1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
NONPRESCRIPTION DRUGS ADVISORY COMMITTEE
IN JOINT SESSION WITH THE DERMATOLOGIC
AND OPHTHALMIC DRUGS ADVISORY
COMMITTEE
Advisors and Consultants Staff
Conference Room
2
PARTICIPANTS
Louis R. Cantilena, Jr., M.D., Ph.D.,
Chair
LCDR Dornette Spell-LeSane, MHA, NP-C,
Executive
Secretary
DERMATOLOGIC AND OPHTHALMIC DRUGS
ADVISORY
COMMITTEE MEMBERS
Roselyn E. Epps, M.D.
Robert Katz, M.D.
Paula Knudson (Consumer Rep)
Peter A. Kresel, M.B.A.
(Industry Rep)
Sharon S. Raimer, M.D.
Eileen W. Ringel, M.D.
Jimmy D. Schmidt, M.D.
Thomas R. Ten Have, Ph.D.
Elizabeth S. Whitmore, M.D.
Michael G. Wilkerson, M.D.
NONPRESCRIPTION DRUGS ADVISORY COMMITTEE
MEMBERS
Michael C. Alfano, D.M.D.,
Ph.D.
(Industry Rep)
Neal L. Benowitz, M.D.
Leslie Clapp, M.D.
Frank F. Davidoff, M.D.
Jack E. Fincham, Ph.D.
Y.W.
Francis Lam, Pharm.D.
Sonia
Patten, Ph.D. (Consumer Rep)
Alastair Wood, M.D.
CONSULTANTS (VOTING)
Alan Bisno, M.D.
Mahmoud Ghannoum, M.Sc., Ph.D.
FDA
Jonca Bull, M.D.
Charles
Ganley, M.D.
Jonathan Wilkin, M.D.
3
C O N T E N T S
PAGE
Call to Order and Introductions:
Louis R. Cantilena, Jr., M.D.,
Ph.D. 5
Conflict of Interest Statement:
LCDR Dornette Spell-LeSane,
MHA, NP-C 8
Welcome and Introductory Remarks:
Charles Ganley, M.D. 11
Efficacy and Labeling Issues
for the Over-the-Counter Drug
Products
Used in Treatment of tinea
pedis
in Patients 12 years of Age
and Over
FDA Presentation
Natural History of tinea pedis and
Dermatophyte
Infections:
Joseph Porres, M.D., Ph.D. 12
Study Design and Efficacy Results for
tinea pedis
Clinical Trials (Rx and OTC):
Kathleen Fritsch, Ph.D. 44
History and Overview of OTC Topical
Antifungal Drug
Products Monograph:
Houda Mahayni, Ph.D. 67
Topical Antifungal Drug Product Labeling:
Daiva Shetty, M.D. 94
Infectious Disease Complications of tinea
pedis:
Alan Bisno, M.D. 127
Microbiology and Dermatophyte Resistance
Related to
the Treatment of tinea pedis:
Mahmoud Ghannoum, M.Sc.,
Ph.D. 154
Committee Discussion 178
4
C O N T E N T S (Continued)
Open Public Hearing
Consumer Healthcare Products Association:
Doug Bierer, Ph.D. 193
Boni E. Elewski, M.D. 194
Doug Bierer, Ph.D. 214
Schering-Plough:
John Clayton, M.D. 220
Novartis:
Helmut H. Albrecht, M.D., M.S.,
FFPM 231
Committee Discussion 299
5
1 P R O C E E D I N G S
2 Call to Order and
Introductions
3
DR. CANTILENA: Good morning. I am Louis
4
Cantilena. I am Director of the
Division of
5
Clinical Pharmacology and Medical Toxicology at the
6
Uniformed
7
Sciences in
8
chairing this joint session of the Nonprescription
9
Drugs Advisory Committee and the Dermatologic and
10
Ophthalmic Drugs Advisory Committee held here in
11
12
Before we get started with the agenda and
13 the
conflict of interest statement, I would like to
14 go
around the room and have everyone introduce
15
themselves and state their affiliation.
We can
16
start to my right since there are more filled seats
17 to
the right than left.
18
DR. RINGEL: I am Dr. Eileen
Ringel. I am
19 a
dermatologist in
20
affiliated with
21
DR. LAM: Francis Lam from the
University
22 of
6
1
Antonio, a member of NDAC.
2
DR. PATTEN: Sonia Patten. I am consumer
3
representative on NDAC. I am an
anthropologist on
4
faculty at Macalester College in St. Paul,
5
Minnesota.
6
DR. WILKERSON: Michael Wilkerson,
Tulsa,
7
Oklahoma, Hillcrest Healthcare Systems.
8
DR. RAIMER: Sharon Raimer,
dermatologist,
9
University of Texas in Galveston.
10
DR. EPPS: Roselyn Epps, Chief,
Division
11 of
Dermatology, Children's National Medical Center,
12
Washington, D.C.
13
DR. BENOWITZ: I am Neal Benowitz
from
14
U.C., San Francisco, internal medicine, clinical
15
pharmacology, medical toxicology, and on the
16
Nonprescription Drug Committee.
17
MS. KNUDSON: Paula Knudson on the
18
Dermatology Committee as the community
19
representative. I am an IRB
administrator.
20
MR. KRESEL: I am Peter A. Kresel,
Senior
21
Vice President of Global Regulatory Affairs with
22
Allergan in Irvine, California. I
am the industry
7
1
representative for the Dermatologic and Ophthalmic
2
Drugs Advisory Committee.
3
DR. ALFANO: I am Michael C.
Alfano, Dean,
4
College of Dentistry at New York University.
5
DR. TEN HAVE: Tom Ten Have,
biostatistics
6 and
epidemiology at the University of Pennsylvania.
7 DR. WOOD: I am Alastair Wood from
8
Vanderbilt.
9
DR. GANLEY: I am Charlie Ganley,
Director
10 of
Over-the-Counter Drugs at FDA.
11
DR. WILKIN: I am Jonathan Wilkin,
12
Director of the Division of Dermatologic and Dental
13
Drug Products, FDA.
14
DR. KATZ: I am Robert Katz,
15
dermatologist, Rockville, Maryland and Clinical
16
Assistant Professor of Medicine at Georgetown. I
17 am
part of the FDA Advisory Committee.
18 DR. SCHMIDT: I am Jimmy Schmidt from
19
Houston, Texas.
20
DR. DAVIDOFF: I am Frank
Davidoff. I am
21 on
NDAC. I am an internist and Editor
Emeritus of
22 the
Annals of Internal Medicine.
8
1
DR. WHITMORE: Beth Whitmore. I am a
2
dermatologist in private practice, Wheaton,
3
Illinois.
4
LCDR SPELL-LeSANE: Dornette
Spell-Lesane,
5
Acting Executive Secretary for NDAC.
6
DR. CANTILENA: Did we miss
anyone?
7
Go ahead, Dr. Bisno.
8
DR. BISNO: I am Alan Bisno,
Professor
9
Emeritus of Internal Medicine, University of Miami,
10
School of Medicine.
11 DR. CANTILENA: Thank you.
12
Dornette will read the conflict of
13
interest statement for this meeting.
14 Conflict of Interest
Statement
15
LCDR SPELL-LeSANE: Good
morning. The
16
following announcement addresses the issue of
17
conflict of interest with respect to this meeting
18 and
is made a part of the record to preclude even
19 the
appearance of such at this meeting.
20
Based on the agenda, it has been
21 determined
that the topics of today's meeting are
22
issues of broad applicability and there are no
9
1
products being approved at this meeting.
Unlike
2
issues before a committee in which a particular
3
product is discussed, issues of broader
4
applicability involve many industrial sponsors and
5
academic institutions.
6
All Special Government Employees have been
7
screened for their financial interests as they may
8
apply to the general topics at hand.
To determine
9 if
any conflict of interest existed, the Agency has
10
reviewed the agenda and all relevant financial
11
interests reported by the meeting participants.
12 The Food and Drug Administration has
13
granted general matters waivers to the Special
14
Government Employees participating in this meeting
15 who
require a waiver under Title 18, United States
16
Code, Section 208.
17
A copy of the waiver
statements may be
18
obtained by submitting a written request to the
19
Agency's Freedom of Information Office, Room 12A-30
20 of
the Parklawn Building.
21
Because general topics impact so many
22 entities,
it is not prudent to recite all potential
10
1
conflicts of interest as they apply to each member,
2
consultant, and guest speaker.
3
FDA acknowledges that there may be
4
potential conflicts of interest, but because of the
5
general nature of the discussion before the
6
committee, these potential conflicts are mitigated.
7
With respect to FDA's invited industry
8
representatives, we would like to disclose that Mr.
9
Peter Kresel and Dr. Michael Alfano are
10
participating in this meeting as industry
11
representatives acting on behalf of regulated
12
industry. Mr. Kresel is employed
by Allergan, Dr.
13 Alfano
is the Dean of College of Dentistry at New
14
York University.
15
In the event that the discussions involve
16 any
other products or firms not already on the
17
agenda for which FDA participants have a financial
18
interest, the participants' involvement and their
19
exclusion will be noted for the record.
20
With respect to all other participants, we
21 ask
in the interest of fairness that they address
22 any
current or previous financial involvement with
11
1 any
firm whose product they may wish to comment
2
upon.
3
Thank you.
4
DR. CANTILENA: Thank you,
Dornette.
5
Now we will have our kickoff from Dr.
6
Charlie Ganley of FDA.
7 Welcome and Introductory
Comments
8
DR. GANLEY: Thank you. I am just going
9 to
say a few words.
10
First, I wanted to thank the members of
11 the
Nonprescription Drugs Advisory Committee and
12 the
Dermatologic and Ophthalmic Drugs Advisory
13
Committee for participating in this discussion.
14
Today, we are going to talk about tinea
15
pedis. It is not a high profile
disease, but it
16
does affect millions of people in the United States
17
each year, and it is important to those individuals
18 who
have the disease.
19
So, we are looking forward to the
20
discussion today. I think the
executive summary
21 and
the questions provide you with some of the
22
concerns we have, the current products, and the
12
1
current development programs that are going on
2
right now.
3
I think John Wilkin is going to talk a
4
little later, prior to answering the questions
5
about some of the issues, so I think we ought to
6
just start with the FDA presentations.
