginning the drug due to an ulnar nerve abscess.
		So, in conclusion ‑‑ at least on this part of my talk ‑‑ I think I have now presented to you four lines of evidence that this drug is efficacious in treating ENL, the first being our own study, showing that our formulation is effective in treating ENL, as judged by the loss of skin lesions and fever, and that stopping the drug leads to disease recrudescence.
		Then I went to the Carville experience, which is the U.S. Public Health Service experience, which is the major way Americans have legally obtained thalidomide in the United States.  There the experience of the database, which we had actually 17 years worth of data, showed it was efficacious by various measures.
		I then talked about our reanalysis of the medical records from Carville, which looked at Dr. Hastings' experience, which confirmed that short‑term therapy was efficacious for healing lesions and stopping fever.  
		Finally, I glossed over the extensive literature, which is unanimous that this drug is efficacious.
		I'd like to now change our attention towards safety.
		Again, our safety database basically is composed of three types of data.  The first is the PK studies, which were performed by Celgene.  The next is the experience with ENL, and the third is for the use of thalidomide in non‑ENL complications.
		Now, I would like to summarize our conclusions, before I go into the data, very briefly.
		First of all, despite the multiplicity of manufacturers and formulations out there, what we are finding when we went through this database is the frequency and type of adverse events noted were independent of manufacture and formulation.  Celgene's drug is no different than anybody else's drug as far as causing adverse events.  We found nothing unique.
		The most frequent adverse events that we noted, that are noted in ENL trials, are sedation, rash, and constipation.  While peripheral neuropathy can occur, it is an infrequent occurrence ‑‑ usually occurring in less than 1 percent of patients with ENL.  Furthermore, no drug‑related serious or adverse events have been described in the ENL studies and the published literature.  And that is quite a strong statement, but I am going to show you the database, which is quite large.
		When we look at non‑ENL trials, the situation is similar, but different.  Again, sedation, rash, and constipation are the most frequent adverse events, but now peripheral neuropathy plays a role and, in some respects, a major role.  But also you find that disease‑related adverse events also were quite frequent.  Because, oftentimes, thalidomide is used as a drug of last resort for desperate patients with desperate disease, and so it is not unusual to find adverse events coming in.
		Granulocytopenia has been noted more frequently in HIV trials, and I'll talk about that a little bit later.
		Furthermore, since 1965, when Dr. Sheskin publicized the fact that this drug works for ENL, in no clinical trial, under no controlled condition, has fetal malformations or fetal exposure been reported.
		The data sources.  As I said, there are three of them.  They are the PK studies by Celgene.  We now have data on 83 patients.  The ENL trials.  We have information on over 3,100 patients.  But if you go in the published literature, it gets even larger, because of that large Hansen's disease survey.
		Of the ENL trials, we have data on 23.  If you look at the non‑ENL trials, for all the other indications, we are talking about over 2,200 patient exposures, of which 231 are in HIV trials conducted by Celgene, and 671 for other indications on physician INDs, emergency INDs, and other small trials which Celgene is conducting.  And then, the published literature, which is composed of 93 studies from which we could glean safety information on 1,315 additional patients.
		Going into the PK studies, again, no serious adverse events or severe adverse events were noted in these studies.  The most frequently reported symptoms were dizziness, somnolence and headache.  HIV‑positive subjects also complained of confusion, and symptoms were more frequent at higher doses.
		One subject did discontinue the study because of an adverse event.  And, again, now, this is an adverse event which is consistent with the FDA rules.  This patient had an upper respiratory tract infection and pharyngitis, and therefore dropped out of the study.  It was not felt to be drug related.
		On the other hand, there were some changes in vital signs noted.  In healthy human volunteers, a 5 millimeter mercury drop of blood pressure was noted in seated and standing systolic blood pressure and standing diastolic blood pressure.  These were not clinically significant.
		In HIV‑positive subjects, mild orthostasis was most marked for 4 hours after ingestion and could manifest itself as feeling a little light-headed or dizzy.
		Two healthy human volunteers, in a study which went up to 400 milligrams, did develop orthostatic hypotension at the 200‑milligram dose.  These episodes were not prolonged, and both patients were able to walk out of the clinic in a non‑orthostatic state.
		No other clinically significant ECG, laboratory, or physical findings were noted in this study.
		I'd like to now turn our attention to the ENL studies.
		If you look at the three large experiences, where we have the data on safety, you have the two Celgene studies, encompassing 23 patient exposures, and the Carville experience.  The interesting thing about the Carville experience is that we have data for at least 6 months on 1,387 patients, and for over 2 years on 377 patients.
		In the Philippines study, which I described earlier, again, a 7‑day treatment, with either 100 milligrams or 300 milligrams a day of thalidomide, followed by a taper if you respond.  10 of the 17 patients, where we have been able to evaluate safety, had an adverse event, at least one.  No AE's were judged to be severe, and the most frequent AE's were somnolence ‑‑ it is still a sedative ‑‑ rash and vertigo.  The rashes were not felt to be severe.
		When we looked at E‑001, which is a U.S. ENL study, which has recruited 6 patients so far, 5 of the 6 had AE's.  Again, none severe.  The most common AE's were fatigue or asthenia, arthralgias in 2, fevers and chills in 2.
		When we looked at the Carville experience, 1,387 subjects evaluated over a 17‑year period, 279, or 20 percent of the people, had adverse events.  Approximately half of them had more than one adverse event.  The most frequent adverse events were somnolence, constipation, peripheral edema, which also can be an effect of ENL by itself, fatigue, dry skin, dizziness, and then, finally, you get to paresthesias, which is the first evidence of peripheral neuropathy.
		When you look at why patients either discontinued therapy or had dose reductions in ENL due to adverse events, in our studies, there were none.  In the Carville experience, of the 1,387 patients in the 17‑year experience, only 2 people were noted to discontinue therapy due to an adverse event.  1 person had peripheral neuropathy after 7 years, and the other for dizziness, but the patient was also taking rifampin.  And when rifampin was discontinued and the thalidomide was discontinued, the patient no longer was dizzy, and the patient was able to then successfully be placed on thalidomide again without this problem.
		When we look at the published literature, a few themes emerge.  The first is that clinicians realized very shortly after beginning therapy on a large number of patients that you shouldn't give the drug during the day, because it's a sedative.  Give it at night as a sleeping pill.  So, the dose was changed because of that.
		There have been dose reductions consistent with the adverse events I just mentioned ‑‑ somnolence, some because of peripheral neuropathy, and constipation.  I should just mention that constipation and abdominal pain ‑‑ this dose reduction often occurred in patients who also were receiving clofazimine.
		There are four discontinuations.  One for intestinal obstruction in a patient who also was on clofazimine, one for exfoliating dermatitis, and two for anorexia and fatigue.
		When you look at neuritis in patients treated with ENL, you find that, in our studies ‑‑ and, again, the n is only 23 ‑‑ but there was no cases where the neuritis was noted to worsen.
		In the published literature, there is no case of neurotoxicity mentioned.  And in the Carville experience, there were 18 episodes described among the 1,387 patients.  However, some of these episodes are redundant and occurred in the same patient.
		As far as serious adverse events, we had none in our trials.
		In L‑002, there was only one death noted in the electronic case report form.  Now, I will just say parenthetically that when you follow large numbers of patients over a 17‑year period, there will be deaths.  But talking to Dr. Yoder and others, it's our impression that any patient who may have died was off drug.
		If you look at the published literature, there were three deaths.  None were on thalidomide at the time of death.
		Moving over to other indications.  If you look at an AIDS wasting trial that we performed, patients were randomized to either placebo or two doses of thalidomide.  The only adverse events which were more common in the thalidomide group than the placebo group were somnolence, neutropenia, dizziness, asthenia, and headache.
		In an open‑label AIDS wasting trial involving 113 patients, the most common adverse events were leukopenia, diarrhea, peripheral neuropathy, rash, fever, pneumonia, and somnolence again.
		I'd like to just make one point about leukopenia.  Most of the patients in the AIDS trial start out with very low white counts, and therefore they then dipped into clinically significant range.  When you saw leukopenia in the literature for ENL, patients would go into a technically low range, but not into a clinically significant low range.
		I'd like to now show you this study, which was performed at Rockefeller, in which patients developed fever, rash, somnolence, constipation, dry mouth, perioral numbness, which is peripheral neuropathy, and tachycardia.  This is Chemie Gruenenthal's drug, not our drug.  The other studies were our drug.  The types of adverse events seen were the same.
		When we looked at our emergency use of thalidomide ‑‑ this slide is slightly old ‑‑ but at that point we had about a fourth patients were women, and they were given the drug for various indications, usually at the end of the disease.  Again, it is a drug of last resort for HIV wasting, aphthous ulcers, graft versus host disease, cancer, Behcet's syndrome, both discoid and systemic lupus, and prurigo nodularis.  
		And we have just updated this last night.  The U.S. experience is that 528 people received drug.  And these are the most common AE's:  constipation, peripheral neuropathy, rash, numbness, xerostomia, tingling, et cetera.
		Now, if you assume that there is no overlap, that each person reported is a different patient, peripheral neuropathy becomes the most common adverse event.  There it's running at around 6.8 percent, as opposed to 2.5, which is in this figure.
		If you look at our study, which looked at rheumatoid arthritis, which used our drug, drowsiness, constipation, dry mouth, rash, and leg swelling were the most common adverse events.
		Another study performed with our drug showed somnolence, change in alertness, malaise.  And this was probably one patient who had both upper and lower neuropathy.
		If you look at the entire published literature, where you can glean adverse events, that is 1,315 patients.  The most common adverse events that occurred ‑‑ again, different formulations of the same manufacturer and many different manufacturers ‑‑ somnolence, constipation, increased appetite and weight ‑‑ which may be an adverse event to some, but in others would be a good thing and this may be a subject of a future hearing -- rash, dry mouth, neuropathy, dizziness.
		When you look at discontinuations or dose reductions, you find that the type and prevalence of the adverse event profile is the same reason as to why people discontinue or have dose reductions.  And in these patients, it is for rash, peripheral neuropathy, sedation, hypersensitivity, and also disease‑related adverse events.  Again, these were very sick people.
		Of those people who died, none of the deaths were attributed by the treating clinicians as being attributable to our drug.
		In our non‑ENL‑sponsored trials, all SAE's were deemed to be AIDS‑related.  In the AIDS wasting trial, there were 40 events of 103 patients.  In the open‑label AIDS wasting trial, 44 events in 28 patients of the 113 patients, and in an AIDS diarrhea study we are conducting, only 1 in 15 patients.  
		But, of note, of these 95 adverse events, 12 were for neutropenia.  These people started out with very low white counts, and it got lower.
		Anecdotally, I will tell you that there was one patient who derived so much benefit from the drug that, despite a white count below 750, the patient insisted on being treated.  The patient would go on thalidomide holidays to allow the white count to go up above 1,000.  And, finally, the patient was treated with a colony stimulating factor and was able to be treated both with thalidomide and not go off the drug and maintain a white count above 1,000.
		There have been no episode of sepsis that we are aware of associated with a low white count on a patient on thalidomide.
		As far as deaths, there have been 20 deaths for non‑ENL studies conducted by us.  None were felt to be related ‑‑ all were felt to be related to the underlying disease.
		In our emergency use and compassionate use IND program, in both the U.S. and Canada, there have been 22 deaths.  And all were deemed to be secondary to the underlying disease.  And the deaths were basically in patients with graft versus host disease, cancer, and AIDS.
		As far as laboratory abnormalities, we only really found one.  And that is leukopenia or neutropenia, which, in the ENL studies, is between 0 to 8.4 percent, and in our non‑ENL studies, in Celgene's studies, it is about 20 percent.  In the Chemie Gruenenthal study, it was about one‑third.  And in the literature, it is about 2 percent.
		As far as the potential for drug abuse, overdose problems, and drug interactions, there have been no reports of drug dependency to thalidomide.  There have been no case reports of death occurring from an overdose.  And this goes all the way back into the 1950s when the drug was being used as a sedative, and people were killing themselves with barbiturate overdoses.
		There have been no known drug interactions, and this was discussed earlier.  
		And as also discussed earlier, there is no effect on the cytochrome P450 metabolism of drugs, or these enzymes do not really affect the major metabolism of thalidomide, either.
		So, I'd like to summarize the safety aspect of this presentation by saying that the ENL and non‑ENL adverse events are complementary but not identical.  In ENL, you find sedation, constipation, and rash as the major adverse events, followed very rarely by peripheral neuropathy.
		On the other hand, for non‑ENL indications, again, sedation, constipation, and rash are prominent, as well as peripheral neuropathy.  
		In HIV, you find granulocytopenia is more a problem, because patients usually start with a lower granulocyte count to begin with.  
		And then the other AE's are mostly disease‑related.
		Discontinuations due to AEs and dose reductions mirror the AE profiles that occur in these two ave the expectation that one was showing something statistically because of the realities of the disease entity being treated.  We would use a trial design to eliminate bias so that the observations that you make on the product under review can be believed to be more robust so that you have to make a kind of a scientifically clinically relevant decision of has this product offered anything of value to the patient.
		So, I don't want you to think that there's some magic in a regulatory decision versus a scientific decision.  These are all scientific decisions.  Ours have regulatory implications but it's still a scientific decision.  It's a clinically relevant decision and that's what we need input on.
		DR. McGUIRE:  Dr. Gelber, did you want to speak to the issue of efficacy?  Let's leave toxicity out right now.
