1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

 

 

 

 

                NONPRESCRIPTION DRUGS ADVISORY COMMITTEE

 

                IN JOINT SESSION WITH THE  DERMATOLOGIC

 

                 AND OPHTHALMIC DRUGS ADVISORY COMMITTEE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                         Thursday, May 6, 2004

 

                               8:00 a.m.

 

 

 

             Advisors and Consultants Staff Conference Room

                           5630 Fishers Lane

                          Rockville, Maryland

                                                                 2

 

                              PARTICIPANTS

 

      Louis R. Cantilena, Jr., M.D., Ph.D., Chair

      LCDR Dornette Spell-LeSane, MHA, NP-C, Executive

      Secretary

 

      DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY

      COMMITTEE MEMBERS

 

                Roselyn E. Epps, M.D.

                Robert Katz, M.D.

                Paula Knudson (Consumer Rep)

                Peter A. Kresel, M.B.A. (Industry Rep)

                Sharon S. Raimer, M.D.

                Eileen W. Ringel, M.D.

                Jimmy D. Schmidt, M.D.

                Thomas R. Ten Have, Ph.D.

                Elizabeth S. Whitmore, M.D.

                Michael G. Wilkerson, M.D.

 

      NONPRESCRIPTION DRUGS ADVISORY COMMITTEE MEMBERS

 

                Michael C. Alfano, D.M.D., Ph.D.

                  (Industry Rep)

                Neal L. Benowitz, M.D.

                Leslie Clapp, M.D.

                Frank F. Davidoff, M.D.

                Jack E. Fincham, Ph.D.

                Y.W. Francis Lam, Pharm.D.

                Sonia Patten, Ph.D. (Consumer Rep)

                Alastair Wood, M.D.

      CONSULTANTS (VOTING)

 

                Alan Bisno, M.D.

                Mahmoud Ghannoum, M.Sc., Ph.D.

      FDA

 

                Jonca Bull, M.D.

                Charles Ganley, M.D.

                Jonathan Wilkin, M.D.

                                                                 3

 

                            C O N T E N T S

 

                                                              PAGE

 

      Call to Order and Introductions:

                Louis R. Cantilena, Jr., M.D., Ph.D.             5

      Conflict of Interest Statement:

                LCDR Dornette Spell-LeSane, MHA, NP-C            8

 

      Welcome and Introductory Remarks:

                Charles Ganley, M.D.                            11

 

                      Efficacy and Labeling Issues

                 for the Over-the-Counter Drug Products

                    Used in Treatment of tinea pedis

                  in Patients 12 years of Age and Over

 

      FDA Presentation

 

      Natural History of tinea pedis and Dermatophyte

         Infections:

                Joseph Porres, M.D., Ph.D.                      12

 

      Study Design and Efficacy Results for tinea pedis

         Clinical Trials (Rx and OTC):

                Kathleen Fritsch, Ph.D.                         44

 

      History and Overview of OTC Topical Antifungal Drug

         Products Monograph:

                Houda Mahayni, Ph.D.                            67

 

      Topical Antifungal Drug Product Labeling:

                Daiva Shetty, M.D.                              94

 

      Infectious Disease Complications of tinea pedis:

                Alan Bisno, M.D.                               127

 

      Microbiology and Dermatophyte Resistance Related to

        the Treatment of tinea pedis:

                Mahmoud Ghannoum, M.Sc., Ph.D.                 154

 

      Committee Discussion                                     178

                                                                 4

 

                      C O N T E N T S (Continued)

 

      Open Public Hearing

 

      Consumer Healthcare Products Association:

                Doug Bierer, Ph.D.                             193

                Boni E. Elewski, M.D.                          194

                Doug Bierer, Ph.D.                             214

 

      Schering-Plough:

                John Clayton, M.D.                             220

 

      Novartis:

                Helmut H. Albrecht, M.D., M.S., FFPM           231

 

      Committee Discussion                                     299

 

                                                                 5

 

  1                      P R O C E E D I N G S

 

  2                 Call to Order and Introductions

 

  3             DR. CANTILENA:  Good morning.  I am Louis

 

  4   Cantilena.  I am Director of the Division of

 

  5   Clinical Pharmacology and Medical Toxicology at the

 

  6   Uniformed Services University of the Health

 

  7   Sciences in Bethesda, Maryland.  I am going to be

 

  8   chairing this joint session of the Nonprescription

 

  9   Drugs Advisory Committee and the Dermatologic and

 

 10   Ophthalmic Drugs Advisory Committee held here in

 

 11   Rockville.

 

 12             Before we get started with the agenda and

 

 13   the conflict of interest statement, I would like to

 

 14   go around the room and have everyone introduce

 

 15   themselves and state their affiliation.  We can

 

 16   start to my right since there are more filled seats

 

 17   to the right than left.

 

 18             DR. RINGEL:  I am Dr. Eileen Ringel.  I am

 

 19   a dermatologist in Waterville, Maine and loosely

 

 20   affiliated with Mary Hitchcock Medical Center.

 

 21             DR. LAM:  Francis Lam from the University

 

 22   of Texas of Texas Health Science Center at San

 

                                                                 6

 

  1   Antonio, a member of NDAC.

 

  2             DR. PATTEN:  Sonia Patten.  I am consumer

 

  3   representative on NDAC.  I am an anthropologist on

 

  4   faculty at Macalester College in St. Paul,

 

  5   Minnesota.

 

  6             DR. WILKERSON:  Michael Wilkerson, Tulsa,

 

  7   Oklahoma, Hillcrest Healthcare Systems.

 

  8             DR. RAIMER:  Sharon Raimer, dermatologist,

 

  9   University of Texas in Galveston.

 

 10             DR. EPPS:  Roselyn Epps, Chief, Division

 

 11   of Dermatology, Children's National Medical Center,

 

 12   Washington, D.C.

 

 13             DR. BENOWITZ:  I am Neal Benowitz from

 

 14   U.C., San Francisco, internal medicine, clinical

 

 15   pharmacology, medical toxicology, and on the

 

 16   Nonprescription Drug Committee.

 

 17             MS. KNUDSON:  Paula Knudson on the

 

 18   Dermatology Committee as the community

 

 19   representative.  I am an IRB administrator.

 

 20             MR. KRESEL:  I am Peter A. Kresel, Senior

 

 21   Vice President of Global Regulatory Affairs with

 

 22   Allergan in Irvine, California.  I am the industry

 

                                                                 7

 

  1   representative for the Dermatologic and Ophthalmic

 

  2   Drugs Advisory Committee.

 

  3             DR. ALFANO:  I am Michael C. Alfano, Dean,

 

  4   College of Dentistry at New York University.

 

  5             DR. TEN HAVE:  Tom Ten Have, biostatistics

 

  6   and epidemiology at the University of Pennsylvania.

 

  7             DR. WOOD:  I am Alastair Wood from

 

  8   Vanderbilt.

 

  9             DR. GANLEY:  I am Charlie Ganley, Director

 

 10   of Over-the-Counter Drugs at FDA.

 

 11             DR. WILKIN:  I am Jonathan Wilkin,

 

 12   Director of the Division of Dermatologic and Dental

 

 13   Drug Products, FDA.

 

 14             DR. KATZ:  I am Robert Katz,

 

 15   dermatologist, Rockville, Maryland and Clinical

 

 16   Assistant Professor of Medicine at Georgetown.  I

 

 17   am part of the FDA Advisory Committee.

 

 18             DR. SCHMIDT:  I am Jimmy Schmidt from

 

 19   Houston, Texas.

 

 20             DR. DAVIDOFF:  I am Frank Davidoff.  I am

 

 21   on NDAC.  I am an internist and Editor Emeritus of

 

 22   the Annals of Internal Medicine.

 

                                                                 8

 

  1             DR. WHITMORE:  Beth Whitmore.  I am a

 

  2   dermatologist in private practice, Wheaton,

 

  3   Illinois.

 

  4             LCDR SPELL-LeSANE:  Dornette Spell-Lesane,

 

  5   Acting Executive Secretary for NDAC.

 

  6             DR. CANTILENA:  Did we miss anyone?

 

  7             Go ahead, Dr. Bisno.

 

  8             DR. BISNO:  I am Alan Bisno, Professor

 

  9   Emeritus of Internal Medicine, University of Miami,

 

 10   School of Medicine.

 

 11             DR. CANTILENA:  Thank you.

 

 12             Dornette will read the conflict of

 

 13   interest statement for this meeting.

 

 14                  Conflict of Interest Statement

 

 15             LCDR SPELL-LeSANE:  Good morning.  The

 

 16   following announcement addresses the issue of

 

 17   conflict of interest with respect to this meeting

 

 18   and is made a part of the record to preclude even

 

 19   the appearance of such at this meeting.

 

 20             Based on the agenda, it has been

 

 21   determined that the topics of today's meeting are

 

 22   issues of broad applicability and there are no

 

                                                                 9

 

  1   products being approved at this meeting.  Unlike

 

  2   issues before a committee in which a particular

 

  3   product is discussed, issues of broader

 

  4   applicability involve many industrial sponsors and

 

  5   academic institutions.

 

  6             All Special Government Employees have been

 

  7   screened for their financial interests as they may

 

  8   apply to the general topics at hand.  To determine

 

  9   if any conflict of interest existed, the Agency has

 

 10   reviewed the agenda and all relevant financial

 

 11   interests reported by the meeting participants.

 

 12             The Food and Drug Administration has

 

 13   granted general matters waivers to the Special

 

 14   Government Employees participating in this meeting

 

 15   who require a waiver under Title 18, United States

 

 16   Code, Section 208.

 

 17             A copy of the waiver statements may be

 

 18   obtained by submitting a written request to the

 

 19   Agency's Freedom of Information Office, Room 12A-30

 

 20   of the Parklawn Building.

 

 21             Because general topics impact so many

 

 22   entities, it is not prudent to recite all potential

 

                                                                10

 

  1   conflicts of interest as they apply to each member,

 

  2   consultant, and guest speaker.

 

  3             FDA acknowledges that there may be

 

  4   potential conflicts of interest, but because of the

 

  5   general nature of the discussion before the

 

  6   committee, these potential conflicts are mitigated.

 

  7             With respect to FDA's invited industry

 

  8   representatives, we would like to disclose that Mr.

 

  9   Peter Kresel and Dr. Michael Alfano are

 

 10   participating in this meeting as industry

 

 11   representatives acting on behalf of regulated

 

 12   industry.  Mr. Kresel is employed by Allergan, Dr.

 

 13   Alfano is the Dean of College of Dentistry at New

 

 14   York University.

 

 15             In the event that the discussions involve

 

 16   any other products or firms not already on the

 

 17   agenda for which FDA participants have a financial

 

 18   interest, the participants' involvement and their

 

 19   exclusion will be noted for the record.

 

 20             With respect to all other participants, we

 

 21   ask in the interest of fairness that they address

 

 22   any current or previous financial involvement with

 

                                                                11

 

  1   any firm whose product they may wish to comment

 

  2   upon.

 

  3             Thank you.

 

  4             DR. CANTILENA:  Thank you, Dornette.

 

  5             Now we will have our kickoff from Dr.

 

  6   Charlie Ganley of FDA.

 

  7                Welcome and Introductory Comments

 

  8             DR. GANLEY:  Thank you.  I am just going

 

  9   to say a few words.

 

 10             First, I wanted to thank the members of

 

 11   the Nonprescription Drugs Advisory Committee and

 

 12   the Dermatologic and Ophthalmic Drugs Advisory

 

 13   Committee for participating in this discussion.

 

 14             Today, we are going to talk about tinea

 

 15   pedis.  It is not a high profile disease, but it

 

 16   does affect millions of people in the United States

 

 17   each year, and it is important to those individuals

 

 18   who have the disease.

 

 19             So, we are looking forward to the

 

 20   discussion today.  I think the executive summary

 

 21   and the questions provide you with some of the

 

 22   concerns we have, the current products, and the

 

                                                                12

 

  1   current development programs that are going on

 

  2   right now.

 

  3             I think John Wilkin is going to talk a

 

  4   little later, prior to answering the questions

 

  5   about some of the issues, so I think we ought to

 

  6   just start with the FDA presentations.

 

  7             DR. CANTILENA:  Thank you, Dr. Ganley.

 

  8   For the members of the committee, your blue folder

 

  9   in front of you has slides for all FDA speakers

 

 10   except for the last person, so as soon as we get

 

 11   those, we will hand those out to you.

 

 12             We would like to then start.  Dr. Porres

 

 13   from FDA will be the first FDA speaker, and he will

 

 14   then be followed by four other speakers.

 

 15                         FDA Presentation

 

 16                Natural History of Tinea Pedis and

 

 17                     Dermatophyte Infections

 

 18             DR. PORRES:  I am Joseph Porres, a medical

 

 19   officer in the Division of Dermatological and

 

 20   Dental Drug Products.  I don't suppose that is a

 

 21   conflict of interest for this presentation.

 

 22             [Slide.]

 

                                                                13

 

  1             I would like to start by sharing with you

 

  2   a few points about the natural history of tinea

 

  3   pedis.  Later on, I would also like to share some

 

  4   points with you about clinical trials for tinea

 

  5   pedis, just to set the tone.

 

  6             In the first part, we talk about natural

 

  7   history, and I will cover the types of clinical

 

  8   presentations for tinea pedis, dermatophyte

 

  9   species, which most often cause this infection, the

 

 10   so-called dermatomycosis syndrome, some of the

 

 11   factors which may predispose someone to develop

 

 12   tinea pedis, factors that complicate tinea pedis

 

 13   and complications that may develop from tinea

 

 14   pedis.

 

 15             I will try to give you a brief outlook of

 

 16   epidemiology, and will talk about recurrence, some

 

 17   people who have been treated.  We talk about

 

 18   diagnosis of tinea pedis and a little bit about

 

 19   treatment.

 

 20             [Slide.]

 

 21             There are two main anatomic subtypes of

 

 22   tinea pedis - interdigital, which some people refer

 

                                                                14

 

  1   to as intertriginous, in between the toes, and

 

  2   plantar.

 

  3             Within the plantar, there are two distinct

 

  4   types - moccasin and vesicobullous.

 

  5             Let's talk a little bit more about each

 

  6   one of these.

 

  7             The interdigital often comes with

 

  8   pruritus, erythema, some scaling, occasionally

 

  9   fissure and maceration particularly if there has

 

 10   been overgrowth with some bacterial or candida

 

 11   species.

 

 12             The moccasin type, which is the one

 

 13   affecting the sides of the foot, tends to be

 

 14   dry-looking and scaling, sometimes there may be

 

 15   pruritus, sometimes there may be some erythema.

 

 16             The vesicobullous usually affects the

 

 17   plantar of the foot or the arch of the foot, and

 

 18   the vesicles is the main component.  Oftentimes,

 

 19   there may be itching, scaling, and erythema.

 

 20             Most patients seem to present with a

 

 21   combination of some of these features.  It is rare

 

 22   to find someone who has just one pure type.

 

                                                                15

 

  1             Then, we have the term "athlete's foot,"

 

  2   which is sort of a generic term that the layman

 

  3   uses when they refer to just about any type of

 

  4   fungus infection on the foot.  It is a loose term,

 

  5   it is hard to define.  It is not really a medical

 

  6   term.

 

  7             [Slide.]

 

  8             Now, about the organisms that tend to

 

  9   cause these infections.  The most common is

 

 10   Trichophyton rubrum, which is the predominant

 

 11   organism in this country since World War II, and it

 

 12   tends to account for about anywhere from 60 to 80

 

 13   percent of cases of tinea pedis, mainly tends to

 

 14   cause the plantar, moccasin type.

 

 15             Occasionally, there are some teeny tiny

 

 16   blisters on the plantar of the foot that quickly

 

 17   dry up and leave a collarette of scales, which has

 

 18   been described as very typical for Trichophyton

 

 19   rubrum.

 

 20             It may spread to the nail and then

 

 21   particularly is responsible for cases of distal

 

 22   subungual onychomycosis.  It can also spread to

 

                                                                16

 

  1   other body parts, which we will see in a minute.

 

  2             The second most common species of

 

  3   dermatophyte is Trichophyton mentagrophytes,

 

  4   usually responsible for about 15 percent of cases.

 

  5   It tends to be causative for the vesicular type,

 

  6   and it may also spread to the nails, but it tends

 

  7   to mostly cause superficial white nail involvement.

 

  8             Finally, we have Epidermophyton floccosum,

 

  9   which tends to affect about 7 percent of the cases,

 

 10   and then there are other species, which are rare,

 

 11   also recovered in cultures of larger studies.