7
DR. CANTILENA: Thank you, Dr.
Ganley.
8 For
the members of the committee, your blue folder
9 in
front of you has slides for all FDA speakers
10
except for the last person, so as soon as we get
11
those, we will hand those out to you.
12
We would like to then start. Dr. Porres
13
from FDA will be the first FDA speaker, and he will
14
then be followed by four other speakers.
15 FDA Presentation
16 Natural History of Tinea Pedis
and
17 Dermatophyte Infections
18
DR. PORRES: I am Joseph Porres, a
medical
19
officer in the Division of Dermatological and
20
Dental Drug Products. I don't
suppose that is a
21
conflict of interest for this presentation.
22
[Slide.]
13
1
I would like to start by sharing with you
2 a
few points about the natural history of tinea
3
pedis. Later on, I would also like
to share some
4
points with you about clinical trials for tinea
5
pedis, just to set the tone.
6
In the first part, we talk about natural
7
history, and I will cover the types of clinical
8
presentations for tinea pedis, dermatophyte
9
species, which most often cause this infection, the
10
so-called dermatomycosis syndrome, some of the
11
factors which may predispose someone to develop
12
tinea pedis, factors that complicate tinea pedis
13 and
complications that may develop from tinea
14
pedis.
15
I will try to give you a brief outlook of
16
epidemiology, and will talk about recurrence, some
17
people who have been treated. We
talk about
18
diagnosis of tinea pedis and a little bit about
19
treatment.
20
[Slide.]
21
There are two main anatomic subtypes of
22
tinea pedis - interdigital, which some people refer
14
1 to as intertriginous, in between the toes, and
2
plantar.
3
Within the plantar, there are two distinct
4
types - moccasin and vesicobullous.
5
Let's talk a little bit more about each
6 one
of these.
7
The interdigital often comes
with
8
pruritus, erythema, some scaling, occasionally
9
fissure and maceration particularly if there has
10
been overgrowth with some bacterial or candida
11
species.
12
The moccasin type, which is the one
13
affecting the sides of the foot, tends to be
14
dry-looking and scaling, sometimes there may be
15
pruritus, sometimes there may be some erythema.
16
The vesicobullous usually affects the
17
plantar of the foot or the arch of the foot, and
18 the
vesicles is the main component.
Oftentimes,
19
there may be itching, scaling, and erythema.
20
Most patients seem to present with a
21
combination of some of these features.
It is rare
22 to
find someone who has just one pure type.
15
1
Then, we have the term "athlete's foot,"
2
which is sort of a generic term that the layman
3
uses when they refer to just about any type of
4
fungus infection on the foot. It
is a loose term,
5 it
is hard to define. It is not really a
medical
6
term.
7
[Slide.]
8
Now, about the organisms that tend to
9
cause these infections. The most
common is
10
Trichophyton rubrum, which is the predominant
11
organism in this country since World War II, and it
12
tends to account for about anywhere from 60 to 80
13
percent of cases of tinea pedis, mainly tends to
14
cause the plantar, moccasin type.
15
Occasionally, there are some teeny tiny
16
blisters on the plantar of the foot that quickly
17 dry
up and leave a collarette of scales, which has
18
been described as very typical for Trichophyton
19
rubrum.
20
It may spread to the nail and then
21
particularly is responsible for cases of distal
22
subungual onychomycosis. It can
also spread to
16
1
other body parts, which we will see in a minute.
2
The second most common species of
3
dermatophyte is Trichophyton mentagrophytes,
4
usually responsible for about 15 percent of cases.
5 It
tends to be causative for the vesicular type,
6 and
it may also spread to the nails, but it tends
7 to
mostly cause superficial white nail involvement.
8
Finally, we have Epidermophyton floccosum,
9
which tends to affect about 7 percent of the cases,
10 and
then there are other species, which are rare,
11
also recovered in cultures of larger studies.
12
[Slide.]
13
This is a typical representation of an
14
interdigital tinea pedis.
15
[Slide.]
16
Here we have the tinea plantaris with the
17
tiny collarettes. These were
vesicles that broke
18
readily, and as you can see, clearly resembles
19
dryness of the foot. Many
patients will look at
20
these and think it is just dryness, and even some
21
physicians may consider this dryness and not treat
22
it. Rarely, it will be
symptomatic.
17
1
[Slide.]
2
Here we have the vesicular type, more
3
abrupt, more acute, more likely to have symptoms.
4
[Slide.]
5
This is the typical moccasin type, which
6
again many patients will look at this and think,
7 oh,
my God, my feet are very dry, and they won't
8
even suspect they have a fungus.
Oftentimes, it
9
will itch, and even some physicians may call this
10
just dry skin.
11
[Slide.]
12
Now, let's talk about the dermatomycosis
13
syndrome described for Trichophyton rubrum. The
14
hallmark is the moccasin type infection, and from
15
here it can spread. There can be
spreading between
16
household members back and forth. It can spread
17
directly to the nails or to the interdigital area
18 of
the feet.
19
Then, by spreading distally, it can go
20
into the hands and from there to the fingernails.
21 It
can go to areas of the body, sometimes it may
22
infect the hair follicles, producing a distinct
18
1
clinical picture referred to as Majocchi's
2
granuloma.
3
It can go to the groin also, and then it
4 is
called tinea cruris. These types of
spreading
5 usually
occur when we dress and bring our clothes
6 up,
passing by the foot, or with towels we may use
7 for
different areas of the body.
8
[Slide.]
9
Now, there are some predisposing factors
10
that could be important. It has
been said
11
repeatedly that tinea pedis is far more common in
12
closed communities like army barracks and boarding
13
schools, or among people who frequent public baths
14 and
swimming pools.
15
It is probably important to have some
16
local trauma for the infection to set in, trauma
17
like you can develop if you go on a long march and
18
your feet are going to be sweaty and hot and
19
occluded by occlusive foot gear, and you may suffer
20 from immersion into water or end up with wet
feet
21
just from your own perspiration.
22
If the shoes are very tight fitting, there
19
1 may
be repeated friction and trauma, which also may
2
contribute to set up a portal of infection for the
3
dermatophyte.
4
It has been said that usually, it is
5
important to have a species of organism to be able
6 to
cause infection. This was demonstrated
in
7
Vietnam, for instance, until they found that it was
8 the
hair of rats that was the vehicle for the
9
infection of many of the soldiers with
10
Trichophyton.
11
Again, if you look at a household, it is
12 said,
at least in one study, that about 17 percent
13 of
the members of the household are likely to have
14
concomitant tinea pedis, and there may be a
15
familial predisposition based on perhaps inadequate
16
immunological response that may facilitate these
17
patients to develop a chronic infection.
18
[Slide.]
19
Now, tinea pedis may become complicated if
20 the
patient is either immunosuppressed or has any
21
atopic constitution, or is diabetic, or has
22
compromised circulation, or there is repeated
20
1
trauma, again ill-fitting shoes or tight-fitting
2
shoes, and many of these things are more likely to
3
appear among the geriatric population.
4
[Slide.]
5
One interesting complication from tinea
6
pedis could be cellulitis. It is
probably not
7
exceedingly common, but among people who do have
8
cellulitis of the lower extremities, a great number
9 of
them seem to have a pre-existing tinea pedis.
10
This might have been unrecognized for a long time
11 by
patient and physician.
12
Treatment may not have been given, or, if
13
given, maybe was used too short a period of time,
14 or
perhaps the nail was not treated and reinfection
15
kept taking place, or maybe it was a diabetic
16
patient who had decreased sensory perception and
17
would not recognize the pruritus that otherwise may
18
alert one of having the infection.
19
[Slide.]
20
Let's talk a little bit about
21
epidemiology. A number of studies
have rated the
22
degree of infection among the population at large,
21
1 and
do find rates as low as 15 percent and as high
2 as
70 percent.
3
It has been said that among people who
4
attend the general clinic, if one were to look at
5
their feet, about 40 percent of them tend to have
6
tinea pedis, oftentimes unsuspected by the patient.
7
However, among the patients who do go to a
8
doctor to seek treatment for the tinea pedis,
9
interestingly, many of them do have already nail
10
involvement with a fungus. There are a number of
11
cases that remain undiagnosed for a long time.
12
Interestingly, dermatophytes have been
13
isolated from the feet of normal individuals in
14
varying rates. They have been
isolated from public
15
showers, from swimming pools, and from shoes and
16
socks of affected individuals.
17
[Slide.]
18
Now, what happens to a person who has been
19
treated afterwards? It has been
very hard to find
20
some data that I can share with you about this.
21
Luckily, I found one set of two papers
22
which look at the same population, one by
22
1 Bergstresser, where they treated a number of
people
2
with 200 fungals, twice a day, either for one week
3 or
for four weeks, and then, a second paper by
4
Elewski and others, where they look at the same
5
patients 15 to 18 months later.
6
[Slide.]
7
So, let me show you what they found.
8
There were 193 evaluable patients with interdigital
9
tinea pedis. Again, the treatment
was twice a day,
10 and
it was either terbinafine cream in this case or
11
clotrimazole cream, and there were 2 ounces for
12
each drug treatment, one week or four weeks.
13
They looked at it 15 to 18 months later,
14 and
for this particular part of the study, they
15
only reported the mycology cure rates.
16
[Slide.]
17
There were 193 patients evaluable in the
18
study. Of these, 130 were
declared mycology cure
19 at
the end of 12 weeks of the study. Of
these,
20
they were able to follow up 93 during the 15 to 18
21
months of the second part of the study, and, of
22
these 93, 44 felt that they needed more treatments,
23
1 so
we consider this either insufficiently treated,
2 or
a relapse, or a reinfection, and there is really
3 no
way at this point to distinguish which one of
4 the
three possibilities we are dealing with here.
5
Then, they looked at the patients who
6
didn't feel they had need for more treatment.
7
There was it appeared to be cure, and they took
8
cultures. Of these 49, 24
developed a positive
9
culture anyway.
10
As a sideline, of these 24, 8 of them had
11 an
organism that this time was identified with a
12
different name than the one given at baseline. It
13 is
hard to tell whether one of the two might have
14
been misdiagnosed or whether this actually
15
represents infection with a different organism.
16
So, all together, we see that there were
17 78
percent of the people who had originally been
18
called "mycology cure," who relapsed or reinfected
19 at
some time after the treatment.