		DR. GELBER:  First of all, I want to thank the clinicians for believing us.  I rather thought that our opinions, no matter how long we've been in the field and how many patients we've seen, you might conceive that we've been duped over a prolonged period of time.  
		Actually I understand proof, as well as most of you do, and I understand controlled clinical trials.
		First of all, let me say my experience, you already know, has been over nearly 30 years.  I was in on the IND from its initiation.  I respect the considered reviewers who are looking as academics at a body of data that I might add I reviewed for Celgene and signed the reports that the FDA received.  I looked over a lot of literature and, frankly, was surprised that there was so much.  When I saw the literature, I saw the very same flaws that all of you saw, and yet I think I was impressed with the body of the data and the unanimity of the opinion.
		Clinical trials in ENL are very difficult.  I am infections disease person and not a dermatologist.  I'd hate to see what penicillin would do here at this meeting because one can't do those trials either.  But that in a sense is an aside.
		Clinical trials in ENL are very difficult.  First of all, the endpoints in almost all of the trials vary from place to place.  This is not a syndrome where we have a readily available number like an SGOT or a blood pressure or things that can be easily measured.  A lot of it is patient response and a lot of it is fairly subjective.  It is not easy to do a careful controlled clinical trial.  
		Yet, I think there have been attempts and I think most of the attempts have been honest ones and I think the results have been uniformly similar.
		Furthermore, when I write textbooks on this, I say ENL is a systemic disease and probably it's a vasculitis, and I suspect that most of the manifestations are really more a function of where the immune complexes land than anything else.  My belief would be that if thalidomide is effective against skin lesions and fever, it's likely to be effective against the other manifestations, which is certainly my own and other's clinical experience.
		Yet, when you look for the data on that, it really is rather hard to come by in anything that approaches controlled clinical trials, but there are an awful lot of large open-label trials that attest to its use.  And the reason why it's hard is that skin lesions and fever are far and away the most common manifestations.  So, it's hard to do studies.
		I think the next-to-the-last point is that I think that a lot has been placed on the Celgene product.  I think it has been fairly clear, at least in steady state, that this is equivalent to at least other historical thalidomides, and I think it's fair to extrapolate that this product at least is equivalent in its bioavailability.  Hence, I think it's fair to extrapolate that one needn't create a massive database on the Celgene product itself.
		The last thing I want to square -- and I think this is important.  You've seen a lot of different response data analyses from Celgene itself, from my reviews of the literature, and from independent and carefully considered  considerations.  I think these are largely explainable by endpoint decisions and how one views the natural history of the disease.
		Dr. O'Connell, I think you felt that one patient got put down in the lower response category because there were ulcers present or ulceration occurred during the course.  Well, thalidomide does not affect the natural course of individual lesions, nor does anything.  Really what it does is prevent new lesions from occurring.
		I think, Dr. Weintraub, in your analysis of the L.A. data, you found that there were treatment failures that occurred that we would have called successes or at least partial successes because there were some skin lesions.  So, your endpoint was a little more stringent than would have been called failures by the criteria that were used.
		So, I think I just wanted to share.  I've had some diverse views here on diverse issues, but I did want to share some of these opinions and leave you with the view that I appreciate your considered thought.  Having spent a lot of time on these reports and a lot of time with these patients, I'm fully convinced that the massive database in the literature and the clinical experience there leaves little doubt in my mind that this drug is effective in all manifestations of erythema nodosum leprosum.
		DR. McGUIRE:  Thank you, Dr. Gelber.  The committee appreciates the clinical experience that you bring to this and also your willingness to analyze the data.
		Are there other questions from the committee?  Yes, Eva.
		DR. SIMMONS-O'BRIEN:  Not that there's a question but just to further take up that point.  It is very difficult to look at objective measurements in a small population and in skin, but it can be done.  It's timely and it's very expensive, but just not photographs as the only mechanism.  Photographs are helpful.  Reevaluating the tissue histologically can be helpful.  Having the patients fill out a survey as to how they consider or how their symptoms are doing in terms of burning, swelling, induration, redness.  There are also instruments out available now that can measure the erythema as well as the melanin index in a lesion.  
		So, there are a whole bunch of things that can be done and then looked at to see if that also correlates with a good response, a complete response, or a partial response, but yet they are very expensive and they take a lot of time, but it can be done.
		DR. McGUIRE:  Yes, Joel.  Dr. Mindel.
		DR. MINDEL:  I'd like to disagree with Dr. Lumpkin a little bit in that he seems to feel that this is a scientific and a regulatory meshing.  But for me, this is a divergence of scientific and regulatory decisions.  I have a faith that the drug is effective, but scientifically I don't believe the data support that it's effective.  This is the first discussion of a drug where nobody has mentioned .05 probability.  Statistics have not come into this discussion at all.  If this weren't an orphan drug, it would not have been at this level of a meeting.
		I think we really have to throw the weight back to the FDA that it's going to be an act of faith to some extent and the reports and the literature and the experts who feel that it's effective and the faith maybe of the people around the table that's going to make you approve or disapprove the drug.
		DR. WOODCOCK:  Yes.  I think Mack and I both would like to respond to that perhaps.
		There are different ways to arrive at a level of certainty and we use different methods when prevalence in the population is very small or for other reasons we cannot do randomized trials.  Oncology is a good example.  For the first approval of oncology agents and for many other types of treatments, randomized trials often cannot be done.  
		That doesn't mean, though, it isn't a scientific judgment based on the natural history of the disease, the robustness of the data, the multiplicity of observations that have been made, the independence of observations.  These are not simply specific to this discussion.  These are things that we have laid out and discussed publicly as far as the bases for decision making when randomized controlled trials are not available.
		DR. McGUIRE:  I'm getting close to asking for a vote on the first question, but I'm going to modify the first question very slightly.  Mike, I'm not going to do anything bad to it.  I'm just going to leave a part of the sentence off.
		Has the efficacy of Celgene's thalidomide in the treatment of systemic erythema nodosum leprosum or any subset of ENL, such as cutaneous ENL, been demonstrated?  What I'd like to do is put a period after "syndrome," and then if we want to consider efficacy for subset, we can do that as a second question.  
		So, the question now reads, has the efficacy of Celgene's thalidomide -- this is not Chemie Gruenenthal's thalidomide, and it's not Tortuga's thalidomide.  Has the efficacy of Celgene's thalidomide in the treatment of systemic erythema nodosum leprosum syndrome been demonstrated?
		DR. WOODCOCK:  Could I just add one more clarification?
		DR. McGUIRE:  Dr. Woodcock.
		DR. WOODCOCK:  I apologize for interrupting the flow. 
		But as far as Celgene's thalidomide versus other thalidomides, we would like the committee to tell us what they think about the efficacy of thalidomide.  
		Dr. Weintraub and Dr. Lumpkin and I don't agree with the statement that was made that formal bridging bioequivalence data should be obtained to the other formulations that were used in the past.  The reason for that is those were not defined formulations, and it isn't at all clear that even if a number of those were tested, that you would know what the dose that was received in the historical database for any specific patient who responded was and what the absorbed dose was.  
		Therefore, we are interested in the question of whether the committee believes that thalidomide itself is effective and the questions about Celgene's thalidomide is effective relate really to dose and safety at the dose.
		DR. McGUIRE:  So, you're suggesting that we amend the question?  I think it's your question.  It's not my question.
		DR. WOODCOCK:  Well, we would like to have the answer to that question as well is what I'm saying.  It might be useful if you entertain that question first, but it might not.  I would say it's up to you.
		DR. McGUIRE:  Mrs. Cohen.
		MS. COHEN:  Could you make it a two-part question, a little different?  Has the efficacy of the data on thalidomide, because it is a lot of data there that doesn't come from Celgene.  I think if you use the word Celgene and nothing else -- I used to draft my own cease and desist agreements.  I'm not a lawyer, but I've done a lot of it.  I'm a little uncomfortable with it because as we go on and we vote, it kind of ties us into Celgene, and maybe we shouldn't be in the other things we're going to say.  So, I don't know if you can divide it into two questions:  the data, one; Celgene for another.
		DR. McGUIRE:  Well, we have several kinds of data.  We have anecdotal data.  We have clinical data.  We have historic data.  We have Bob Hastings' data.  We have current data from a pretty clean study going on in the Philippines.  And the question is where do you put your bets.
		The other issue that comes up is that Dr. Woodcock has suggested that we consider not just Celgene thalidomide, but global thalidomide, and we can do that as a separate issue.  
		I think what I would like to do now, Susan, if you'll let me, is --
		MS. COHEN:  It's a free country.
		(Laughter.)
		DR. McGUIRE:  -- to deal with Celgene.  Has the efficacy of Celgene's thalidomide in the treatment of systemic erythema nodosum leprosum, ENL, syndrome been demonstrated?
		DR. BERGFELD:  Can I ask for clarification?  At this point in time or our projected feelings about the future reporting of a study that's under way?  We're prematurely making decision on a current study because the only study they have is that Philippine study.
		DR. McGUIRE:  Wilma, you know, you got me there. I didn't write this question.
		MS. COHEN:  Well, that was my point.
		DR. McGUIRE:  Fred, help me out here.
		DR. MILLER:  I think the adjective "meaningful"  is important here.  Again, I guess I'm reiterating what I said before.
		But first of all, this study is not unblinded yet and we don't know if 100 milligrams or 300 milligrams is the appropriate dose or some other dose.  And we have too few patients to really make a decision on.  I think as Eva said, we have the opportunity to have a study here from which you can get some really good data, and now is the time to do it.  Until we see all 30 patients and the data from these 30 patients, I don't think we can say, yes, this is truly meaningfully efficacious in the treatment of ENL.
		DR. BERGFELD:  I want to comment again.  I have never had a committee vote on a study under way as to whether it was going to have an outcome that was beneficial or not.  So, I refuse to vote on this question as stated.
		DR. WEINTRAUB:  Excuse me.  Can I make a point here?
		This study was never intended to be one of the ones upon which this decision would be made.  It in fact was designed as a phase IV study, although it was begun now.  It was to be completed after the approval -- if the drug were to be approved, it would be continued on and finished after the approval process.  So, it's not that it should be such a major part of it.  If you want to back away from it, that would be acceptable as well, and just look at the database without the Philippine data.  
		Actually it's coming in in piecemeal, but we have been required to do that both by the fact that this is a priority drug and reviewed very rapidly and also by the fact that we wanted to get all the information we could for the committee to look at.  
		And the other thing is that this, remember, is it is an efficacy trial, but it's also a dose-ranging trial.  That's one of the things we want to look at in this case, is which dose, what dose, how will people respond to different doses.
		DR. McGUIRE:  But the question we're being asked is one of efficacy, and Dr. Bergfeld's point is pretty straightforward, which is that you are putting us in a position of advising you on the basis of a partial study, a study with few patients in it.  To be sure, it's a blind study and it's a very good study, but it hasn't been broken yet.
		I'm coming back to the same question over and over.  Do you want us to consider the totality of thalidomide experience in ENL and forget about the Celgene?
		DR. WOODCOCK:  We are not asking you to say has the efficacy of Celgene's thalidomide -- only in trials that have used Celgene's thalidomide.  Now, we recognize that that issue relates to dose, dose response, and safety as far as what the dose of that product is, but we're asking about the efficacy of thalidomide.
		DR. McGUIRE:  It's the easiest thing in the world for me to mark out Celgene.  Okay.
		Has the efficacy of thalidomide in the treatment of systemic erythema nodosum leprosum syndrome been demonstrated?
		I think the only way to do this is to walk around the table and vote.  Fred, are you prepared to vote?
		DR. MILLER:  Again, we've heard from the experts, and I think that it is effective.  But we've also heard the caveats about the published studies on thalidomide and the reasons for those caveats.  But, yes, it does appear to be an effective drug.  
		At what point do you use the drug?  Are there less teratogenic drugs that can be used for the same entity?  I think there are big questions.
		The thing that bothers me the most about this is that this is a teratogen which has caused significant problems and now we're looking at it before the one study that might be available is not even finished, and it just does not seem to be consistent.
		But I think yes, thalidomide is --
		DR. McGUIRE:  That's a very long yes.
		DR. MILLER:  Yes.
		DR. McGUIRE:  Dr. Hashimoto.
		DR. HASHIMOTO:  Well, I think it depends on what you define the syndrome.  I think fever probably evaluated and probably effective to control fever.  Skin lesions.  I heard many experts say it works, so I think it works.  But when you talk about orchitis, uveitis, neuritis, there's no evaluable quantity of data there, so I have no idea what it is.  I should say in a selected area, it's effective.
		DR. McGUIRE:  So, you would vote yes if this were cutaneous.
		DR. HASHIMOTO:  Yes, cutaneous and maybe fever.
		DR. McGUIRE:  Cutaneous and fever.
		Mrs. Cohen.
		MS. COHEN:  Well, you were trying to subdue me before, so I'm going to try and be subdued, but I'm not sure I can.
		Efficacy is a very interesting word in terms of definition.  Has the efficacy of thalidomide and possibly other drugs -- I mean, because we don't know enough.  But if you want me to vote yes, I'll vote yes.
		(Laughter.)
		MS. COHEN:  But I'm not thrilled, I can tell you.  When I hear that the lesions can go in 48 hours, that really kind of says something to me.  
		I feel the FDA wants some direction on how we feel about thalidomide as one possibility, and it isn't the only possibility I suspect.  This is really focusing in on thalidomide and nothing else, and that's what concerns me.
		The questions are very difficult and it's hard to draft them and it's to answer them.  Sometimes I think we ought to have input into the questions too.
