FOOD AND DRUG ADMINISTRATION



































                         Thursday, May 6, 2004


                               8:00 a.m.




             Advisors and Consultants Staff Conference Room

                           5630 Fishers Lane

                          Rockville, Maryland





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

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






                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.




                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.



                Alan Bisno, M.D.

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



                Jonca Bull, M.D.

                Charles Ganley, M.D.

                Jonathan Wilkin, M.D.



                            C O N T E N T S




      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


                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



                      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



                John Clayton, M.D.                             220



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


      Committee Discussion                                     299




  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




  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




  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.




  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




  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




  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




  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




  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.]




  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




  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.




  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




  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.




  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




  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




  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




  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,




  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




  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,




  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




  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,




  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




  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.




  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.]




  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




  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.




  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.




  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




  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




  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




  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.




  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




  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. 




  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--




  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




  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




  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.




  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




  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




  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




  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




  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




  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




  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




  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




  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.




  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.]




  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




  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




  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




  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




  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




  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,




  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




  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.




  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




  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




  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




  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?




  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




  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.




  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




  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




  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.]




  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.




  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




  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




  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




  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




  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.




  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




  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




  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.




  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




  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.




  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




  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




  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




  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




  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.




  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




  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




  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




  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




  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




  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?




  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,




  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




  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




  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.




  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. 




  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.




  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




  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.]




  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




  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




  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




  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




  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.]




  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




  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




  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.




  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




  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.




  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




  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




  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




  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




  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




  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




  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




  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




  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.




  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




  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.




  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?




  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




  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.




  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




  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




  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.




  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,




  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




  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