 

 12             [Slide.]

 

 13             This is a typical representation of an

 

 14   interdigital tinea pedis.

 

 15             [Slide.]

 

 16             Here we have the tinea plantaris with the

 

 17   tiny collarettes.  These were vesicles that broke

 

 18   readily, and as you can see, clearly resembles

 

 19   dryness of the foot.  Many patients will look at

 

 20   these and think it is just dryness, and even some

 

 21   physicians may consider this dryness and not treat

 

 22   it.  Rarely, it will be symptomatic.

 

                                                                17

 

  1             [Slide.]

 

  2             Here we have the vesicular type, more

 

  3   abrupt, more acute, more likely to have symptoms.

 

  4             [Slide.]

 

  5             This is the typical moccasin type, which

 

  6   again many patients will look at this and think,

 

  7   oh, my God, my feet are very dry, and they won't

 

  8   even suspect they have a fungus.  Oftentimes, it

 

  9   will itch, and even some physicians may call this

 

 10   just dry skin.

 

 11             [Slide.]

 

 12             Now, let's talk about the dermatomycosis

 

 13   syndrome described for Trichophyton rubrum.  The

 

 14   hallmark is the moccasin type infection, and from

 

 15   here it can spread.  There can be spreading between

 

 16   household members back and forth. It can spread

 

 17   directly to the nails or to the interdigital area

 

 18   of the feet.

 

 19             Then, by spreading distally, it can go

 

 20   into the hands and from there to the fingernails.

 

 21   It can go to areas of the body, sometimes it may

 

 22   infect the hair follicles, producing a distinct

 

                                                                18

 

  1   clinical picture referred to as Majocchi's

 

  2   granuloma.

 

  3             It can go to the groin also, and then it

 

  4   is called tinea cruris.  These types of spreading

 

  5   usually occur when we dress and bring our clothes

 

  6   up, passing by the foot, or with towels we may use

 

  7   for different areas of the body.

 

  8             [Slide.]

 

  9             Now, there are some predisposing factors

 

 10   that could be important.  It has been said

 

 11   repeatedly that tinea pedis is far more common in

 

 12   closed communities like army barracks and boarding

 

 13   schools, or among people who frequent public baths

 

 14   and swimming pools.

 

 15             It is probably important to have some

 

 16   local trauma for the infection to set in, trauma

 

 17   like you can develop if you go on a long march and

 

 18   your feet are going to be sweaty and hot and

 

 19   occluded by occlusive foot gear, and you may suffer

 

 20   from immersion into water or end up with wet feet

 

 21   just from your own perspiration.

 

 22             If the shoes are very tight fitting, there

 

                                                                19

 

  1   may be repeated friction and trauma, which also may

 

  2   contribute to set up a portal of infection for the

 

  3   dermatophyte.

 

  4             It has been said that usually, it is

 

  5   important to have a species of organism to be able

 

  6   to cause infection.  This was demonstrated in

 

  7   Vietnam, for instance, until they found that it was

 

  8   the hair of rats that was the vehicle for the

 

  9   infection of many of the soldiers with

 

 10   Trichophyton.

 

 11             Again, if you look at a household, it is

 

 12   said, at least in one study, that about 17 percent

 

 13   of the members of the household are likely to have

 

 14   concomitant tinea pedis, and there may be a

 

 15   familial predisposition based on perhaps inadequate

 

 16   immunological response that may facilitate these

 

 17   patients to develop a chronic infection.

 

 18             [Slide.]

 

 19             Now, tinea pedis may become complicated if

 

 20   the patient is either immunosuppressed or has any

 

 21   atopic constitution, or is diabetic, or has

 

 22   compromised circulation, or there is repeated

 

                                                                20

 

  1   trauma, again ill-fitting shoes or tight-fitting

 

  2   shoes, and many of these things are more likely to

 

  3   appear among the geriatric population.

 

  4             [Slide.]

 

  5             One interesting complication from tinea

 

  6   pedis could be cellulitis.  It is probably not

 

  7   exceedingly common, but among people who do have

 

  8   cellulitis of the lower extremities, a great number

 

  9   of them seem to have a pre-existing tinea pedis.

 

 10   This might have been unrecognized for a long time

 

 11   by patient and physician.

 

 12             Treatment may not have been given, or, if

 

 13   given, maybe was used too short a period of time,

 

 14   or perhaps the nail was not treated and reinfection

 

 15   kept taking place, or maybe it was a diabetic

 

 16   patient who had decreased sensory perception and

 

 17   would not recognize the pruritus that otherwise may

 

 18   alert one of having the infection.

 

 19             [Slide.]

 

 20             Let's talk a little bit about

 

 21   epidemiology.  A number of studies have rated the

 

 22   degree of infection among the population at large,

 

                                                                21

 

  1   and do find rates as low as 15 percent and as high

 

  2   as 70 percent.

 

  3             It has been said that among people who

 

  4   attend the general clinic, if one were to look at

 

  5   their feet, about 40 percent of them tend to have

 

  6   tinea pedis, oftentimes unsuspected by the patient.

 

  7             However, among the patients who do go to a

 

  8   doctor to seek treatment for the tinea pedis,

 

  9   interestingly, many of them do have already nail

 

 10   involvement with a fungus. There are a number of

 

 11   cases that remain undiagnosed for a long time.

 

 12             Interestingly, dermatophytes have been

 

 13   isolated from the feet of normal individuals in

 

 14   varying rates.  They have been isolated from public

 

 15   showers, from swimming pools, and from shoes and

 

 16   socks of affected individuals.

 

 17             [Slide.]

 

 18             Now, what happens to a person who has been

 

 19   treated afterwards?  It has been very hard to find

 

 20   some data that I can share with you about this.

 

 21             Luckily, I found one set of two papers

 

 22   which look at the same population, one by

 

                                                                22

 

  1   Bergstresser, where they treated a number of people

 

  2   with 200 fungals, twice a day, either for one week

 

  3   or for four weeks, and then, a second paper by

 

  4   Elewski and others, where they look at the same

 

  5   patients 15 to 18 months later.

 

  6             [Slide.]

 

  7             So, let me show you what they found.

 

  8   There were 193 evaluable patients with interdigital

 

  9   tinea pedis.  Again, the treatment was twice a day,

 

 10   and it was either terbinafine cream in this case or

 

 11   clotrimazole cream, and there were 2 ounces for

 

 12   each drug treatment, one week or four weeks.

 

 13             They looked at it 15 to 18 months later,

 

 14   and for this particular part of the study, they

 

 15   only reported the mycology cure rates.

 

 16             [Slide.]

 

 17             There were 193 patients evaluable in the

 

 18   study.  Of these, 130 were declared mycology cure

 

 19   at the end of 12 weeks of the study.  Of these,

 

 20   they were able to follow up 93 during the 15 to 18

 

 21   months of the second part of the study, and, of

 

 22   these 93, 44 felt that they needed more treatments,

 

                                                                23

 

  1   so we consider this either insufficiently treated,

 

  2   or a relapse, or a reinfection, and there is really

 

  3   no way at this point to distinguish which one of

 

  4   the three possibilities we are dealing with here.

 

  5             Then, they looked at the patients who

 

  6   didn't feel they had need for more treatment.

 

  7   There was it appeared to be cure, and they took

 

  8   cultures.  Of these 49, 24 developed a positive

 

  9   culture anyway.

 

 10             As a sideline, of these 24, 8 of them had

 

 11   an organism that this time was identified with a

 

 12   different name than the one given at baseline.  It

 

 13   is hard to tell whether one of the two might have

 

 14   been misdiagnosed or whether this actually

 

 15   represents infection with a different organism.

 

 16             So, all together, we see that there were

 

 17   78 percent of the people who had originally been

 

 18   called "mycology cure," who relapsed or reinfected

 

 19   at some time after the treatment.

 

 20             [Slide.]

 

 21             Now, let's go a little bit into how we

 

 22   make a diagnosis of tinea pedis.  The main part

 

                                                                24

 

  1   here is clinical. We look at the signs and symptoms

 

  2   and try to recognize what may be part of the

 

  3   typical picture.

 

  4             It can be aided by mycology, which

 

  5   consists of a direct microscopic examination,

 

  6   usually referred to as KOH, and of which there are

 

  7   many variants, and then the culture.

 

  8             The nice thing about the KOH is that it

 

  9   can provide a quick diagnosis, confirming the

 

 10   clinical impression, and therefore it would help to

 

 11   avoid delaying giving the indicated treatment or

 

 12   avoid prescribing a treatment that may not be

 

 13   appropriate.

 

 14             [Slide.]

 

 15             Now, if a physician wants to treat tinea

 

 16   pedis and goes to the literature to see how to

 

 17   treat it, you will find information similar to

 

 18   this.  This is just one example.

 

 19             I look at this current textbook,

 

 20   "Treatment of Skin Disease," by Lebohl, published

 

 21   by Mosby in 2003, and they report results for

 

 22   terbinafine from different studies, clotrimazole,

 

                                                                25

 

  1   miconazole, and a couple of others.

 

  2             Oftentimes, they give the results for

 

  3   mycology cure and other times they just say cure

 

  4   rates and do not specify what kind of cure it was,

 

  5   but looking at the numbers here in the right

 

  6   column, I suspect that they are mostly referring to

 

  7   mycology cures.

 

  8             Sometimes they tell us how long were those

 

  9   patients treated that reached these rate numbers,

 

 10   and oftentimes they will tell us the dosage that

 

 11   was used, but sometimes they don't tell us.  They

 

 12   just say, well, terbinafine 97 percent cures, and

 

 13   we don't know what this means.  It is unfortunate

 

 14   that this information is so scant that it is hard

 

 15   for the clinician to really figure out what these

 

 16   numbers represent.

 

 17             I would like you to sort of keep an idea

 

 18   in mind about the magnitude of these rates when the

 

 19   statistician brings data from the studies that she

 

 20   had reviewed, just keep this in mind.

 

 21             [Slide.]

 

 22             Now, let's talk a little bit about

 

                                                                26

 

  1   clinical trials for tinea pedis.  I would like to

 

  2   focus a little bit on dose ranging studies and on

 

  3   clinical trials for safety and efficacy.

 

  4             [Slide.]

 

  5             Dose ranging studies for tinea pedis are

 

  6   particularly always recommended by the Agency when

 

  7   drug developers come here for meetings and

 

  8   orientation. Unfortunately, most of the time this

 

  9   recommendation is ignored.  This is too bad because

 

 10   with dose ranging studies, it could be helpful to

 

 11   try to determine what is the most interesting dose

 

 12   that may have the best safety and efficacy profile.

 

 13             Now, in dose ranging studies, usually,

 

 14   there are three elements that can be studied:  drug

 

 15   strength, drug concentration, the frequency of

 

 16   application, and the duration of treatment.

 

 17             We have some limitations here.  Drug

 

 18   strength, sometimes there are certain higher doses

 

 19   that we cannot study either because they may have

 

 20   an unsafe profile or for chemistry reasons, perhaps

 

 21   the drug reaches maximum solubility and we cannot

 

 22   study any concentrations above that.

 

                                                                27

 

  1             Now, frequency of application also has

 

  2   some limitations.  We can expect compliance of

 

  3   patients to reach up to a certain limit.  If we

 

  4   tell a patient to apply something once a day or

 

  5   twice a day, they are likely to do it.  If we tell

 

  6   them to use it 74 times a day, they are not likely

 

  7   to do it, so studying things more than twice a day

 

  8   probably is not very practical.

 

  9             So, we are left with duration of treatment

 

 10   which is where we have the greatest latitude,

 

 11   however, marketing pressures seem to make drug

 

 12   developers aim for ever decreasing durations of

 

 13   treatment, perhaps so they can advertise that a

 

 14   product can kill the organism in fewer days than

 

 15   the other competing product.  Sometimes these may

 

 16   be at the expense of efficacy.

 

 17             [Slide.]

 

 18             Now, in clinical safety and efficacy

 

 19   trials, I would like to focus about how do we

 

 20   assess results of these trials and what the

 

 21   outcomes from these assessments will be.

 

 22             [Slide.]

 

                                                                28

 

  1             What we assess or what has been assessed

 

  2   routinely is mycology, again direct microscopic

 

  3   examination and mycology culture, and clinical, a

 

  4   variety of signs and symptoms, and there are

 

  5   studies which have just looked at a couple of

 

  6   these, others that look at many.

 

  7             Others make a composite of this, others

 

  8   may use what is called the investigator's global

 

  9   assessment, which is kind of like a comprehensive

 

 10   picture of what the disease looks like at that

 

 11   particular point.

 

 12             [Slide.]

 

 13             The outcomes from these assessments are

 

 14   usually mycology cure, which involves having a

 

 15   negative KOH in a negative culture.  We don't like

 

 16   this term very much at the FDA.  We would like to

 

 17   refer to it as negative culture because perhaps it

 

 18   is not really a cure in many cases unless it is

 

 19   accompanied by a clinical cure, as well.

 

 20             Then, we have clinical outcomes.  One is

 

 21   effective treatment, which requires not only

 

 22   negative mycology or mycology cure, but also

 

                                                                29

 

  1   absence of symptoms and at most, some residual

 

  2   signs remaining.

 

  3             Here, I should introduce or remind you of

 

  4   a concept of skin turnover.  The epidermis has a

 

  5   maximum speed at which it can turn over its cells,

 

  6   which is about four weeks, so you could have a

 

  7   patient who is actually a cure, and may still have

 

  8   some residual erythema or some residual scaling.

 

  9             However, after these four weeks, we should

 

 10   be expecting that these residual signs should not

 

 11   be present in a patient who is a cure.

 

 12             Then, we go into complete cure, which is

 

 13   the gold standard, where mycology is negative or

 

 14   mycology cure, and there are no signs or symptoms

 

 15   left of the disease.

 

 16             [Slide.]

 

 17             Now, in clinical safety and efficacy

 

 18   studies, oftentimes the inclusion/exclusion

 

 19   criteria that come with the protocols do not seem

 

 20   to mimic the population which could be expected to

 

 21   actually use these products in the real world once

 

 22   the product is approved.

 

                                                                30

 

  1             For instance, they tend to include only

 

  2   people who are very healthy and who perhaps have

 

  3   disease limited to just a small area, such as toe

 

  4   webs, and exclude more difficult cases to treat

 

  5   that might reduce their overall efficacy rate, so

 

  6   they exclude people with onychomycosis or who have

 

  7   the moccasin type, which they apparently think is

 

  8   harder to treat, and they will exclude people who

 

  9   are diabetic or immunosuppressed, or who may have

 

 10   compromised circulation, but all of these patients

 

 11   would be expected, they will be users of the

 

 12   product later on.

 

 13             At this point, I would like to introduce

 

 14   Dr. Kathleen Fritsch, who will give you a summary

 

 15   of her review of some studies.

 

 16             Thank you for your attention.

 

 17             DR. GANLEY:  If anyone had questions for

 

 18   Dr. Porres now, they could probably ask them.

 

 19             DR. CANTILENA:  We actually have time

 

 20   slotted, actually, plenty of time before lunch, but

 

 21   I guess if there are specific questions, perhaps we

 

 22   have time for one or two specific questions for Dr.

 

                                                                31

 

  1   Porres before we go to the next speaker.

 

  2             Yes, Dr. Ten Have.

 

  3             DR. TEN HAVE:  I have a question regarding

 

  4   the definition of the efficacy rates on page 9 that

 

  5   were reported.  I missed the definition.  Could you

 

  6   just repeat it?

 

  7             DR. PORRES:  In the handout, page 9?

 

  8             DR. TEN HAVE:  Handout, page 9.

 

  9             DR. PORRES:  The question, if I

 

 10   understood, is how is cure defined here?  Okay.

 

 11             DR. TEN HAVE:  How are the efficacy rates

 

 12   defined based on a cure definition?

 

 13             DR. PORRES:  I am glad you asked that

 

 14   question, because the clinician, looking at this

 

 15   information in textbooks, should be asking the same

 

 16   question.  The point is that when you look at the

 

 17   sources in the literature, they don't tell you

 

 18   anything.  They just give you some rates and hope

 

 19   that you will think that these products are all

 

 20   wonderful, and they don't tell you how these

 

 21   numbers are derived, and you are lost.

 

 22             So, that is precisely the point I was

 

                                                                32

 

  1   trying to make.

 

  2             DR. CANTILENA:  So, the answer is they are

 

  3   really not well defined.

 

  4             DR. PORRES:  They don't tell us, they just

 

  5   give us a summary.