		DR. McGUIRE:  Well, Susan, in the first place, I'm not at all persuaded that if you thought I really wanted you to vote yes, you'd vote yes.
		(Laughter.)
		MS. COHEN:  That's why we get along.  He understands me very well.  And we do need a little levity once in a while, if you'll forgive me.
		DR. McGUIRE:  So, are you voting yes?
		MS. COHEN:  May I think about it a little bit more, please, and come back?
		DR. McGUIRE:  You sure can.
		Dr. Kilpatrick.
		DR. KILPATRICK:  In short, yes.
		DR. McGUIRE:  Dr. Simmons-O'Brien.
		DR. SIMMONS-O'BRIEN:  Yes, and if you review the literature, you'll see it.
		DR. McGUIRE:  Dr. McGuire, yes.
		Dr. Bergfeld.
		DR. BERGFELD:  Yes.
		DR. McGUIRE:  Dr. Orkin.
		DR. ORKIN:  Yes, for skin and fever.
		DR. McGUIRE:  Dr. Mindel.
		DR. MINDEL:  No.
		DR. McGUIRE:  Dr. Mathews.
		DR. MATHEWS:  Yes, for skin and fever.
		DR. McGUIRE:  So, in fact, we put that question back together after I took it apart, and what we did was eliminate -- I believe it's my sense of what the advisory committee wants is that we're voting yes on efficacy for skin and fever, and we don't know about the other pieces of it.  
		MS. COHEN:  That makes me more comfortable.
		DR. McGUIRE:  Everyone is going with that?
		MS. COHEN:  Yes.
		DR. McGUIRE:  Susan, would you care --
		MS. COHEN:  Yes, sir.  As long as it's skin and fever, I'll be more comfortable.
		DR. McGUIRE:  Okay.
		The second question.  Dr. Woodcock -- oh, I'm sorry.  Madeleine Duvic's vote?
		DR. BERGFELD:  She was yes.
		DR. McGUIRE:  Is yes.
		Dr. Woodcock, do you want to delete Celgene from question 2?
		DR. WOODCOCK:  Yes.
		DR. McGUIRE:  Has the safety of Celgene's thalidomide been described in the treatment of systemic ENL syndrome or any subset of ENL such as cutaneous ENL been adequately described?  Okay, I didn't write that question either.
		I think the sense of the question is, has the safety of thalidomide been adequately described in systemic ENL or any subset of ENL, such as cutaneous?
		DR. LUMPKIN:  Joe, just for clarification on that.  You know, as people obviously see, when we get to question 3, it's the basic risk-benefit there.  We're not asking people here to say is this drug safe.  We've spent a day and a half talking about all the various concerns people have.  
		What this question is asking, has the safety profile been adequately characterized so that when we get to number 3, you've got a premise upon which to do a benefit-risk assessment.  That's really what this question number 2 is getting to.
		DR. McGUIRE:  Well, before we address that question, I would like to ask Dr. Crawford his views on that because as I sat here in November and listened to the data on neuropathy, axonopathy, it seems to me there were different measures in different studies and there were different results in different studies.  I was left without a clear view of what the neurological toxicity is.
		DR. CRAWFORD:  I don't think the neurotoxicity has been amply demonstrated.
		I support Dr. Miller's point, that ENL is chronic, it's recurrent, it lasts for years, and thalidomide has been given for many months or years.  
		As I tried to point out, the toxicity we know for a fact, in well-documented studies in non-leprosy disorders, the frequency of thalidomide neuropathy is at least 21 percent, and as somebody has pointed out, in one British study it may reach 50 percent.  That is based on electrophysiological studies which have not been performed on leprosy patients.
		Now, experienced leprologists have stated they have not observed this neuropathy in leprosy patients.  We really have to ask the question, why is this difference occurring, a difference of between lower than 1 percent and upwards of 21 percent? 
		One answer is I noted from the Hansen's Disease Center form, that the information on that form showed details of the classification of leprosy, but there was nothing about the clinical examination of the peripheral nervous system.  Now, this is not a difficult thing to do.  You need a pen, a piece of cotton, a reflex hammer.  That should be recorded at the very start before thalidomide is administered, and that will give you a baseline as to whether the drug is safe or not.
		Now, we're told from the leprologists they carry out careful sensory codings, but we haven't seen any clinical data on that. 
		So, I think in summary that the evidence suggests that thalidomide neuropathy has not been excluded.
		I'm also very concerned about the advocates of thalidomide, including Dr. Gelber, when they're writing about this in textbooks -- I think he has written in Mandel's Infectious Disease -- he doesn't mention thalidomide neuropathy as a side effect, and I think that's a serious omission.
		DR. McGUIRE:  Dr. Simmons-O'Brien, would you make a comment about some of the literature you've looked at with neuropathy?
		DR. SIMMONS-O'BRIEN:  Yes, and I have to say I am not a neurologist and I wish sometimes I had paid more attention to neurology in medical school now in reviewing some of this.
		But as a dermatologist in reviewing literature and being concerned about some of the patients that I used thalidomide in compassionately -- and that thalidomide has not been obtained from Celgene, I'll say that -- I think that in the ENL patients specifically -- and that's what we're talking about -- the literature -- and I agree with Dr. Crawford -- does not look like the thalidomide neuropathy as it is characterized was looked at in the past.  And it doesn't seem like from Celgene's report that it is being looked at today in a very standardized way using a standardized history, neurologic examination, looking at sensory nerve action potentials, and the median in sural nerves, looking at somatosensory VOC potentials, and looking at quantitative sensory testing to measure vibration and temperature, all of which has shown to be helpful in further elucidating a toxic neuropathy as demonstrated by Dr. David Cornblath, who was here yesterday.  I think that it must be done prior to a patient ever beginning the medication and it should be done at systematic intervals.
		So, I don't know that ENL patients do not get thalidomide-induced neuropathy.  It seems to me that it has not thus far been looked for.
		DR. McGUIRE:  Is there more discussion on that point?  Yes?
		DR. MATHEWS:  If I recall correctly, at the November meeting there was a discussion about whether a clinical examination was sufficient once a drug is licensed or made available for clinical practice to detect neuropathy due to thalidomide or any other medication that has neurotoxicity, or should electrophysiologic studies be required.  I think, if I recall, it was Dr. Cornblath's comment at that time that careful clinical examination was likely to be adequate to detect reversible neuropathy.
		In the data that has been discussed so far yesterday on reversibility of this entity, the neuropathy, I don't recall hearing any data that detecting it when the nerve action potential decreased by any specified amount was any more likely to be reversible than discontinuing the medication at the first sign of paresthesias, for example.
		It's a big difference to require nerve action potentials be measured in a clinical trial setting versus stating that that has to be part of the monitoring of the drug whenever it's used in any clinical care setting because it's simply not available in many contexts.  So, I think we have to grapple with that issue.
		DR. McGUIRE:  That's my recollection of Dr. Cornblath's testimony.
		Yes, Eva.
		DR. SIMMONS-O'BRIEN:  I think the problem gets into reversibility of neuropathy and reversibility of symptoms.  I was not at that meeting and you did not hear any data yesterday to suggest that.  However, in my experience, clinical evidence has shown that there seems to be a window that you can actually reverse the neuropathy if you are using all those measurements and there is a time when the neuropathy most likely is still present based on depression of those synaptic responses.  However, the patient off of medication is no longer symptomatic or the patient on lower dose medication is no longer symptomatic.
		So, it's a very gray area.  It's a very difficult area but it's one that we need, to the best of our ability, to try to understand and look at.  The benefit will be that hopefully we'll have a better understanding of neuropathies in general.
		DR. McGUIRE:  The question is has the safety of thalidomide in the treatment of systemic ENL or any subset of ENL been adequately described.  What I'm hearing is that we need to fill in some data in the neurologic exam and perhaps make predictive observations.
		Dr. Bergfeld.
		DR. BERGFELD:  Well, I'd like to respond to that question as well.  I think that the safety information as to where we should be looking for the risk areas has been adequately described.  We've heard about the embryo toxicity, the neuropathy.  We haven't mentioned the hematopoietic changes that occur in some individuals.  But I think that all of the studies paint sort of the same picture, and so we know where our issue areas are.  
		So, I would answer that question yes.
		Now, as to the total effect as to percentage, prevalence, however you define that, embryo toxicity I gather is 100 percent if the window is appropriate when the drug is given.  The neuropathy ranges, in my estimation looking over the clinical information, from 60 percent.  It may be higher than 50 percent.  So, that needs to be better clarified as stated.
		Some of the hematopoietic changes, specifically the low white counts, perhaps need to be dialed up a little bit to more carefully.
		But on a whole, we do know the safety parameters and where the issue areas are, and so again, I'd answer that question yes.
		DR. McGUIRE:  Well, that just goes to show you.  You and I have the same information, Wilma, and I would vote no on it because I think the axonopathy has not been adequately described and we don't have predictive measurements.
		DR. CRAWFORD:  Could I just add or just repeat that the British experience is the committee has recommended sensory action nerve potentials to be done on all patients before they start thalidomide.
		DR. McGUIRE:  I can't hear you.
		DR. CRAWFORD:  The Committee on the Safety of Medicines in the U.K., the equivalent committee to this one, has recommended that sensory action nerve potentials be done before any patient is given thalidomide.
		DR. McGUIRE:  Okay.
		DR. MATHEWS:  Dr. McGuire, could I make one follow-up comment on that?
		DR. McGUIRE:  Please do.
		DR. MATHEWS:  Perhaps because of my experience on the Antiviral Committee, at least in HIV-related applications, we have used for over 10 years medications which have predictable neurotoxicity and because of the severity of the underlying disease, those risks are taken.  In some cases, it's clearly dose-related; other cases, not so.
		So, in my mind, it depends on what is the indication for the treatment, what are the other treatment options.  Of course, it's not only in HIV medicine.  In oncology routinely these drugs with neurotoxic potential are used.  So, it's not in my mind a question, does it cause it or doesn't it?  Is it severe enough?  Is it reversible and is it worth the risk?
		DR. McGUIRE:  The question really is whether we've described it fully, whether we know what we're dealing with.  It's not whether it's a neurotoxin or not a neurotoxin and whether the axonopathy is permanent.  I think the question, as I read it, is whether it has been adequately described.
		DR. BERGFELD:  Or identified?
		MS. COHEN:  I would use the word -- it has been described and substantiated.  I mean, you can have all kinds of things about safety, but unless it's substantiated, you really don't know if it's safe.  This is all in the mind, but it's the actuality that it's about.  It seems to me if it has been substantiated, that's the part of the safety --
		DR. BERGFELD:  I don't think any committee member here would say that the two major issues here are not the two that we've been talking about, the embryo toxicity and the neuropathy.  I think that those are real and I think we all agree to that.
		MS. COHEN:  Yes, I understand that.
		DR. McGUIRE:  Dr. Miller?
		DR. MILLER:  Just one other area that was mentioned by the reviewers was the area of postural hypotension was I think 12 percent in healthy volunteers, but there were no data for the patients with leprosy.
		The other question gets back to the teratogenicity issue, what are the long-term effects on reproductive potential.
		DR. KILPATRICK:  Joe?
		DR. McGUIRE:  Yes.
		DR. KILPATRICK:  I think it depends how you read and interpret the question.  From my point of view, I would vote no.  It has not been adequately described because we don't have point estimates and confidence limits.  There have been all sorts of figures thrown at us.  I'm not denying the knowledge of the existence of these effects, but in terms of precise knowledge, I don't think we have it.
		DR. McGUIRE:  Yes.  That's amazing.  I think you and I agree 100 percent.
		(Laughter.)
		DR. McGUIRE:  Yes.
		DR. ORKIN:  I'd like to ask Dr. Miller to clarify.  I think I made an implication of the point that you made yesterday and I wonder if we're on the same wavelength.  Are you talking about pregnancies in the future, not toward the end of the current pregnancy, but what happens 10 years --
		DR. MILLER:  Right.
		DR. ORKIN:  Then I would agree with that completely.
		DR. MILLER:  It got to the issue of what happens to this drug and what does it do to sperm.  Wilma brought this up several times yesterday too.  Is it deposited in fat or wherever?  And we just didn't know the pharmacokinetics of the medication.
		DR. McGUIRE:  Mr. Warren.
		MR. WARREN:  I know I'm just a layperson, but I have healthy brothers and sisters.  Most of the thalidomiders who are the oldest child quite often -- their parents went on to have other children just for posterity's sake I guess.
		DR. McGUIRE:  I think most of us would be happy for you and your family, and we'd like to see a larger data set.
		(Laughter.)
		DR. McGUIRE:  I think we've beat up on this question pretty much.  I'm ready to vote.  Fred, do you mind going first again?
		DR. MILLER:  No.
		DR. McGUIRE:  We are doing question number 2.  Has the safety of thalidomide in the treatment of systemic ENL or any subset of ENL, such as cutaneous ENL, been adequately described?
		And Dr. Miller says no.
		DR. HASHIMOTO:  Well, yesterday someone mentioned that TNF-alpha increases or fluctuates -- not very certain.  But in the literature, TNF-alpha induced HIV -- activated or enhanced expression of HIV.  If the drug goes to AIDS patient community, this issue wasn't addressed.
		The other one is erythema nodosum is often a complication of birth control pills.  Actually that's one of the most common complications of young female patients.  If a patient is put on birth control, what happens if a large population trial goes on?  Maybe erythema nodosum may be added on ENL.  That issue we haven't discussed yet.
		So, I'm not quite sure all the possible risks are disclosed at this point.  So, I should say no.
		DR. McGUIRE:  Thank you.