20
[Slide.]
21
Now, let's go a little bit into how we
22
make a diagnosis of tinea pedis.
The main part
24
1
here is clinical. We look at the signs and symptoms
2 and
try to recognize what may be part of the
3 typical picture.
4
It can be aided by mycology, which
5
consists of a direct microscopic examination,
6
usually referred to as KOH, and of which there are
7
many variants, and then the culture.
8
The nice thing about the KOH is that it
9 can
provide a quick diagnosis, confirming the
10
clinical impression, and therefore it would help to
11
avoid delaying giving the indicated treatment or
12
avoid prescribing a treatment that may not be
13 appropriate.
14
[Slide.]
15
Now, if a physician wants to treat tinea
16
pedis and goes to the literature to see how to
17
treat it, you will find information similar to
18
this. This is just one example.
19 I look at this current textbook,
20
"Treatment of Skin Disease," by Lebohl, published
21 by
Mosby in 2003, and they report results for
22
terbinafine from different studies, clotrimazole,
25
1
miconazole, and a couple of others.
2
Oftentimes, they give the results for
3
mycology cure and other times they just say cure
4
rates and do not specify what kind of cure it was,
5 but
looking at the numbers here in the right
6
column, I suspect that they are mostly referring to
7
mycology cures.
8
Sometimes they tell us how long were those
9
patients treated that reached these rate numbers,
10 and
oftentimes they will tell us the dosage that
11 was
used, but sometimes they don't tell us.
They
12
just say, well, terbinafine 97 percent cures, and
13 we
don't know what this means. It is
unfortunate
14
that this information is so scant that it is hard
15 for
the clinician to really figure out what these
16
numbers represent.
17
I would like you to sort of keep an idea
18 in
mind about the magnitude of these rates when the
19
statistician brings data from the studies that she
20 had
reviewed, just keep this in mind.
21
[Slide.]
22
Now, let's talk a little bit about
26
1
clinical trials for tinea pedis.
I would like to
2
focus a little bit on dose ranging studies and on
3
clinical trials for safety and efficacy.
4
[Slide.]
5
Dose ranging studies for tinea pedis are
6
particularly always recommended by the Agency when
7
drug developers come here for meetings and
8
orientation. Unfortunately, most of the time this
9
recommendation is ignored. This
is too bad because
10
with dose ranging studies, it could be helpful to
11 try
to determine what is the most interesting dose
12
that may have the best safety and efficacy profile.
13
Now, in dose ranging studies, usually,
14
there are three elements that can be studied: drug
15
strength, drug concentration, the frequency of
16
application, and the duration of treatment.
17
We have some limitations here.
Drug
18
strength, sometimes there are certain higher doses
19
that we cannot study either because they may have
20 an
unsafe profile or for chemistry reasons, perhaps
21 the
drug reaches maximum solubility and we cannot
22
study any concentrations above that.
27
1
Now, frequency of application also has
2
some limitations. We can expect
compliance of
3
patients to reach up to a certain limit.
If we
4
tell a patient to apply something once a day or
5
twice a day, they are likely to do it.
If we tell
6
them to use it 74 times a day, they are not likely
7 to
do it, so studying things more than twice a day
8
probably is not very practical.
9
So, we are left with duration of treatment
10
which is where we have the greatest latitude,
11
however, marketing pressures seem to make drug
12
developers aim for ever decreasing durations of
13
treatment, perhaps so they can advertise that a
14
product can kill the organism in fewer days than
15 the
other competing product. Sometimes these
may
16 be
at the expense of efficacy.
17
[Slide.]
18
Now, in clinical safety and efficacy
19
trials, I would like to focus about how do we
20
assess results of these trials and what the
21
outcomes from these assessments will be.
22 [Slide.]
28
1
What we assess or what has been assessed
2
routinely is mycology, again direct microscopic
3
examination and mycology culture, and clinical, a
4
variety of signs and symptoms, and there are
5
studies which have just looked at a couple of
6
these, others that look at many.
7
Others make a composite of this, others
8 may
use what is called the investigator's global
9
assessment, which is kind of like a comprehensive
10
picture of what the disease looks like at that
11
particular point.
12
[Slide.]
13
The outcomes from these assessments are
14
usually mycology cure, which involves having a
15
negative KOH in a negative culture.
We don't like
16
this term very much at the FDA.
We would like to
17
refer to it as negative culture because perhaps it
18 is
not really a cure in many cases unless it is
19 accompanied
by a clinical cure, as well.
20
Then, we have clinical outcomes.
One is
21
effective treatment, which requires not only
22
negative mycology or mycology cure, but also
29
1
absence of symptoms and at most, some residual
2
signs remaining.
3
Here, I should introduce or remind you of
4 a
concept of skin turnover. The epidermis
has a
5
maximum speed at which it can turn over its cells,
6
which is about four weeks, so you could have a
7
patient who is actually a cure, and may still have
8
some residual erythema or some residual scaling.
9
However, after these four weeks, we should
10 be
expecting that these residual signs should not
11 be
present in a patient who is a cure.
12
Then, we go into complete cure, which is
13 the
gold standard, where mycology is negative or
14
mycology cure, and there are no signs or symptoms
15
left of the disease.
16
[Slide.]
17
Now, in clinical safety and efficacy
18
studies, oftentimes the inclusion/exclusion
19
criteria that come with the protocols do not seem
20 to
mimic the population which could be expected to
21
actually use these products in the real world once
22 the
product is approved.
30
1
For instance, they tend to include only
2
people who are very healthy and who perhaps have
3
disease limited to just a small area, such as toe
4
webs, and exclude more difficult cases to treat
5
that might reduce their overall efficacy rate, so
6
they exclude people with onychomycosis or who have
7 the
moccasin type, which they apparently think is
8
harder to treat, and they will exclude people who
9 are
diabetic or immunosuppressed, or who may have
10
compromised circulation, but all of these patients
11
would be expected, they will be users of the
12
product later on.
13
At this point, I would like to introduce
14 Dr.
Kathleen Fritsch, who will give you a summary
15 of
her review of some studies.
16
Thank you for your attention.
17
DR. GANLEY: If anyone had
questions for
18 Dr.
Porres now, they could probably ask them.
19
DR. CANTILENA: We actually have
time
20
slotted, actually, plenty of time before lunch, but
21 I
guess if there are specific questions, perhaps we
22
have time for one or two specific questions for Dr.
31
1
Porres before we go to the next speaker.
2
Yes, Dr. Ten Have.
3
DR. TEN HAVE: I have a question regarding
4 the
definition of the efficacy rates on page 9 that
5
were reported. I missed the
definition. Could you
6
just repeat it?
7
DR. PORRES: In the handout, page
9?
8
DR. TEN HAVE: Handout, page 9.
9
DR. PORRES: The question, if I
10
understood, is how is cure defined here?
Okay.
11
DR. TEN HAVE: How are the
efficacy rates
12
defined based on a cure definition?
13
DR. PORRES: I am glad you asked that
14
question, because the clinician, looking at this
15
information in textbooks, should be asking the same
16
question. The point is that when
you look at the
17
sources in the literature, they don't tell you
18
anything. They just give you some
rates and hope
19
that you will think that these products are all
20
wonderful, and they don't tell you how these
21
numbers are derived, and you are lost.
22
So, that is precisely the point I was
32
1
trying to make.
2
DR. CANTILENA: So, the answer is
they are
3
really not well defined.
4
DR. PORRES: They don't tell us,
they just
5
give us a summary.
6
DR. CANTILENA: Dr. Wood.
7
DR. WOOD: My question may be an
extension
8 of
the last one. On the last slide, you
talk about
9 the
exclusion criteria that include harder cases to
10
treat. I presume you mean by
that, that the
11
outcome is poorer, is that right, that the cure
12
rate is lower?
13
DR. PORRES: The people who may be
harder
14 to
treat--
15
DR. WOOD: I understand that is what
it
16
says, but do you mean by that, that they are harder
17 to
treat because the efficacy is lower in that
18
group? I mean diabetics aren't
harder to treat per
19 se,
and they must either have poorer outcome, or do
20 you
mean that diabetics can't rub the stuff on
21
their foot, you know, what do you mean by that?
22
Just to finish the question, I assume what
33
1 is
meant there is that the outcome is poorer in
2
these patients, what are the data to support that?
3
DR. PORRES: I think you will have
to ask
4 the
drug developers why do they want to exclude
5
those patients in the first place.
They don't give
6 us a rationale, they just want to exclude them
7
maybe to keep the study neater, and I am not aware
8 of
any data that actually shows whether they are
9
easier to treat or more difficult to treat, but
10
that is the way they design their protocols.
11
Now, the moccasin type--
12
DR. WOOD: So, the slide says you
excluded
13
harder cases.
14
DR. PORRES: Yes.
15
DR. WOOD: Are there data to
support them
16
being harder, or is that just--
17
DR. PORRES: They assumed they are
going
18 to
be harder.
19
DR. WOOD: I see.
20
DR. PORRES: For instance, if
there is
21
nail involvement, they may be more prone to have
22
reinfection from the nail if they are not treating
34
1 the
nail at the same time, so they suspect that
2
those are going to complicate the outcomes.
3
DR. WOOD: But you have no data to
say
4
that the outcome is poorer in these patients?
5
DR. PORRES: No.
6
DR. WOOD: That is what I am
trying to get
7 at.
8
DR. PORRES: We don't have the
data.
9
DR. WOOD: It relates directly to
the
10
question. That is why I am
pushing this part.
11
DR. PORRES: No.
12
DR. CANTILENA: Dr. Fincham.
13
DR. FINCHAM: Dr. Porres, I am
assuming
14
that these criteria, either inclusion or exclusion,
15 are
set by the manufacturer, there is no
16
constraints on those designs.
17
DR. PORRES: Well, they send us
the
18
protocols. We look at them, and
sometimes, you
19
know, we make suggestions. We encourage the study
20 of
all comers. Sometimes they insist they
want to
21
study just a very narrow group, and sometimes we
22 are
more influential than others.
35
1
DR. CANTILENA: A comment from Dr. Wilkin.
2
DR. WILKIN: Actually, you caught
it right
3 at
the very end, and sometimes they do. We
have
4 had
some tinea pedis trials where patients with
5
onychomycosis, often the same fungus that is
6
affecting the plantar surface of the foot is also
7 in
the nail.