 

  6             DR. CANTILENA:  Dr. Wood.

 

  7             DR. WOOD:  My question may be an extension

 

  8   of the last one.  On the last slide, you talk about

 

  9   the exclusion criteria that include harder cases to

 

 10   treat.  I presume you mean by that, that the

 

 11   outcome is poorer, is that right, that the cure

 

 12   rate is lower?

 

 13             DR. PORRES:  The people who may be harder

 

 14   to treat--

 

 15             DR. WOOD:  I understand that is what it

 

 16   says, but do you mean by that, that they are harder

 

 17   to treat because the efficacy is lower in that

 

 18   group?  I mean diabetics aren't harder to treat per

 

 19   se, and they must either have poorer outcome, or do

 

 20   you mean that diabetics can't rub the stuff on

 

 21   their foot, you know, what do you mean by that?

 

 22             Just to finish the question, I assume what

 

                                                                33

 

  1   is meant there is that the outcome is poorer in

 

  2   these patients, what are the data to support that?

 

  3             DR. PORRES:  I think you will have to ask

 

  4   the drug developers why do they want to exclude

 

  5   those patients in the first place.  They don't give

 

  6   us a rationale, they just want to exclude them

 

  7   maybe to keep the study neater, and I am not aware

 

  8   of any data that actually shows whether they are

 

  9   easier to treat or more difficult to treat, but

 

 10   that is the way they design their protocols.

 

 11             Now, the moccasin type--

 

 12             DR. WOOD:  So, the slide says you excluded

 

 13   harder cases.

 

 14             DR. PORRES:  Yes.

 

 15             DR. WOOD:  Are there data to support them

 

 16   being harder, or is that just--

 

 17             DR. PORRES:  They assumed they are going

 

 18   to be harder.

 

 19             DR. WOOD:  I see.

 

 20             DR. PORRES:  For instance, if there is

 

 21   nail involvement, they may be more prone to have

 

 22   reinfection from the nail if they are not treating

 

                                                                34

 

  1   the nail at the same time, so they suspect that

 

  2   those are going to complicate the outcomes.

 

  3             DR. WOOD:  But you have no data to say

 

  4   that the outcome is poorer in these patients?

 

  5             DR. PORRES:  No.

 

  6             DR. WOOD:  That is what I am trying to get

 

  7   at.

 

  8             DR. PORRES:  We don't have the data.

 

  9             DR. WOOD:  It relates directly to the

 

 10   question.  That is why I am pushing this part.

 

 11             DR. PORRES:  No.

 

 12             DR. CANTILENA:  Dr. Fincham.

 

 13             DR. FINCHAM:  Dr. Porres, I am assuming

 

 14   that these criteria, either inclusion or exclusion,

 

 15   are set by the manufacturer, there is no

 

 16   constraints on those designs.

 

 17             DR. PORRES:  Well, they send us the

 

 18   protocols.  We look at them, and sometimes, you

 

 19   know, we make suggestions. We encourage the study

 

 20   of all comers.  Sometimes they insist they want to

 

 21   study just a very narrow group, and sometimes we

 

 22   are more influential than others.

 

                                                                35

 

  1             DR. CANTILENA:  A comment from Dr. Wilkin.

 

  2             DR. WILKIN:  Actually, you caught it right

 

  3   at the very end, and sometimes they do.  We have

 

  4   had some tinea pedis trials where patients with

 

  5   onychomycosis, often the same fungus that is

 

  6   affecting the plantar surface of the foot is also

 

  7   in the nail.

 

  8             We have had some trials like that, so I

 

  9   think it is not all or none, and it is true that we

 

 10   don't know for sure that they are harder, but we

 

 11   sense that there may be some lower efficacy, but we

 

 12   don't have good numbers on that, that is correct.

 

 13             DR. CANTILENA:  Dr. Alfano.

 

 14             DR. ALFANO:  My question relates to the

 

 15   fact that you spoke about predisposing factors, and

 

 16   you mentioned trauma is regularly associated to get

 

 17   this infection started.

 

 18             What happens with those predisposing

 

 19   factors in the course of the disease, i.e., if the

 

 20   subject doesn't change their tight shoes, do they

 

 21   start with hyperkeratosis from the irritation from

 

 22   the shoes, and is it appropriate to expect that to

 

                                                                36

 

  1   go away if they don't change their predisposing

 

  2   factors?

 

  3             DR. PORRES:  There is really no hard data

 

  4   looking at what happens on a series of cases from

 

  5   the beginning to the end, but this is the general

 

  6   gestalt, the general feel for what is felt, how

 

  7   this disease evolves, and it is felt that these

 

  8   factors are important in either facilitating

 

  9   development of the disease or in making it worse,

 

 10   but there is no hard data that anyone would show if

 

 11   you wear your shoes 10 minutes longer, you are more

 

 12   prone to have disease than it you wear them 10

 

 13   minutes less, but it is felt that usually, that is

 

 14   the case, but there is no hard data for any of

 

 15   this.  This is kind of like a field that has

 

 16   developed through the years, that most people seem

 

 17   to agree as a general concept.

 

 18             DR. CANTILENA:  Our final question over

 

 19   here.  Dr. Benowitz.

 

 20             DR. BENOWITZ:  Two questions.  The first

 

 21   one, you had said that as many as 70 percent of the

 

 22   general population can have positive cultures. 

 

                                                                37

 

  1   Given that in the recurrent studies, does a

 

  2   persistent positive culture with a clinical

 

  3   response mean that there will be a clinical

 

  4   recurrence?

 

  5             DR. PORRES:  Could you rephrase the

 

  6   question again?  I am sorry.

 

  7             DR. BENOWITZ:  You said that as many as 70

 

  8   percent of the population, assumingly not

 

  9   clinically infected, can have positive cultures.

 

 10             DR. PORRES:  No, no, that is not what I

 

 11   said, I am sorry.  What I said is that some people,

 

 12   published reports looking at the incidence of tinea

 

 13   pedis in a particular population like maybe in

 

 14   India or Canada, or somewhere, and they report that

 

 15   they found 70 percent of the people at large had

 

 16   the disease.

 

 17             DR. BENOWITZ:  Oh, had the clinical

 

 18   infection.  I guess the other part is still valid.

 

 19             If you have a positive culture, but you

 

 20   have a clinical response, does that always

 

 21   translate into a later clinical recurrence?

 

 22             DR. PORRES:  If you have--

 

                                                                38

 

  1             DR. BENOWITZ:  You have been treated, you

 

  2   have a clinical response, but you do not have a

 

  3   mycologic response, does that always predict a

 

  4   clinical recurrence?

 

  5             DR. PORRES:  Well, if there is clinical

 

  6   cure, you say, but the culture is still positive?

 

  7             DR. BENOWITZ:  Yes.

 

  8             DR. PORRES:  That would never be called a

 

  9   success by definition, so I don't think anybody has

 

 10   ever looked to see what happened to the patient

 

 11   afterwards.  It is just declared a failure, and

 

 12   there is no follow-up.

 

 13             DR. BENOWITZ:  Is there any issue of a

 

 14   carrier state, like we see with other infections?

 

 15   Is that an issue here?

 

 16             DR. PORRES:  Possibly, there is no hard

 

 17   data, there is contamination with other household

 

 18   members or other school members or other army

 

 19   fellows, you know, but there is really no hard data

 

 20   for any of these things.

 

 21             DR. BENOWITZ:  Okay.  The second question

 

 22   is if an expert dermatologist is seeing a patient

 

                                                                39

 

  1   who has these infections, and they are diabetic or

 

  2   they are immunocompromised, would they be treated

 

  3   any differently from any other patient?  What is

 

  4   the standard of care for treatment of these more

 

  5   high risk patients?

 

  6             DR. PORRES:  The dermatologist would want

 

  7   to make sure that whoever is taking care of the

 

  8   diabetes for that patient would have provided

 

  9   adequate treatment or if they are

 

 10   immunocompromised, that they have the adequate

 

 11   treatment, you know, just as a general feel for my

 

 12   practice, I have seen people who have maybe HIV or

 

 13   something else, and they have tinea, and I can

 

 14   figure they are much harder to treat and the

 

 15   treatment is much, much longer, and oftentimes they

 

 16   stop because they get tired of treating these for

 

 17   months or they stop when they feel better, thinking

 

 18   that maybe they have cured the problem, but it was

 

 19   just a little bit too early, and within a few

 

 20   months they come back with full-blown disease.

 

 21             So, the dermatologist can treat the skin,

 

 22   but usually, we need the concurrence of the other

 

                                                                40

 

  1   types of physicians who treat the other components

 

  2   like vascular disease or whatever.

 

  3             DR. BENOWITZ:  I guess my point is would a

 

  4   dermatologist initiate systemic antifungal therapy

 

  5   rather than try topical therapy first if someone is

 

  6   at high risk?

 

  7             DR. PORRES:  Well, that is an interesting

 

  8   question and I didn't want to address it here

 

  9   because we are talking about topical antifungals,

 

 10   but if you look at the textbooks and references on

 

 11   how to treat the disease, there are many who would

 

 12   say that you need to use also systemic treatment

 

 13   for tinea pedis together with topical antifungals.

 

 14   Some still say that.

 

 15             DR. BENOWITZ:  I think it is important for

 

 16   us because that really affects labeling for high

 

 17   risk patients. We need to know what patients need

 

 18   to understand about their disease.

 

 19             DR. PORRES:  You are absolutely correct,

 

 20   and that is why we are here today.

 

 21             DR. CANTILENA:  Thank you, Dr. Benowitz.

 

 22             We have one final comment from Dr.

 

                                                                41

 

  1   Schmidt, and then, since you work here, Dr. Wilkin,

 

  2   you can have the final, final comment.

 

  3             DR. SCHMIDT:  I think at least in Texas, I

 

  4   don't think we really cure these people of any of

 

  5   these things, and I think that moccasin type tinea,

 

  6   if someone has an immunologic defect where they

 

  7   just can't process and kill the T. rubrum, then, in

 

  8   your first slide of the person pulling the toes

 

  9   apart, the little piggies, you know, are too close.

 

 10             I think the mechanical trauma comes first,

 

 11   and then the tinea is secondary, so I think it

 

 12   behooves us to have some like education, you know,

 

 13   for the patients, because unless you can keep the

 

 14   air flowing with Thinsulate socks, spacers, drying

 

 15   agents, powders, changing shoes, wearing wooden

 

 16   shoe trees, you know, there are a million things

 

 17   that you can do, you will never cure these people

 

 18   with this interdigital tinea, never ever in your

 

 19   lifetime.

 

 20             Then, I think, the same way with this

 

 21   moccasin type tinea, I mean I think this stuff is

 

 22   in the environment, and these people are going to

 

                                                                42

 

  1   get it recurrently, because it seems like people

 

  2   come in during the summer and their fungus flares

 

  3   up, and during the winter, even if you don't treat

 

  4   them, these things tend to clear up.

 

  5             Now, I wanted to comment on this thing of

 

  6   whether we treat people more aggressively when they

 

  7   have problems. It's hard to treat patients who have

 

  8   diabetes or they have recurrent cellulitis.

 

  9   Usually, these people, it comes from the fourth and

 

 10   fifth toe web, you know, from this macerated

 

 11   interdigital tinea is the point of entry, and, yes,

 

 12   I do, I will sometimes treat these people

 

 13   systemically, but I think drying agents and good

 

 14   foot care is probably the most important thing.

 

 15             The same thing with the onychomycosis, you

 

 16   know, just simple things will help this, but I

 

 17   never tell anybody I am going to cure them.  I just

 

 18   say, listen, when this stuff comes back, you are

 

 19   just going to treat it again.

 

 20             DR. CANTILENA:  Dr. Wilkin.

 

 21             DR. WILKIN:  I would like to respond to

 

 22   Dr. Benowitz's question about after treatment, can

 

                                                                43

 

  1   you still get the dermatophytes, and there is a

 

  2   paper in the Journal of the American Academy of

 

  3   Dermatology, February 1995, Dr. Elewski is the

 

  4   first author, it's a multi-authored publication.

 

  5             Long-term outcome of patients with

 

  6   interdigital tinea pedis, treated with terbinafine

 

  7   or clotrimazole, and one of the points made is that

 

  8   even after successful treatment in the sense that

 

  9   the inflammatory signs and symptoms have gone away,

 

 10   one can still culture the organism.

 

 11             So, I think this is the experience that

 

 12   most dermatologists have, as well, and then I was

 

 13   going to add the part that Dr. Schmidt has already

 

 14   taken care of, you know, the dermatologist, I

 

 15   think, attacks the tropical environment inside the

 

 16   shoe, which is what keeps the fungus going.

 

 17             Also, sometimes the dermatophyte can

 

 18   actually survive on the inside surface of the shoe,

 

 19   so we know that some patients actually, eventually

 

 20   need to get a new pair of shoes, and there is a lot

 

 21   of weekly applications of topical products.

 

 22             Certainly, that is off label, but I know

 

                                                                44

 

  1   that that is done, a lot of drying powders, and,

 

  2   yes, there is a lot of attention, but I think in

 

  3   general the first approach is topical, but it is

 

  4   with a fairly comprehensive strategy for making it

 

  5   the wrong environment for the dermatophyte.

 

  6             DR. CANTILENA:  Thank you.  Thank you, Dr.

 

  7   Porres.

 

  8             Dr. Fritsch.

 

  9              Study Design and Efficacy Results for

 

 10             Tinea Pedis Clinical Trials (Rx and OTC)

 

 11             DR. FRITSCH:  Good morning.  I am Kathleen

 

 12   Fritsch.  I am a biostatistician with the Division

 

 13   of Biometrics III.  I will be presenting some more

 

 14   background information on the study design for

 

 15   tinea pedis clinical trials, and then I will be

 

 16   presenting some efficacy data from NDA submissions.

 

 17             [Slide.]

 

 18             First, I will be looking at the basic

 

 19   clinical trial design.

 

 20             [Slide.]

 

 21             Generally, these trials are randomized,

 

 22   double-blind, multicenter, vehicle-controlled

 

                                                                45

 

  1   trials.

 

  2             In the past, there generally have been two

 

  3   indications, the tinea pedis indication, the OTC

 

  4   equivalent of athlete's foot, and these trials will

 

  5   usually evaluate either all comers, with both the

 

  6   plantar and the interdigital variant, or study the

 

  7   subtypes individually, or if they focus their

 

  8   clinical trials primarily on the interdigital type,

 

  9   then, they get a more limited indication of

 

 10   athlete's foot between the toes or interdigital

 

 11   tinea pedis.

 

 12             Most of the development over the last

 

 13   decade has focused on the interdigital variant.

 

 14   Most of the products approved for the full

 

 15   indication were approved more than a decade ago.

 

 16             [Slide.]

 

 17             In terms of patients that are evaluated in

 

 18   these studies, for randomization into the trial and

 

 19   receiving treatment, you need a positive KOH and

 

 20   clinical signs and symptoms.

 

 21             In order to verify that tinea pedis is

 

 22   actually the diagnosis, in order to be analyzed for

 

                                                                46

 

  1   efficacy, usually, the patients are also required

 

  2   to have a positive baseline culture, however, since

 

  3   it can take up to four weeks to get the results of

 

  4   a culture, the treatment is often completed by the

 

  5   time those baseline culture results are known.

 

  6             However, the solution then is to just

 

  7   analyze for efficacy, what we call the modified

 

  8   intent to treat, or MITT population, those that

 

  9   have positive KOH, positive culture, and the

 

 10   appropriate clinical signs and symptoms.

 

 11             In most clinical trials, we will find that

 

 12   about two-thirds of the patients will end up having

 

 13   a positive baseline culture, and that can have an

 

 14   impact on choosing the sample size for a study.

 

 15             [Slide.]

 

 16             As Dr. Porres mentioned, there are three

 

 17   efficacy endpoints that are analyzed in these

 

 18   clinical trials that involve mycological and

 

 19   clinical outcomes.  They are nested within each

 

 20   other in that negative mycology is required for

 

 21   both effective treatment and complete cure.

 

 22             The effective treatment is getting to a

 

                                                                47

 

  1   mild state and also includes the patients that get

 

  2   to the complete cure state, and the complete cure

 

  3   state is the absence of the signs and symptoms.

 

  4             So, they are nested within each other.

 

  5             [Slide.]

 

  6             Again, to put up the specific definitions

 

  7   for these three endpoints, negative mycology, also

 

  8   referred to as mycological cure, is a negative KOH

 

  9   and culture.

 

 10             An effective treatment also requires the

 

 11   negative mycology and is some sort of a mild state

 

 12   of the disease, the clinical presentation.

 

 13   Generally, we say mild or no signs and no symptoms.

 

 14   From trial to trial, the specific definition for

 

 15   effective treatment does vary.