		Mrs. Cohen.
		MS. COHEN:  No.
		DR. McGUIRE:  Jim, you haven't changed your vote just because I voted with you.
		DR. KILPATRICK:  No.  That is, no, I haven't changed my vote.  On number 2, as amended, I vote no.
		DR. McGUIRE:  Dr. Simmons-O'Brien.
		DR. SIMMONS-O'BRIEN:  No.
		DR. McGUIRE:  Okay, McGuire, no.
		Dr. Bergfeld.
		DR. BERGFELD:  I'm voting yes.
		DR. McGUIRE:  Dr. Orkin.
		DR. ORKIN:  No.
		DR. McGUIRE:  Dr. Mindel?
		DR. MINDEL:  Yes.  I don't like voting opposite everybody all the time.
		(Laughter.)
		DR. MINDEL:  It seems to me in the first question "demonstrated" is a very strong word.  I find "defined" is a much softer word.  Dr. Kilpatrick talked about confidence limits in terms of defined.  I'm a little perplexed by that.
		DR. McGUIRE:  Well, Joel, I think it's okay for you to vote yes.
		(Laughter.)
		DR. MINDEL:  But I find that the question is a lot softer, and I can vote yes for it.
		DR. McGUIRE:  Okay.
		Dr. Mathews.
		DR. MATHEWS:  I vote yes also and it primarily relates to the experience of the physicians who have taken care of these patients.  While I don't doubt that there is some clinical neuropathy in perhaps a significant proportion, if it hasn't observed and diagnosed, then I suspect it's not as clinically significant.
		DR. McGUIRE:  We have a vote for Dr. Duvic?
		DR. BERGFELD:  I'm sorry.  Yes, we do.  Yes.  She votes yes.
		DR. McGUIRE:  She votes yes.
		And Dr. Crawford?
		DR. CRAWFORD:  I vote no.
		DR. McGUIRE:  Oh, he's not voting.
		DR. KILPATRICK:  Dr. McGuire?
		DR. McGUIRE:  Yes.
		DR. KILPATRICK:  May I point out that Dr. Duvic who voted yesterday was probably answering in terms of the original questions and not the amended questions and that may make a difference.
		DR. McGUIRE:  I'm sure that's right.  Just note that, Tracy.
		We're moving right along to lunch.  What I would like to do is to get started at 1:10 here and we'll begin with discussion of question 3.
		(Whereupon, at 12:14 p.m., the committee was recessed, to reconvene at 1:10 p.m., this same day.)

AFTERNOON SESSION
(1:16 p.m.)
		DR. McGUIRE:  Good afternoon.  This is the last session of meeting number 47, and we are now into the part of the meeting in which the agency has asked us to consider a number of questions.  Today we have eight questions.  We've covered two of them, and I hope those were the hard questions, but we'll see.
		(Laughter.)
		DR. McGUIRE:  We don't need to introduce anyone.  I think it's the same cast that we had this morning.
		Let me read question 3.  Do the benefits outweigh the risks of Celgene's thalidomide in the treatment of systemic ENL syndrome or any subset of ENL, such as cutaneous ENL; i.e., does the committee recommend that Celgene's thalidomide be approved for systemic ENL syndrome or any subset of ENL, such as cutaneous ENL?
		Once again, that question needs reading several times, and it gets a little more complicated on each reading.  So, I think I'm going to strip it to do the benefits outweigh the risks, and then we can talk about cutaneous ENL versus other systemic forms of ENL.
		Janet, how say you?  Do you want Celgene left in here or out of here?
		DR. LUMPKIN:  No, out.
		DR. McGUIRE:  Out.  Okay.  Did everyone get that?  We're talking about thalidomide global.
		Actually, Tom Rea, where are you?  Dr. Rea, who has been mentioned in the meetings many times, is a very experienced clinician and leprologist.  Tom, if you could give us just a couple of minutes on thalidomide risks and benefits.
		DR. REA:  Yes.  I have been using thalidomide since 1971 and approximately experienced with about 300 patients with at least four different forms of four different drug products being administered and getting a good response with all four.
		The risks and benefits.  I think the benefits are large.
		The population of patients are those pretty much at the bottom of the economic barrel.  A lot are illegal immigrants.  A lot are recent immigrants to this country trying to hack it, and as most of you know, that is not necessarily easy.  Then they're not particularly happy with the diagnosis of leprosy, but they can function with that diagnosis and they can accept that diagnosis and they can work or raise their family with that diagnosis.
		When the acute ENL comes on -- and it's episodic and these episodes can be infrequent or they can be occurring unremittently every three or four days.
		The real therapeutic choices are high dose of steroids, and we certainly have patients where we've chased up to prolonged doses of prednisone at the level of 60 milligrams a day, which inflicts its own cost and does not give particularly good control.
		When these people are started on thalidomide, whether they've been on steroids before or not, the response is usually quite striking, within a week.  For the patients it means that they can go back to work and when you're at the bottom of the barrel economically, this is very important because the employers with these people are quite ruthless usually and if they don't show up for work, they're soon out of a job.  
		So, the benefits here are enormous when you consider that most of these men are fairly young, they have young families.  The median age of our patients I think at the onset of ENL is in their mid-30s, so they usually have families and plenty of mouths to feed.
		The difficulties that we encounter with the medication are usually overcome quite easily.  The somnolence.  There is a tachyphylaxis to that or the dose can be reduced or steroids can be added in a fairly low dose, say, prednisone 20 milligrams a day, and get a very good result.
		For the men, it means that they can function and they can work and they can support their family.  For the women, it means that they can take care of their children rather than lie around the house in bed much of the time and really neglecting their family because they are simply not well enough to do what they do.
		I would accept actually greater risks than what the present proposal allows.  For example, I would welcome returning to the time from 1971 to 1975 when we could use thalidomide in women who were on two methods of birth control.  We did that.  We selected patients very carefully.  They were reliable.  They kept their clinic appointments and they understood what was going on.
		The neuropathy.  I concede there is a -- and the patients know it.  They have informed consent.  We have not really seen what we would call a clinical progression in the peripheral neuropathy which virtually all have at the beginning.
		This has been for these people a marvelous boon.  For the County of Los Angeles, the amount of money that they have saved by keeping these people out of the hospital must be a considerable amount of money because prior to use of thalidomide, a lot of these people were in the hospital for prolonged periods of time.
		There is no question in my mind that the benefits that I have seen well outweigh the risks.  
		I expect that over time in any kind of protocol, eventually that a thalidomide baby will be born and it will be a very sad day, and I don't know what I will do when I look that child in the eye or that parent in the eye.
		I am here as an advocate for the patients that I am taking care of, and if I cannot be their advocate, I really don't know who will be.
		Thank you very much, Joe.
		DR. McGUIRE:  Tom, wait just a minute.  Would you weigh in on cutaneous ENL versus systemic ENL?
		DR. REA:  The way we practice in our clinic and we see starting in two ways.  One, it can arise full-blown like Venus in the half shell arising virtually overnight, the full-blown systemic syndrome.  
		It can also start occurring as the small dermal nodules looking a lot like mosquito bites occurring in various numbers, arising in crops, occurring intermittently.  We usually note that down as incipient ENL, but don't treat it because the patients aren't sick yet.  We don't want any more thalidomide out there than absolutely necessary.  When the systemic symptoms develop or when the cutaneous lesions become interfering with one's occupation, then we treat.  Usually they are systemic.
		In the L.A. data that you read about, the 52 percent that were free of skin lesions, there was a remainder called a partial response by Dr. Weintraub's interpretation.  By our interpretation, if they were free of the systemic part of the disease and just a few skin lesions, we considered that a good response.  Actually, we like to see those few almost asymptomatic lesions because it lets us know that the patients really need to continue this medication. 
		So, our treatment endpoint is the control of the systemic aspects of the illness with a little bit of cutaneous lesions being very acceptable because when such people do fail to keep a clinic appointment and run out of their thalidomide, they exacerbate very quickly.
		DR. McGUIRE:  How much do you dispense to a patient in terms of days, weeks, months?
		DR. REA:  We usually go up to 200 milligrams, and if there is not what we consider a complete systemic response, we add prednisone.  The reason why is I do not want people on 300 milligrams a day driving on the freeways to come into the clinic.  That seems to be a very bad risk to take.
		The length of time.  Initially we will see the patient back in a week and then adjust the dose.
		DR. McGUIRE:  That's an entry patient.
		DR. REA:  That's an entry patient.
		Once stable, we are now using 3 months as our routine.
		We have a young man from the Philippines whose job is with a fishing fleet off of Alaska, and he can only come to the clinic twice a year.  We are keeping him on the job, Joe, and maybe bending the protocol a little bit.
		DR. McGUIRE:  Let me ask you a rather loose question.  What do you think the incidence of noncompliance is if we consider noncompliance to be using the medicine for some other issue or giving the medicine to someone else or not returning to clinic at the expected date?
		DR. REA:  The returning to clinic at the expected date I think is much higher with the patients on thalidomide than it is on the routine because they know that this medication is keeping them out of trouble.  Where for, say, an ordinary lepromatous patient who doesn't have any reactional state, that is, they're not feeling terribly ill anyway, so there is not as big a premium in returning as there would be if you were on thalidomide.
		I don't know how much goes on of that.  We've got no way to really check on it.  We can tell when the patients say they don't need any more thalidomide and if they were taking one a day, they should have run out.  We try with a fair degree of accuracy to have the patients routinely bring in all of the medications that they are on, so we will try and get some handle on what's going on.
		They are cautioned at the beginning and we do try to reiterate repeatedly that this is a drug that nobody else in the family should take, and in a pregnant woman, it is devastating.
		DR. McGUIRE:  Tom, if you would just stay there, maybe other people from the advisory committee could question you.  Dr. Orkin has a question.
		DR. ORKIN:  Have you seen, Tom -- and I think you may have already intimated -- any pregnancies?
		DR. REA:  No.  We have not seen any pregnancies in women on thalidomide.  We have seen, going back over 20 years, at least one of the women on thalidomide, which was discontinued subsequently, she had had no children at that time.  She was about 18 years old and now has I think two or three children.  I don't know just when they were born.  I think the first one was probably about a year after the thalidomide was stopped.
		DR. ORKIN:  Also, have you seen them on their own use it for other conditions or pass it on to somebody else?
		DR. REA:  We have not knowingly observed it.  Whether it has happened or not, I really don't know.  The nightmare that has not yet become a reality is the, quote, sterilization with tubal ligation, which has a failure rate of around 1 percent.
		DR. McGUIRE:  Are there other questions from the committee?  Dr. Hashimoto?
		DR. HASHIMOTO:  Do you see any great need for making this prescription drug released out of the institution?  What is the reason, if any, that this should be outside of the institution?
		DR. REA:  As an advocate for my patients, I think it is important that there be a good supplier, a reliable supplier within the United States.  Otherwise, they are at risk.  We had, as Dr. Yoder mentioned, a crisis when Chemie Gruenenthal took the stuff away and there was a short supply.  I don't think there's any real hardship there.  
		But as an advocate for my patients -- and I'm under this privileged umbrella.  So, that is why I am here.  But as a physician who has seen a group of patients benefit greatly, I expect there are other patients that will benefit greatly with other diseases, as witnessed, the Behcet's syndrome.
		DR. McGUIRE:  Dr. Rea, which suppliers are you using?  Are you using only the Celgene product?
		DR. REA:  No.  I have never used the Celgene product.  We started out with Chemie Gruenenthal, then the Carville kind of Tulane homegrown supply, then the Brazilian tablet that was sort of like chewing on marbles.  I don't know if any patients broke their teeth on it.  They might have.  And then the Brazilian product that comes as a capsule.
		DR. McGUIRE:  Dr. Miller.
		DR. MILLER:  Just two questions, Dr. Rea.  The first one is, do you worry about the sperm with these gentlemen?
		DR. REA:  This was actually looked at in the 1960s, and there was no evidence.  If you're taking lepromatous men, that is a very poor place to start to look because untreated, lepromatous patients, or treated -- there was no difference in our data -- 85 percent have an elevated FSH.  80 percent have an elevated LH.  About 33 percent have clearly subnormal testosterone levels, and male infertility is not an uncommon complaint.  It is not easy for a machismo Mexican male to admit to this or a retarded libido, so I expect the complaint is much more prevalent just judging by our own biochemical data.
		DR. McGUIRE:  Mrs. Cohen?
		MS. COHEN:  Go ahead.
		DR. MILLER:  I have one more question.  How do you select which subset actually receives thalidomide?  Is it all patients with ENL or how many lesions do you need and how do you define that?
		DR. REA:  It's the being ill with it.  There is no magic threshold on a numerical count.  It's not like neurofibromatosis.  You got it if you got six or seven cafe au lait spots.  That is not the therapeutic motive.  The therapeutic motive is you have a sick patient.  It's like perhaps analogous to when a patient goes to garden variety psoriasis to pustular psoriasis, von zumbush, you got a sick patient on your hand and you're going to wheel out a big gun.  And steroids won't do much good either.
		DR. McGUIRE:  Mrs. Cohen.
		MS. COHEN:  How many patients do you have, men and women, and how many are successfully treated and leave?
		DR. REA:  As of the end of 1996, under the Carville IND, we've had on thalidomide 291 patients.  If I include those that have enrolled this year and those that enrolled in the early 1970s, it is certainly over 300.  I think at the end of 1996, the last time I counted noses, we had close to 50 patients receiving thalidomide.
		MS. COHEN:  Is that a pretty steady amount?