8
We have had some trials like that, so I
9
think it is not all or none, and it is true that we
10
don't know for sure that they are harder, but we
11
sense that there may be some lower efficacy, but we
12
don't have good numbers on that, that is correct.
13
DR. CANTILENA: Dr. Alfano.
14
DR. ALFANO: My question relates
to the
15
fact that you spoke about predisposing factors, and
16 you
mentioned trauma is regularly associated to get
17
this infection started.
18
What happens with those predisposing
19
factors in the course of the disease, i.e., if the
20
subject doesn't change their tight shoes, do they
21
start with hyperkeratosis from the irritation from
22 the
shoes, and is it appropriate to expect that to
36
1 go
away if they don't change their predisposing
2
factors?
3
DR. PORRES: There is really no
hard data
4
looking at what happens on a series of cases from
5 the
beginning to the end, but this is the general
6
gestalt, the general feel for what is felt, how
7
this disease evolves, and it is felt that these
8
factors are important in either facilitating
9
development of the disease or in making it worse,
10 but
there is no hard data that anyone would show if
11 you
wear your shoes 10 minutes longer, you are more
12
prone to have disease than it you wear them 10
13
minutes less, but it is felt that usually, that is
14 the
case, but there is no hard data for any of
15
this. This is kind of like a
field that has
16 developed
through the years, that most people seem
17 to
agree as a general concept.
18
DR. CANTILENA: Our final question
over
19
here. Dr. Benowitz.
20
DR. BENOWITZ: Two questions. The first
21
one, you had said that as many as 70 percent of the
22
general population can have positive cultures.
37
1
Given that in the recurrent studies, does a
2
persistent positive culture with a clinical
3
response mean that there will be a clinical
4
recurrence?
5
DR. PORRES: Could you rephrase
the
6
question again? I am sorry.
7
DR. BENOWITZ: You said that as
many as 70
8
percent of the population, assumingly not
9
clinically infected, can have positive cultures.
10
DR. PORRES: No, no, that is not
what I
11
said, I am sorry. What I said is
that some people,
12
published reports looking at the incidence of tinea
13 pedis
in a particular population like maybe in
14
India or Canada, or somewhere, and they report that
15
they found 70 percent of the people at large had
16 the
disease.
17
DR. BENOWITZ: Oh, had the
clinical
18
infection. I guess the other part
is still valid.
19
If you have a positive culture, but you
20
have a clinical response, does that always
21
translate into a later clinical recurrence?
22
DR. PORRES: If you have--
38
1
DR. BENOWITZ: You have been
treated, you
2
have a clinical response, but you do not have a
3
mycologic response, does that always predict a
4
clinical recurrence?
5 DR. PORRES: Well, if there is clinical
6
cure, you say, but the culture is still positive?
7
DR. BENOWITZ: Yes.
8
DR. PORRES: That would never be
called a
9
success by definition, so I don't think anybody has
10
ever looked to see what happened to the patient
11
afterwards. It is just declared a
failure, and
12
there is no follow-up.
13
DR. BENOWITZ: Is there any issue
of a
14
carrier state, like we see with other infections?
15 Is
that an issue here?
16
DR. PORRES: Possibly, there is no
hard
17
data, there is contamination with other household
18
members or other school members or other army
19
fellows, you know, but there is really no hard data
20 for
any of these things.
21
DR. BENOWITZ: Okay. The second question
22 is
if an expert dermatologist is seeing a patient
39
1 who
has these infections, and they are diabetic or
2
they are immunocompromised, would they be treated
3 any
differently from any other patient? What
is
4 the
standard of care for treatment of these more
5
high risk patients?
6
DR. PORRES: The dermatologist
would want
7 to
make sure that whoever is taking care of the
8
diabetes for that patient would have provided
9
adequate treatment or if they are
10
immunocompromised, that they have the adequate
11
treatment, you know, just as a general feel for my
12
practice, I have seen people who have maybe HIV or
13
something else, and they have tinea, and I can
14
figure they are much harder to treat and the
15
treatment is much, much longer, and oftentimes they
16 stop
because they get tired of treating these for
17
months or they stop when they feel better, thinking
18
that maybe they have cured the problem, but it was
19
just a little bit too early, and within a few
20
months they come back with full-blown disease.
21
So, the dermatologist can treat the skin,
22 but
usually, we need the concurrence of the other
40
1
types of physicians who treat the other components
2
like vascular disease or whatever.
3
DR. BENOWITZ: I guess my point is
would a
4
dermatologist initiate systemic antifungal therapy
5
rather than try topical therapy first if someone is
6 at
high risk?
7
DR. PORRES: Well, that is an interesting
8
question and I didn't want to address it here
9
because we are talking about topical antifungals,
10 but
if you look at the textbooks and references on
11 how
to treat the disease, there are many who would
12 say
that you need to use also systemic treatment
13 for
tinea pedis together with topical antifungals.
14
Some still say that.
15
DR. BENOWITZ: I think it is
important for
16 us
because that really affects labeling for high
17
risk patients. We need to know what patients need
18 to
understand about their disease.
19
DR. PORRES: You are absolutely
correct,
20 and
that is why we are here today.
21
DR. CANTILENA: Thank you, Dr.
Benowitz.
22
We have one final comment from Dr.
41
1
Schmidt, and then, since you work here, Dr. Wilkin,
2 you
can have the final, final comment.
3 DR. SCHMIDT: I think at least in Texas, I
4
don't think we really cure these people of any of
5
these things, and I think that moccasin type tinea,
6 if
someone has an immunologic defect where they
7
just can't process and kill the T. rubrum, then, in
8
your first slide of the person pulling the toes
9
apart, the little piggies, you know, are too close.
10
I think the mechanical trauma comes first,
11 and
then the tinea is secondary, so I think it
12
behooves us to have some like education, you know,
13 for
the patients, because unless you can keep the
14 air
flowing with Thinsulate socks, spacers, drying
15
agents, powders, changing shoes, wearing wooden
16
shoe trees, you know, there are a million things
17
that you can do, you will never cure these people
18
with this interdigital tinea, never ever in your
19
lifetime.
20
Then, I think, the same way with this
21
moccasin type tinea, I mean I think this stuff is
22 in
the environment, and these people are going to
42
1 get
it recurrently, because it seems like people
2
come in during the summer and their fungus flares
3 up,
and during the winter, even if you don't treat
4
them, these things tend to clear up.
5
Now, I wanted to comment on this thing of
6
whether we treat people more aggressively when they
7
have problems. It's hard to treat patients who have
8
diabetes or they have recurrent cellulitis.
9
Usually, these people, it comes from the fourth and
10
fifth toe web, you know, from this macerated
11
interdigital tinea is the point of entry, and, yes,
12 I
do, I will sometimes treat these people
13
systemically, but I think drying agents and good
14
foot care is probably the most important thing.
15
The same thing with the onychomycosis, you
16
know, just simple things will help this, but I
17
never tell anybody I am going to cure them. I just
18
say, listen, when this stuff comes back, you are
19
just going to treat it again.
20
DR. CANTILENA: Dr. Wilkin.
21
DR. WILKIN: I would like to
respond to
22 Dr.
Benowitz's question about after treatment, can
43
1 you
still get the dermatophytes, and there is a
2
paper in the Journal of the American Academy of
3
Dermatology, February 1995, Dr. Elewski is the
4
first author, it's a multi-authored publication.
5
Long-term outcome of patients with
6
interdigital tinea pedis, treated with terbinafine
7 or
clotrimazole, and one of the points made is that
8
even after successful treatment in the sense that
9 the
inflammatory signs and symptoms have gone away,
10 one
can still culture the organism.
11
So, I think this is the experience that
12
most dermatologists have, as well, and then I was
13
going to add the part that Dr. Schmidt has already
14
taken care of, you know, the dermatologist, I
15
think, attacks the tropical environment inside the
16
shoe, which is what keeps the fungus going.
17
Also, sometimes the dermatophyte
can
18
actually survive on the inside surface of the shoe,
19 so
we know that some patients actually, eventually
20
need to get a new pair of shoes, and there is a lot
21 of
weekly applications of topical products.
22
Certainly, that is off label, but I know
44
1
that that is done, a lot of drying powders, and,
2
yes, there is a lot of attention, but I think in
3 general the first approach is topical, but it
is
4
with a fairly comprehensive strategy for making it
5 the
wrong environment for the dermatophyte.
6
DR. CANTILENA: Thank you. Thank you, Dr.
7
Porres.
8
Dr. Fritsch.
9
Study Design and Efficacy Results for
10
Tinea Pedis Clinical Trials (Rx and OTC)
11
DR. FRITSCH: Good morning. I am Kathleen
12
Fritsch. I am a biostatistician
with the Division
13 of
Biometrics III. I will be presenting
some more
14
background information on the study design for
15
tinea pedis clinical trials, and then I will be
16
presenting some efficacy data from NDA submissions.
17
[Slide.]
18
First, I will be looking at the basic
19
clinical trial design.
20
[Slide.]
21
Generally, these trials are randomized,
22
double-blind, multicenter, vehicle-controlled
45
1
trials.
2
In the past, there generally have been two
3
indications, the tinea pedis indication, the OTC
4
equivalent of athlete's foot, and these trials will
5
usually evaluate either all comers, with both the
6
plantar and the interdigital variant, or study the
7
subtypes individually, or if they focus their
8
clinical trials primarily on the interdigital type,
9
then, they get a more limited indication of
10
athlete's foot between the toes or interdigital
11
tinea pedis.
12
Most of the development over the last
13
decade has focused on the interdigital variant.
14
Most of the products approved for the full
15
indication were approved more than a decade ago.
16
[Slide.]
17
In terms of patients that are evaluated in
18
these studies, for randomization into the trial and
19
receiving treatment, you need a positive KOH and
20
clinical signs and symptoms.
21
In order to verify that tinea
pedis is
22
actually the diagnosis, in order to be analyzed for
46
1
efficacy, usually, the patients are also required
2 to
have a positive baseline culture, however, since
3 it
can take up to four weeks to get the results of
4 a
culture, the treatment is often completed by the
5
time those baseline culture results are known.
