1
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`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DERMATOLOGIC AND OPHTHALMIC DRUGS
`ADVISORY COMMITTEE
`
`Thursday,
`November 4, 1999
`
`Ballroom
`Hilton Hotel
`620 Perry Parkway
`Gaithersburg, Maryland
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`11923 Parklawn Drive, Suite 203
`Rockville, MD 20852
`(301) 881-8132
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`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DERMATOLOGIC AND OPHTHALMIC DRUGS
`ADVISORY COMMITTEE
`
`Thursday,
`November 4, 1999
`
`Ballroom
`Hilton Hotel
`620 Perry Parkway
`Gaithersburg, Maryland
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`11923 Parklawn Drive, Suite 203
`Rockville, MD 20852
`(301) 881-8132
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`2
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`IN ATTENDANCE:
`
`LYNN A. DRAKE, M.D., Acting Chairman
`Professor and Chairman
`Department of Dermatology
`University of Oklahoma Health Sciences Center
`619 N.E. 13th Street
`Oklahoma City, OK 73104
`
`TRACY RILEY, Executive Secretary
`Advisors and Consultants Staff
`Center for Drug Evaluation and Research
`Fishers Building, Room 1093
`5630 Fishers Lane, HFD-21
`Rockville, MD 20857
`
`Members
`
`JACQUELYN L. GOLDBERG, J.D., Consumer Representative
`Review Board Administrator
`Clinical Trials Management Branch
`NCI/NIH, Room 712
`6130 Executive Boulevard
`Bethesda, MD 20892
`
`ROBERT E. JORDON, M.D.
`J. Josey Professor of Derm & Ch
`Department of Dermatology, MSB 1.204
`6431 Fannin
`Houston, TX 77030
`
`HENRY LIM, M.D.
`Chairman, Department of Dermatology
`Henry Ford Hospital
`2799 West Grand Boulevard
`Detroit, MI 48202
`
`O. FRED MILLER, III, M.D.
`Director, Department of Dermatology
`Geisinger Medical Center
`North Academy Avenue
`Danville, PA 17822-1406
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`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`11923 Parklawn Drive, Suite 203
`Rockville, MD 20852
`(301) 881-8132
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`3
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`ROBERT S. STERN, M.D.
`Beth Israel Deaconness Medical Center
`330 Brookline Avenue
`Boston, MA 02215
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`FRIEDMAN & ASSOCIATES, COURT REPORTERS
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`4
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`IN ATTENDANCE:
`
`Special Government Employee Consultants
`
`ELIZABETH A. ABEL, M.D.
`Stanford University School of Medicine
`2500 Hospital Drive, Building 9
`Mountain View, CA 94040
`
`SUSAN COHEN, B.S.
`9814 Inglemere Drive
`Bethesda, MD 20817
`
`JOHN J. DiGIOVANNA, M.D.
`Dermatology Clinical Research Unit
`NIH Building 10, Room 9N228
`NIAMS/IRPH
`Bethesda, MD 20892-1820
`
`S. JAMES KILPATRICK, JR., Ph.D.
`Professor of Biostatistics, Medical College of Virginia
`Virginia Commonwealth University
`1101 East Marshall Street
`Sanger Hall, Room B-1-039-A
`Richmond, VA 23298-0032
`
`PHILIP T. LAVIN, Ph.D.
`Boston Biostatistics Research Foundation
`615 Concord Street
`Framingham, MA 01702
`
`JOSEPH McGUIRE, M.D.
`Carol Herzog Professor of Dermatology and Pediatrics
`Stanford University School of Medicine
`Department of Dermatology
`MSLS Building, Room P-204
`Stanford, CA 94305
`
`JOEL MINDEL, M.D., Ph.D.