 

 16             Our recommendation these days is to define

 

 17   it as, at most, mild erythema and scaling, but in

 

 18   the past trials, there may be other ways to define

 

 19   a mild state that have been used.  Sometimes

 

 20   effective treatment is designated in the clinical

 

 21   trials as the primary endpoint.

 

 22             Of course, the strongest endpoint is the

 

                                                                48

 

  1   complete cure, which is the absence of signs and

 

  2   symptoms, negative mycology.  This is often the

 

  3   primary endpoint in the clinical trials, and the

 

  4   Agency generally recommends to use complete cure as

 

  5   the primary endpoint.

 

  6             Again, the signs and symptoms that are

 

  7   evaluated usually include erythema, pruritus, and

 

  8   scaling, and may include any of the other signs and

 

  9   symptoms, as well.

 

 10             [Slide.]

 

 11             For the study phases, there is usually a

 

 12   treatment period and a post-treatment follow-up

 

 13   period.

 

 14             Most products have a treatment duration

 

 15   between one and four weeks.  Then, the patients are

 

 16   followed for, at a minimum of at least two weeks

 

 17   after treatment.  The amount of follow-up will

 

 18   generally depend on the length of treatment.

 

 19             For a one-week product, the treatment

 

 20   period usually is at least five to eight weeks.  If

 

 21   the treatment is for four weeks, the follow-up

 

 22   period may be shorter, it may be only two to four

 

                                                                49

 

  1   weeks.  In both cases, this puts the patients at

 

  2   about six to nine weeks after they have started

 

  3   their treatment for when they will be primarily

 

  4   evaluated.

 

  5             [Slide.]

 

  6             Again, the reason for following patients

 

  7   into the post-treatment follow-up period is to

 

  8   allow for the epidermal turnover, as Dr. Porres

 

  9   mentioned, may take at least four weeks, so we may

 

 10   not expect the clearance of signs until some point

 

 11   after treatment has ended, say, at least six weeks

 

 12   after the start of treatment even if the fungus is

 

 13   eradicated earlier.

 

 14             Because of this, there may be a

 

 15   significant time lag in either weeks or possibly

 

 16   months between when treatment ends and when a cure

 

 17   could be assessed.

 

 18             [Slide.]

 

 19             The second part of my presentation will

 

 20   focus in on specific data that have been submitted

 

 21   to the Agency.  I will be presenting the efficacy

 

 22   results from selected clinical trials.

 

                                                                50

 

  1             [Slide.]

 

  2             The clinical trials that I have selected

 

  3   for my presentation come from NDA reviews.  The

 

  4   oldest one dates back to 1988, and all of the

 

  5   studies come from vehicle-controlled trials and

 

  6   were in general considered the pivotal trials for a

 

  7   particular drug product.

 

  8             Using these criteria, I have identified

 

  9   nine drug products.  They may involve different

 

 10   formulations or treatment regimens, and they

 

 11   represent six different active ingredients, so

 

 12   there are some multiple formulations and treatment

 

 13   regimens.

 

 14             The nine products are roughly split

 

 15   between those that are available OTC and by

 

 16   prescription, and also split between those that are

 

 17   recommended for one week's use and for four weeks'

 

 18   use.

 

 19             Of the nine, seven were designed for the

 

 20   indication of interdigital tinea pedis, and the two

 

 21   oldest ones have the indication for tinea pedis.

 

 22             [Slide.]

 

                                                                51

 

  1             To take a look at the size of the database

 

  2   that is available for each of these products, I

 

  3   will be presenting the products only by code letter

 

  4   A through I.

 

  5             We see that the products have a database

 

  6   of roughly about 50 patients on an active

 

  7   ingredient up to about 250, and in some cases, we

 

  8   have two trials that were two vehicle-controlled

 

  9   trials, and in some cases, we have one.  So, we do

 

 10   have a variety of sample sizes represented for our

 

 11   products here, so A through I.

 

 12             [Slide.]

 

 13             As I move into the displays of the actual

 

 14   data from these trials, I want to make a caveat

 

 15   that these data do not represent head-to-head

 

 16   comparisons of the products, therefore, we cannot

 

 17   make any direct comparisons of relative efficacy

 

 18   from one product to another.

 

 19             Success rates in these trials are greatly

 

 20   influenced by the particular patients that are

 

 21   enrolled in a trial, types of concomitant diseases

 

 22   they may have, whether they have onychomycosis, how

 

                                                                52

 

  1   severe the baseline clinical signs and symptoms

 

  2   must be could affect the success rates.

 

  3             The specific clinical study procedures,

 

  4   how the samples are collected, who analyzes the

 

  5   skin samples, whether a target lesion is analyzed,

 

  6   whether the whole foot is analyzed, all that can

 

  7   influence the success rate.

 

  8             As I mentioned before, the endpoints are

 

  9   identified differently in a trial, is it a global,

 

 10   is it specific symptoms, what symptoms are

 

 11   evaluated, all of that, how is missing data

 

 12   handled, all that can influence the success rates.

 

 13             So, we will look at this in terms of

 

 14   trying to pick up general trends and patterns that

 

 15   we can.

 

 16             [Slide.]

 

 17             I have got data on the negative mycology,

 

 18   effective treatment, and complete cure rates for

 

 19   the nine products, so we will present those next.

 

 20             [Slide.]

 

 21             This first graph represents the negative

 

 22   mycology.  These are the negative mycology rates at

 

                                                                53

 

  1   end of treatment, so Week 1 for the one-week

 

  2   products, and Week 4 for the four-week products.

 

  3             The orange bars represent the active.  We

 

  4   can see what kind of eradication we can expect to

 

  5   find for a one-week treatment.  For a one-week

 

  6   treatment, we can see that, for the most part,

 

  7   about 40 to 50 percent of patients will have

 

  8   negative KOH and negative culture by the end of

 

  9   treatment.

 

 10             For the products that are used for four

 

 11   weeks, the negative mycology rate is somewhat

 

 12   higher at Week 4, about 60 to 70 percent of

 

 13   patients will have the negative mycology at the end

 

 14   of treatment.

 

 15             [Slide.]

 

 16             If we go to the primary timepoint that was

 

 17   specified in each particular protocol for the time

 

 18   of assessment, usually, Week 6, 8, or 9, we see

 

 19   that, in general, at this timepoint, patients can

 

 20   get to about 60, 70, or 80 percent negative

 

 21   mycology rates by the primary timepoint for

 

 22   evaluation, so that is about what we can expect for

 

                                                                54

 

  1   getting rid of the dermatophyte, and it is fairly

 

  2   consistent across the products here.

 

  3             Again, the endpoints that involve the

 

  4   clinical signs and symptoms are based on these

 

  5   patients that achieve negative mycology only.

 

  6             [Slide.]

 

  7             In terms of effective treatment, this will

 

  8   be getting negative KOH in culture and getting down

 

  9   to some sort of a mild state of disease.

 

 10             We see that for Week 1, only a relatively

 

 11   small proportion of patients are actually able to

 

 12   get to the mild state by the time they are finished

 

 13   with their treatment regimen, about 2 percent to 18

 

 14   percent of patients.  So, the remaining subjects

 

 15   would have some sort of symptoms beyond just mild

 

 16   erythema and mild scaling remaining by the end of

 

 17   treatment.

 

 18             At four weeks, where they have had a

 

 19   longer time to wait before they stop their

 

 20   treatment, roughly around half of the patients are

 

 21   able to get to a mild state of disease, and the

 

 22   remaining half would still have more severe signs

 

                                                                55

 

  1   and symptoms remaining.

 

  2             So, that is what a patient may be able to

 

  3   expect to see by the time they are finished with

 

  4   their treatment.

 

  5             [Slide.]

 

  6             By the time we get out to the Week 6 to 9,

 

  7   where the skin may have had a chance to turn over a

 

  8   little bit, we see again about 40, 50, 60 percent

 

  9   of patients will be able to get to the mild state

 

 10   with the negative mycology, and the remaining

 

 11   subjects would have more symptoms remaining.

 

 12             [Slide.]

 

 13             Finally, the gold standard of complete

 

 14   cure where we can completely eradicate these signs

 

 15   and symptoms, as well as the dermatophyte, for one

 

 16   week treatment, as may be expected because of the

 

 17   time for skin turnover, very few patients will be

 

 18   actually completely clear of their signs and

 

 19   symptoms.

 

 20             Almost everybody has some signs or

 

 21   symptoms remaining or dermatophyte remaining by the

 

 22   end of one week of treatment.  Even for those that

 

                                                                56

 

  1   continue to four weeks, roughly, 15 percent of

 

  2   patients are able to get completely rid of their

 

  3   signs and symptoms, and the remainder will have at

 

  4   least something remaining even at the end of four

 

  5   weeks of treatment.

 

  6             [Slide.]

 

  7             To go out to the primary timepoint, again

 

  8   we see about the same value across the board.

 

  9   About 20 percent, maybe 30 percent in some cases,

 

 10   of patients are able to completely get rid of their

 

 11   signs and symptoms six to nine weeks after starting

 

 12   treatment, which is about two to four weeks after

 

 13   treatment for the four-week treatments and five to

 

 14   eight weeks after treatment for the one-week

 

 15   treatments.

 

 16             [Slide.]

 

 17             Next, I will go into some specific tables

 

 18   for the specific signs and symptoms, and I will

 

 19   present this information by visit.  The visits that

 

 20   are evaluated in a particular clinical trial depend

 

 21   on the design.

 

 22             I will be presenting data for erythema,

 

                                                                57

 

  1   scaling, and pruritus, and for this presentation,

 

  2   since signs and symptoms have not been collected in

 

  3   the same way in all trials, I have the data

 

  4   available in the format I want for only two

 

  5   products, a one-week product and a four-week

 

  6   product.

 

  7             [Slide.]

 

  8             We start with erythema.  This will be the

 

  9   percentage of subjects that will be clear of their

 

 10   erythema at a particular visit.  On the left, Drug

 

 11   Product D is a one-week treatment, and Drug Product

 

 12   F is a four-week treatment.

 

 13             If we take a look at the percentage of

 

 14   subjects, in this case, we started off with about

 

 15   15 percent of subjects were clear of their erythema

 

 16   at baseline in this trial.  After one week of

 

 17   treatment, that number improved to about 25

 

 18   percent, and then as we go out in time to the time

 

 19   we may expect to see the skin turnover, by Week 4

 

 20   to 6, we are getting up to about 50 percent.

 

 21             This trial went out to 12 weeks, and by

 

 22   that point, we have about 50 to 60 percent of

 

                                                                58

 

  1   patients clear of their erythema by the end of the

 

  2   trial, compared to about 30 percent on vehicle.

 

  3             A similar pattern for this four-week

 

  4   treatment.  It takes a while for the number of

 

  5   patients to get clear of their erythema.  By about

 

  6   Week 4, again we are about 45 percent, 50 percent

 

  7   of patients.  So, we can see kind of the time

 

  8   trajectory of how many weeks it takes to start to

 

  9   see clearance of the erythema.

 

 10             [Slide.]

 

 11             Scaling.  In this case, all of the

 

 12   subjects that have scaling at baseline, and we see

 

 13   that for the one-week treatment, if we look at the

 

 14   number of patients that are clear of their scaling,

 

 15   about 2 percent of patients were clear of scaling

 

 16   by the end of treatment.  Again, not too surprising

 

 17   based on the length of epidermal turnover.

 

 18             By four weeks, we are up to a little over

 

 19   10 percent, and we max out at about 25 percent.

 

 20   So, this may be the rate-limiting factor for why we

 

 21   see little complete clearance is scaling is

 

 22   persistent in the vast majority of patients.

 

                                                                59

 

  1             Similarly, over here, by about Week 4, we

 

  2   are up to 20 percent, maxing out at about 30

 

  3   percent of patients able to completely clear of

 

  4   their scaling.

 

  5             [Slide.]

 

  6             Finally, for pruritus, we will see that on

 

  7   this drug, for the one-week treatment, we do

 

  8   actually see a substantial bump from baseline to

 

  9   the end of treatment at Week 1, go from about 15

 

 10   percent with no pruritus at baseline to about 45

 

 11   percent by the end of treatment.

 

 12             Again, we do see continued improvement for

 

 13   this product after treatment has ended, getting up

 

 14   to about 75 percent of patients by Week 9 who are

 

 15   clear of their pruritus, and the vehicle rate drops

 

 16   off, although interestingly, during the one week of

 

 17   treatment, the active and the vehicle have the same

 

 18   benefit in terms of pruritus, however, the active

 

 19   patients do continue to improve.

 

 20             Similarly, for Drug Product F, we see

 

 21   continued improvement on the pruritus, in this case

 

 22   during the course of treatment, maxing out at about

 

                                                                60

 

  1   70 percent again for the number of patients clear

 

  2   of their pruritus.

 

  3             Again, also substantial vehicle benefit,

 

  4   however, the vehicle rate does drop off after

 

  5   treatment.

 

  6             [Slide.]

 

  7             The summary of the efficacy results.  From

 

  8   this data, we can see that there is a time lag of

 

  9   several weeks between the end of treatment and when

 

 10   the signs and symptoms may be cleared, particularly

 

 11   for the one-week products where the treatment is

 

 12   stopped before the epidermal turnover can take

 

 13   place.

 

 14             In most cases, patients will have signs

 

 15   and symptoms remaining into the post-treatment

 

 16   period, and rough ballpark figures of the typical

 

 17   cure rates for the various endpoints, complete cure

 

 18   rates are roughly 20, maybe 30 percent for most

 

 19   products.

 

 20             Effective treatment may be about half of

 

 21   the patients.  Negative mycology rates, around

 

 22   two-thirds to three-fourths of the patients will be

 

                                                                61

 

  1   able to get to the negative mycology in the

 

  2   post-treatment period.

 

  3             Thank you.

 

  4             DR. CANTILENA:  Thank you, Dr. Fritsch.

 

  5             We have time for a couple of questions for

 

  6   Dr. Fritsch.

 

  7             Dr. Benowitz.

 

  8             DR. BENOWITZ:  I am just curious.  What is

 

  9   the basis for someone doing a one-week trial versus

 

 10   a four-week trial, are the products different, why

 

 11   is that done?

 

 12             DR. FRITSCH:  Basically, it is the

 

 13   sponsor's preference.  If they want to market a

 

 14   one-week product and they think they can get the

 

 15   efficacy that they want in one week.  We have not

 

 16   seen very much data that compares a product across

 

 17   multiple durations.

 

 18             That is one of the reasons we have been

 

 19   asking for dose ranging.  It is usually we either

 

 20   get results for one week, or we get results for

 

 21   four weeks.  We have not seen much comparative

 

 22   data, but generally, it is the sponsor's decision

 

                                                                62

 

  1   on what type of product they would like to market.

 

  2             DR. BENOWITZ:  So, if we looked at the

 

  3   products, they would basically be the same in both

 

  4   groups in terms of active ingredients?

 

  5             DR. FRITSCH:  In terms of for the data

 

  6   presentation I made, there is six different active

 

  7   ingredients that were represented.

 

  8             DR. BENOWITZ:  I understand.  I am just

 

  9   saying that if you look at drugs that were selected

 

 10   for a one-week trial versus a four-week trial, they

 

 11   are basically the same medications in both, same

 

 12   active ingredients?

 

 13             DR. FRITSCH:  There is only one case where

 

 14   we have data both on a one-week use and a four-week

 

 15   use.  Otherwise, the products that are one week are

 

 16   different than the products that are four weeks.

 

 17             DR. BENOWITZ:  I understand that the

 

 18   specific product name is different, but in terms of

 

 19   the active ingredients.

 

 20             DR. FRITSCH:  The active ingredients, yes.

 

 21             DR. BENOWITZ:  Are they also generally

 

 22   different or are they basically the same?

 

                                                                63

 

  1             DR. FRITSCH:  Generally, they are

 

  2   different.  There is one product that is

 

  3   recommended for use for either one week or four

 

  4   weeks, and then there are products that are only

 

  5   recommended for one week, and there are products

 

  6   that are only recommended for four weeks.

 

  7             So, generally, the one-week products are

 

  8   different from the four-week products in terms of

 

  9   active ingredients.

 

 10             DR. BENOWITZ:  Thanks.

 

 11             DR. CANTILENA:  Ms. Knudson.

 

 12             MS. KNUDSON:  I want to know, on these

 

 13   studies that you have just presented, do you have

 

 14   any idea how many patients dropped out of the

 

 15   studies and at what timepoints did they drop out?