		DR. REA:  It has been higher in years past. When the Vietnamese immigration to this country was at its peak in the mid-1980s, we were at a higher level.  We were up to about 60 or 65.
		DR. McGUIRE:  Susan, let me ask another part of your question.  How many patients are you accessing per year now?  Let's say for 1996 or 1955.  I'm not talking about patients in the system.
		DR. REA:  How many new ones?
		DR. McGUIRE:  Yes.
		DR. REA:  This year there have been approximately 10 patients so far.  If you want to reduce the number of leprosy patients in your clinic, a good way to get leprosy control is to get politicians to start to blame immigrants for all of your local problems.  These people are very sensitive to what's going on, and there was a big drop in our numbers of cases when proposition 187 was passed.  And that trough lasted for about a year, and I think we're getting a little wave in response to that trough now.
		MS. COHEN:  I'm still curious to know in terms of treatment how long you keep them and are you successful?  How often do they leave?  And also, if they're really illegal aliens, I'm surprised that they would come in a system and even identify who they are.
		DR. REA:  The one question we never ask is their immigration status because that is an inherently pejorative question and an intimidating question.
		Dr. Yoder's figure of the mean time on thalidomide was 3.3 years.  I expect ours is a little longer.  We've got a lot of Mexican men and they seem to be a prime candidate for prolonged -- we have a few patients that are pushing the 10-year mark.  Just flying by the seat of my pants, I expect the median time is about 5 years.
		DR. McGUIRE:  Yes.
		MR. WARREN:  I was just wondering.  You said some people took themselves off of thalidomide.
		DR. McGUIRE:  I recognized Colin.  Just a minute.  Go ahead.
		DR. CRAWFORD:  Presumably these patients are on multi-drug therapy, including clofazimine.  Do you think the frequency and the severity of ENL has diminished?
		DR. REA:  I can't answer that question.  We don't use a lot of clofazimine.  Dr. Gelber and I did a study 10 years ago where 1 out of 101 patients were dapsone resistant.  The rationale of including clofazimine is to cover bets that patients might have a primary dapsone resistance.  That's the rationale for triple drugs.
		The people in Brazil say since MDT has come along, there is more ENL and more reversal reactions than what there was before.  I cannot comment on that.
		DR. McGUIRE:  Mr. Warren?
		MR. WARREN:  I was just wondering.  You said some people said they took themselves off of thalidomide.  Do they bring back the pills?
		DR. REA:  That is not a very dependable thing.  We do ask them to flush them down the toilet.  We are not worried about malformed rates in the sewer system.  But there's a strong injunction for them to get rid of it.  It's an excellent suggestion to ask them to bring it back.  I don't know what the compliance rate would be on that, but it's a very good idea.  Thank you.
		DR. McGUIRE:  Tom, your testimony is very helpful.  Are there other questions from the committee? 
		(No response.)
		DR. McGUIRE:  Thanks very much, Tom.
		DR. REA:  Thank you, Joe.
		DR. McGUIRE:  What other questions do we have about the risk-benefit ratio?  Dr. Lumpkin, you're getting closer and closer to the microphone.
		(Laughter.)
		DR. LUMPKIN:  That's why I raised my hand.
		The only thing I would like to say in relation to this question, when we were forming the question, clearly as the implication is, this is the question where we're asking do you think this should be approved for this indication or not.
		I think what's always hard in trying to put these questions together is for the committee to say -- we're asking you to look at the entirety of the system in which it might be used here.  Do the benefits outweigh the risks?
		Now, obviously if we were saying do the benefits outweigh the risks for the use of this product over the counter, that would obviously put people in one frame of mind.  And that we are not.
		Obviously, as has been said here previously, we're talking about use if this product were to be approved as a prescription product.
		But as we get into some of the other questions, I would just say, as we say to all of our committee members, think about it and if there are caveats that you think are important in trying to come to your benefit-risk equation here, this is the time to put those forward.  I just didn't want people to be confused.  If you think the benefits outweigh the risks if this thing were labeled in a certain way or if you think this thing were in a restricted distribution pattern or if you did neuropathy screens or whatever, if there are caveats, by all means put them in.  We don't mean for you to take it in kind of a blinded fashion or a blinder fashion.
		DR. McGUIRE:  Thanks very much, Mack. 
		What we're doing is anticipating questions 5 and 6 and some of the other issues that will be dealt with.  So, rather than deal with all of these issues at this moment, I would rather deal with the safety/efficacy, and then we will observe question 4, what additional information, and then go right ahead to questions 5 and 6.
		Is there more discussion before we move?  Yes.
		DR. MOORE:  I'd just like to make a brief comment.  I believe this is an extremely difficult task for the committee because we're talking about risk to the patients themselves and risk to our next generation.  But I would respectfully ask that the committee realistically consider the risk as being not only for use in ENL but also for many other conditions, some of which will be more prevalent in women of childbearing potential.  
		As I mentioned yesterday, we had had some discussions with a couple of individuals who work at Carville who now say they only have 5 patients who are on this drug for ENL and have enough thalidomide stockpiled for the next millennium.  So, we're really talking about the risk for a much larger group of patients.
		DR. McGUIRE:  That's an important observation.  It has come up several times in the deliberations and it will come up again after we take care of the risk-benefit issue.
		So, I'm ready to ask how you feel about the risk-benefit.  Cynthia, we can start with you.
		DR. MOORE:  I'm not on the committee.
		DR. McGUIRE:  Oh, you're not voting.  Well, all the more reason.
		(Laughter.)
		DR. McGUIRE:  Chris.  Dr. Mathews.
		DR. MATHEWS:  Understanding the question as you formulated it regarding ENL patients, yes, I think it's clearly a favorable risk-benefit ratio.
		DR. McGUIRE:  Dr. Mindel.
		DR. MINDEL:  Yes, I think it's clearly favorable.
		DR. McGUIRE:  Dr. Orkin.
		DR. ORKIN:  Yes.
		DR. McGUIRE:  Dr. Bergfeld.
		DR. BERGFELD:  Yes.
		DR. McGUIRE:  Dr. McGuire, yes.
		Dr. Simmons.
		DR. SIMMONS-O'BRIEN:  Yes.
		DR. KILPATRICK:  This is Kilpatrick speaking.
		DR. McGUIRE:  Dr. Kilpatrick.
		DR. KILPATRICK:  I should point out that the ultimate authority in my life, my wife, has just walked into the room.
		(Laughter.)
		DR. KILPATRICK:  So, I have to be very careful in what I say, but she knows me well enough to know that I am somewhat perverse and I vote no because, again, as I read the question as changed, I tend to look at things not from a patient perspective, from a population perspective, and I am not convinced that the benefits outweigh the risks in a population sense.  In a sense, I have no information on this because no information has been collected that would convince me otherwise.
		DR. McGUIRE:  I think the question is framed so that we're talking about the population with ENL.  We're not talking about general population problems, which is another issue that we have to deal with in a few minutes.
		DR. KILPATRICK:  In that case, not being a clinician, I defer to my colleagues.
		DR. McGUIRE:  Which one?
		(Laughter.)
		DR. KILPATRICK:  Anyone but yourself, sir.
		(Laughter.)
		DR. McGUIRE:  That proves that I'm a neutral chairman.  That's very important.
		Mrs. Cohen?
		MS. COHEN:  If it's just the ENL, it still is a distribution problem, and I need to know what plans there are for distribution.  I mean, it isn't just the risk.  This is a very complicated question that really involves a lot of things.  It isn't just giving it.  It's how do they get it, how do they monitor it, and what additional information, which is the next question.  I must have about 20 things written here as to what information I need more before I make that decision.  So, I have to in good conscience say no.
		DR. McGUIRE:  Okay.
		Dr. Hashimoto.
		DR. HASHIMOTO:  I shall say yes, as far as this definition of ENL limited efficacy is.
		DR. McGUIRE:  Dr. Miller.
		DR. MILLER:  Yes.  Again, with the subset clearly defined as Dr. Rea pointed out.
		DR. McGUIRE:  Thank you very much.
		Question 4 I'm going to read because I think question 4 is really a segue.
		DR. BERGFELD:  Excuse me.  Did I say that Dr. Duvic said yes?
		DR. McGUIRE:  Yes, and her vote would count if that question has not been changed, has not been altered.  And the question has been altered so that "Celgene" now reads "all thalidomide."  So, someone else can consider that, but as I understand it, her vote would not be counted.
		Does anyone want to tell me better?  
		A little side bar there that I didn't understand.
		Question number 4 is what additional information, if any, should the sponsor be asked to provide before approval can be considered?
		Now, this is a very big question and I'm not going to deal with it head on.  What I'd like to do is go to question 5 which will carve a little piece out of question 4.  If that's acceptable to the advisory committee, could we go directly to question 5?  No objection?  Thank you.
		Question 5 is, can Celgene's thalidomide be safely used only if distribution or use is restricted?  If so, what kind of restriction of distribution would the committee recommend?  
		Dr. Lumpkin, I gather here we would also eliminate Celgene?
		DR. LUMPKIN:  Yes, yes.
		DR. McGUIRE:  So, can thalidomide be safely used only if distribution or use is restricted?  
		I don't think we even have to vote on that.  Let me say yes and see if anyone disagrees.  Does anyone disagree that it should not be restricted?
		MS. COHEN:  I hate to tell you that I reworded the question.
		DR. McGUIRE:  Susan, you would like to what?
		MS. COHEN:  I reworded the question.
		DR. McGUIRE:  Go ahead.
		MS. COHEN:  Should thalidomide be safely used only if all the criteria of the FDA be met and any distribution be highly restricted under a fail-safe plan?
		DR. McGUIRE:  Okay.  We can deal with all of those restrictions in a moment.  If we will just answer the first part of that.  Can thalidomide be safely used only if distribution or use is restricted?  
		My sense is that the committee feels that it should be restricted.
		DR. BERGFELD:  I think adding to that would be mandated and monitored.
		DR. McGUIRE:  Okay.  Well, then let's talk about what kind of restriction of distribution, what kind of monitoring would the committee recommend.
		DR. KILPATRICK:  Mr. Chairman?
		DR. McGUIRE:  Yes.
		DR. KILPATRICK:  I'm in the position where I'm uncertain that any type of restriction or limitation of distribution can effectively meet the criteria which I would like to see.  So, I'm maybe not answering the question, or am I again off in left field?
		DR. McGUIRE:  No, you're not off in left field.  But I think we should take a serious attempt at defining what restrictions there should be that would give us some degree of comfort.  
		Can we protect every consumer from this drug?  If you're asking that question, I think everyone, beginning with Dr. Hanson yesterday who spoke for the American Academy of Pediatrics, thinks that once the drug is out there, there will be misuse.  
		The question is, is it possible to control its use and what regulations do we build into its use?  
		But the question you're answering, if you want an absolute answer, I think it is not possible to provide absolute assurance, and I accept that as a fact.
		But the question is what should we be doing.  Should we simply give up at this point and say we could not provide enough safety --
		DR. KILPATRICK:  I see.  I understand.
		DR. McGUIRE:  So, let's have some discussion.  Dr. Bergfeld.
		DR. BERGFELD:  I'd like to add to my comments of mandated and monitored restricted distribution that this be specific for ENL and that any other uses be subject to INDs and future NDAs.
		DR. McGUIRE:  That's a very important issue.  I hope everyone on the committee understands it.  We are talking about restricting the use of thalidomide only for the treatment ENL, not the other disorders for which it might be used, and I support Dr. Bergfeld's suggestion.
		Chris.
		DR. MATHEWS:  While I'm in great sympathy with what the goal that you articulated is, I think we should consider what are the problems with the current distribution system under the IND mechanism.  I'm sharing with you very small experience but enough to make me concerned that the present system is not adequate in the controls in place.
		My experience with this drug was in participating in a clinical trial in HIV wasting.  I think we enrolled 7 patients.  There were no problems that came to my attention as the local investigator on that study.
		The IND mechanism.  I've treated 2 patients within the last year and a half, had to get IRB approval, had to get the FDA to give me an IND number, had to call through a list of companies that they gave me the names of that were willing to make the drug available.  That takes a lot of time, so I was in sympathy with that family practitioner whose letter was read yesterday on how difficult this can be.
		Having said that, I have one patient who came into my practice having obtained thalidomide for aphthous ulcers from another physician a year previously.  He still had a supply of the drug, and a couple of weeks ago had an outbreak of severe aphthous ulceration.  I phoned in a prescription for prednisone because I knew I couldn't get thalidomide right away.  He says, oh, I have a bottle right here.  How about if I take that?  So, there are people out there with this drug.
		The other case was even more disturbing.  This was a young man who was deaf and dumb who had horrible aphthous ulcerations and he had lost 40 pounds because he couldn't eat.  He finally agreed to take thalidomide.  We got through the approved mechanisms.  He took it.  The ulcerations healed completely.  He gained weight. 
		And one day he showed up in the clinic and told our pharmacist that he wanted another bottle of thalidomide, which we didn't have, and his ulcers were healed, so we didn't pursue it.
		Shortly thereafter, it comes to my attention that one of the practitioners in my clinic, which is an academic clinic with about 20 different people working there, had another patient with aphthous ulcers, a woman who came in with horrible disease.  It just so happens that the patient, the gentleman who was deaf and dumb, had brought in this huge bag of medicines, one of which was a bottle of thalidomide, properly labeled.  And she, who wasn't involved with obtaining the IND or anything else, took some pills out of that bottle, put it in a sterile container cup, and gave it to this woman to take for her aphthous ulcers.  She fortunately knew enough to make sure she wasn't pregnant and all this.