`Director, Neuro-Ophthalmology
`Mount Sinai Medical Center
`Annenburg Building, 22-14
`Box 1183
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`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`11923 Parklawn Drive, Suite 203
`Rockville, MD 20852
`(301) 881-8132
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`5
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`New York, NY 10029-6574
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`FRIEDMAN & ASSOCIATES, COURT REPORTERS
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`6
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`IN ATTENDANCE:
`
`Guest Speakers
`
`DONALD BELSITO, M.D.
`Kansas University Medical Center
`6516 Aberdeen Road
`Mission Hills, KS 66208
`
`WILLIAM P. JORDAN, M.D.
`2004 Bremo Road
`Richmond, VA 23226
`
`ELIZABETH SHERERTZ, M.D.
`Faculty Services
`Wake Forest University School of Medicine
`Medical Center B
`Winston-Salem, NC 27157
`
`FDA Participants
`
`E. DENNIS BASHAW, Pharm.D.
`Senior Regulatory Reviewer
`
`DENISE COOK, M.D.
`Medical Officer, Division of Dermatologic
`and Dental Drug Products (DDDDP)
`
`ROBERT DeLAP, M.D.
`Director, Office of Drug Evaluation V
`
`LINDA GOSEY
`Microbiology Reviewer, DSPIDP
`
`R. SRINIVASAN, Ph.D.
`Team Leader, Biostatistics, Division of Biometrics III
`
`STEVEN THOMSON
`Mathematical Statistician, DOB III
`
`BRENDA VAUGHAN, M.D.
`Medical Officer, DDDDP
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
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`7
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`SUSAN WALKER, M.D.
`Team Leader, DDDDP
`
`JONATHAN WILKIN, M.D.
`Director, DDDDP
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`FRIEDMAN & ASSOCIATES, COURT REPORTERS
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`8
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`IN ATTENDANCE:
`
`Sponsor Participants, Hoechst Marion Roussel
`
`HANS-HEINRICH DONAUBAUER, Ph.D.
`Head of General Toxicology, HMR
`Drug Safety (Toxicology)
`Kastengrund
`65795 Hattersheim
`
`ALBERTO GRIGNOLO, Ph.D.
`Senior Vice President and General Manager
`PAREXEL International
`195 West Street
`Waltham, MA 02451
`
`PHILIP FLECKMAN, M.D.
`Associate Professor of Dermatology
`Division of Dermatology
`University of Washington
`Box 356524
`Seattle, WA 98195-6524
`
`ADITYA K. GUPTA, M.D.
`Associate Professor of Dermatology
`Division of Dermatology, Department of Medicine
`University of Toronto
`490 Wonderland Road South, Suite 6
`London, Ontario, Canada N6K 1L6
`
`RICHARD SCHER, M.D.
`Professor of Dermatology
`Department of Dermatology
`Clinical Pharmacology Unit
`College of Physicians and Surgeons of Columbia
`University
`161 Washington Avenue
`New York, NY 10032
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`11923 Parklawn Drive, Suite 203
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`9
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`C O N T E N T S
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`PAGE
`
`Open Session: NDA 21-022 Loprox (Ciclopirox
`Nail Lacquer) for Treatment of Onychomycosis
`
`Call to Order and Welcome
`
`Lynn A. Drake, M.D., Chair
`
`Conflict of Interest Statement
`
`Tracy Riley, Executive Secretary
`
`Overview of the Issues
`
`Jonathan Wilkin, M.D.
`
`Sponsor Presentation by Hoechst Marion Roussel
`
`Introduction
`
`Alberto Grignolo, Ph.D.
`
`Preclinical Data: Pharmacology/Toxicology and PK
`
`Hans-Heinrich Donaubauer, Ph.D.
`
`Clinical Efficacy Data
`
`Richard Scher, M.D.
`
`Clinical Safety Data
`
`Philip Fleckman, M.D.
`
`Benefit/Risk Evaluations
`
`Aditya K. Gupta, M.D.