6
However, the solution then is to just
7
analyze for efficacy, what we call the modified
8
intent to treat, or MITT population, those that
9
have positive KOH, positive culture, and the
10
appropriate clinical signs and symptoms.
11
In most clinical trials, we will find that
12
about two-thirds of the patients will end up having
13 a
positive baseline culture, and that can have an
14
impact on choosing the sample size for a study.
15
[Slide.]
16
As Dr. Porres mentioned, there are three
17
efficacy endpoints that are analyzed in these
18
clinical trials that involve mycological and
19
clinical outcomes. They are
nested within each
20
other in that negative mycology is required for
21
both effective treatment and complete cure.
22
The effective treatment is getting to a
47
1
mild state and also includes the patients that get
2 to
the complete cure state, and the complete cure
3
state is the absence of the signs and symptoms.
4
So, they are nested within each other.
5
[Slide.]
6
Again, to put up the specific definitions
7 for
these three endpoints, negative mycology, also
8
referred to as mycological cure, is a negative KOH
9 and
culture.
10
An effective treatment also requires the
11
negative mycology and is some sort of a mild state
12 of
the disease, the clinical presentation.
13
Generally, we say mild or no signs and no symptoms.
14
From trial to trial, the specific definition for
15
effective treatment does vary.
16
Our recommendation these days is to define
17 it
as, at most, mild erythema and scaling, but in
18 the
past trials, there may be other ways to define
19 a
mild state that have been used.
Sometimes
20
effective treatment is designated in the clinical
21
trials as the primary endpoint.
22
Of course, the strongest endpoint is the
48
1
complete cure, which is the absence of signs and
2
symptoms, negative mycology. This
is often the
3
primary endpoint in the clinical trials, and the
4
Agency generally recommends to use complete cure as
5 the
primary endpoint.
6
Again, the signs and symptoms that are
7
evaluated usually include erythema, pruritus, and
8
scaling, and may include any of the other signs and
9
symptoms, as well.
10
[Slide.]
11
For the study phases, there is usually a
12
treatment period and a post-treatment follow-up
13
period.
14
Most products have a treatment duration
15
between one and four weeks. Then,
the patients are
16
followed for, at a minimum of at least two weeks
17
after treatment. The amount of
follow-up will
18
generally depend on the length of treatment.
19
For a one-week product, the treatment
20
period usually is at least five to eight weeks. If
21 the
treatment is for four weeks, the follow-up
22
period may be shorter, it may be only two to four
49
1
weeks. In both cases, this puts
the patients at
2
about six to nine weeks after they have started
3
their treatment for when they will be primarily
4
evaluated.
5
[Slide.]
6
Again, the reason for following patients
7
into the post-treatment follow-up period is to
8
allow for the epidermal turnover, as Dr. Porres
9
mentioned, may take at least four weeks, so we may
10 not
expect the clearance of signs until some point
11
after treatment has ended, say, at least six weeks
12
after the start of treatment even if the fungus is
13
eradicated earlier.
14
Because of this, there may be a
15
significant time lag in either weeks or possibly
16
months between when treatment ends and when a cure
17
could be assessed.
18
[Slide.]
19
The second part of my presentation will
20
focus in on specific data that have been submitted
21 to
the Agency. I will be presenting the
efficacy
22
results from selected clinical trials.
50
1
[Slide.]
2
The clinical trials that I have selected
3 for
my presentation come from NDA reviews.
The
4
oldest one dates back to 1988, and all of the
5
studies come from vehicle-controlled trials and
6
were in general considered the pivotal trials for a
7
particular drug product.
8
Using these criteria, I have identified
9
nine drug products. They may
involve different
10
formulations or treatment regimens, and they
11
represent six different active ingredients, so
12
there are some multiple formulations and treatment
13
regimens.
14
The nine products are roughly split
15
between those that are available OTC and by
16
prescription, and also split between those that are
17
recommended for one week's use and for four weeks'
18
use.
19
Of the nine, seven were designed for the
20
indication of interdigital tinea pedis, and the two
21
oldest ones have the indication for tinea pedis.
22
[Slide.]
51
1
To take a look at the size of the database
2
that is available for each of these products, I
3
will be presenting the products only by code letter
4 A
through I.
5
We see that the products have a database
6 of
roughly about 50 patients on an active
7
ingredient up to about 250, and in some cases, we
8
have two trials that were two vehicle-controlled
9
trials, and in some cases, we have one.
So, we do
10
have a variety of sample sizes represented for our
11
products here, so A through I.
12
[Slide.]
13
As I move into the displays of the actual
14
data from these trials, I want to make a caveat
15
that these data do not represent head-to-head
16
comparisons of the products, therefore, we cannot
17
make any direct comparisons of relative efficacy
18
from one product to another.
19
Success rates in these trials are greatly
20
influenced by the particular patients that are
21
enrolled in a trial, types of concomitant diseases
22
they may have, whether they have onychomycosis, how
52
1
severe the baseline clinical signs and symptoms
2
must be could affect the success rates.
3
The specific clinical study
procedures,
4 how
the samples are collected, who analyzes the
5
skin samples, whether a target lesion is analyzed,
6
whether the whole foot is analyzed, all that can
7
influence the success rate.
8 As I mentioned before, the endpoints
are
9
identified differently in a trial, is it a global,
10 is
it specific symptoms, what symptoms are
11
evaluated, all of that, how is missing data
12
handled, all that can influence the success rates.
13
So, we will look at this in terms of
14
trying to pick up general trends and patterns that
15 we
can.
16
[Slide.]
17
I have got data on the negative mycology,
18
effective treatment, and complete cure rates for
19 the
nine products, so we will present those next.
20
[Slide.]
21
This first graph represents the negative
22
mycology. These are the negative
mycology rates at
53
1 end
of treatment, so Week 1 for the one-week
2
products, and Week 4 for the four-week products.
3
The orange bars represent the active.
We
4 can
see what kind of eradication we can expect to
5
find for a one-week treatment.
For a one-week
6
treatment, we can see that, for the most part,
7
about 40 to 50 percent of patients will have
8
negative KOH and negative culture by the end of
9
treatment.
10
For the products that are used for four
11
weeks, the negative mycology rate is somewhat
12
higher at Week 4, about 60 to 70 percent of
13
patients will have the negative mycology at the end
14 of
treatment.
15
[Slide.]
16 If we go to the primary timepoint
that was
17
specified in each particular protocol for the time
18 of
assessment, usually, Week 6, 8, or 9, we see
19
that, in general, at this timepoint, patients can
20 get
to about 60, 70, or 80 percent negative
21
mycology rates by the primary timepoint for
22
evaluation, so that is about what we can expect for
54
1
getting rid of the dermatophyte, and it is fairly
2
consistent across the products here.
3
Again, the endpoints that involve the
4
clinical signs and symptoms are based on these
5
patients that achieve negative mycology only.
6
[Slide.]
7
In terms of effective treatment, this will
8 be
getting negative KOH in culture and getting down
9 to
some sort of a mild state of disease.
10
We see that for Week 1, only a relatively
11
small proportion of patients are actually able to
12 get
to the mild state by the time they are finished
13
with their treatment regimen, about 2 percent to 18
14
percent of patients. So, the
remaining subjects
15
would have some sort of symptoms beyond just mild
16
erythema and mild scaling remaining by the end of
17
treatment.
18
At four weeks, where they have had a
19
longer time to wait before they stop their
20
treatment, roughly around half of the patients are
21
able to get to a mild state of disease, and the
22
remaining half would still have more severe signs
55
1 and
symptoms remaining.
2
So, that is what a patient may be able to
3
expect to see by the time they are finished with
4
their treatment.
5
[Slide.]
6
By the time we get out to the Week 6 to 9,
7
where the skin may have had a chance to turn over a
8
little bit, we see again about 40, 50, 60 percent
9 of
patients will be able to get to the mild state
10
with the negative mycology, and the remaining
11
subjects would have more symptoms remaining.
12
[Slide.]
13
Finally, the gold standard of complete
14
cure where we can completely eradicate these signs
15 and
symptoms, as well as the dermatophyte, for one
16
week treatment, as may be expected because of the
17
time for skin turnover, very few patients will be
18
actually completely clear of their signs and
19
symptoms.
20
Almost everybody has some signs or
21
symptoms remaining or dermatophyte remaining by the
22 end
of one week of treatment. Even for those
that
56
1
continue to four weeks, roughly, 15 percent of
2
patients are able to get completely rid of their
3
signs and symptoms, and the remainder will have at
4
least something remaining even at the end of four
5
weeks of treatment.
6
[Slide.]
7
To go out to the primary timepoint, again
8 we
see about the same value across the board.
9
About 20 percent, maybe 30 percent in some cases,
10 of
patients are able to completely get rid of their
11
signs and symptoms six to nine weeks after starting
12
treatment, which is about two to four weeks after
13
treatment for the four-week treatments and five to
14
eight weeks after treatment for the one-week
15
treatments.
16
[Slide.]
17
Next, I will go into some specific tables
18 for
the specific signs and symptoms, and I will
19
present this information by visit.
The visits that
20 are
evaluated in a particular clinical trial depend
21 on
the design.
22
I will be presenting data for erythema,
57
1
scaling, and pruritus, and for this presentation,
2
since signs and symptoms have not been collected in
3 the
same way in all trials, I have the data
4
available in the format I want for only two
5
products, a one-week product and a four-week
6
product.
7
[Slide.]
8
We start with erythema. This will
be the
9
percentage of subjects that will be clear of their
10
erythema at a particular visit.
On the left, Drug
11
Product D is a one-week treatment, and Drug Product
12 F
is a four-week treatment.
13
If we take a look at the percentage of
14
subjects, in this case, we started off with about
15 15
percent of subjects were clear of their erythema
16 at
baseline in this trial. After one week
of
17
treatment, that number improved to about 25
18
percent, and then as we go out in time to the time
19 we
may expect to see the skin turnover, by Week 4
20 to
6, we are getting up to about 50 percent.
21
This trial went out to 12 weeks, and by
22
that point, we have about 50 to 60 percent of
58
1
patients clear of their erythema by the end of the
2
trial, compared to about 30 percent on vehicle.
3
A similar pattern for this four-week
4
treatment. It takes a while for
the number of
5
patients to get clear of their erythema.