 

 16             DR. FRITSCH:  Yes, that is generally

 

 17   included.  For the most part, roughly, in maybe a

 

 18   six-week trial, there might be about 10 to 15

 

 19   percent of patients that drop out. One of the

 

 20   difficulties with the data I have presented, our

 

 21   current standards would be to generally either

 

 22   count the patients that drop out as either failures

 

                                                                64

 

  1   or last observation carried forward.

 

  2             For the older trials, often the results

 

  3   that I have presented exclude the dropouts.  I did

 

  4   not go back and try and correct for intent to treat

 

  5   the way that the older trials did, so that is one

 

  6   variability, that the older trials often ignored

 

  7   dropouts.  Recently, we definitely count them in

 

  8   our results.

 

  9             DR. CANTILENA:  Thank you.

 

 10             Dr. Ringel.

 

 11             DR. RINGEL:  I have a question about

 

 12   negative mycology.  I was wondering if that is

 

 13   considered negative KOH and culture or only

 

 14   negative culture.

 

 15             The reason I am asking is that most

 

 16   physicians consider culture in other areas of

 

 17   mycobiology to be a gold standard, whereas, as with

 

 18   dermatophytes, there are various reasons why a

 

 19   culture might be negative, where the KOH would be

 

 20   positive, either bacterial contamination, sampling

 

 21   error, the patient has been using topical

 

 22   antifungals.

 

                                                                65

 

  1             So, I guess the question is if a KOH is

 

  2   positive, a culture is negative, is that considered

 

  3   positive mycology or negative mycology?

 

  4             DR. FRITSCH:  You must have both negative

 

  5   KOH and negative culture to be counted as negative

 

  6   mycology.

 

  7             DR. RINGEL:  Thank you.

 

  8             DR. CANTILENA:  Thank you.  Now we have

 

  9   Mr. Kresel.

 

 10             MR. KRESEL:  My question was answered

 

 11   earlier.

 

 12             DR. CANTILENA:  Dr. Epps.

 

 13             DR. EPPS:  Partially, my question was

 

 14   addressed with the positive KOH, negative mycology,

 

 15   but how much within your group was just positive

 

 16   KOH and negative culture?  Do you have any data

 

 17   regarding that?

 

 18             DR. FRITSCH:  Yes, the positive KOH and

 

 19   negative culture, I have seen a few.  There is

 

 20   definitely some that come through with positive KOH

 

 21   and negative culture.

 

 22             DR. EPPS:  Because it may be that this is

 

                                                                66

 

  1   not viable, but present--

 

  2             DR. FRITSCH:  There is lots of problems

 

  3   with the four-week, you know, a negative culture,

 

  4   did you have the fungus in the plate or not, that

 

  5   is definitely a problem, so there are definitely

 

  6   some that do come through.

 

  7             DR. CANTILENA:  Thank you.

 

  8             Dr. Lam.

 

  9             DR. LAM:  I just want to clarify just to

 

 10   make sure.  The data that you present only

 

 11   represent one strength of each of the products.

 

 12             DR. FRITSCH:  One strength of each

 

 13   product, yes.

 

 14             DR. CANTILENA:  Thank you.  Any other

 

 15   questions from the committee?  Dr. Wood.

 

 16             DR. WOOD:  The elephant in the room here

 

 17   is what the efficacy is with systemic therapy, as

 

 18   well.  Is somebody going to talk about that?

 

 19             I realize we are here to consider topical

 

 20   therapy, but as we get to some of these questions,

 

 21   my feelings about them would be substantially

 

 22   influenced by knowing what we are going to accept

 

                                                                67

 

  1   as the expected efficacy rate from systemic

 

  2   therapy.

 

  3             Clearly, given the efficacy rate shown

 

  4   here, and consumers' views of that will be

 

  5   different if there is effective therapy out there

 

  6   that is of an order of magnitude different.

 

  7             So, is someone going to, for the record,

 

  8   show us that, an efficacy rate from terbinafine

 

  9   systemically?

 

 10             DR. CANTILENA:  Dr. Ganley, do you have

 

 11   anyone?  If you have to look that up, we can

 

 12   certainly have that after lunch.  So, why don't we

 

 13   have someone be checking on that.  That is a good

 

 14   point.

 

 15             Our next speaker from FDA, Dr. Mahayni.

 

 16               History and Overview of OTC Topical

 

 17                Antifungal Drug Products Monograph

 

 18             DR. MAHAYNI:  Good morning, ladies and

 

 19   gentlemen. My name is Houda Mahayni.  I am

 

 20   interdisciplinary scientist in the Division of

 

 21   Over-the-Counter Drug Products.

 

 22             [Slide.]

 

                                                                68

 

  1             I will give you a brief introduction about

 

  2   the mechanism by which OTC drugs are regulated.

 

  3   Then, I will describe an overview of the OTC Drug

 

  4   Monograph System. Finally, I will discuss the OTC

 

  5   drug monograph for topical antifungals with special

 

  6   emphasis on those ingredients used to treat

 

  7   athlete's foot tinea pedis.

 

  8             [Slide.]

 

  9             Most of you are familiar with the NDA

 

 10   process, so in order to introduce the monograph

 

 11   system, I am going to briefly contrast the two

 

 12   mechanisms by which OTC drug products are

 

 13   regulated, highlighting the key differences between

 

 14   the two mechanisms.

 

 15             NDA is drug product-specific.  It requires

 

 16   pre-market approval, and information submitted

 

 17   under the NDA is confidential, whereas, in the OTC

 

 18   drug monograph, is an active ingredient-specific,

 

 19   and ingredients are designate as GRASE, which is

 

 20   generally recognized as safe and effective. There

 

 21   is no need for pre-market approval.  Finally, the

 

 22   information is public.

 

                                                                69

 

  1             [Slide.]

 

  2             I hope this introduction gives you a

 

  3   flavor of how the two mechanisms differ.  I will

 

  4   not be talking about the NDA mechanism in this

 

  5   talk, but I will focus for the rest of this talk on

 

  6   the OTC Drug Monograph System.

 

  7             [Slide.]

 

  8             The OTC drug review began in 1972 as a

 

  9   review of the safety and effectiveness of OTC drugs

 

 10   on the market at that time.  FDA initiated the OTC

 

 11   drug review by identifying a number of therapeutic

 

 12   categories for which FDA is to establish OTC drug

 

 13   monographs.

 

 14             OTC drug monographs list the conditions of

 

 15   use that are generally recognized as safe and

 

 16   effective or GRASE, and on the next slide I will be

 

 17   talking to you about what is meant by the condition

 

 18   of use.

 

 19             [Slide.]

 

 20             What is really included in the monograph

 

 21   system is the conditions of use, and those include

 

 22   the active ingredients, whether it's single

 

                                                                70

 

  1   ingredient or combination, dosage strength, dosage

 

  2   form, labeling requirements, such as uses,

 

  3   directions, and warnings, and finally, in some

 

  4   cases, final formulation testing.

 

  5             [Slide.]

 

  6             The OTC drug review is a four-step public

 

  7   rulemaking process, and each step builds upon the

 

  8   other.  Here, I will be listing all the four steps

 

  9   and I will go over these steps in more detail in

 

 10   subsequent slides.

 

 11             First, the advisory review panel meets.

 

 12   Then, after the panel meets, the FDA publishes the

 

 13   Advance Notice of Proposed Rulemaking, which is

 

 14   generally referred to as the ANPR.

 

 15             Next, FDA publishes the tentative final

 

 16   monograph, or TFM, and finally, the FDA publishes

 

 17   the final rule, or FM.

 

 18             [Slide.]

 

 19             The panel is a group of experts in a

 

 20   particular OTC drug category.  The panel was

 

 21   charged with reviewing the data of OTC ingredients

 

 22   marketed prior to 1975 and assessing whether these

 

                                                                71

 

  1   ingredients are safe and effective for GRASE

 

  2   conditions for the OTC drug monograph.

 

  3             The panel give the nomenclature Category I

 

  4   for ingredients, all conditions under which

 

  5   products are generally recognized as safe and

 

  6   effective, and are not misbranded.

 

  7             Category II are for ingredients or

 

  8   conditions under which products are generally

 

  9   recognized not as safe and effective or are

 

 10   misbranded.

 

 11             Category III are for ingredients or

 

 12   conditions when the available data are insufficient

 

 13   to permit final classification at the time.

 

 14             Keep in mind that these classifications

 

 15   are not only given for ingredients, but for

 

 16   condition of use as defined earlier, which includes

 

 17   labeling requirements and final formulation

 

 18   testing.

 

 19             [Slide.]

 

 20             Next, the FDA publishes the Advance Notice

 

 21   of Proposed Rule, or ANPR, in the Federal Register

 

 22   to announce its intention of creating the OTC drug

 

                                                                72

 

  1   monograph.  The ANPR also contains the panel

 

  2   report, which lists recommended GRASE conditions.

 

  3             Then, following the publication of the

 

  4   ANPR, interested persons may submit comments or

 

  5   additional data to the panel, and they are given 90

 

  6   days to make those comments in.

 

  7             [Slide.]

 

  8             FDA next publishes the tentative final

 

  9   monograph, or TFM, in the Federal Register as its

 

 10   preliminary position regarding the safety and

 

 11   effectiveness of each active ingredient in

 

 12   particular category.

 

 13             The TFM is based on FDA interpretation of

 

 14   data provided by the panel, the panel

 

 15   recommendations, and any new data submitted in

 

 16   response to the Advance Notice of Proposed Rule.

 

 17             Following its publication, there is also

 

 18   an additional 90 days comment period for interested

 

 19   persons who may want to submit comments and

 

 20   additional data on what was contained in the TFM.

 

 21             [Slide.]

 

 22             FDA reviews all comments and data

 

                                                                73

 

  1   submitted during the tentative final monograph

 

  2   comment period and amends the TFM to create the

 

  3   final monograph or final rule. The monograph is a

 

  4   set of rules published in the Federal Register.

 

  5             The regulation gets published in the Code

 

  6   of Federal Regulations.  That includes an effective

 

  7   date after which any product marketed under the

 

  8   monograph must comply with the conditions used that

 

  9   were described in the monograph.

 

 10             As I said, each step in the monograph

 

 11   builds upon and is a continuation of the previous

 

 12   step.  Although the FM is the final step in the OTC

 

 13   Drug Monograph System, FDA can amend the final

 

 14   monograph to include additional GRASE conditions,

 

 15   such as adding new active ingredients.

 

 16             [Slide.]

 

 17             Now that I gave you a general overview of

 

 18   the OTC Drug Monograph System, I am going to shift

 

 19   and talk specifically about the history of OTC

 

 20   topical antifungal monograph with special emphasis

 

 21   on those ingredients used to treat athlete's foot

 

 22   tinea pedis.

 

                                                                74

 

  1             [Slide.]

 

  2             The panel met in the late seventies and

 

  3   early eighties, and then FDA published the Advance

 

  4   Notice of Proposed Rulemaking in 1982.

 

  5             The panel expressed its concern about the

 

  6   ingredients only mitigating symptoms rather than

 

  7   curing condition as is apparent by the statement

 

  8   that in order to best serve the consumers, an OTC

 

  9   product must provide more than temporary

 

 10   symptomatic relief of athlete's foot, jock itch,

 

 11   and ringworm.

 

 12             The panel required at least one

 

 13   well-designed clinical study demonstrating an

 

 14   active ingredient treat athlete's foot as evidence

 

 15   of effectiveness, and it recommended an ingredient

 

 16   as GRASE if it was significantly more effective

 

 17   than vehicle.

 

 18             [Slide.]

 

 19             In reviewing the clinical trial, the panel

 

 20   defined a well-controlled study as one that met the

 

 21   following criteria:  To be double-blinded and

 

 22   randomized, vehicle-controlled, test groups of

 

                                                                75

 

  1   adequate size, entry criteria based on clinical

 

  2   signs and symptoms with diagnosis verified by

 

  3   positive KOH and culture, and standardized dosing

 

  4   regimen usually four weeks treatment for athlete's

 

  5   foot, and finally, the follow-up examinations

 

  6   performed at the end of treatment and final

 

  7   evaluation of clinical results corroborated by

 

  8   negative KOH and negative culture two weeks after

 

  9   treatment ends.

 

 10             A relatively small percentage of the

 

 11   studies submitted to NDA met these criteria.

 

 12             [Slide.]

 

 13             The panel reviewed approximately 50

 

 14   clinical studies along with in vitro and animal

 

 15   studies to assess the safety and effectiveness of

 

 16   about 35 active ingredients.

 

 17             Of these clinical studies, roughly 10 were

 

 18   designed to demonstrate the effectiveness of active

 

 19   ingredients in treating athlete's foot, but most

 

 20   were poorly designed.  This was because there was

 

 21   considerable variability in the study protocol.

 

 22             Enrollment for most studies was based on

 

                                                                76

 

  1   the diagnosis of tinea pedis by a physician instead

 

  2   of these studies, this diagnosis was confirmed by

 

  3   positive KOH and positive culture.

 

  4             Treatment duration varied between two to

 

  5   six weeks with treatment duration being four weeks

 

  6   in most studies.

 

  7             These studies assessed the efficacy at

 

  8   different timepoints and used different criteria

 

  9   for cure.

 

 10             All these factors make it difficult to

 

 11   compare the cure rates of the monograph products to

 

 12   those of the NDA products.  Based on this review of

 

 13   the study, the panel recommended that six active

 

 14   ingredients be classified as GRASE, and I will

 

 15   share with you these ingredients in the slide

 

 16   talking about the final monograph.

 

 17             [Slide.]

 

 18             In addition, the panel proposed the idea

 

 19   of simple and concise labeling that should enable

 

 20   the consumers to clearly understand the results

 

 21   that can be anticipated from the use of the

 

 22   product.

 

                                                                77

 

  1             Example of indication recommended by the

 

  2   panel includes treat athlete's foot for the

 

  3   treatment of athlete's foot or for the relief of

 

  4   itching.

 

  5             Labeling or products used for the

 

  6   treatment of athlete's foot should include the

 

  7   following warning:  If irritation occurs or of

 

  8   there is no improvement within four weeks,

 

  9   discontinue use and consult a doctor or pharmacist.

 

 10             Furthermore, the panel stated that

 

 11   directions should be clear and direct.  They should

 

 12   provide the user with sufficient information to

 

 13   enable safe and effective use of the product.

 

 14             Based on the clinical study, which

 

 15   generally involved four weeks' treatment, the panel

 

 16   determined that OTC topical antifungals should be

 

 17   applied twice a day for four weeks to be most

 

 18   effective.

 

 19             [Slide.]

 

 20             Seven years later, after the NPR was

 

 21   published, the Agency published the TFM.  In the

 

 22   TFM, FDA reviewed 25 clinical studies.  Those

 

                                                                78

 

  1   studies were submitted following the publication of

 

  2   the ANPR or Advance Notice of Proposed Rule.

 

  3             Six of these 25 studies addressed

 

  4   athlete's foot. Based on these studies, FDA agreed

 

  5   with the panel recommendation in terms of

 

  6   ingredients to be included in the monograph with

 

  7   the exception of two active ingredients, nystatin

 

  8   was classified as not GRASE, and they decided to

 

  9   include povidone and iodine as GRASE.

 

 10             [Slide.]

 

 11             After the TFM was published, FDA published

 

 12   the FM, the final monograph four years later.  In

 

 13   the final monograph, FDA reviewed about 10 studies

 

 14   submitted after the tentative final monograph and

 

 15   found the following active ingredients as GRASE for

 

 16   the treatment of athlete's foot.

 

 17             FDA found all other ingredients considered

 

 18   in this rulemaking not to be GRASE for us in OTC

 

 19   topical antifungals.  In addition, the final

 

 20   monograph includes labeling similar to that

 

 21   recommended by the panel in the Advance Notice of

 

 22   Proposed Rule.

 

                                                                79

 

  1             All of the active ingredients listed here,

 

  2   they were indicated for the treatment of athlete's

 

  3   foot, as well as for the relief of symptoms.  Only

 

  4   one product tolnaftate was also indicated for the

 

  5   prevention of athlete's foot.  In addition, all

 

  6   these active ingredients were also indicated for

 

  7   the treatment of ringworm, tinea corporis, and jock

 

  8   itch, tinea cruris.

 

  9             [Slide.]

 

 10             As I told you, final monograph can be

 

 11   amended following its publication.  FDA published a

 

 12   proposed amendment and subsequently, a final rule

 

 13   in August 2000 to modify the labeling of OTC

 

 14   topical antifungal.

 

 15             This amendment added the word "most" to

 

 16   the indication statement between the introductory

 

 17   phrase and the name of the condition for which the

 

 18   product was to be used, for instance, cures "most"

 

 19   athlete's foot.