		Well, you can imagine.  I went ballistic, contacted the IRB and everything else.  But this is in a fairly sophisticated medical care environment.  
		As I saw the presentation yesterday of the educational program that was planned, if this drug is ever licensed, the use of blister packs, label things and so on, a lot of these little incidents, many of which nobody knows about, would be more likely to be prevented.
		So, I don't think the simple IND mechanism, by way of sharing these anecdotes, is a fail-safe system and needs to be improved.
		DR. McGUIRE:  Well, I'm glad you shared those clinical experiences.  That must have been a terrible week.
		(Laughter.)
		DR. McGUIRE:  I can't imagine what I would tell my IRB if that happened to me.  Well, I would tell them the truth, but I don't know what would happen to me.
		Is there more discussion to the point?  I think the question is can we make the existing system better or is the existing system going to continue as it is at least with regard to ENL.  Dr. Bergfeld's point I want to leave out there because, as far as I'm concerned, we're talking about ENL at this point, and the recommendations that we will give the agency for controlling the drug and providing the drug, we're restricting that to ENL.  
		Is everyone comfortable with that?  Yes?  Susan, you're saying no.  You want to restrict it to another disorder, or you want to open it up to other disorders?
		MS. COHEN:  I'm not being contentious.  I just am concerned about the distribution, and if Chris is an example, it's probably a small example of what happens.  There are so many things that are unanswerable and ponderable in all of this.  It's like you have already decided that the distribution is going to be fail-safe, it will be wonderful.  I really don't know.  I've seen their package.  I've seen what's here.  
		When I asked yesterday about the experience we've had in this country with the buying clubs and what's happened, that was not a facetious question.  That was a question to know what the actuality is and what's really going on out there.  I have been told that there's thalidomide out there on the streets.
		DR. McGUIRE:  There is.
		MS. COHEN:  So, I don't know how to answer because I don't understand enough.  So, I have to pass because I need to know more, and if I don't know more, it isn't fair for me to vote on what I don't think I know.  But that's just me, and remember I come from a consumer protection background.
		DR. McGUIRE:  Thalidomide is out there, and we're talking about a specific application of thalidomide for a disease and can we control it.  
		Susan, you know, I don't believe there is a fail-safe system for anything I can think of.
		MS. COHEN:  But at least we can try.  That should be our standard.
		DR. McGUIRE:  And so, what we're attempting to do is to craft a program that will protect as many people as we can and provide benefit.
		MS. COHEN:  I understand.  Chris mentioned IND.  I'm intellectually curious.  I want to know how you're going to do it, how you're going to restrict it.  I understand the fever in the ENL.  That much I understand, but I don't know enough about the distribution.
		DR. McGUIRE:  The granting of an IND controls the process only at a single point.
		MS. COHEN:  I understand that.
		DR. McGUIRE:  And this is a multi-point process.
		MS. COHEN:  And that's my concern.
		DR. McGUIRE:  And this is what we're attempting to address now.
		Dr. Hashimoto.
		DR. HASHIMOTO:  Well, considering only a very small number of ENL patients treated right now, and considering that current IND program working fairly well, unless someone really push for off-label use, I really don't think any need for releasing this medicine for prescription category.  If you talk about ENL, that's a very small number of patients.  The company probably never makes money on that.  So, there are different interests in this procedure.  But current program, as I hear from experts, it's mostly institutional and working very well.  Why not change at this point?
		DR. McGUIRE:  Ken, that's an excellent point and I hope everyone understood Dr. Hashimoto's issue.  
		The financial issues, whether they bring the drug to market, are not of concern to me.  That's their decision, and they can decide the market is too small, too large.  That's their decision.  
		You have heard from Dr. Mathews that the IND doesn't protect the public.  As I mentioned earlier, that is a control only on one point in the process.  So, we're looking at ways to protect the greatest number of people.
		And the issue as to whether the market is large enough to support their effort, I think that's not -- well, I'm not going to worry about it.
		DR. KILPATRICK:  Dr. McGuire?
		DR. McGUIRE:  Dr. Miller.  Oh, I'm sorry.  Dr. Kilpatrick.
		DR. KILPATRICK:  I just want to make sure that I understand, not being a clinician, what is being said.  Dr. Hashimoto, do I understand that under the current IND rubric, only caregivers are dispensing the drug to patients or are patients being given drugs to take home and self-medicate?  If the former, I would think that would be much more secure than sending supplies home with individuals.
		DR. HASHIMOTO:  Well, actually IND is a program which individual institutional physicians should apply to FDA and justify the use and documentation and then drug distribution.  Drug is given to patient.  Patient can take a drug home or whatever, but it's under control, supervision.
		DR. McGUIRE:  Dr. Rea addressed that, Jim.  His patients take the drug home for 2 weeks, 2 months, one patient 6 months.  So, the drug is dispensed under that program to the patient.
		Dr. Miller, you had a comment?
		DR. MILLER:  No.
		DR. BERGFELD:  Can I enter here?
		DR. McGUIRE:  Dr. Bergfeld.
		DR. BERGFELD:  The package that we saw in the communication package, which was the educational package, dealt with a number of individuals being put into the safe program or they hope to make a fail-safe program.  And that included the pharmacists, which was an interesting idea, where it would be a monthly prescription only, not a bag of pills for six months, and the individual with the prescription would have to present with it certain documentation to have the refill, not just the prescription.  That certainly is better than what we have right now.  Just that one piece is better than what we have right now.
		DR. McGUIRE:  Absolutely.
		Dr. Mathews.
		DR. MATHEWS:  My evolving thought on this is that what needs to happen is that whenever thalidomide is dispensed for whatever reason, whether it's under an IND or part of a prescription program, that there be a uniform educational package which I should think the agency would review and sign off on, rather than what's happening now where it's just sort of an ad hoc process with every institution having to sign off on something with no clear uniformity of what's required even at the local level.
		DR. WOODCOCK:  That's one of the subjects of the meeting next week.  There are many new indications or diseases under investigation for treatment with thalidomide.  The goal is to have some uniformity of message.  As Lou Morris said yesterday, the most important thing is to know what your message is and have a consistent message and program out there.
		But with the situation that has been present in the country -- and I think Debbie Birnkrant knows most about this -- for quite a long time we've had no consistent sources of product, and therefore we haven't been able to ensure this kind of uniformity and sort of regularization of the product.
		DR. McGUIRE:  That's very important and added to the anecdote that you heard from Dr. Mathews, which is that the current method of distribution is a very leaky method.  It's a very dangerous method.  So, at the very least, we can improve what's happening.
		Milt, do you have anything to say?
		DR. ORKIN:  I was just thinking and this is probably redundant and already been addressed, but perhaps I can address this to Dr. Woodcock or anyone else.  
		When they order the prescription for the thalidomide, clearly a date is put on and perhaps no refill, and would it be appropriate, must be transmitted to the pharmacist by a certain date?  In other words, put a restriction on it to avoid the refills that may be inappropriate.
		DR. WOODCOCK:  I think that's a question you can address to the firm as far as could their program include that element.
		DR. ORKIN:  Okay.
		DR. McGUIRE:  Would you like to address that?  This is Mr. Bruce Williams who I gather is one of the designers of the STEPS program.
		MR. WILLIAMS:  Yes.  
		The possibility of building into the system a check on the age of the prescription when it comes in certainly does exist.  Pharmacists would be asked, as the system is currently designed, to check not only has informed consent been signed, but also if it's a subsequent prescription, has at least some proportion of the time elapsed on the last dispense so that you don't have a patient who might be getting 4 weeks of drug and a week later coming back to get another 4 weeks of drug.  We don't want that to be possible either.  
		So, to build an additional element in that if a prescription was written on the first of the month, it must be filled by 10 days later, 5 days later is certainly possible, and I guess we would be looking for advice and input if people think that that's important not only as to what parameters but whatever details might be needed.  But that's certainly something we could do and we'd like to hear more discussion on that.
		DR. ORKIN:  There's also the implication that it be filled by the same pharmacy so that pharmacists would have some input in terms of the continuity.
		MR. WILLIAMS:  Yes.  The other thing is that the way the system is being developed, it would be designed to utilize some of the systems that are currently in place within pharmacy practice where there are central computer databases that pharmacists log in and out on when they are filling prescriptions.  A portion of one of those databases will be carved out to actually have the pharmacist tracking and recording information on this patient so that we'd be in a position to monitor that the pharmacist was in fact complying with the program.
		DR. McGUIRE:  Yes, Cynthia, go ahead.
		DR. MOORE:  I have a question for you, a little bit of follow-up of what we talked about yesterday when I asked if somewhere on this documentation would be the patient's diagnosis or the indication for using it, and you said yes.
		MR. WILLIAMS:  Yes.
		DR. MOORE:  I guess my concern with all of this is that thalidomide may be prescribed for less than very serious disorders such as one or two aphthous ulcers in a patient who's a non-HIV patient or some sort of indiscriminate use, using a very dangerous and powerful drug for something that is not life-threatening or not even terribly serious although certainly annoying in that patient.
		You had at one point talked about looking for ‑‑ I don't know if I should call it failures, but times in which all of the measures that you had recommended weren't being followed and getting back to the pharmacy or the physician with this information.
		MR. WILLIAMS:  That's correct.
		DR. MOORE:  Does that include looking at the reason this prescription was written and making some sort of attempt to say back to that prescriber, you're prescribing this very powerful drug in a way it was never intended to be used and for a disorder in which there really is no data about its effectiveness?
		MR. WILLIAMS:  Yes.  I guess it's hard to be specific in answering that question certainly because there's a lot of hypothesis in it, but I share the concern.  The last thing in the world we would want is to see the drug used in what I will call somewhat judgmentally trivial indications or indications that are not serious.  That to us would be unacceptable.
		We have had some discussions with Allen Mitchell and his colleagues in Boston because that data would first be coming in to them.  I know in the current Accutane situation, if they see data coming in that suggests what might be inappropriate use, there is some follow-up if I'm not mistaken.  
		Allen, do you want to address that?
		DR. McGUIRE:  This is Allen Mitchell who has been tracking the Roche program for a while.
		DR. MITCHELL:  Yes.  Allen Mitchell from Boston University, Slone Epidemiology Unit. 
		Just in the spirit of disclosure, we have been negotiating with Celgene, as Bruce had indicated, yesterday to perform a survey if the drug is approved.
		In the Accutane survey, there was one component when we were doing a telephone arm of the follow-up where if we identified women who identified themselves as sexually active but not using contraception, we would read them what we called the riot act, which was a very stern warning about the risks of that kind of behavior and the need to discontinue drug immediately.  
		And I also asked them for permission if we could contact their physician since we maintain confidentiality and we couldn't contact their physician without their permission.  And if we were given their permission, we would then contact the physician and inform him or her of the practice as well.
		That was for the patients who were identified through the telephone survey.  That kind of mechanism exists in a survey mode.  We haven't talked about it specifically in this context.  It might be something worth pursuing.
		MR. WILLIAMS:  Yes.  I think it's a very important consideration, Dr. Moore.
		DR. McGUIRE:  The issues that have been defined are the issues of a stale prescription would not be honored.  A prescription would only be honored for a given length of time.  A limited amount of drug would be dispensed, and the drug would be identified with the diagnosis.  And then the post-marketing surveillance would be crafted by the company.
		I think those are the large issues, but I'd like to hear if there are other things that I've missed.  Chris?
		DR. MATHEWS:  There's a concern about the number of pharmacies involved with the program because the staff at pharmacies obviously rotates.  It's possible to get an inexperienced person in who could dispense the medication without the proper fail-safe mechanisms in place and so on.  
		One option which could be considered is a very restricted or even single distribution system as was done with one of the protease inhibitors initially in HIV medicine where they would be totally responsible for the quality control and have staff assigned who know that they're responsible and not dealing with hundreds of other medications simultaneously and in between.
		DR. McGUIRE:  Dr. Bergfeld.
		DR. BERGFELD:  One thing I think you left out in your list, Joe, was the fact that it might be very interesting and important to track the physician ordering and, when inappropriate, there be a means of contacting that physician.
		DR. SIMMONS-O'BRIEN:  Joe?
		DR. McGUIRE:  Yes.
		DR. SIMMONS-O'BRIEN:  I was thinking along the same lines as Dr. Bergfeld.  We all hate long paper trails, but oftentimes they keep us doing the right thing.  Maybe prior to the patient getting the prescription, whether the prescribing physician can send a letter to a designated pharmacist at the pharmacy saying that they would like for this patient to get this prescription and have that kept in some sort of file with the pharmacist saying that they are aware the patient is being treated for blanekty-blank and will be followed by this particular physician for ENL, but just have communication between those two people to go in files on that particular patient.  
		My concern would be a physician who writes a prescription for a patient -- and hopefully they will have ENL -- and have no plans on following that patient and following them while they are on the medication.
		DR. McGUIRE:  Susan?
		MS. COHEN:  Since many Americans don't live near major medical centers, how do people who live in rural areas or small areas get treated, and how are they taken care of if they have these particular kinds of problems?
		DR. McGUIRE:  Who would like to address that?
		DR. YODER:  You're asking specifically about patients with ENL?
		MS. COHEN:  Yes, it can be ENL.  Yes.
		DR. YODER:  I would be talking specifically about ENL.
		This is a problem.  It's inherent in the current system, and I would just comment on some of the problems with the current system.
		Patients in rural areas -- and I know of a specific situation like that in south Texas where the physician does not have an IRB in the local hospital and  therefore she has a problem getting this done.  The patient consequently will either have to come to Carville or travel 75 miles or so to San Antonio where they have access to thalidomide.  So, it is a problem.