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`FRIEDMAN & ASSOCIATES, COURT REPORTERS
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`9
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`11
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`14
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`18
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`23
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`26
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`42
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`56
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`10
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`C O N T E N T S
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`PAGE
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`FDA Presentation
`
`Clinical Considerations
`
`Brenda Vaughan, M.D.
`
`76, 90, 93
`
`Statistical Considerations
`
`Steven Thomson
`
`Biopharmaceutics
`
`E. Dennis Bashaw, Pharm.D.
`
`Clinical Microbiology
`
`Linda Gosey, Ph.D.
`
`Questions for the Committee
`
`Jonathan Wilkin, M.D.
`
`Committee Discussion
`
`Vote on Questions
`
`79, 92
`
`96
`
`102
`
`106
`
`113
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`153
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`11
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`C O N T E N T S
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`PAGE
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`172
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`174
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`176
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`179
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`210
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`226
`
`Open Session: Clinical Trials Design
`Issues for Hand Dermatitis
`
`Call to Order and Welcome
`
`Lynn A. Drake, M.D., Chair
`
`Conflict of Interest Statement
`
`Tracy Riley, Executive Secretary
`
`Introductory Remarks
`
`Jonathan Wilkin, M.D.
`
`Importance of Hand Dermatitis Epidemiology
`(Prevalence) and Quality of Life Issues
`
`Donald Belsito, M.D.
`
`Evaluation of the Patient with Hand Dermatitis:
`Elements of the Workup: Presentations of Hand
`Dermatitis, Clinical Case Photos, and How
`Subtype of Hand Dermatitis Was Diagnosed
`
`William P. Jordan, M.D.
`
`Current Therapy of Hand Dermatitis
`
`Elizabeth Sherertz, M.D.
`
`Questions for the Committee
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
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`12
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`Jonathan Wilkin, M.D.
`
`Committee Discussion
`
`238
`
`240
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`13
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`P R O C E E D I N G S
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`(8:35 a.m.)
`
`DR. DRAKE: Good morning. I would like to
`
`call the 51st meeting of the Dermatologic and Ophthalmic
`
`Drugs Advisory Committee meeting to order. One of the
`
`first things I would like to do is have our
`
`distinguished table introduce themselves, but as part of
`
`that, may I please remind everybody to speak directly
`
`into the mike. These meetings are recorded. The agency
`
`uses the comments carefully and reviews them, and so
`
`they want to have an accurate transcript that reflects
`
`the sense of the meeting.
`
`My name is Lynn Drake. I'm professor and
`
`chairman of the Department of Dermatology at the
`
`University of Oklahoma Health Sciences Center, and I'm a
`
`senior lecturer at Harvard Medical School in the
`
`Department of Dermatology.
`
`With that, I would like to introduce first
`
`our executive secretary. Tracy, would you like to
`
`start? Then we'll start down there.
`
`MS. RILEY: Thank you. Good morning. My
`
`name is Tracy Riley. I'm the executive secretary of the
`
`Dermatologic and Ophthalmic Drugs Advisory Committee.
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`DR. KILPATRICK: Good morning. Jim
`
`Kilpatrick, biostatistics, Medical College of Virginia.
`
`DR. MINDEL: Joel Mindel, Departments of
`
`Ophthalmology and Pharmacology, Mt. Sinai Medical
`
`School, New York.
`
`DR. ABEL: Elizabeth Abel, clinical professor
`
`of dermatology at Stanford, and in private practice of
`
`dermatology in Mountain View, California.
`
`DR. JORDON: Robert Jordon, chairman of the
`
`Department of Dermatology, University of Texas Medical
`
`School, Houston.
`
`MR. THOMSON: Steve Thomson, Division of
`
`Biometrics III, FDA.
`
`DR. SRINIVASAN: Dr. Srinivasan,
`
`biostatistics team leader, Division of Biometrics III.
`
`DR. VAUGHAN: Brenda Vaughan, Division of
`
`Dermatologic and Dental Drug Products, FDA.