By about
6
Week 4, again we are about 45 percent, 50 percent
7 of
patients. So, we can see kind of the
time
8
trajectory of how many weeks it takes to start to
9 see
clearance of the erythema.
10
[Slide.]
11
Scaling. In this case, all of the
12
subjects that have scaling at baseline, and we see
13
that for the one-week treatment, if we look at the
14
number of patients that are clear of their scaling,
15
about 2 percent of patients were clear of scaling
16 by
the end of treatment. Again, not too
surprising
17
based on the length of epidermal turnover.
18
By four weeks, we are up to a little over
19 10
percent, and we max out at about 25 percent.
20 So,
this may be the rate-limiting factor for why we
21 see
little complete clearance is scaling is
22
persistent in the vast majority of patients.
59
1
Similarly, over here, by about Week 4, we
2 are
up to 20 percent, maxing out at about 30
3
percent of patients able to completely clear of
4
their scaling.
5
[Slide.]
6
Finally, for pruritus, we will see that on
7
this drug, for the one-week treatment, we do
8
actually see a substantial bump from baseline to
9 the
end of treatment at Week 1, go from about 15
10
percent with no pruritus at baseline to about 45
11
percent by the end of treatment.
12
Again, we do see continued improvement for
13
this product after treatment has ended, getting up
14 to
about 75 percent of patients by Week 9 who are
15
clear of their pruritus, and the vehicle rate drops
16
off, although interestingly, during the one week of
17
treatment, the active and the vehicle have the same
18
benefit in terms of pruritus, however, the active
19
patients do continue to improve.
20
Similarly, for Drug Product F, we see
21
continued improvement on the pruritus, in this case
22
during the course of treatment, maxing out at about
60
1 70
percent again for the number of patients clear
2 of
their pruritus.
3
Again, also substantial vehicle benefit,
4
however, the vehicle rate does drop off after
5
treatment.
6
[Slide.]
7
The summary of the efficacy results.
From
8
this data, we can see that there is a time lag of
9
several weeks between the end of treatment and when
10 the
signs and symptoms may be cleared, particularly
11 for
the one-week products where the treatment is
12
stopped before the epidermal turnover can take
13
place.
14
In most cases, patients will have signs
15 and
symptoms remaining into the post-treatment
16
period, and rough ballpark figures of the typical
17
cure rates for the various endpoints, complete cure
18
rates are roughly 20, maybe 30 percent for most
19
products.
20
Effective treatment may be about half of
21 the
patients. Negative mycology rates,
around
22
two-thirds to three-fourths of the patients will be
61
1
able to get to the negative mycology in the
2
post-treatment period.
3
Thank you.
4
DR. CANTILENA: Thank you, Dr.
Fritsch.
5
We have time for a couple of questions for
6 Dr.
Fritsch.
7
Dr. Benowitz.
8
DR. BENOWITZ: I am just
curious. What is
9 the
basis for someone doing a one-week trial versus
10 a
four-week trial, are the products different, why
11 is
that done?
12
DR. FRITSCH: Basically, it is the
13
sponsor's preference. If they
want to market a
14
one-week product and they think they can get the
15
efficacy that they want in one week.
We have not
16
seen very much data that compares a product across
17
multiple durations.
18
That is one of the reasons we have been
19
asking for dose ranging. It is
usually we either
20 get
results for one week, or we get results for
21
four weeks. We have not seen much
comparative
22
data, but generally, it is the sponsor's decision
62
1 on
what type of product they would like to market.
2
DR. BENOWITZ: So, if we looked at
the
3
products, they would basically be the same in both
4
groups in terms of active ingredients?
5
DR. FRITSCH: In terms of for the
data
6
presentation I made, there is six different active
7
ingredients that were represented.
8
DR. BENOWITZ: I understand. I am just
9
saying that if you look at drugs that were selected
10 for
a one-week trial versus a four-week trial, they
11 are
basically the same medications in both, same
12
active ingredients?
13
DR. FRITSCH: There is only one
case where
14 we
have data both on a one-week use and a four-week
15
use. Otherwise, the products that
are one week are
16 different
than the products that are four weeks.
17
DR. BENOWITZ: I understand that
the
18
specific product name is different, but in terms of
19 the
active ingredients.
20
DR. FRITSCH: The active
ingredients, yes.
21
DR. BENOWITZ: Are they also
generally
22
different or are they basically the same?
63
1
DR. FRITSCH: Generally, they are
2
different. There is one product
that is
3
recommended for use for either one week or four
4
weeks, and then there are products that are only
5
recommended for one week, and there are products
6
that are only recommended for four weeks.
7
So, generally, the one-week products are
8
different from the four-week products in terms of
9
active ingredients.
10
DR. BENOWITZ: Thanks.
11
DR. CANTILENA: Ms. Knudson.
12
MS. KNUDSON: I want to know, on
these
13
studies that you have just presented, do you have
14 any
idea how many patients dropped out of the
15
studies and at what timepoints did they drop out?
16
DR. FRITSCH: Yes, that is
generally
17
included. For the most part,
roughly, in maybe a
18
six-week trial, there might be about 10 to 15
19
percent of patients that drop out. One of the
20
difficulties with the data I have presented, our
21
current standards would be to generally either
22
count the patients that drop out as either failures
64
1 or
last observation carried forward.
2
For the older trials, often the results
3
that I have presented exclude the dropouts. I did
4 not
go back and try and correct for intent to treat
5 the
way that the older trials did, so that is one
6
variability, that the older trials often ignored
7
dropouts. Recently, we definitely
count them in
8 our
results.
9
DR. CANTILENA: Thank you.
10
Dr. Ringel.
11
DR. RINGEL: I have a question
about
12
negative mycology. I was
wondering if that is
13
considered negative KOH and culture or only
14
negative culture.
15
The reason I am asking is that most
16
physicians consider culture in other areas of
17
mycobiology to be a gold standard, whereas, as with
18
dermatophytes, there are various reasons why a
19
culture might be negative, where the KOH would be
20
positive, either bacterial contamination, sampling
21
error, the patient has been using topical
22
antifungals.
65
1
So, I guess the question is if a KOH is
2
positive, a culture is negative, is that considered
3
positive mycology or negative mycology?
4
DR. FRITSCH: You must have both
negative
5 KOH
and negative culture to be counted as negative
6 mycology.
7
DR. RINGEL: Thank you.
8
DR. CANTILENA: Thank you. Now we have
9 Mr.
Kresel.
10
MR. KRESEL: My question was
answered
11
earlier.
12
DR. CANTILENA: Dr. Epps.
13
DR. EPPS: Partially, my question was
14
addressed with the positive KOH, negative mycology,
15 but
how much within your group was just positive
16 KOH
and negative culture? Do you have any
data
17
regarding that?
18
DR. FRITSCH: Yes, the positive
KOH and
19
negative culture, I have seen a few.
There is
20
definitely some that come through with positive KOH
21 and
negative culture.
22
DR. EPPS: Because it may be that
this is
66
1 not
viable, but present--
2
DR. FRITSCH: There is lots of
problems
3
with the four-week, you know, a negative culture,
4 did
you have the fungus in the plate or not, that
5 is
definitely a problem, so there are definitely
6
some that do come through.
7
DR. CANTILENA: Thank you.
8
Dr. Lam.
9
DR. LAM: I just want to clarify
just to
10
make sure. The data that you present
only
11
represent one strength of each of the products.
12
DR. FRITSCH: One strength of each
13
product, yes.
14
DR. CANTILENA: Thank you. Any other
15
questions from the committee? Dr.
Wood.
16
DR. WOOD: The elephant in the room here
17 is
what the efficacy is with systemic therapy, as
18
well. Is somebody going to talk
about that?
19
I realize we are here to consider topical
20
therapy, but as we get to some of these questions,
21 my
feelings about them would be substantially
22
influenced by knowing what we are going to accept
67
1 as
the expected efficacy rate from systemic
2
therapy.
3
Clearly, given the efficacy rate shown
4
here, and consumers' views of that will be
5
different if there is effective therapy out there
6
that is of an order of magnitude different.
7
So, is someone going to, for the record,
8
show us that, an efficacy rate from terbinafine
9
systemically?
10
DR. CANTILENA: Dr. Ganley, do you
have
11
anyone? If you have to look that
up, we can
12
certainly have that after lunch.
So, why don't we
13
have someone be checking on that.
That is a good
14
point.
15
Our next speaker from FDA, Dr. Mahayni.
16 History and Overview of OTC
Topical
17 Antifungal Drug Products
Monograph
18 DR. MAHAYNI: Good morning, ladies and
19
gentlemen. My name is Houda Mahayni.
I am
20
interdisciplinary scientist in the Division of
21
Over-the-Counter Drug Products.
22
[Slide.]
68
1
I will give you a brief introduction about
2 the
mechanism by which OTC drugs are regulated.
3
Then, I will describe an overview of the OTC Drug
4
Monograph System. Finally, I will discuss the OTC
5
drug monograph for topical antifungals with special
6
emphasis on those ingredients used to treat
7
athlete's foot tinea pedis.
8
[Slide.]
9
Most of you are familiar with the NDA
10
process, so in order to introduce the monograph
11
system, I am going to briefly contrast the two
12
mechanisms by which OTC drug products are
13
regulated, highlighting the key differences between
14 the
two mechanisms.
15
NDA is drug product-specific. It
requires
16
pre-market approval, and information submitted
17
under the NDA is confidential, whereas, in the OTC
18
drug monograph, is an active ingredient-specific,
19 and
ingredients are designate as GRASE, which is
20
generally recognized as safe and effective. There
21 is
no need for pre-market approval.
Finally, the
22
information is public.
69
1
[Slide.]
2
I hope this introduction gives you a
3
flavor of how the two mechanisms differ.
I will
4 not
be talking about the NDA mechanism in this
5
talk, but I will focus for the rest of this talk on
6 the
OTC Drug Monograph System.
7
[Slide.]
8
The OTC drug review began in 1972 as a
9
review of the safety and effectiveness of OTC drugs
10 on
the market at that time. FDA initiated
the OTC
11
drug review by identifying a number of therapeutic
12
categories for which FDA is to establish OTC drug
13
monographs.
14
OTC drug monographs list the conditions of
15 use
that are generally recognized as safe and
16
effective or GRASE, and on the next slide I will be
17
talking to you about what is meant by the condition
18 of
use.