		Another alternative is they can come to Carville, for example, and get thalidomide from there, but that is one of the limitations on the current system.
		Certainly that's one of the things that could be relieved.
		I think another comment I would make along the lines we were just discussing, certainly that accessibility would be an improvement, also the reporting that would be done under what has been proposed here would, in my opinion, be a definite improvement over what we have at the current time.
		DR. McGUIRE:  Thank you.
		Dr. Bergfeld.
		DR. BERGFELD:  I just want to remind the panel that yesterday was presented a package of an educational package, along with the packaging and everything else.  My remarks have been based on the fact that that is a done-did, that will be done.  So, the education of the physician and perhaps signing off an informed consent and then having restricted use by a physician according to their training and whatever else is developed would be very important here.
		DR. McGUIRE:  Yes.  I'm sorry.  Dr. Miller.
		DR. MILLER:  Joe, could there be designated pharmacies which would be contacted by the physicians who are prescribing and then the prescription would be sent to those pharmacies and then they in turn would send the medication to the physician who would dispense it to the patient?  That would certainly keep it under some control, but you would have maybe six, seven centers in the country and then the physician specifically sends the prescription to that person with, on the prescription, what's being diagnosed.
		DR. McGUIRE:  Yes.  That's a novel idea.  Don't ask me if it can be done.  I haven't any idea.  The question is, where is there greater control?  At the physician or at the pharmacy?  I don't know.  You need maybe both in place, yes.
		Dr. Weintraub, this is not a yes/no question.  You asked for restrictions, advice on distribution, ascertainment of diagnosis, lots of issues.  We've talked about that for a while and you must have a lot of stuff on your yellow pad now.
		DR. WEINTRAUB:  It's white but I did take a lot of notes.  As far as I'm concerned, you may move on.
		DR. McGUIRE:  Okay.
		DR. MATHEWS:  Dr. McGuire.
		DR. McGUIRE:  Dr. Mathews.
		DR. MATHEWS:  Let me criticize some of the limitations of the IND mechanism.  I do feel that there is something very positive about requiring the physician to contact the FDA and somehow be registered.  I'd feel more comfortable that that be with the FDA than just with the pharmacy.  
		Now, I don't know technically how it can work out.  If the drug is licensed, say, for ENL but not for these other indications, there are problems of payment.  Right now the medication is shipped to a physician who is responsible for paying for the drug which is obviously a disincentive for physicians who don't have mechanisms to pay for medications and then try and recoup from the patient if they're able to pay.  It's not an inexpensive medicine right now.
		So, I'm not sure that we've directly tackled this off-label issue.  One issue with the off-label use is to be sure that the same quality of educational programs pertain to off-label use through whatever mechanism, and the other is the payment for the drug by third parties and the registration of the physicians.  So, I don't know what regulatory options there are to deal with that once a drug is licensed for one indication.
		DR. McGUIRE:  Well, Dr. Mathews, let me get into this and out of it.  There is ENL.  There is off-label, and then there are other orphan applications.  There are other disorders for which it might be used.  I think we should be wary of the off-label because that's where the biggest mistakes are going to be made and that's where most people are going to be at risk.  
		I think, as I mentioned yesterday, we need to make this system as leak-proof as possible.  It's still, I grant you, not going to be a perfect system, but I think we should deal with the ENL issue and then the agency will probably pick up bits and pieces of our discussion and use them in other applications, including the orphan applications, and will attempt to eliminate, minimize off-label use.
		Are you and I talking about the same thing?
		DR. MATHEWS:  Well, the point is that the drug is being used right now.
		DR. McGUIRE:  Oh, I understand that.
		DR. MATHEWS:  It's not off-label because there is no label, but it's being used for a variety of indications.  In my judgment it should continue to be used under controlled circumstances.  If ENL is the first indication for which a label is granted, then I'm hopeful that all of the mechanisms in place to ensure the quality of that distribution program are simultaneously applied to the other mechanisms of drug distribution.  
		In other words, I could envision something unfortunate happening whereby a particular sponsor gets a label for one indication and has this elaborate system in place which works very well, but then every other physician who tries to obtain the drug will go through a list of six or seven suppliers, and all of the problems that are currently potential issues would be unchanged.
		DR. McGUIRE:  I think that is a regulatory problem.  Janet?
		DR. WOODCOCK:  We hear you and we agree that this is a problem and we will do everything we can to try and deal with it, including the meeting next week which I urge people to attend.
		DR. KILPATRICK:  Dr. McGuire?
		DR. McGUIRE:  Yes.
		DR. KILPATRICK:  May I come back to a statement Dr. Moore from CDC made yesterday referring to off-label uses?  She said, if I correctly quote her, that off-label uses should be banned or made illegal.  Could you elaborate, ma'am, on that and tell us if that is feasible in any sense?
		DR. MOORE:  The last part of the question I think I would redirect back to our colleagues from FDA.
		What I said was and what I gave yesterday were suggestions that individuals who attended our meeting in March of this year gave us, ways to limit fetal exposure, and that was one of the suggestions that off-label use should be prohibited.  It's not a recommendation from CDC.  It's one of the suggestions.
		But as far as whether that can actually be done or not, I can't really answer that question.  I think that's a question for the other table.
		DR. McGUIRE:  Dr. Kilpatrick, did that meet your question?
		DR. KILPATRICK:  FDA has not responded, but I take it that their nonresponse means that it's not possible to affect off-label use.  We're going in circles here.  There is no label as yet.
		DR. WOODCOCK:  Right.  It has not been done.  This is not something that we have invoked.  I think it would be very difficult.  I think the question Dr. Mathews is raising is if we develop a perfect distribution system for ENL, are we sacrificing the practical and the best solution for the ideal? 
		We understand the sentiment and we will certainly take these issues under consideration.  Thank you.
		DR. McGUIRE:  Would the committee please look at question 6 and see if there's anything to be -- we are not voting on 5.  We have given the agency a lot and they don't need a yes/no.  They're getting a consensus and a strong feeling.
		(Laughter.)
		DR. McGUIRE:  Let's go to issue 6 and see if there's anything left to be discussed there.  If so, we should certainly do that at this time.  Are there recommendations other than those associated with restricted distribution the committee would make regarding ways to minimize the risk and safety concerns regarding the product?
		Well, we've talked about restricted distribution.  We've talked about certifying physicians, certifying pharmacists, and putting a stale date on prescriptions, and several other issues.
		Is there more to be brought to question 6?  Joel?
		DR. MINDEL:  I was disturbed that there are buying clubs that can get the drug legally.
		DR. WOODCOCK:  No.
		DR. MINDEL:  No.  So, this is illegal.
		DR. WOODCOCK:  Correct.  We have taken legal action against the buyers' club and we have also talked to other buyers' clubs and ensured that they stopped making thalidomide available.  But apparently it's still available.  That's what the CDC representative said yesterday and other people have said it is still available illegally.  It's difficult to totally suppress this.
		DR. MINDEL:  I'm concerned a little bit that by being very strict in your control of the drug, we'll have the situation that we have now with cocaine where if I try as a physician to get some to test for Horner's syndrome, it's virtually impossible, but if I go down to the street corner, I can get all that I need.  And we're going to have this situation with this drug.
		DR. McGUIRE:  Dr. Mindel, you bring up an issue that I would have given anything to have avoided today.  Now that thalidomide has achieved the status of a street drug, how do we deal with that?  I have no confidence.  
		The sponsor has several comments.
		DR. THOMAS:  Hi.  It's actually Steve Thomas again from Celgene.
		It is our experience, our received wisdom that the primary reason why the buyers' organizations are stocking the drug is that it is very hard to come by because it is not approved.  It is not easily obtainable in a regulated manner.  There are numerous instances in which after drugs have actually been approved that a number of the buyers' clubs have actually ceased to continue to make that particular compound available.
		DR. McGUIRE:  Dr. Zeldis, did you want to comment?
		DR. ZELDIS:  It was the same comment.
		DR. McGUIRE:  We're still dealing with issue 6.  Are there recommendations other than the ones that we've been discussing that you would like to make at this time?  Yes, Chris Mathews.
		DR. MATHEWS:  Just a brief comment on the neuropathy issue.  I think that some consensus that we haven't achieved here needs to evolve in terms of how it is monitored, whether specific clinical examinations are recommended, and those should all be spelled out, whether physiologic testing is required and so on.
		DR. McGUIRE:  Yes.  I think everyone is in agreement with that, and that was discussed at the meetings in November.
		Obviously, the more highly technical the examination is, the less likely it is to be done well in lots of different sites, and so we were looking for simple techniques for peripheral axonal performance.
		DR. SIMMONS-O'BRIEN:  I'd like to ask a question.  Is the renewal of the prescription the following month dependent on the patient having been seen by that prescribing physician and evaluated and examined?  And if that is the case, then is that physician required then to send documentation to Celgene that they have in fact seen the patient that month and have given the go-ahead for the continuation of the medication?
		DR. McGUIRE:  Are you asking the sponsor?
		DR. SIMMONS-O'BRIEN:  I guess so, yes.
		DR. McGUIRE:  Well, let me ask you.  What would you like?
		DR. SIMMONS-O'BRIEN:  Well, I guess I would like to know that, and I'm not saying that every patient needs to be seen every month necessarily who has ENL.  But I'd like to know whether it would be required -- and I think it would be a good idea to be required -- at least initially and to be modified in the future, if necessary, to have a treatment plan designed for that particular patient where the patient will undergo q 6-week or q monthly evaluation and that evaluation will include a history, a physical examination, blood work if necessary, neurologic testing again if necessary at that particular time.  
		I think that will benefit the patient obviously, but will also continually help us accrue data that should be meaningful because we can't begin to think that we know all about this medication and how it has worked and how it's going to affect all of these patients.
		DR. McGUIRE:  So, you're suggesting that we put a standard of care piece into this.
		DR. SIMMONS-O'BRIEN:  Yes.
		DR. McGUIRE:  Susan.
		MS. COHEN:  For better or for worse, has the Drug Enforcement Agency and Customs Service been informed of thalidomide coming into the country?
		DR. BIRNKRANT:  The appropriate government agencies have been informed.
		MS. COHEN:  Have you had any idea of what has been going on?  Have they responded to you in any way?
		DR. BIRNKRANT:  I'm sure they're keeping the agency informed of the situation.
		But I'd like to say a couple of things.  If you're interested, I can elaborate on the current situation with regard to the IND process in general for those patients who don't have access either because there is no clinical trial or, as was brought out before, those patients in rural areas, patients in Alaska, et cetera, et cetera.
		Because the indications today are so diverse, the agency felt that in order to ensure consistent advice to all practitioners, that they develop a thalidomide working group, and we were charged with developing some guidelines to be able to assist physicians and other health care providers about how to use this drug safely.  So, the group is made up of about 20 researchers at the FDA, including legal counsel, obstetricians, immunologists, neurologists, et cetera.  
		The group over time has developed an informed consent document.  It's available to every health care provider who requests compassionate use thalidomide and anyone else actually who wants to look at the document.
		Then we went a step further for an experimental therapy, and that is, we developed a patient education brochure which we view as a tool to the informed consent document that a patient can carry with them so that they can refer to it as frequently as they like to get the current information about how to use the drug safely.
		With this program in place with regard to AIDS-related indications -- and I can speak best to those ‑‑ we currently have approximately 500 patients receiving thalidomide who are outside of clinical trials.  The way the process works is that the physician or dentist calls in and requests thalidomide.  Our first response is that we encourage patients to enroll in clinical trials so that the drug does get developed properly.  
		If for whatever reason they cannot enroll in a clinical trial, then they have to provide us with sufficient data so that we're satisfied that the patient could possibly benefit from the use of this product.  In particular, we ask for the diagnosis, and in the case of aphthous ulceration, just as in the clinical trial, we want to make sure that this drug is used for the particular indication and not something that resembles the indication.  So, we ask for a biopsy report for that particular indication.
		In addition, we ask for pregnancy testing in women of childbearing potential.  We ask for the presence or absence of neuropathy.  We are now asking about absolute neutrophil counts and we ask that physicians are aware of the recent New England Journal of Medicine article where aphthous ulcer patients were treated with thalidomide and where they did see an increase in viral load.
		After that has been satisfied, we issue what's called an IND number, and that allows the health care provider to call from a list of pharmaceutical sponsors.  They call and they tell them that they've been authorized by the FDA to use thalidomide.  Then the paperwork continues.  The drug gets shipped and records are kept.  
		We ask that all IRBs get informed, and subsequently we ask for progress reports on the patients.  We ask for the informed consent document to make sure that the patient was adequately consented while receiving thalidomide, and we keep this in a database of regulatory information at the agency.
		In addition, we have collected data on birth control methods in these women of childbearing potential, and I can tell you that out of the 500 patients who have received it, approximately 80 of those patients have been women of childbearing potential.  I can tell you that a third of those have used the birth control method of surgical sterilization, not at our recommendation, but they just happen to have had a surgical procedure.
		The rest of the female patients have, at our request, used two methods of birth control, usually one hormonal, one barrier, and if there's a contraindication, we request two barriers, and we accept abstinence as a means of birth control.
		The process is cumbersome not only for the patients, for the physicians, it's cumbersome for the FDA.  As Dr. Woodcock was saying, if you have a standard that is for ENL, we would hope that that standard could be applied to some of the other indications as well because at present what we have is the best that we can have, given the situation, but clearly more can be done.  Whatever is done for a particular indication, I would hope that it could extend at some point in time to the other indications as well so that all patients could benefit from an adequate safety monitoring program.