`
`DR. WALKER: Susan Walker, clinical team
`
`leader, Division of Dermatologic and Dental Drug
`
`Products.
`
`DR. WILKIN: Jonathan Wilkin, Director,
`
`Division of Dermatologic and Dental Drug Products.
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`DR. DeLAP: Robert DeLap, Director, Office of
`
`Drug Evaluation V, FDA.
`
`DR. DRAKE: And then I would like to move --
`
`I'm going to interrupt and go this way. I wanted to
`
`introduce our distinguished panelist, my predecessor,
`
`Dr. McGuire, who chaired this committee just prior to
`
`me, and then we'll go that way.
`
`DR. McGUIRE: I'm Joe McGuire, Dermatology
`
`and Pediatrics, Stanford.
`
`DR. LIM: I'm Henry Lim, chairman of
`
`dermatology at Henry Ford Hospital, Detroit, Michigan.
`
`MS. GOLDBERG: Jackie Goldberg, consumer
`
`representative.
`
`DR. DiGIOVANNA: John DiGiovanna. I'm
`
`director of the Division of Dermatopharmacology at Brown
`
`University School of Medicine, and an adjunct
`
`investigator at NIH.
`
`DR. MILLER: Fred Miller, Director of
`
`Dermatology, Geisinger Clinic, Danville, Pennsylvania.
`
`DR. STERN: I'm Rob Stern. I'm professor of
`
`dermatology at Harvard Medical School at the Beth Israel
`
`Deaconess Medical Center.
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`MS. COHEN: I'm Susan Cohen, and I'm a
`
`consumer member.
`
`DR. DRAKE: Thank you very much.
`
`I will now turn this over to Ms. Riley for
`
`our conflict of interest statement.
`
`MS. RILEY: Thank you. The following
`
`announcement addresses the issue of conflict of interest
`
`with regard to this meeting, and is made a part of the
`
`record to preclude even the appearance of such at this
`
`meeting.
`
`Based on the submitted agenda and information
`
`provided by the participants, the agency has determined
`
`that all reported interests in firms regulated by the
`
`Center for Drug Evaluation and Research present no
`
`potential for a conflict of interest at this meeting,
`
`with the following exceptions.
`
`Dr. Philip Lavin has been excluded from
`
`participation in today's discussion and vote concerning
`
`Loprox. In addition, in accordance with 18 U.S. Code
`
`208(b), a full waiver has been granted to Dr. Joel
`
`Mindel. A copy of this waiver statement may be obtained
`
`by submitting a written request to FDA's Freedom of
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`17
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`Information Office, located in Room 12A-30 of the
`
`Parklawn Building.
`
`We would also like to disclose for the record
`
`that Dr. Lynn Drake has passed unrelated interests in
`
`Janssen and Novartis, which should not constitute
`
`financial interests within the meaning of 18 U.S. Code
`
`208(a), but which could create the appearance of a
`
`conflict. In addition, Dr. Robert Stern has passed
`
`unrelated interests in Janssen which does not constitute
`
`financial interest within the meaning of 18 U.S. Code
`
`208(a), but which could create the appearance of a
`
`conflict.
`
`The agency has determined, notwithstanding
`
`these interests, that the interest of the government in
`
`their participation outweighs the concern that the
`
`integrity of the agent's programs and operations may be
`
`questioned. Therefore, Drs. Drake and Stern may
`
`participate in today's discussions with full voting
`
`privileges.
`
`Further, several of our committee members
`
`have had interests relating to Loprox that we believe
`
`should be disclosed. FDA believes that it is important
`
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`18
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`to acknowledge these participants' involvement so that
`
`their participation can be objectively evaluated.
`
`Dr. Lynn Drake's former employer was involved
`
`in a past study of Loprox. While Dr. Drake was listed
`
`as a subinvestigator on the study, she was not directly
`
`involved. Dr. Fred Miller served as principal
`
`investigator on Loprox Protocol Number 211.