19
[Slide.]
20
What is really included in the monograph
21
system is the conditions of use, and those include
22 the
active ingredients, whether it's single
70
1
ingredient or combination, dosage strength, dosage
2
form, labeling requirements, such as uses,
3
directions, and warnings, and finally, in some
4
cases, final formulation testing.
5
[Slide.]
6
The OTC drug review is a four-step public
7
rulemaking process, and each step builds upon the
8
other. Here, I will be listing
all the four steps
9 and
I will go over these steps in more detail in
10
subsequent slides.
11
First, the advisory review panel meets.
12
Then, after the panel meets, the FDA publishes the
13
Advance Notice of Proposed Rulemaking, which is
14
generally referred to as the ANPR.
15
Next, FDA publishes the tentative final
16
monograph, or TFM, and finally, the FDA publishes
17 the
final rule, or FM.
18
[Slide.]
19
The panel is a group of experts in a
20
particular OTC drug category. The
panel was
21
charged with reviewing the data of OTC ingredients
22
marketed prior to 1975 and assessing whether these
71
1
ingredients are safe and effective for GRASE
2
conditions for the OTC drug monograph.
3
The panel give the nomenclature Category I
4 for
ingredients, all conditions under which
5
products are generally recognized as safe and
6
effective, and are not misbranded.
7
Category II are for ingredients or
8
conditions under which products are generally
9
recognized not as safe and effective or are
10
misbranded.
11
Category III are for ingredients or
12
conditions when the available data are insufficient
13 to
permit final classification at the time.
14
Keep in mind that these classifications
15 are
not only given for ingredients, but for
16
condition of use as defined earlier, which includes
17
labeling requirements and final formulation
18
testing.
19
[Slide.]
20
Next, the FDA publishes the Advance Notice
21 of
Proposed Rule, or ANPR, in the Federal Register
22 to
announce its intention of creating the OTC drug
72
1
monograph. The ANPR also contains
the panel
2
report, which lists recommended GRASE conditions.
3
Then, following the publication of the
4
ANPR, interested persons may submit comments or
5
additional data to the panel, and they are given 90
6
days to make those comments in.
7
[Slide.]
8
FDA next publishes the tentative final
9
monograph, or TFM, in the Federal Register as its
10
preliminary position regarding the safety and
11
effectiveness of each active ingredient in
12
particular category.
13
The TFM is based on FDA interpretation of
14
data provided by the panel, the panel
15
recommendations, and any new data submitted in
16
response to the Advance Notice of Proposed Rule.
17
Following its publication, there is also
18 an
additional 90 days comment period for interested
19
persons who may want to submit comments and
20
additional data on what was contained in the TFM.
21
[Slide.]
22
FDA reviews all comments and data
73
1
submitted during the tentative final monograph
2
comment period and amends the TFM to create the
3
final monograph or final rule. The monograph is a
4 set
of rules published in the Federal Register.
5
The regulation gets published in the Code
6 of
Federal Regulations. That includes an
effective
7
date after which any product marketed under the
8
monograph must comply with the conditions used that
9
were described in the monograph.
10
As I said, each step in the monograph
11
builds upon and is a continuation of the previous
12
step. Although the FM is the
final step in the OTC
13
Drug Monograph System, FDA can amend the final
14
monograph to include additional GRASE conditions,
15
such as adding new active ingredients.
16
[Slide.]
17
Now that I gave you a general overview of
18 the
OTC Drug Monograph System, I am going to shift
19 and
talk specifically about the history of OTC
20
topical antifungal monograph with special emphasis
21 on
those ingredients used to treat athlete's foot
22
tinea pedis.
74
1
[Slide.]
2
The panel met in the late seventies and
3
early eighties, and then FDA published the Advance
4
Notice of Proposed Rulemaking in 1982.
5
The panel expressed its concern about the
6
ingredients only mitigating symptoms rather than
7
curing condition as is apparent by the statement
8 that in order to best serve the consumers, an
OTC
9
product must provide more than temporary
10
symptomatic relief of athlete's foot, jock itch,
11 and
ringworm.
12
The panel required at least one
13
well-designed clinical study demonstrating an
14
active ingredient treat athlete's foot as evidence
15 of
effectiveness, and it recommended an ingredient
16 as
GRASE if it was significantly more effective
17
than vehicle.
18
[Slide.]
19
In reviewing the clinical trial,
the panel
20
defined a well-controlled study as one that met the
21
following criteria: To be
double-blinded and
22
randomized, vehicle-controlled, test groups of
75
1
adequate size, entry criteria based on clinical
2
signs and symptoms with diagnosis verified by
3
positive KOH and culture, and standardized dosing
4
regimen usually four weeks treatment for athlete's
5 foot,
and finally, the follow-up examinations
6
performed at the end of treatment and final
7
evaluation of clinical results corroborated by
8
negative KOH and negative culture two weeks after
9
treatment ends.
10
A relatively small percentage of the
11
studies submitted to NDA met these criteria.
12
[Slide.]
13
The panel reviewed approximately 50
14
clinical studies along with in vitro and animal
15
studies to assess the safety and effectiveness of
16
about 35 active ingredients.
17
Of these clinical studies, roughly 10 were
18
designed to demonstrate the effectiveness of active
19
ingredients in treating athlete's foot, but most
20
were poorly designed. This was
because there was
21
considerable variability in the study protocol.
22
Enrollment for most studies was based on
76
1 the
diagnosis of tinea pedis by a physician instead
2 of
these studies, this diagnosis was confirmed by
3
positive KOH and positive culture.
4
Treatment duration varied between two to
5 six
weeks with treatment duration being four weeks
6 in
most studies.
7 These studies assessed the efficacy
at
8
different timepoints and used different criteria
9 for
cure.
10
All these factors make it difficult to
11
compare the cure rates of the monograph products to
12
those of the NDA products. Based
on this review of
13 the
study, the panel recommended that six active
14
ingredients be classified as GRASE, and I will
15
share with you these ingredients in the slide
16
talking about the final monograph.
17 [Slide.]
18
In addition, the panel proposed the idea
19 of
simple and concise labeling that should enable
20 the
consumers to clearly understand the results
21
that can be anticipated from the use of the
22
product.
77
1
Example of indication recommended by the
2
panel includes treat athlete's foot for the
3
treatment of athlete's foot or for the relief of
4
itching.
5 Labeling or products used for the
6
treatment of athlete's foot should include the
7
following warning: If irritation
occurs or of
8
there is no improvement within four weeks,
9
discontinue use and consult a doctor or pharmacist.
10
Furthermore, the panel stated that
11
directions should be clear and direct.
They should
12
provide the user with sufficient information to
13
enable safe and effective use of the product.
14
Based on the clinical study, which
15
generally involved four weeks' treatment, the panel
16
determined that OTC topical antifungals should be
17
applied twice a day for four weeks to be most
18
effective.
19
[Slide.]
20
Seven years later, after the NPR was
21
published, the Agency published the TFM.
In the
22
TFM, FDA reviewed 25 clinical studies.
Those
78
1
studies were submitted following the publication of
2 the
ANPR or Advance Notice of Proposed Rule.
3
Six of these 25 studies addressed
4
athlete's foot. Based on these studies, FDA agreed
5
with the panel recommendation in terms of
6
ingredients to be included in the monograph with
7 the
exception of two active ingredients, nystatin
8 was
classified as not GRASE, and they decided to
9
include povidone and iodine as GRASE.
10
[Slide.]
11
After the TFM was published, FDA published
12 the
FM, the final monograph four years later.
In
13 the
final monograph, FDA reviewed about 10 studies
14
submitted after the tentative final monograph and
15
found the following active ingredients as GRASE for
16 the
treatment of athlete's foot.
17
FDA found all other ingredients considered
18 in
this rulemaking not to be GRASE for us in OTC
19
topical antifungals. In addition,
the final
20
monograph includes labeling similar to that
21
recommended by the panel in the Advance Notice of
22
Proposed Rule.
79
1
All of the active ingredients listed here,
2
they were indicated for the treatment of athlete's
3
foot, as well as for the relief of symptoms. Only
4 one
product tolnaftate was also indicated for the
5
prevention of athlete's foot. In
addition, all
6
these active ingredients were also indicated for
7 the
treatment of ringworm, tinea corporis, and jock
8
itch, tinea cruris.
9
[Slide.]
10
As I told you, final monograph can be
11
amended following its publication.
FDA published a
12
proposed amendment and subsequently, a final rule
13 in
August 2000 to modify the labeling of OTC
14
topical antifungal.
15
This amendment added the word "most" to
16 the
indication statement between the introductory
17
phrase and the name of the condition for which the
18 product
was to be used, for instance, cures "most"
19
athlete's foot.
20
FDA recognized that OTC topical
21
antifungals do not cure or treat all conditions
22
commonly thought by consumers to be athlete's foot
80
1 or
jock itch.
2
FDA also noted that varying percentages of
3
subjects were clinically and mycologically cured of
4
athlete's foot infection, therefore, inserting the
5 word
"most" in this case would give and help the
6
consumers know what to expect from these products.
7
This is important since consumers
8
self-select OTC topical antifungals, and do not
9
diagnose. The Agency believed
that this labeling
10
should more accurately inform the consumers what to
11
expect from using these products.
12
Also, FDA pointed out that this amended
13
label is consistent with the current labeling
14
approved for OTC vaginal antifungal drug products
15
marketed under NDA. Since these
are also topical
16
antifungals with different sites of administration
17 and
for consistency, OTC labeling for this
18
particular class should be the same.
19
In addition to this amendment, in February
20
2002, after reviewing approximately eight clinical
21
studies submitted after the FM, FDA proposed to add
22
clotrimazole as GRASE active ingredients for the
81
1
treatment of athlete's foot, jock itch, and
2
ringworm.
3
[Slide.]
4
In summary, OTC drug monographs allow
5
determination of safety and effectiveness of an
6
entire therapeutic drug class.
7
OTC topical antifungal monograph lists
8
GRASE active ingredients and labeling for OTC drug
9
products that treat athlete's foot, jock itch, and
10
ringworm, as well as prevent athlete's foot,
11
because ingredients found GRASE for one condition
12 is
given the same GRASE classification for other
13
conditions because of the similarity of these
14
conditions.