 

 20             FDA recognized that OTC topical

 

 21   antifungals do not cure or treat all conditions

 

 22   commonly thought by consumers to be athlete's foot

 

                                                                80

 

  1   or jock itch.

 

  2             FDA also noted that varying percentages of

 

  3   subjects were clinically and mycologically cured of

 

  4   athlete's foot infection, therefore, inserting the

 

  5   word "most" in this case would give and help the

 

  6   consumers know what to expect from these products.

 

  7             This is important since consumers

 

  8   self-select OTC topical antifungals, and do not

 

  9   diagnose.  The Agency believed that this labeling

 

 10   should more accurately inform the consumers what to

 

 11   expect from using these products.

 

 12             Also, FDA pointed out that this amended

 

 13   label is consistent with the current labeling

 

 14   approved for OTC vaginal antifungal drug products

 

 15   marketed under NDA.  Since these are also topical

 

 16   antifungals with different sites of administration

 

 17   and for consistency, OTC labeling for this

 

 18   particular class should be the same.

 

 19             In addition to this amendment, in February

 

 20   2002, after reviewing approximately eight clinical

 

 21   studies submitted after the FM, FDA proposed to add

 

 22   clotrimazole as GRASE active ingredients for the

 

                                                                81

 

  1   treatment of athlete's foot, jock itch, and

 

  2   ringworm.

 

  3             [Slide.]

 

  4             In summary, OTC drug monographs allow

 

  5   determination of safety and effectiveness of an

 

  6   entire therapeutic drug class.

 

  7             OTC topical antifungal monograph lists

 

  8   GRASE active ingredients and labeling for OTC drug

 

  9   products that treat athlete's foot, jock itch, and

 

 10   ringworm, as well as prevent athlete's foot,

 

 11   because ingredients found GRASE for one condition

 

 12   is given the same GRASE classification for other

 

 13   conditions because of the similarity of these

 

 14   conditions.

 

 15             From the data submitted the monographs, it

 

 16   is difficult to directly compare the cure rates for

 

 17   monograph and NDA drug products that treat

 

 18   athlete's foot because they were not directly

 

 19   comparable due to considerable variability in the

 

 20   study protocol.

 

 21             Finally, by including the word "most" in

 

 22   the indication, we can say to consumers what to

 

                                                                82

 

  1   expect from using these products and what to expect

 

  2   from them.

 

  3             Thank you.

 

  4             DR. CANTILENA:  Thank you, Dr. Mahayni.

 

  5             I guess we should ask that all depends

 

  6   what you mean by "most," but we will actually talk

 

  7   about that this afternoon.

 

  8             Questions from the committee?  Dr. Wood.

 

  9             DR. WOOD:  Well, that was going to be my

 

 10   question. "Most" certainly means, as you said, it

 

 11   is the last thing, it helps the consumer.

 

 12             If I look at the slides in the last talk,

 

 13   on page 10, which of these studies support "most"

 

 14   in your view?  On the Slide 19 on page 10, you

 

 15   added the word "most" because you felt that

 

 16   reflected the data.

 

 17             Which of the studies specifically on Slide

 

 18   19 do you think tell you that, or would tell me

 

 19   that?

 

 20             DR. MAHAYNI:  Actually, the word "most"

 

 21   was added because at the time, there was not a

 

 22   specific study, but because of the lower percentage

 

                                                                83

 

  1   of cure rate for these ingredients, the word "most"

 

  2   was added to the monograph to indicate to consumers

 

  3   that it is not going to treat every clinical

 

  4   condition that will be presented.

 

  5             DR. WOOD:  Right, but "most" implies at

 

  6   least more than 50 percent, and most people I think

 

  7   would assume that it was closer to 100 than 50

 

  8   percent.  I don't think any interpretation of

 

  9   "most" implies less than 50 percent, does it?  I

 

 10   mean is there a definition that you are aware of

 

 11   that implies that most people do something, implies

 

 12   less than 50 percent?

 

 13             DR. CANTILENA:  How about if we have

 

 14   actually Dr. Ganley answer the question, since he

 

 15   probably had more to do with that than Dr. Mahayni.

 

 16             DR. GANLEY:  This whole process started

 

 17   before I got to D.C., but I am generally

 

 18   accountable for it.

 

 19             DR. CANTILENA:  All right, there is the

 

 20   copout, so now you can answer.

 

 21             DR. GANLEY:  No, I accept responsibility

 

 22   for it.

 

                                                                84

 

  1             I guess at the time, it is a rather

 

  2   complicated thing, is that it will treat most

 

  3   dermatophytes.  Also, the thinking was that if you

 

  4   put just cures there without some qualifier, that

 

  5   people think that it is closer to 100 percent cure.

 

  6             Now, "most" may not have been the

 

  7   appropriate adjective and maybe some other

 

  8   qualifying term, but I think that is one of the

 

  9   issues that we need to discuss, whether that really

 

 10   was a good idea and whether we need to revise the

 

 11   language a little bit.  It gets back to how you

 

 12   convey information to the consumer as what their

 

 13   expectation can be, but I think I would acknowledge

 

 14   that it actually didn't accomplish what I think the

 

 15   original intent of the Agency was in that, to give

 

 16   some perception that it's not 100 percent cure,

 

 17   that it is something less than that.

 

 18             I think if you look at the data for

 

 19   effective treatment and cures most, people will

 

 20   argue that effective treatment is a reasonable

 

 21   level of success also, and that generally is above

 

 22   50 percent, so I mean you can discuss that today

 

                                                                85

 

  1   and the logic, but I would acknowledge that it

 

  2   didn't solve the situation at all.

 

  3             DR. WOOD:  I guess there are two issues,

 

  4   does it cure and is it most, and I am thinking of

 

  5   this in terms of the treatment of heart failure.

 

  6   You know, it is perfectly legitimate to have a

 

  7   treatment for heart failure that is effective in

 

  8   most patients, but we probably wouldn't allow

 

  9   labeling that said it cured most patients, or HIV,

 

 10   or whatever it was we were treating.

 

 11             I mean I think it is the juxtaposition of

 

 12   both that we need to be discussing.

 

 13             DR. GANLEY:  I think the difference I

 

 14   would argue there is that in heart failure, you are

 

 15   not going to cure the underlying condition, you are

 

 16   going to treat the symptoms and improve their

 

 17   survival potentially, you don't cure them of the

 

 18   disease, but infectious disease, you can cure

 

 19   people's disease, and that is where the difference

 

 20   is.

 

 21             So, it does get a little tricky in how you

 

 22   are going to convey that information to the

 

                                                                86

 

  1   consumer and what their expectation may be.

 

  2             DR. WOOD:  That is why I think it is

 

  3   important to have in the discussion, what the

 

  4   efficacy is for systemic therapy, because I think

 

  5   that was exactly my point earlier, where there is

 

  6   alternative therapy available that may have a very

 

  7   different efficacy rate, it is important then to

 

  8   revisit this to make sure that this provides some

 

  9   information that is at least contemporaneous for

 

 10   what the other therapies can do.

 

 11             DR. CANTILENA:  That is a very good point.

 

 12   We will have an opportunity this afternoon to

 

 13   discuss that further.

 

 14             Dr. Lam.

 

 15             DR. LAM:  For the product to be classified

 

 16   as Category I, what type of cure are we talking

 

 17   about, are we talking about mycology cure or

 

 18   complete cure?

 

 19             DR. MAHAYNI:  No, Category I does not

 

 20   relate to actually cure, because most of these

 

 21   studies did not define the complete cure.  The

 

 22   category is really reflected on what the

 

                                                                87

 

  1   ingredients, Category I is ingredients that are

 

  2   seen as safe and effective, or generally recognized

 

  3   as safe and effective, and not misbranded.

 

  4             But as far as cure rate, there were a

 

  5   variety of studies that had a different way of

 

  6   qualifying what is cure rate, and no way to compare

 

  7   them or say what is the cutoff rate for that.

 

  8             DR. HOLEMAN:  Matthew Holeman.  If I could

 

  9   just sort of clarify real quick.

 

 10             DR. CANTILENA:  Okay.

 

 11             DR. HOLEMAN:  Basically, remember that

 

 12   most of the studies that these were based on were

 

 13   submitted to the Agency in the seventies, the late

 

 14   seventies, so the standards there were very

 

 15   different than our standards today.

 

 16             So, as Houda pointed out in her talk

 

 17   today, there was a great variability in how these

 

 18   studies were designed, and some of these studies, I

 

 19   think the majority looked at just mycological

 

 20   cures.  Some of them did include some clinical

 

 21   cure.

 

 22             I don't know that any actually looked at

 

                                                                88

 

  1   complete clinical cure, most of them were probably

 

  2   mycological, but it is really hard.  There is a lot

 

  3   of variability in all these studies.

 

  4             DR. CANTILENA:  Dr. Fincham.

 

  5             DR. FINCHAM:  I just have more of a

 

  6   comment than a question.  I think this is all very

 

  7   interesting, how we are deciding what cure means

 

  8   and what most means, but I guess at some point, we

 

  9   are all consumers, but I am concerned about the

 

 10   consumers that aren't in this room that see the

 

 11   advertisements for these products and see cure,

 

 12   they may not even look at most, but just see the

 

 13   word "cure" and make assumptions based upon that.

 

 14             I don't expect anybody to have an answer

 

 15   to that, but it is a comment that I think we need

 

 16   to perhaps consider later.

 

 17             DR. CANTILENA:  Yes, I think we will have

 

 18   an answer this afternoon.

 

 19             Go ahead, Mr. Kresel.

 

 20             MR. KRESEL:  I am sure that when the

 

 21   monograph was developed, there was probably debate

 

 22   over the terminology and what it should say, but

 

                                                                89

 

  1   since the labeling doesn't define cure, and

 

  2   therefore I think it is very difficult for the

 

  3   consumer to really know what they are getting when

 

  4   it says "cures most," we might want to go back and

 

  5   talk about that debate between treats and cures.

 

  6             DR. CANTILENA:  Dr. Benowitz, the final

 

  7   question.

 

  8             DR. BENOWITZ:  Just a question about the

 

  9   GRASE criteria.  For example, nystatin was not

 

 10   accepted as GRASE, so is that because of efficacy,

 

 11   or are there some safety issues with some of these

 

 12   products, as well?

 

 13             DR. MAHAYNI:  I don't recall for what

 

 14   purpose that was taken out of the GRASE category or

 

 15   classification.

 

 16             DR. BENOWITZ:  But just do you know, are

 

 17   there any safety issues for any of these products?

 

 18             DR. MAHAYNI:  For nystatin itself?

 

 19             DR. BENOWITZ:  No, just for the variety of

 

 20   antifungals.  I know some probably don't work, but

 

 21   should we be thinking about any safety issues for

 

 22   any of these antifungals?

 

                                                                90

 

  1             DR. MAHAYNI:  For most what I have done

 

  2   for preparation of the advisory committee meeting,

 

  3   we focused on the efficacy.  I didn't particularly

 

  4   look at the safety, I didn't go over what study was

 

  5   submitted to the monograph for safety purpose,

 

  6   because we were focusing here on efficacy rate, so

 

  7   I reviewed all the effectiveness studies that were

 

  8   listed in the monograph, so I can't answer your

 

  9   question.

 

 10             DR. BENOWITZ:  I am wondering if anyone at

 

 11   FDA has information about hypersensitivity or other

 

 12   safety issues involving these agents.

 

 13             DR. CANTILENA:  Dr. Ganley, does your

 

 14   staff have that?

 

 15             DR. GANLEY:  We can look for that, but I

 

 16   suspect that, you know, today, when we look at

 

 17   today, what we asked for in studies and what they

 

 18   may have looked at back in the seventies, there may

 

 19   have been safety information that looked at

 

 20   exposure, you know, to a group of individuals.  It

 

 21   wasn't a specific study that would address that.

 

 22             Today, there are irritation studies,

 

                                                                91

 

  1   photocarcinogenicity studies, and a whole variety

 

  2   of different studies that may be asked of a topical

 

  3   agent, and John could probably address it better

 

  4   than I can.

 

  5             But I would suspect that if you go back

 

  6   and look at that, it was basically data that was

 

  7   submitted about use in various populations, and

 

  8   there was no significant adverse effects.

 

  9             DR. CANTILENA:  We have a comment over

 

 10   here from Kresel.

 

 11             MR. KRESEL:  I was just going to say,

 

 12   because I am the oldest one here, and remember back

 

 13   then, there were very skimpy studies that were

 

 14   done, and there probably wasn't enough to really

 

 15   come to a conclusion, not that there was any

 

 16   particularly negative data and probably the sponsor

 

 17   didn't do an awful lot.

 

 18             DR. CANTILENA:  Thank you.

 

 19             Did you have a comment, Dr. Bisno, that is

 

 20   related to this?

 

 21             DR. BISNO:  Just a comment which I will

 

 22   deal with slightly in my talk, which is if you look

 

                                                                92

 

  1   at the 13 episodes that have been reported to the

 

  2   FDA, according to the information we got, about

 

  3   cellulitis related to these topical products, most

 

  4   of them, if you look at them, look like their

 

  5   hypersensitivity reactions someone got.  They got

 

  6   it and then a day later they developed inflammation

 

  7   of some sort, it wasn't really compatible with what

 

  8   one would think would be a cellulitis.

 

  9             So, at least in those very scanty reports,

 

 10   one would suspect that at least a number of them

 

 11   were actually hypersensitivity related in one way

 

 12   or another.

 

 13             DR. CANTILENA:  Dr. Katz.

 

 14             DR. KATZ:  In response to a previous

 

 15   question as far as nystatin, why that was excluded

 

 16   from the GRASE, I would assume that it was because

 

 17   it is in not effective, it is not effective for

 

 18   these conditions.

 

 19             DR. CANTILENA:  Dr. Schmidt.

 

 20             DR. SCHMIDT:  Ladies and gentlemen, you

 

 21   all are very lucky today, because you have somebody

 

 22   who is older than Dr. Kresel, and also we were

 

                                                                93

 

  1   interested in these medications in the seventies,

 

  2   and actually, when I was a resident, I helped in

 

  3   some of these studies.

 

  4             These studies, at least the ones we did,

 

  5   were very well done and I think, you know, as I

 

  6   recall, there were very few side effects with these

 

  7   different medications although some of these

 

  8   things, it seemed like the vehicles were almost as

 

  9   good as the medications.

 

 10             So, I just want to say that you all are

 

 11   lucky.

 

 12             DR. CANTILENA:  We are very lucky.  We

 

 13   have an investigator here, as well as an advisory

 

 14   committee member.

 

 15             Dr. Whitmore.

 

 16             DR. WHITMORE:  With regard to contact

 

 17   hypersensitivity and such, I think the chemicals

 

 18   themselves are not big-time contact allergens by

 

 19   any means, and it would be more likely the

 

 20   excipient agents.

 

 21             DR. CANTILENA:  Thank you very much.

 

 22             Our next FDA presenter is Dr. Shetty.

 

                                                                94

 

  1             Topical Antifungal Drug Product Labeling

 

  2             DR. SHETTY:  My name is Daiva Shetty.  I

 

  3   am a medical officer in the Division of

 

  4   Over-the-Counter Drug Products.

 

  5             [Slide.]

 

  6             My talk will consist of several different

 

  7   topics. First, I will briefly present some

 

  8   marketing and postmarketing safety data for topical

 

  9   and antifungal drug products.  I will focus more in

 

 10   detail on labeling issues for this class of drugs

 

 11   and also provide some examples how we convey

 

 12   efficacy information to consumers.

 

 13             [Slide.]

 

 14             First, I will start with the marketing

 

 15   data.

 

 16             [Slide.]

 

 17             There are 11 active ingredients approved

 

 18   for tinea pedis indication through New Drug

 

 19   Applications for prescription and over-the-counter

 

 20   use.  There are also, as mentioned earlier, 7

 

 21   monograph active ingredients that the Agency found

 

 22   to be generally recognized as safe and effective. 

 

                                                                95

 

  1   Both prescription and over-the-counter products are

 

  2   widely used for the treatment of dermal fungal

 

  3   infections.

 

  4             [Slide.]

 

  5             The Division of Surveillance analyze the

 

  6   prescription and over-the-counter sales trends and

 

  7   drug use patterns for topical antifungals.

 

  8             Two IMS health databases were used to

 

  9   gather this information, National Sales

 

 10   Perspectives and National Disease and Therapeutic

 

 11   Index.

 

 12             [Slide.]