`
`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 of fairness that they address any
`
`current or previous financial involvement with any firm
`
`whose products they may wish to comment upon.
`
`Thank you.
`
`DR. DRAKE: Thank you, Ms. Riley.
`
`I'm going to ask Dr. Jonathan Wilkin to give
`
`us an overview of the issues regarding this meeting.
`
`DR. WILKIN: Thank you, Dr. Drake.
`
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`19
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`Of course, crucial to the discussion today is
`
`ultimately the recommendation of the committee either
`
`for approval or against approval of the Loprox product,
`
`and in thinking about the risk/benefit relationship to
`
`help the committee to get to that decision, one can
`
`think about what the primary efficacy variable should
`
`be.
`
`If we could look at the first slide, please.
`
`The sponsor had a teleconference with the FDA
`
`on October 25th, 1993. This is the heading of, I
`
`believe, the sponsor's meeting minutes.
`
`Next slide, please.
`
`At the bottom of the first page, they
`
`captured the question that they posed to the FDA: "Will
`
`the FDA approve a drug which controls but does not
`
`necessarily cure toenail onychomycosis?" And the FDA
`
`response in 1993 was: "The FDA's defining treatment
`
`success for all topical and systemic agents is 100
`
`percent clearing of the nail plate, absence of clinical
`
`signs. Complete cure is being defined as mycological
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`cure, negative KOH and culture, and 100 percent clearing
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`of clinical signs maintained for at least three to six
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`20
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`months post-treatment." Then they had in parentheses,
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`"The division is leaning more toward six months.
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`Control of disease -- that is, partial improvement -- is
`
`not an option."
`
`So this was October of 1993, and those of us
`
`who are in the division now were not in the predecessor
`
`of our division in 1993, so it's hard for me to actually
`
`go through the thinking of the FDA group that gave this
`
`advice. But I do know folks that write about what
`
`should be the efficacy endpoint for onychomycosis today,
`
`and there are some folks who think of onychomycosis as
`
`an infectious disease, sort of the model of pneumonia,
`
`and the goal is one completely eradicates the pneumonia.
`
` Partially treating a pneumonia is probably not a great
`
`idea.
`
`So we had a very nice meeting -- next slide,
`
`please -- of the Dermatologic Drugs Advisory Committee
`
`in 1994, and the focus of that meeting, the centerpiece
`
`of that meeting -- and the discussion lasted over two
`
`days -- we discussed regulatory issues and clinical
`
`trials for onychomycosis. We literally had nine pages
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`of questions that we posed to the committee and received
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`21
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`answers back on.
`
`Next slide, please.
`
`One of the recommendations of the committee
`
`was that treatment success be measured by clinical
`
`parameters -- in other words, a clear nail bed -- that
`
`normal appearance of the nail is what patients want, and
`
`the clinical endpoint is a cleared nail. But I think it
`
`was very helpful for us before closing that meeting to
`
`ask another question.
`
`Next slide, please.
`
`We asked, is a lesser indication, namely
`
`clinical improvement without cure, acceptable for
`
`therapies without any significant risk? The committee
`
`generally agreed. The answer to that was yes. The
`
`longer statement is there should be measures of efficacy
`
`that are less rigid for products that are safer, and I
`
`think it embraced the view that onychomycosis is
`
`infectious, it's true, but it's not an infection in the
`
`same way that pneumococcal pneumonia is, where one has
`
`the chance for a complete eradication, that many of the
`
`patients who have toenail onychomycosis, it's going to
`
`be something that's with them on and off through life.
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`22
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`It's a very difficult entity to treat.
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`So these are the things that the committee
`
`will be thinking about in terms of risk/benefit today
`
`when you make your recommendation to us. In addition to
`
`the recommendation for approval or not approval, we'll
`
`be very interested in what you'll have to tell us
`
`regarding the labeling, and we have some specific areas
`
`that we would like some feedback on, and I would like to
`
`mention them now before the sponsor and the FDA give
`
`their presentations so you can actually be thinking
`
`about these topics while you hear the discussion.