		Thank you.
		DR. McGUIRE:  Dr. Orkin.
		Thank you, Dr. Birnkrant.
		DR. ORKIN:  May I ask Debbie or Dr. Woodcock, do we know anything about these clubs -- the source of the thalidomide, for example, from Brazil or South America?  Is there any overlap that's known to other sources of what's sometimes called recreational drugs?
		DR. BIRNKRANT:  There doesn't appear to be an overlap.  Apparently the pills are not marked at all.  It could be confused with aspirin, acetaminophen.  They're completely unmarked, the buyers' club type of product.
		DR. ORKIN:  Do we actually know that in most instances that they are thalidomide?
		DR. BIRNKRANT:  They do get tested.  It gets tested periodically.
		DR. ORKIN:  But we don't know the source.
		DR. BIRNKRANT:  No, we don't know the source.
		DR. McGUIRE:  We have two more issues.  Let's once again focus on issue 6.  Are there recommendations other than those associated with restricted distribution the committee would make regarding ways to minimize the risk and safety concerns regarding this product?
		Yes, Dr. Miller.
		DR. MILLER:  I thought the suggestion yesterday about using an actual photo of an affected child was reasonable.  The photo in here doesn't come through very well, but certainly with technology, that could be done and that could be on every package.
		DR. McGUIRE:  I think that's the intention of the sponsor.
		MR. WILLIAMS:  It is.
		DR. McGUIRE:  It is.
		DR. MILLER:  The other question I had is in your packet I think they were 50-milligram tablets and there were 14 in a packet.  Is that correct?
		DR. WILLIAMS:  Yes.
		DR. MILLER:  If someone is taking even just 100 milligrams a day, that's only a week's supply.  If you're doling out packets, that would be a lot of packets to put in a drawer.
		DR. McGUIRE:  Fred, let's hold onto that one because we're going to talk about dosing.
		DR. MILLER:  Okay, I'm sorry.
		DR. McGUIRE:  And dosing I think is going to influence packaging.
		DR. MILLER:  The way they do it, okay.
		DR. McGUIRE:  Who is willing to walk away from item 6?  Everyone?
		(Laughter.)
		DR. McGUIRE:  Fine.
		Question 7.  Does the committee have any recommendations regarding appropriate dosing regimens?
		What we heard from Dr. Rea was that an initial or low dose would be 100 to 200 milligrams a day I think taken in the evening and the larger dose would be 300 to 400 milligrams a day.  Tom, did I recall what you said?
		DR. REA:  Yes, that is correct.  Usually we start at 100 or 200 milligrams a day as outpatients, and because of the sleepfulness that occurs in that, I'm reluctant to go to 300 or 400 milligrams a day.  I want to keep the sleepy people off the roads.
		DR. McGUIRE:  But you start with 100 to 200 milligrams a day in the evening as a single dose.
		DR. REA:  Yes.
		DR. McGUIRE:  And then if you increase that after the patient is accommodated to the drug or needs more drug, then you use 300 to 400.
		DR. REA:  I go to supplemental corticosteroids, yes.
		DR. McGUIRE:  Yes, Dr. Gelber.
		DR. GELBER:  My good friend, Dr. Rea, lives in L.A. and he hates freeways and I know he avoids them at all costs.  
		I use little higher doses at times.  Most of the historical studies started at 300 and 400 milligrams a day, and I certainly have generally used 100 or 200.  But I do see some patients that are not responding well or fully to 200 where I do go higher.  At times it's necessary to spread the dose out twice a day or three times a day, but generally a nighttime dose.  But I just thought I'd give you the broad view of how it's generally used.
		DR. McGUIRE:  So, there is something I missed there.  That the Bay Bridge is safer than the L.A. freeway?
		(Laughter.)
		DR. GELBER:  Tom just is afraid of freeways.
		DR. KILPATRICK:  May I ask these clinicians, Dr. McGuire, if body weight is any consideration and how did they arrive at these magical figures which are rounded off to 00s?  I'm coming at this as a nonclinician from a scientific point of view and it seems that, with respect, gentlemen, you've determined these figures from what source?  Just experience presumably, but this is not science.  This is clinical expertise.
		DR. McGUIRE:  Dr. Yoder.
		DR. YODER:  Just a comment about dosing.  I see the patients in a hospital setting primarily, and therefore we frequently use 300 to 400 milligrams a day, usually spread out in that situation.  Of course, as they respond, we will reduce it down to the lower doses.
		There is no strict calculation by body weight.  We do take that into consideration at times.  A very small Vietnamese lady obviously would be considered for a smaller dose.  This is based mainly on experience and the past history of knowing what works primarily.
		DR. McGUIRE:  Dr. Gelber?
		DR. GELBER:  I just want to insist that we're not entirely arbitrary.  Although there aren't a lot of dose comparison studies in the literature, what we generally do is use as small a dose as we can to control the systemic manifestations.
		DR. McGUIRE:  I think the agency wants the advisory committee to give you recommendations regarding appropriate dosing, and clearly the recommendations are going to come from the professional leprologists.  And I would leave it at that.
		DR. BERGFELD:  I would just like to state that what was handed to us yesterday by the company suggested that the acute dosing would be 100 to 200 milligrams a day at bedtime, and for severe ENL, 300 to 400 milligrams a day at bedtime, which is not dissimilar to what has been presented.
		DR. McGUIRE:  Now, the question that Dr. Miller raised a few minutes ago is how the packaging should reflect the recommended dosing, and that's sort of a technical issue but it needs to be read into our activities.
		Now, number 8 is really interesting.  What additional phase IV studies, if any, would the committee recommend be performed, e.g., clinical trials, pharmacokinetic studies, safety studies, special investigations? 
		Who would like to begin?
		DR. BERGFELD:  I would.  I have an opinion on this.  I believe that the phase IV study that is in the Philippines should be finished.  That's of utmost importance, and the data from that should be synthesized and hopefully this committee might see it, but realizing that we may not be the end group to make this decision.
		Under the pharmacokinetic studies, I strongly believe we have to understand more about the metabolites, the elimination, and the storage of this drug.  Specifically in that area, one might be looking for a metabolite that would work better with less of the side effects as has been stated today.
		Under the safety studies, there's no doubt in my mind the neuropathy has to be better worked out and recommendations for safety monitoring of patients who take this drug need to be put in place.  I will just say that and quit.
		DR. McGUIRE:  I would like to say something.  I'm not speaking for the sponsor, but I would guess that the sponsor would like to have a better product than thalidomide.  They would like to have a product with the efficacy and without the toxicity.  If I'm wrong, tell me.
		DR. THOMAS:  You're not wrong, sir.  You're absolutely right.  It's actually Steve Thomas again.
		As I alluded to all those many years ago -- actually yesterday morning -- our company is actively involved in the development of a range of analogs and derivatives of this compound which are being used to explore actually both the unique mechanisms of action of the parent compound, to provide us actually with extra information which will enable us, hopefully, to retain efficacy in specific indications, having engineered out a range of toxicities, obviously the most important of which is birth defects.
		That's not simple.  That's the holy grail of drug development.  It isn't actually going to happen overnight.  It is actually something which our company is completely committed to.  It is the future of our company, and there is nothing that -- our company and me personally would like to be able to provide to this advisory committee in the future is the successor actually to this compound.
		DR. McGUIRE:  I'm not surprised at what you said, but I'm still very happy to hear you say it.  
		I think what all of us would like to learn through your efforts is what the target was in the first place because I think we don't know how the drug works.  It's very likely people who are in your kind of business who will discover that.
		What else would we like the sponsor to do in the next several years?  Susan.
		MS. COHEN:  It's more the packaging.  Are home pregnancy tests going to be considered pregnancy tests, or is that going to be excluded?  Are these things expensive for people to do since you talked about the socioeconomic class of the people who are using thalidomide?  But I think you have to.  If you don't want home pregnancy tests, you're going to have to say that it has to be done at a certain, specific place.
		MR. WILLIAMS:  Yes, Ms. Cohen.  We recognize that it is important that these tests be administered in a professional setting.  We've had some discussion with the agency and I know the agency is seeking advice from other sources, including the American College of Obstetrics and Gynecology, as to the most effective and most practical forms of pregnancy tests.  We expect that in the final labeling that will be reflected.
		DR. McGUIRE:  Other comments from the committee?  Dr. Miller.
		DR. MILLER:  I would just like to bring up an issue that Dr. Duvic brought up yesterday about the name, that she had a concern that Synovir sounded like another antiviral.  And should the name be thalidomide or how would that be used?  That certainly should be discussed.
		DR. McGUIRE:  Yes.  We discussed that at our November meeting.  I felt very strongly that to some degree, foolishly, that thalidomide should be in big letters, and someone pointed out to me that I was practically the only one in there who knew what thalidomide really was because everybody else is of an age that they came on the scene after thalidomide.  So, it's not the brand name that we'd like for it to be.
		Nonetheless, I think there was a consensus that thalidomide should be associated with any other name that's used for it and there shouldn't be a whole family of names.  It should be very distinctive, very straightforward.
		Now, the question is its similarity to an antiviral, and I don't know how the sponsor wants to deal with that.  It does sound like it ought to be good for HSV.
		DR. WEINTRAUB:  Dr. McGuire, the company has been informed some weeks ago that the Nomenclature Committee had reviewed the name and not found it the right name to be used. 
		DR. McGUIRE:  It's the right name for another product.
		(Laughter.)
		DR. WEINTRAUB:  Perhaps.
		DR. KILPATRICK:  Dr. McGuire?
		DR. McGUIRE:  Yes, Jim.
		DR. KILPATRICK:  Following on Dr. Weintraub's comment and indeed to indicate my confusion, I'd like some clarification of where we are.  We started off with a set of questions from FDA which were specific to Synovir.  We proceeded to delete the word "Celgene" in front of thalidomide, so we were talking about generic thalidomide.  But we now appear to be talking as though we had already voted to recommend approval for Synovir as opposed to thalidomide by this company.  Can you clarify what the situation is?
		DR. McGUIRE:  Well, this sponsor is interested in Synovir and this committee is interested in thalidomide.  We asked the agency if we could drop the Celgene as a modifier of thalidomide.
		DR. LUMPKIN:  Dr. McGuire, do you want me to speak to that from our perspective?
		DR. McGUIRE:  Please.
		DR. LUMPKIN:  I think people need to remember from the agency perspective what we needed from the committee today was a basic medical policy kind of perspective.  Here the drug thalidomide -- and perhaps we ought not to say the generic drug thalidomide.  That takes us down a whole other road.  The general term for the drug thalidomide is one obviously that has a tremendous amount of baggage and it has a tremendous history that we've all talked about the last two days.  
		What we needed from the committee here was a perspective from the medical community of are we in 1997 at a point where, in the treatment of ENL, you feel that the benefits outweigh the risks, and I think we got that message from you as clinicians.
		I think people need to remember that generally, no matter what it is, when we come to a committee, even though the questions are often worded "would you approve such and such product," you generally only look at the clinical implications of it.  We, for example, don't bring manufacturing issues up, but the manufacturing procedures are part of the marketing application.  When we, at the end of the day, have to make the decision, we have to make the decision on not only whether the clinical data support the use of the product, but whether the company can manufacture it and several other different things that come into it.
		What we did not want to have happen today was for people to somehow confuse Celgene's thalidomide with the basic issue of thalidomide, which is what we wanted to get from you, and I think we did get that today.  At least that's what I'm taking away from here.
		Joe, is that a fair expression from your perspective as Chair?
		DR. McGUIRE:  I wouldn't have said it so well, but thank you.
		(Laughter.)
		DR. McGUIRE:  I think we've just fallen off the end of question 8 unless there is more to be added to question 8.
		DR. WOODCOCK:  Is the committee member's question satisfied, however, around Celgene thalidomide versus thalidomide?
		DR. KILPATRICK:  I'm very disturbed because I came prepared to answer the specific questions.  In mid-field the questions were changed.  I accordingly changed some of my recommendations, and as I've indicated, I don't know what this committee's recommendation to the FDA is now because I came to speak to a specific product being produced by a specific company and now I'm talking about something which will go back to historical data, to clinical experience, et cetera as opposed to the evidence put forward by a company specifically on their product.  And those two things are quite distinct in my mind.
		DR. WOODCOCK:  I think if you have opinions you'd like to contribute on that bridge between the historical data and the particular data on Celgene's thalidomide, we'd be interested to hear them.
		DR. KILPATRICK:  Well, I doubt, madam, that I'm competent to do so because I'm one of the few nonclinicians here, but apparently my colleagues are satisfied.
		DR. McGUIRE:  Before we adjourn the 47th meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee, I would really like to thank all of those who participated, especially those who spoke from the public sector.  All of us remember Cynthia Pearson.  You exhorted us to do the right thing.  You can let us know in a year or so if we did the right thing.
		I'd like to thank the senior members of the agency for being here and supporting us and smoothing over the rough spots.  
		Especially I'd like to thank the advisory committee and guests.  It has been two days that you might have spent doing something more fun, but thanks very much for helping.
		Did you want to have the last word, Janet?
		DR. WOODCOCK:  Yes.  I just simply want to add my thanks.  I know this is a set of extremely difficult issues, complicated by an extremely difficult data set.  But I really think this reflects the benefits of the process of getting all the voices of all the affected community and the experts to the table.  I really thank you for your courage and your openness in debating this issue and providing us with very good advice.  Thank you very much.
		DR. McGUIRE:  We're adjourned.
		(Whereupon, at 2:51 p.m., the committee was adjourned.)