 

 13             The first database, National Sales

 

 14   Perspectives, measures the volume of drug products,

 

 15   prescription and nonprescription, going from

 

 16   manufacturers into a market in terms of eaches.  An

 

 17   each is IMS's unit of measure for single items,

 

 18   such as tubes, jars, or individual retail packages.

 

 19             This database does not provide the

 

 20   demographics of consumers purchasing the drugs.  It

 

 21   does not give the indication for use or the amount

 

 22   of drug actually used.

 

                                                                96

 

  1             [Slide.]

 

  2             This slide shows the National Sales

 

  3   Perspectives data for topical antifungals in 2003.

 

  4   Over-the-counter topical antifungal drug products

 

  5   accounted for over 20 million eaches, while

 

  6   prescription products accounted for around 16

 

  7   million eaches in 2003.

 

  8             This is somewhat surprising to us given

 

  9   that over-the-counter products are freely available

 

 10   to consumers for their purchase and use.  Keep in

 

 11   mind that the sales data are for topical antifungal

 

 12   ingredients in general, and do not reflect the

 

 13   tinea pedis indication.

 

 14             [Slide.]

 

 15             Here is the table from the same database

 

 16   listing active ingredients, prescription and

 

 17   nonprescription, approved for the treatment of

 

 18   tinea pedis in terms of sales. We can see that

 

 19   monograph ingredients highlighted on this slide in

 

 20   yellow account for the highest volume sold.

 

 21             [Slide.]

 

 22             The second IMS health database, National

 

                                                                97

 

  1   Disease and Therapeutic Index, estimates the use of

 

  2   drugs by collecting data on drug products

 

  3   mentioned, but not necessarily prescribed, during

 

  4   visits to a panel of approximately 2,000 to 3,000

 

  5   office-based physicians.

 

  6             These data are collected and projected

 

  7   nationally to reflect national prescribing

 

  8   patterns.  It may include profiles and trends of

 

  9   diagnoses, patients, and treatment patterns.  It

 

 10   does not, however, capture patients who

 

 11   self-diagnose and purchase over-the-counter drugs.

 

 12             [Slide.]

 

 13             My final slide on marketing displays data

 

 14   from National Disease and Therapeutic Index.  The

 

 15   vertical axis shows the numbers of users, and the

 

 16   percentages of bar graphs reflect a fraction of all

 

 17   drugs.

 

 18             In 2003, the most common agents

 

 19   recommended by a physician to treat tinea pedis

 

 20   were those listed on this slide, and all of them

 

 21   except for terbinafine are prescription products.

 

 22             [Slide.]

 

                                                                98

 

  1             In the second part of my talk, I will

 

  2   briefly summarize findings from the FDA's Adverse

 

  3   Event Reporting System.  There is a full review

 

  4   included in your background packages.

 

  5             [Slide.]

 

  6             We requested the Office of Drug Safety to

 

  7   review all the adverse event reports received

 

  8   through the Adverse Event Reporting System for all

 

  9   topical antifungal agents focusing on two issues:

 

 10   lack of efficacy and cellulitis cases.

 

 11             [Slide.]

 

 12             There are certain limitations to these

 

 13   data.  There are no adverse event reporting

 

 14   requirements for monograph ingredients.  Therefore,

 

 15   reporting for those drug products may be

 

 16   significantly underrepresented.

 

 17             The report gives only crude numbers for

 

 18   the active ingredients.  That means that you don't

 

 19   have a denominator and cannot estimate the

 

 20   incidence of each report.  Some ingredients are

 

 21   marketed in multiple formulations for several

 

 22   different indications which will not be reflected

 

                                                                99

 

  1   in the report.

 

  2             Finally, causality of what is the primary

 

  3   suspect drug in the report was not assessed.

 

  4             [Slide.]

 

  5             Given all the limitations, the search

 

  6   found a total of 4,741 reports for 15 active

 

  7   ingredients, of which the most common, 35 percent

 

  8   reported a lack of efficacy.

 

  9             This is a very high percentage.  In our

 

 10   experience, we don't usually see that a third of

 

 11   all reports would be associated with a lack of

 

 12   efficacy of the drug.

 

 13             The majority of the lack of efficacy

 

 14   reports in AERS database were associated with these

 

 15   listed four ingredients, and the numbers in the

 

 16   package reflect year of approval of that particular

 

 17   drug in the U.S.

 

 18             Given this high number of low efficacy

 

 19   reports, we worried if there are some consequences,

 

 20   such as missed or mistreated diagnosis.

 

 21             [Slide.]

 

 22             What we could do is search our database

 

                                                               100

 

  1   for cellulitis reports.  The Office of Drug Safety

 

  2   found 13 cases of cellulitis associated with those

 

  3   15 topical antifungal agents.

 

  4             Cellulitis in these 13 cases was reported

 

  5   as an adverse event, and was not a condition being

 

  6   treated.  Although more cases of cellulitis were

 

  7   reported for terbinafine and miconazole, based on

 

  8   this small number of spontaneously submitted

 

  9   adverse event reports, we are unable to say that

 

 10   particular antifungal agents are associated with

 

 11   more or less cellulitis cases than other agents.

 

 12             [Slide.]

 

 13             More on the issue of cellulitis, you will

 

 14   hear later today presented by Dr. Bisno.  I will

 

 15   summarize 13 AERS cases.

 

 16             All 13 cases were diagnosed as cellulitis

 

 17   and were primarily of U.S. origin.  The patients

 

 18   were using the antifungal agents for a variety of

 

 19   reasons, but tinea pedis is the predominant reason.

 

 20             Cellulitis symptoms typically started one

 

 21   day after application of the topical agent, and the

 

 22   sites most often affected were the lower

 

                                                               101

 

  1   extremities.  One patient reported having diabetes

 

  2   and seven patients reported hospitalization.

 

  3             Of the seven hospitalization cases, one

 

  4   patient was hospitalized for worsening Parkinson's

 

  5   disease, and cellulitis in this patient was

 

  6   diagnosed, but was not the reason for

 

  7   hospitalization.

 

  8             The six remaining cases were for

 

  9   cellulitis, however, it was unclear in two cases

 

 10   that the cellulitis occurred before or after the

 

 11   administration of the antifungal agent.

 

 12             [Slide.]

 

 13             The last part of my presentation is

 

 14   over-the-counter labeling issues.

 

 15             [Slide.]

 

 16             There are three types of labeling for

 

 17   topical antifungal drug products:  prescription

 

 18   labeling for prescription drug products and two

 

 19   types of over-the-counter drug labeling for

 

 20   monograph and NDA drug products.

 

 21             Given the efficacy rates for this class of

 

 22   drugs and numerous consumer complaints on the lack

 

                                                               102

 

  1   of efficacy, it is apparent that consumers may not

 

  2   understand that they may not achieve symptom relief

 

  3   or cure by the end of the treatment.  Current

 

  4   labeling does not specifically communicate this

 

  5   message.

 

  6             [Slide.]

 

  7             I will start with prescription labeling.

 

  8   Information conveyed on prescription labeling is

 

  9   targeted at health care providers.  It has detailed

 

 10   information on drug pharmacology, microbiology,

 

 11   preclinical and clinical data, indications,

 

 12   contraindications, warnings, and dosage and

 

 13   administration.

 

 14             [Slide.]

 

 15             This is an example of the indications and

 

 16   usage section on prescription labeling for topical

 

 17   antifungals drug products.  The point of this slide

 

 18   is to show that at it lists specific conditions,

 

 19   that are in yellow and underlined, and specific

 

 20   fungi that particular ingredient is effective

 

 21   against.

 

 22             [Slide.]

 

                                                               103

 

  1             The Directions for Use Section in

 

  2   Prescription Labeling gives the duration of use for

 

  3   the particular product, for example, two weeks for

 

  4   tinea corporis or tinea cruris, and four weeks for

 

  5   tinea pedis.

 

  6             [Slide.]

 

  7             Expectations of treatment are also

 

  8   specified in Prescription Labeling.  Sample of such

 

  9   a labeling is shown on this slide.  If a patient

 

 10   shows no clinical improvement after four weeks of

 

 11   treatment, the diagnosis should be reviewed.

 

 12             This information does not appear on

 

 13   patients' container labeling, and it is very

 

 14   dependent on a physician who is prescribing and

 

 15   giving instructions to the patient.

 

 16             [Slide.]

 

 17             The second type is labeling for

 

 18   over-the-counter monograph products.

 

 19             [Slide.]

 

 20             This is an example of over-the-counter

 

 21   drug facts labeling format, which appears on the

 

 22   carton of each over-the-counter drug.  Labeling of

 

                                                               104

 

  1   OTC monograph ingredients conveys indication in the

 

  2   Uses Section, which follows Active Ingredient

 

  3   Section.

 

  4             There are two statements in the Uses

 

  5   Section on all monograph antifungal products.

 

  6             The first is a required statement, and it

 

  7   states, "Treats or cures most athlete's foot."

 

  8             The second is an optional statement, and

 

  9   states relieves or for relief of a list of

 

 10   symptoms, such as itching, burning, cracking, and

 

 11   scaling.

 

 12             [Slide.]

 

 13             Labeling for monograph ingredients

 

 14   specifies four week duration of treatment and

 

 15   directs the consumer to seek medical advice if

 

 16   symptoms persist at the end of the treatment.

 

 17             Under the Directions Section, it states,

 

 18   "Use daily for four weeks, and if condition

 

 19   persists longer, ask a doctor."

 

 20             [Slide.]

 

 21             Also, the Warning Section states, "Stop

 

 22   use and ask a doctor if irritation occurs or if

 

                                                               105

 

  1   there is no improvement within four weeks," which

 

  2   is the label duration of treatment.

 

  3             [Slide.]

 

  4             The third type of labeling is for

 

  5   over-the-counter NDA drug products.  There are a

 

  6   few differences between the labeling of monograph

 

  7   ingredients and products marketed under NDAs.

 

  8             [Slide.]

 

  9             The Uses Section of NDA nonprescription

 

 10   product labeling is usually consistent with the

 

 11   Uses Section of the products marketed under the

 

 12   monograph except when conditions studied in

 

 13   clinical trials are somehow different.

 

 14             For instance, if patients enrolled into

 

 15   clinical trials get only interdigital tinea pedis,

 

 16   this will be reflected in the Uses Section, as is

 

 17   shown on this slide, "Cures most athlete's foot

 

 18   between the toes, and effectiveness on bottom or

 

 19   side of foot is unknown."

 

 20             The second bullet is also similar to

 

 21   optional indication statements as monograph

 

 22   ingredients.

 

                                                               106

 

  1             [Slide.]

 

  2             The Directions Section on the

 

  3   over-the-counter NDA drug labeling also reflects

 

  4   the treatment regimen studied in clinical trials.

 

  5   We have two types of over-the-counter antifungal

 

  6   drug products for tinea pedis approved under NDAs.

 

  7             This is an example of product that is

 

  8   approved for four-week duration of treatment.

 

  9             [Slide.]

 

 10             This is an example of the labeling for

 

 11   product that is approved for one-week duration of

 

 12   treatment.

 

 13             [Slide.]

 

 14             The main difference between NDA and

 

 15   monograph product labeling is that NDA labeling

 

 16   does not specifically inform consumer about the

 

 17   time of expected outcome.  The warning simply

 

 18   states, "Stop use and ask a doctor if too much

 

 19   irritation occurs or gets worse."  There is no

 

 20   specific information on expected efficacy.

 

 21             [Slide.]

 

 22             Talking about efficacy, I would like to

 

                                                               107

 

  1   show a few examples of over-the-counter labeling,

 

  2   how we convey this information to consumers.

 

  3             [Slide.]

 

  4             Most of over-the-counter products are

 

  5   indicated for acute symptom relief.  Few have a lag

 

  6   time between the treatment initiation and

 

  7   completion, and the expected results.  Efficacy

 

  8   rates usually are not presented on over-the-counter

 

  9   labeling, which few products have.  If this

 

 10   information is present, it is presented in Drug

 

 11   Facts on the carton or in the package insert.

 

 12             [Slide.]

 

 13             One example is one of the newly-approved

 

 14   over-the-counter products that has a lag time

 

 15   between the initiation of treatment and complete

 

 16   response is omeprazole.  The Uses Section and the

 

 17   Direction Section both state that it may take one

 

 18   to four days for full effect.

 

 19             This information is included on the carton

 

 20   label, so consumers can read this statement when

 

 21   considering to purchase the product.  The same

 

 22   information is included in the package insert.

 

                                                               108

 

  1             [Slide.]

 

  2             The next example is an over-the-counter

 

  3   product with the efficacy information is labeling

 

  4   for minoxidil.  The following warning statement on

 

  5   the carton label is also available to consumers at

 

  6   the time of purchase.

 

  7             Under the section When Using this Product,

 

  8   it states, "It takes time to regrow hair.  Results

 

  9   may occur at two months with twice-a-day usage, and

 

 10   for some it may take four months to see results."

 

 11   The same information is included in the package

 

 12   insert.

 

 13             [Slide.]

 

 14             The last example is labeling for

 

 15   famotidine, which includes information about the

 

 16   efficacy rate of the product in the package insert.

 

 17   Two bar graphs demonstrate heartburn relief,

 

 18   prevention, or reduction for the drug product

 

 19   relative to placebo.

 

 20             Because this information is in the package

 

 21   insert, it is not available to consumers at the

 

 22   time of purchase, and we don't know if consumers

 

                                                               109

 

  1   reach this information at all.

 

  2             [Slide.]

 

  3             Today, we are seeking your advice.  Should

 

  4   the following be in the over-the-counter topical

 

  5   antifungal drug label?  Efficacy rates, time to

 

  6   symptom relief, expected time to cure, when to see

 

  7   a doctor, and whether ancillary measures to prevent

 

  8   tinea pedis, such as changing socks, wearing

 

  9   well-fitting, ventilated shoes, or cleaning showers

 

 10   should be emphasized on the label.

 

 11             This concludes my talk.

 

 12             DR. CANTILENA:  Thank you, Dr. Shetty.

 

 13             We have time for questions from the

 

 14   committee.  Dr. Lam.

 

 15             DR. LAM:  I want to go back to the Adverse

 

 16   Event Reporting System data that you presented,

 

 17   specifically regarding the 35 percent lack of

 

 18   efficacy data.

 

 19             Do you have information whether that was

 

 20   mostly associated with the one-week regimen, or the

 

 21   four-week regimen, or a combination of both?

 

 22             DR. SHETTY:  This is all, combination of

 

                                                               110

 

  1   all.

 

  2             DR. LAM:  Okay.  So, we don't even have a

 

  3   sense whether it is primary one week, because the

 

  4   data clearly showed that one week--

 

  5             DR. SHETTY:  We have more reports for

 

  6   one-week products.  Maybe the reviewer for the

 

  7   database will answer your question.

 

  8             DR. CANTILENA:  Yes, there is a comment

 

  9   over here?

 

 10             DR. PITTS:  My name is Marilyn Pitts.

 

 11   Actually, for the lack of efficacy reports, because

 

 12   of the extreme volume, we were unable to look at

 

 13   those reports individually, so we don't know the

 

 14   duration of treatment.  We don't know if's a

 

 15   one-week or four-week or three-week, or even if the

 

 16   patient used it once a day or twice a day.  So, we

 

 17   don't have that information.

 

 18             DR. LAM:  I will say that if there is a

 

 19   way that we can get a sense, it will be important

 

 20   for us to consider some of the issues either this

 

 21   afternoon or tomorrow.  There is no way to do that?

 

 22             DR. CANTILENA:  There probably are

 

                                                               111

 

  1   thousands, right?

 

  2             DR. PITTS:  There are thousands, there is

 

  3   almost 1,700 reports.  It takes a long time to even

 

  4   pull the images and then to go through and

 

  5   categorize and get that information.  It is

 

  6   extremely time-consuming and difficult to get that.

 

  7             DR. CANTILENA:  You know, we have really

 

  8   about three hours before we come back after lunch.

 

  9             [Laughter.]

 

 10             DR. CANTILENA:  There is a lot of FDA

 

 11   employees.  It is not going to happen, Dr. Lam.

 

 12             DR. LAM:  Are we going to consider the

 

 13   question whether--in your executive summary, you

 

 14   indicated that some of the manufacturers are

 

 15   considering developing products of less than

 

 16   one-week treatment duration--so, are we going to

 

 17   consider that at all today or not?

 

 18             DR. GANLEY:  I think it is done in the

 

 19   context of understanding what the cure rates are or

 

 20   effective treatments that we see, and the lack of

 

 21   dose-response information.

 

 22             In that context, if someone did a study

 

                                                               112

 

  1   that showed three days of treatment was as good as

 

  2   one month of treatment, and they figured out what

 

  3   the correct concentration is, well, that is pretty

 

  4   good, I think.