`
`Next slide, please.
`
`We would like to have your input on the
`
`evidence for penetration of ciclopirox through the nail
`
`to the nail bed. Remember that this is a nail bed
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`disorder. The use of systemic treatment for
`
`onychomycosis, would it be appropriate to combine this
`
`topical therapy with that, with one of those modalities?
`
` The sponsor excluded several groups from studies, and
`
`we'll list those. These include folks who had
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`involvement back to the lunula, insulin-dependent
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`diabetics, and others. We'll talk about those groups.
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`They provided for concomitant tinea pedis
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`therapy. Over half of the patients in the active group
`
`and in the control group received concomitant antifungal
`
`therapy for tinea pedis at some time during the trial,
`
`and there was periodic trimming and debridement by the
`
`investigators, and emery boards and alcohol swabs were
`
`issued to the patients to remove material from the nail
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`site. So these are the things that we'll be interested
`
`in hearing from the committee later this morning.
`
`Thank you.
`
`DR. DRAKE: Thank you, Dr. Wilkin.
`
`We are now at the point of the meeting where
`
`we have time allocated for the open public hearing.
`
`May I have the lights up a little bit, do you
`
`think? That would be helpful right now.
`
`I would ask if there's anybody who has a
`
`comment that they wish to make. If so, they must
`
`approach the mike, identify themselves and any
`
`affiliation or financial interest or support that they
`
`might have in the products under consideration.
`
`(No response.)
`
`DR. DRAKE: Seeing none and hearing none,
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`we'll move then to the active part of the meeting. This
`
`meeting, of course, I may have neglected to identify
`
`this morning, the session is on NDA 21-022, Loprox, or
`
`otherwise known as ciclopirox nail lacquer for the
`
`treatment of onychomycosis.
`
`I think we'll then move to the sponsor
`
`presentation, which is Hoechst Marion Roussel.
`
`We actually have a little extra time that we
`
`can use either for presentation and/or discussion since
`
`the open public hearing was so brief. Do you suppose
`
`that's a comment on my chairmanship? We just saved 30
`
`minutes.
`
`Anyway, we will move to the sponsor, and I
`
`believe that Alberto -- is it Granola?
`
`DR. GRIGNOLO: Grignolo.
`
`DR. DRAKE: Grignolo. Dr. Grignolo, welcome.
`
`DR. GRIGNOLO: Thank you very much.
`
`Dr. Drake, members of the committee, Ms.
`
`Riley --
`
`DR. DRAKE: I guess the mike is not working?
`
`DR. GRIGNOLO: Thank you for your patience.
`
`Dr. Drake, members of the committee, Ms.
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`25
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`Riley, Dr. Wilkin, members of the division, my name is
`
`Alberto Grignolo. I am Senior Vice President of
`
`Worldwide Regulatory Affairs at Parexel International
`
`Corporation, a contract research organization. Parexel
`
`is the agent for the sponsor, Hoechst Marion Roussel,
`
`for NDA 21-022, ciclopirox nail lacquer 8 percent. I
`
`will provide a very brief introduction to our
`
`presentation today and then turn the podium over to my
`
`colleagues.
`
`We have previously provided to the committee
`
`a succinct briefing document for distribution to you and
`
`to the division. The purpose of our presentation today
`
`is to highlight the key elements of NDA 21-022, with
`
`emphasis on the clinical efficacy and safety of
`
`ciclopirox nail lacquer 8 percent. A copy of our
`
`presentation has been provided to the executive
`
`secretary for distribution to you.
`
`Next slide.
`
`Following my brief introduction, the
`
`sponsor's presenters will address the following topics:
`
` nail penetration studies; efficacy in U.S. clinical
`
`trials; clinical safety; and benefit/risk
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`26
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`considerations. We respectfully request that members of
`
`the committee hold substantive questions until the end
`
`of the sponsor's presentation, although we do welcome at
`
`any time your questions seeking clarification. Thank
`
`you.
