DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
NONPRESCRIPTION DRUGS ADVISORY COMMITTEE
IN JOINT SESSION WITH THE DERMATOLOGIC
AND OPHTHALMIC DRUGS ADVISORY COMMITTEE
Advisors and Consultants Staff Conference Room
Louis R. Cantilena, Jr., M.D., Ph.D., Chair
LCDR Dornette Spell-LeSane, MHA, NP-C, Executive
DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY
Roselyn E. Epps, M.D.
Robert Katz, M.D.
Paula Knudson (Consumer Rep)
Peter A. Kresel, M.B.A. (Industry Rep)
Sharon S. Raimer, M.D.
Eileen W. Ringel, M.D.
Jimmy D. Schmidt, M.D.
Thomas R. Ten Have, Ph.D.
Elizabeth S. Whitmore, M.D.
Michael G. Wilkerson, M.D.
NONPRESCRIPTION DRUGS ADVISORY COMMITTEE MEMBERS
Michael C. Alfano, D.M.D., Ph.D.
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
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
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
8 chairing this joint session of the Nonprescription
9 Drugs Advisory Committee and the Dermatologic and
10 Ophthalmic Drugs Advisory Committee held here in
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
21 DR. LAM: Francis Lam from the University
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,
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
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
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
Annals of Internal Medicine.
1 DR. WHITMORE: Beth Whitmore. I am a
2 dermatologist in private practice, Wheaton,
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
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
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
current or previous financial involvement with
1 any firm whose product they may wish to comment
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
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.
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
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
21 There are two main anatomic subtypes of
tinea pedis - interdigital, which some people refer
1 to as intertriginous, in between the toes, and
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
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
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
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
20 It may spread to the nail and then
21 particularly is responsible for cases of distal
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.
13 This is a typical representation of an
14 interdigital tinea pedis.
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
it. Rarely, it will be
2 Here we have the vesicular type, more
3 abrupt, more acute, more likely to have symptoms.
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.
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
infect the hair follicles, producing a distinct
1 clinical picture referred to as Majocchi's
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.
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.
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
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
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.
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
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.
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.
20 Let's talk a little bit about
21 epidemiology. A number of studies have rated the
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.
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
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.
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.
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
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.
21 Now, let's go a little bit into how we
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
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
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.
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.
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
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.
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.
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.
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
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.
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
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
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.
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?
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
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
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
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
shoes, and is it appropriate to expect that to
1 go away if they don't change their predisposing
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
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
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?
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
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,
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.
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
20 Then, I think, the same way with this
21 moccasin type tinea, I mean I think this stuff is
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
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.
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.
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.
18 First, I will be looking at the basic
19 clinical trial design.
21 Generally, these trials are randomized,
double-blind, multicenter, vehicle-controlled
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.
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
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.
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.
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.
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.
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.
11 For the study phases, there is usually a
12 treatment period and a post-treatment follow-up
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
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
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.
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
results from selected clinical trials.
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
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'
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.
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.
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
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.
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.
21 This first graph represents the negative
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
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.
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
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.
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
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
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.
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.
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
20 Almost everybody has some signs or
21 symptoms remaining or dermatophyte remaining by the
of one week of treatment. Even for those
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.
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
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.
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
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
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.
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
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.
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
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
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
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
20 Effective treatment may be about half of
21 the patients. Negative mycology rates, around
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
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
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
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
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
7 DR. RINGEL: Thank you.
8 DR. CANTILENA: Thank you. Now we have
9 Mr. Kresel.
10 MR. KRESEL: My question was answered
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.
DR. EPPS: Because it may be that
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
influenced by knowing what we are going to accept
1 as the expected efficacy rate from systemic
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
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
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.
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.
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
information is public.
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.
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
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.
20 What is really included in the monograph
21 system is the conditions of use, and those include
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.
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.
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
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
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
20 Next, the FDA publishes the Advance Notice
21 of Proposed Rule, or ANPR, in the Federal Register
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.
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.
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.
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
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.
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
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.
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.
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.
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
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
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
20 Seven years later, after the NPR was
21 published, the Agency published the TFM. In the
TFM, FDA reviewed 25 clinical studies.
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.
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
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.
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
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
clotrimazole as GRASE active ingredients for the
1 treatment of athlete's foot, jock itch, and
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
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
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
20 DR. MAHAYNI: Actually, the word "most"
21 was added because at the time, there was not a
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
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
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
21 So, it does get a little tricky in how you
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
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
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
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
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
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
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
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.
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
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
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
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.
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.
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.
14 First, I will start with the marketing
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
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
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
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
drug actually used.
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.
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.
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.
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
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.
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.
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.
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
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.
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.
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.
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
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
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.
13 The last part of my presentation is
14 over-the-counter labeling issues.
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
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
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
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
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.
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.
17 The second type is labeling for
18 over-the-counter monograph products.
20 This is an example of over-the-counter
21 drug facts labeling format, which appears on the
carton of each over-the-counter drug.
1 OTC monograph ingredients conveys indication in the
2 Uses Section, which follows Active Ingredient
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
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."
21 Also, the Warning Section states, "Stop
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.
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.
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
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.
10 This is an example of the labeling for
11 product that is approved for one-week duration of
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.
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.
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.
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
information is included in the package insert.
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
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
time of purchase, and we don't know if consumers
1 reach this information at all.
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?
DR. SHETTY: This is 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?
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.
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.
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,
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
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
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,
21 DR. RAIMER: Yes.
DR. CANTILENA: Well, that is
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
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.
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
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.
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.
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
19 DR. CANTILENA: Dr. Benowitz and then Dr.
21 DR. BENOWITZ: It was striking to me that
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
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
20 DR. SHETTY: Only topical antifungals.
21 DR. WOOD: Are you sure? Are you sure of
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
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
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
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
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
have the condition and who have treated the
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
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
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
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
19 DR. SHETTY: Right, Butenafine is
21 DR. GANLEY: Right, so it does suggest
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.
DR. CANTILENA: Our first speaker
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