 

  5             The issue I think is we don't get that

 

  6   information.  It is really what beats vehicle and

 

  7   what kind of study is done, and I think that is

 

  8   where the committee has to start addressing, you

 

  9   know, from a dose-response, and one of the

 

 10   questions actually addresses that.

 

 11             I think that is the context, but I have no

 

 12   objection to have a one-day or a three, and we have

 

 13   had inquiries about a one-day treatment product.

 

 14   So, it is what is the bar that we want to set here,

 

 15   is it just that you beat vehicle or is it that we

 

 16   try to maximize the efficacy for consumers.

 

 17             DR. CANTILENA:  We have Clapp, Raimer,

 

 18   Schmidt, and Katz.

 

 19             DR. CLAPP:  This is just a question really

 

 20   based on curiosity.  Because of the sheer volume of

 

 21   complaints you have had, or consumer complaints,

 

 22   what is the method by which a consumer's concern of

 

                                                               113

 

  1   lack of efficacy gets to the FDA?

 

  2             DR. MAHAYNI:  Well, they just report like

 

  3   any other adverse event.  It is actually a

 

  4   complaint, but they call to Adverse Event Reporting

 

  5   System.

 

  6             DR. CLAPP:  But how does the consumer get

 

  7   to the Adverse Event Reporting System?  I don't

 

  8   think many physicians do it on this level.

 

  9             DR. MAHAYNI:  Maybe they call the number

 

 10   on the package and then it comes.  I don't know

 

 11   they come to us.

 

 12             MR. KRESEL:  Can I comment because

 

 13   pharmacovigilance is part of my department, as

 

 14   well?  They call the number that is on the bottle,

 

 15   and then we are required to report it to FDA.

 

 16             DR. CANTILENA:  And then FDA holds an

 

 17   advisory committee.

 

 18             Yes.  Did you have a comment about it?

 

 19             DR. PITTS:  Right, the Med Watch form is

 

 20   also available via the internet.  There is also a

 

 21   1-800 number. But I recognize that patients have to

 

 22   recognize that there is a system in place, and I

 

                                                               114

 

  1   don't think the carton actually has that

 

  2   information specifically, because even for health

 

  3   care providers, to recognize there is a system in

 

  4   place where if you have a complaint about a

 

  5   product, then, you should call.

 

  6             DR. CANTILENA:  Thank you.

 

  7             Dr. Raimer.

 

  8             DR. RAIMER:  I was just going to mention

 

  9   that most of the complaints were against agents

 

 10   that you could over the counter, so a lot of the

 

 11   patients probably had psoriasis or probably had

 

 12   eczema or probably did not have tinea in the first

 

 13   place, so there is no way to really judge whether

 

 14   the patient even had tinea to start with.

 

 15             So, a lot of the complaints, they have

 

 16   similar symptoms, so it would be difficult to know

 

 17   what the patient really had in the first place.

 

 18             DR. CANTILENA:  So, you are saying there

 

 19   is a problem in the setting of an OTC, you know,

 

 20   self-diagnosis?

 

 21             DR. RAIMER:  Yes.

 

 22             DR. CANTILENA:  Well, that is another

 

                                                               115

 

  1   issue that is not on our list of issues.

 

  2             DR. PITTS:  I am sorry, could I make a

 

  3   clarification?  Actually, we believe that the

 

  4   reports for the over-the-counter products are

 

  5   underrepresented.  If you look at the number of

 

  6   reports, the topical terbinafine and topical

 

  7   miconazole, those were previously prescription

 

  8   products, and if we were to probably look at that,

 

  9   we probably would see that most of those or some of

 

 10   those occurred more during the prescription process

 

 11   as opposed to the OTC process, so I don't have any

 

 12   idea.

 

 13             DR. RAIMER:  Even then, a lot of

 

 14   physicians do not do the mycology, they don't the

 

 15   KOH, they judge just clinically, so even then, I

 

 16   think a lot of those probably don't really

 

 17   represent tinea.

 

 18             DR. CANTILENA:  Dr. Schmidt.

 

 19             DR. SCHMIDT:  Before too long, I would

 

 20   like to address this about the cellulitis issue and

 

 21   get this on the table.

 

 22             These case reports are real dogs, you

 

                                                               116

 

  1   know, as far as cellulitis.  I don't think any of

 

  2   these people had really an adverse reaction to any

 

  3   of these medications, and I don't think they were

 

  4   cellulitis.  I think they were contact dermatitis.

 

  5             There was one patient that had TEN

 

  6   probably from Enbrel, and I think to put this down

 

  7   as these 13 cases of cellulitis, this really needs

 

  8   to be brought up and discussed.

 

  9             DR. CANTILENA:  I am not sure what that

 

 10   is, but there is an opportunity right after our

 

 11   next speaker, we will be actually talking about the

 

 12   complications.

 

 13             DR. PITTS:  Can I respond to that?

 

 14   Actually, the prescriber or the reporter identified

 

 15   the cases as cellulitis, we did not make any

 

 16   judgment call in terms of whether they were

 

 17   cellulitis or not, but this was what was actually

 

 18   reported by the health care practitioner that

 

 19   submitted the report for those cases.

 

 20             We are not making any judgment call as to

 

 21   whether or not they are good cases or bad cases.

 

 22   These are just the cases that were reported.

 

                                                               117

 

  1             DR. SCHMIDT:  Woof, woof, woof.

 

  2             DR. CANTILENA:  I think Dr. Schmidt has

 

  3   just made a judgment call.

 

  4             [Laughter.]

 

  5             DR. CANTILENA:  Dr. Katz.

 

  6             DR. KATZ:  I wanted to reemphasize that we

 

  7   should keep in mind the likelihood that the reports

 

  8   of lack of efficacy must represent a minuscule,

 

  9   tiny minuscule portion of people who have lack of

 

 10   efficacy, because the average folks out there are

 

 11   going to use this for what they perceive to be, as

 

 12   Dr. Raimer said, tinea pedis, and it doesn't work.

 

 13   They think it says it should relieve symptoms, it

 

 14   doesn't work in two or three applications, so they

 

 15   stop using it, and they take it as a loss.

 

 16             So, I wouldn't be surprised, if a survey

 

 17   was done at the 0.1 percent of reports you are

 

 18   getting.

 

 19             DR. CANTILENA:  Dr. Benowitz and then Dr.

 

 20   Alfano.

 

 21             DR. BENOWITZ:  It was striking to me that

 

 22   there was almost as many prescriptions by

 

                                                               118

 

  1   physicians for topical antifungals as OTC uses, and

 

  2   my question is, is this for insurance purposes, or

 

  3   is there some evidence that the antifungals that

 

  4   are available by prescription only work better or

 

  5   why is this the case?  It is very striking to me

 

  6   that there is such a huge volume of prescriptions.

 

  7             I guess that question might be to my

 

  8   dermatology colleagues about why that is occurring.

 

  9             DR. CANTILENA:  Anyone?  Comments from the

 

 10   Dermatology Committee?

 

 11             MR. KATZ:  Might it be that some of them

 

 12   were prescribed prior to its becoming OTC, for

 

 13   instance, clotrimazole has been OTC probably for,

 

 14   what, five or eight years, so maybe a lot of those

 

 15   reports were when it was prescription?

 

 16             DR. BENOWITZ:  This was 2003.

 

 17             MR. KATZ:  2003.  I would be very

 

 18   surprised because in recent years, we don't write

 

 19   prescriptions for that.  We just write it for the

 

 20   patients to get it at the drugstore.  We may write

 

 21   it down on a prescription, but without its being a

 

 22   signed prescription.

 

                                                               119

 

  1             DR. SHETTY:  Maybe the physicians are

 

  2   still used to prescribe or advice to use products

 

  3   that were prescription recently.

 

  4             DR. SCHMIDT:  May I comment just a minute?

 

  5   I think a lot of this, I don't really write for

 

  6   prescription topical antifungals anymore.  You

 

  7   know, the majority of them, they may have a funny

 

  8   name, but they will have the medication that is a

 

  9   prescription, but I think a lot of this is

 

 10   marketing by some of the drug companies.

 

 11             I think, to me, there are a lot of people

 

 12   who will still write prescriptions for things, and

 

 13   I think a lot of it is a marketing effort by the

 

 14   drug companies.

 

 15             DR. CANTILENA:  Other comments?

 

 16             DR. WOOD:  As I understand this, we don't

 

 17   know that this is OTC, do we?  I mean the Rx's may

 

 18   well be for systemic antifungals for this

 

 19   indication.

 

 20             DR. SHETTY:  Only topical antifungals.

 

 21             DR. WOOD:  Are you sure?  Are you sure of

 

 22   that?

 

                                                               120

 

  1             DR. SHETTY:  Yes.  We took out the

 

  2   systemic and we took out some ketoconazole.

 

  3             DR. WOOD:  So, the 15.7 million

 

  4   prescription were eaches for itches, that were all

 

  5   topical, is that right?

 

  6             DR. SHETTY:  Yes.

 

  7             DR. GANLEY:  I think that it was pointed

 

  8   out that we can't separate out, particularly for

 

  9   the prescription, which ones were for other

 

 10   conditions other than tinea pedis, and even for the

 

 11   OTCs, there is other claims.  I think tinea pedis,

 

 12   of the three that are over the counter, is probably

 

 13   the most common, but that is the difficulty.

 

 14             But is it a little surprising I think when

 

 15   you see the percentages here or the number of

 

 16   eaches for each.  I think what is interesting, too,

 

 17   is if you look at the National Sales Perspective,

 

 18   which was Slide 8, the Clotrimazole and

 

 19   betamethasone was the highest there in the number

 

 20   of eaches.

 

 21             But if you look at Slide 10, only 12

 

 22   percent of those prescriptions accounted for tinea

 

                                                               121

 

  1   pedis, so the 90 percent of those, you would have

 

  2   to assume then were related to other conditions

 

  3   where if someone saw a rash, didn't know if it

 

  4   required an antifungal or a steroid, so they gave

 

  5   them the combination product.

 

  6             So, it is difficult data to look at, but

 

  7   it is the best that we can do with it.

 

  8             DR. CANTILENA:  Thank you.

 

  9             Did you have a comment, Dr. Whitmore, on

 

 10   this topic?

 

 11             DR. WHITMORE:  I was going to agree with

 

 12   Dr. Schmidt as far as why prescriptions are written

 

 13   for prescription antifungals.  Marketing definitely

 

 14   is a big one, and the pharmaceuticals will come out

 

 15   with studies where they have certain efficacy rates

 

 16   in their control study or whatever, which is better

 

 17   than X drug.

 

 18             Also, oftentimes patients will have used

 

 19   their clotrimazole for two or three days or

 

 20   whatever, a short period of time, come in to the

 

 21   physician and say I am not better, so a

 

 22   prescription is written for something else.

 

                                                               122

 

  1             DR. CANTILENA:  Dr. Alfano.

 

  2             DR. ALFANO:  Dr. Shetty, your Slide 12,

 

  3   you said you searched the AERS data as of March

 

  4   16th.  What is the start date on that data?

 

  5             DR. SHETTY:  All the reports that were

 

  6   received.

 

  7             DR. ALFANO:  So, this is all reports like

 

  8   in the history of man?  I guess my point is so we

 

  9   saw 20 million eaches, whatever that translates to

 

 10   in terms of treatments, just for the year of 2003,

 

 11   so we are talking about tens of millions, if not

 

 12   hundreds of millions, of doses, treatments in this

 

 13   database for a condition for which the previous

 

 14   data presented said 40 percent of people who

 

 15   present to hospitals have the condition and 15 to

 

 16   70 percent of free-living Americans have the

 

 17   condition.

 

 18             So, I guess the trouble I am having is,

 

 19   you know, the perception that this is such a large

 

 20   database, it actually seems to be a very tiny

 

 21   database relative to the number of individuals who

 

 22   have the condition and who have treated the

 

                                                               123

 

  1   condition.

 

  2             DR. PITTS:  If I can respond, the AERS

 

  3   database, this is all reports in the database for

 

  4   those agents, for the topical agents, and we know

 

  5   that there is a significant amount of

 

  6   underreporting that occurs between recognizing that

 

  7   there is an adverse event and then having that

 

  8   person report it.

 

  9             With the topical agents, I would suspect

 

 10   that there is even less of a reason for people to

 

 11   draw a correlation, but there is a different time

 

 12   period where they came on the market, so it is

 

 13   really for all the ones that we have for the life

 

 14   that we have, but these are two different databases

 

 15   between the drug use data and the adverse event

 

 16   databases.  Those are different databases.

 

 17             DR. CANTILENA:  Dr. Katz.

 

 18             DR. KATZ:  I just want to clarify

 

 19   something.  What was mentioned, the

 

 20   over-the-counter products are being prescribed,

 

 21   were you referring to page 5 of this last

 

 22   presentation, where in 2003, most physicians

 

                                                               124

 

  1   recommended antifungals for tinea pedis, is that

 

  2   what you were referring to?

 

  3             DR. BENOWITZ:  No, what I was referring to

 

  4   was actually Slide 7, just showing the volume.

 

  5             DR. KATZ:  What page is that?

 

  6             DR. BENOWITZ:  Page 4, I was just

 

  7   referring to the volume of prescribed topicals.

 

  8             DR. KATZ:  That doesn't mean prescribed,

 

  9   number one.

 

 10             DR. SHETTY:  No, this is all in terms of

 

 11   eaches, whatever goes from manufacturer into the

 

 12   marketplace.

 

 13             DR. KATZ:  That is not prescribed.

 

 14             DR. SHETTY:  That is not prescribed.

 

 15             DR. KATZ:  And on page 5, where it says

 

 16   "National Disease and Therapeutic Index 2003"--

 

 17             DR. SHETTY:  This is a different database.

 

 18             DR. KATZ:  That is physician recommended.

 

 19             DR. SHETTY:  That physician mentioned

 

 20   during the visit.

 

 21             DR. KATZ:  That doesn't physician

 

 22   prescribed.

 

                                                               125

 

  1             DR. SHETTY:  No, that doesn't.

 

  2             DR. KATZ:  So, we should have that

 

  3   straight, because frequently, we will write--not

 

  4   frequently--always we will write if we want patient

 

  5   for tinea pedis to use clotrimazole, miconazole, we

 

  6   will write on the prescription, for patient to

 

  7   remember, so we will write on the prescription

 

  8   without signing it, without the patient's name on

 

  9   the top, just so they remember.

 

 10             That is physician recommended.  That

 

 11   includes not OTC, because

 

 12   Clotrimazole/betamethasone is not OTC, I don't know

 

 13   what Naftifine is, so I think that may have been

 

 14   the source of confusion.

 

 15             DR. GANLEY:  I just want to clarify, on

 

 16   that Slide 10, for the National Disease and

 

 17   Therapeutic Index, that could have been OTC or

 

 18   prescription.

 

 19             DR. SHETTY:  Right, Butenafine is

 

 20   nonprescription.

 

 21             DR. GANLEY:  Right, so it does suggest

 

 22   that the Ciclopirox, which I think is the Rx drug,

 

                                                               126

 

  1   is the most prescribed for tinea pedis.  You would

 

  2   have to think that if that is a prescription drug,

 

  3   and that is the most recommended, that they

 

  4   actually prescribed it.  That's the only thing I

 

  5   can take away from it.

 

  6             DR. CANTILENA:  We have a final comment

 

  7   over here from Mr. Kresel.

 

  8             MR. KRESEL:  I was just going to comment

 

  9   on the AERS database again and that is what then

 

 10   you look at a class of drugs that doesn't have a

 

 11   significant serious adverse event profile, it is

 

 12   not uncommon then to see that the most common

 

 13   consumer complaint would be lack of efficacy.

 

 14             My experience in getting consumer

 

 15   complaints is that consumers learn early on that if

 

 16   they call the sponsor and complain that their

 

 17   product didn't work, they will get a refund.

 

 18             DR. CANTILENA:  That certainly is an

 

 19   incentive, and I think we all have an incentive to

 

 20   take a break.  We will return at 10:30.

 

 21             [Break.]

 

 22             DR. CANTILENA:  Our first speaker for

 

                                                               127

 

  1   after the break here will be Dr. Alan Bisno from

 

  2   the University of Miami, School of Medicine,

 

  3   infectious disease complications of tinea pedis.

 

  4         Infectious Disease Complications of Tinea Pedis

 

  5             DR. BISNO:  Good morning.  My assignment

 

  6   this morning has been to discuss the relationship

 

  7   of tinea pedis and cellulitis of the lower