`
`Next slide.
`
`Onychomycosis is a fungal disease of the nail
`
`mostly caused by dermatophytes. The most common form is
`
`distal subungual onychomycosis. Onychomycosis is not
`
`only a cosmetic problem but can impair social,
`
`professional, and recreational activity, and subjects
`
`frequently experience pain, discomfort, and problems
`
`with simple daily activities, such as walking. Even
`
`when asymptomatic, the onychomycotic nail constitutes a
`
`reservoir of fungus that can cause repeated infection of
`
`the skin.
`
`Systemic prescription therapies for
`
`onychomycosis have been approved by the FDA and are
`
`marketed in the United States, but they do have certain
`
`limitations, mainly side effects and drug interactions.
`
` Therefore, a safe and effective topical treatment would
`
`fulfill an unmet medical need.
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`Next slide.
`
`To assure successful topical therapy of the
`
`onychomycotic nail, a drug has to meet the following
`
`criteria, in our opinion: an antifungal agent that is
`
`highly effective against onychomycosis-causing strains
`
`-- for example, T. rubrum, T. mentagrophytes, and E.
`
`floccosum -- a vehicle that guarantees the adhesion of
`
`the formulation to the nail, and a system which provides
`
`a high concentration gradient and allows optimal reuse
`
`of the drug; a drug substance that penetrates the nail
`
`plate; and a fungicidal drug concentration at the site
`
`of infection.
`
`Next slide.
`
`Ciclopirox nail lacquer 8 percent meets these
`
`basic criteria, as the sponsor has demonstrated in the
`
`NDA. It is a synthetic broad-spectrum antifungal agent
`
`which is fungicidal against T. rubrum, T.
`
`mentagrophytes, and E. floccosum. It provides
`
`transungual delivery through proper adherence to the
`
`nail and release of the drug. It has been shown to
`
`penetrate human nails in vivo. It provides effective
`
`drug concentrations at all nail levels.
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`28
`
`Next slide.
`
`The sponsor's approach to the development
`
`program of ciclopirox nail lacquer 8 percent has focused
`
`primarily on clinical development, since several
`
`ciclopirox formulations are already approved for
`
`marketing in the United States for the treatment of a
`
`number of fungal infections. Specifically, the drug is
`
`marketed in the U.S. as a cream and a lotion, and, in
`
`addition, a gel formulation of ciclopirox has recently
`
`been approved by the FDA.
`
`In addition, ciclopirox nail lacquer has been
`
`approved and is marketed in 41 countries around the
`
`world, including nine European countries.
`
`Next slide.
`
`The objective of the clinical development
`
`program has been to demonstrate that ciclopirox nail
`
`lacquer 8 percent is an effective and safe treatment of
`
`mild to moderate onychomycosis without lunula
`
`involvement due to T. rubrum, T. mentagrophytes, and E.
`
`floccosum. The clinical development program has
`
`comprised a series of Phase I, Phase II, and Phase III
`
`clinical trials conducted in the United States. In
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`
`addition, a number of clinical trials have been
`
`conducted in Europe and have provided a great deal of
`
`safety information. The data from these trials will be
`
`presented by my colleagues.
`
`Next slide.
`
`The sponsor believes and has documented in
`
`the New Drug Application that ciclopirox nail lacquer 8
`
`percent is an effective topical treatment of
`
`onychomycosis compared to vehicle when administered over
`
`48 weeks. The results presented in the NDA show that
`
`ciclopirox nail lacquer 8 percent has an excellent
`
`safety profile.
`
`Ciclopirox nail lacquer 8 percent may be
`
`somewhat less effective than systemic therapies of
`
`onychomycosis, though no direct comparative trials have
`
`been conducted by the sponsor. But its excellent safety
`
`profile makes it an important alternative to systemic
`
`agents. This is especially true when physiological
`
`state -- for example, advanced age -- systemic diseases,
`
`interactions with commonly used drugs, and patient
`
`preference preclude the use of systemic antifungals.
`
`Next slide.
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`FRIEDMAN & ASSOCIATES, COURT REPORTERS
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`30
`
`In closing, today's presenters on behalf of
`
`the sponsor include Dr. Hans Donaubauer, head of General
`
`Toxicology, Hoechst Marion Roussel, Frankfurt, Germany;
`
`Dr. Richard Scher, Department of Dermatology, Columbia
`
`University, New York City; Dr. Philip Fleckman, Division
`
`of Dermatology, University of Washington in Seattle; and
`
`Dr. Aditya Gupta, Division of Dermatology, University of
`
`Toronto, Canada.
`
`The sponsor believes that the data presented
`
`in the NDA are consistent with the expectations of the
`
`division and of this advisory committee, as well as with
`
`established criteria for the approval of
`
`antionychomycotic agents.
`
`We thank the members of the committee for
`
`this opportunity to present NDA 21-022. I would now
`
`like to turn the podium over to Dr. Donaubauer for our
`
`first presentation. Thank you.
`
`DR. DONAUBAUER: Good morning. My name is
`
`Hans Donaubauer. The title of my presentation has been
`
`changed, and it now reads: "Ciclopirox Nail Lacquer 8
`
`Percent Nail Penetration."
`
`Ciclopirox is an antifungal drug which is
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`31
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`already approved in three dermatologic products in the
`
`United States.
`
`Next slide, please.
`
`It is a broad spectrum antimicrotic which is
`
`fungicidal against pathogenic dermatophytes, yeasts and
`
`molds. For most of the organisms tested, including the
`
`dermatophytes causing onychomycosis, highlighted in this
`
`slide in yellow, the minimum inhibitory concentration is
`
`between 0.5 and 4 micrograms per milliliter. Ciclopirox
`
`is mycologically effective, but is it penetrating the
`
`nail plate?
`
`Next slide, please.
`
`After repeated application of ciclopirox nail
`
`lacquer 8 percent in vivo to toenails and fingernails of
`
`healthy volunteers, the nail was sectioned into four
`
`equal layers, and the concentration of ciclopirox in
`
`each of the layers was far above the efficacious
`
`concentration. Layer 1 is the outer surface layer,
`
`layer 4 the innermost layer. The application time was 7
`
`to 45 days. Increased concentrations of ciclopirox
`
`occurred over time, and steady state was approached
`
`after approximately 30 days of continuous treatment. In
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`32
`
`yellow are the concentrations in the innermost layer,
`
`which is a part of the nail bed.
`
`Next slide, please.
`
`For fingernails, a similar picture was
`
`obtained. Again, ciclopirox increased over time, and
`
`concentrations in all layers by far exceeded the minimum
`
`fungicidal concentrations. Thus, as shown, ciclopirox
`
`penetrates the healthy nail plate. But what about the
`
`diseased nail?
`
`Next slide, please.
`
`This was studied by the penetration of
`
`labeled ciclopirox applied once to 15 nails removed for
`
`onychomycosis. The nail plates were sectioned into four
`
`layers, and the concentrations measured were 29
`
`micrograms per gram, which is approximately seven times
`
`the minimum fungicidal concentration in the innermost
`
`layer. This level was achieved even though measurements
`
`were made only 24 hours after a single application. As
`
`shown in the previous slides, much higher concentrations
`
`are reached with repeated applications. Ciclopirox
`
`penetrates the diseased nail. In addition, it is also
`
`known from in vitro studies that ciclopirox penetrates
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`FRIEDMAN & ASSOCIATES, COURT REPORTERS
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`33
`
`epidermal keratin. Therefore, penetration can be
`
`expected to occur through the keratin which may be built
`
`up beneath the diseased nail.
`
`Next slide, please.
`
`As the drug clearly penetrates
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