15
From the data submitted the monographs, it
16 is
difficult to directly compare the cure rates for
17
monograph and NDA drug products that treat
18
athlete's foot because they were not directly
19
comparable due to considerable variability in the
20
study protocol.
21
Finally, by including the word "most" in
22 the
indication, we can say to consumers what to
82
1
expect from using these products and what to expect
2
from them.
3
Thank you.
4
DR. CANTILENA: Thank you, Dr. Mahayni.
5
I guess we should ask that all depends
6
what you mean by "most," but we will actually talk
7
about that this afternoon.
8
Questions from the committee? Dr.
Wood.
9 DR. WOOD: Well, that was going to be my
10
question. "Most" certainly means, as you said, it
11 is
the last thing, it helps the consumer.
12
If I look at the slides in the last talk,
13 on
page 10, which of these studies support "most"
14 in
your view? On the Slide 19 on page 10,
you
15
added the word "most" because you felt that
16
reflected the data.
17
Which of the studies specifically on Slide
18 19
do you think tell you that, or would tell me
19
that?
20
DR. MAHAYNI: Actually, the word
"most"
21 was
added because at the time, there was not a
22
specific study, but because of the lower percentage
83
1 of
cure rate for these ingredients, the word "most"
2 was
added to the monograph to indicate to consumers
3
that it is not going to treat every clinical
4
condition that will be presented.
5
DR. WOOD: Right, but "most"
implies at
6
least more than 50 percent, and most people I think
7
would assume that it was closer to 100 than 50
8
percent. I don't think any
interpretation of
9
"most" implies less than 50 percent, does it? I
10
mean is there a definition that you are aware of
11
that implies that most people do something, implies
12
less than 50 percent?
13
DR. CANTILENA: How about if we
have
14
actually Dr. Ganley answer the question, since he
15
probably had more to do with that than Dr. Mahayni.
16
DR. GANLEY: This whole process
started
17
before I got to D.C., but I am generally
18
accountable for it.
19
DR. CANTILENA: All right, there
is the
20
copout, so now you can answer.
21
DR. GANLEY: No, I accept
responsibility
22 for
it.
84
1
I guess at the time, it is a rather
2
complicated thing, is that it will treat most
3
dermatophytes. Also, the thinking
was that if you
4 put
just cures there without some qualifier, that
5
people think that it is closer to 100 percent cure.
6
Now, "most" may not have been the
7
appropriate adjective and maybe some other
8
qualifying term, but I think that is one of the
9
issues that we need to discuss, whether that really
10 was
a good idea and whether we need to revise the
11
language a little bit. It gets
back to how you
12 convey
information to the consumer as what their
13
expectation can be, but I think I would acknowledge
14
that it actually didn't accomplish what I think the
15
original intent of the Agency was in that, to give
16
some perception that it's not 100 percent cure,
17
that it is something less than that.
18
I think if you look at the data for
19
effective treatment and cures most, people will
20
argue that effective treatment is a reasonable
21
level of success also, and that generally is above
22 50
percent, so I mean you can discuss that today
85
1 and
the logic, but I would acknowledge that it
2
didn't solve the situation at all.
3
DR. WOOD: I guess there are two
issues,
4
does it cure and is it most, and I am thinking of
5
this in terms of the treatment of heart failure.
6 You
know, it is perfectly legitimate to have a
7
treatment for heart failure that is effective in
8
most patients, but we probably wouldn't allow
9
labeling that said it cured most patients, or HIV,
10 or
whatever it was we were treating.
11
I mean I think it is the juxtaposition of
12
both that we need to be discussing.
13
DR. GANLEY: I think the
difference I
14
would argue there is that in heart failure, you are
15 not
going to cure the underlying condition, you are
16
going to treat the symptoms and improve their
17 survival
potentially, you don't cure them of the
18
disease, but infectious disease, you can cure
19
people's disease, and that is where the difference
20 is.
21
So, it does get a little tricky in how you
22 are
going to convey that information to the
86
1
consumer and what their expectation may be.
2
DR. WOOD: That is why I think it
is
3
important to have in the discussion, what the
4 efficacy is for systemic therapy, because I
think
5
that was exactly my point earlier, where there is
6
alternative therapy available that may have a very
7
different efficacy rate, it is important then to
8
revisit this to make sure that this provides some
9
information that is at least contemporaneous for
10
what the other therapies can do.
11
DR. CANTILENA: That is a very
good point.
12 We
will have an opportunity this afternoon to
13
discuss that further.
14
Dr. Lam.
15
DR. LAM: For the product to be
classified
16 as
Category I, what type of cure are we talking
17
about, are we talking about mycology cure or
18
complete cure?
19
DR. MAHAYNI: No, Category I does
not
20
relate to actually cure, because most of these
21
studies did not define the complete cure. The
22
category is really reflected on what the
87
1 ingredients,
Category I is ingredients that are
2
seen as safe and effective, or generally recognized
3 as
safe and effective, and not misbranded.
4
But as far as cure rate, there were a
5
variety of studies that had a different way of
6
qualifying what is cure rate, and no way to compare
7
them or say what is the cutoff rate for that.
8
DR. HOLEMAN: Matthew
Holeman. If I could
9
just sort of clarify real quick.
10
DR. CANTILENA: Okay.
11
DR. HOLEMAN: Basically, remember
that
12
most of the studies that these were based on were
13
submitted to the Agency in the seventies, the late
14
seventies, so the standards there were very
15
different than our standards today.
16
So, as Houda pointed out in her talk
17
today, there was a great variability in how these
18
studies were designed, and some of these studies, I
19
think the majority looked at just mycological
20
cures. Some of them did include
some clinical
21
cure.
22
I don't know that any actually looked at
88
1
complete clinical cure, most of them were probably
2
mycological, but it is really hard.
There is a lot
3 of
variability in all these studies.
4
DR. CANTILENA: Dr. Fincham.
5
DR. FINCHAM: I just have more of
a
6
comment than a question. I think
this is all very
7
interesting, how we are deciding what cure means
8 and
what most means, but I guess at some point, we
9 are
all consumers, but I am concerned about the
10
consumers that aren't in this room that see the
11
advertisements for these products and see cure,
12
they may not even look at most, but just see the
13
word "cure" and make assumptions based upon that.
14
I don't expect anybody to have an answer
15 to
that, but it is a comment that I think we need
16 to
perhaps consider later.
17
DR. CANTILENA: Yes, I think we
will have
18 an
answer this afternoon.
19
Go ahead, Mr. Kresel.
20
MR. KRESEL: I am sure that when
the
21
monograph was developed, there was probably debate
22
over the terminology and what it should say, but
89
1
since the labeling doesn't define cure, and
2
therefore I think it is very difficult for the
3
consumer to really know what they are getting when
4 it
says "cures most," we might want to go back and
5
talk about that debate between treats and cures.
6
DR. CANTILENA: Dr. Benowitz, the
final
7
question.
8
DR. BENOWITZ: Just a question
about the
9
GRASE criteria. For example,
nystatin was not
10
accepted as GRASE, so is that because of efficacy,
11 or
are there some safety issues with some of these
12
products, as well?
13
DR. MAHAYNI: I don't recall for
what
14
purpose that was taken out of the GRASE category or
15
classification.
16
DR. BENOWITZ: But just do you
know, are
17
there any safety issues for any of these products?
18
DR. MAHAYNI: For nystatin itself?
19
DR. BENOWITZ: No, just for the
variety of
20
antifungals. I know some probably
don't work, but
21
should we be thinking about any safety issues for
22 any
of these antifungals?
90
1
DR. MAHAYNI: For most what I have
done
2 for
preparation of the advisory committee meeting,
3 we
focused on the efficacy. I didn't
particularly
4
look at the safety, I didn't go over what study was
5
submitted to the monograph for safety purpose,
6
because we were focusing here on efficacy rate, so
7 I
reviewed all the effectiveness studies that were
8
listed in the monograph, so I can't answer your
9
question.
10 DR. BENOWITZ: I am wondering if anyone at
11 FDA
has information about hypersensitivity or other
12
safety issues involving these agents.
13
DR. CANTILENA: Dr. Ganley, does
your
14
staff have that?
15
DR. GANLEY: We can look for that,
but I
16
suspect that, you know, today, when we look at
17
today, what we asked for in studies and what they
18 may
have looked at back in the seventies, there may
19
have been safety information that looked at
20
exposure, you know, to a group of individuals. It
21
wasn't a specific study that would address that.
22
Today, there are irritation studies,
91
1
photocarcinogenicity studies, and a whole variety
2 of
different studies that may be asked of a topical
3
agent, and John could probably address it better
4
than I can.
5
But I would suspect that if you go back
6 and
look at that, it was basically data that was
7
submitted about use in various populations, and
8
there was no significant adverse effects.
9
DR. CANTILENA: We have a comment
over
10
here from Kresel.
11
MR. KRESEL: I was just going to
say,
12
because I am the oldest one here, and remember back
13
then, there were very skimpy studies that were
14
done, and there probably wasn't enough to really
15
come to a conclusion, not that there was any
16
particularly negative data and probably the sponsor
17
didn't do an awful lot.
18
DR. CANTILENA: Thank you.
19
Did you have a comment, Dr. Bisno, that is
20
related to this?
21
DR. BISNO: Just a comment which I
will
22
deal with slightly in my talk, which is if you look
92
1 at
the 13 episodes that have been reported to the
2
FDA, according to the information we got, about
3
cellulitis related to these topical products, most
4 of
them, if you look at them, look like their
5
hypersensitivity reactions someone got.
They got
6 it
and then a day later they developed inflammation
7 of
some sort, it wasn't really compatible with what
8 one
would think would be a cellulitis.
9
So, at least in those very scanty reports,
10 one
would suspect that at least a number of them
11
were actually hypersensitivity related in one way
12 or
another.
13
DR. CANTILENA: Dr. Katz.
14
DR. KATZ: In response to a
previous
15
question as far as nystatin, why that was excluded
16
from the GRASE, I would assume that it was because
17 it
is in not effective, it is not effective for
18
these conditions.
19
DR. CANTILENA: Dr. Schmidt.
20
DR. SCHMIDT: Ladies and
gentlemen, you
21 all
are very lucky today, because you have somebody
22 who
is older than Dr. Kresel, and also we were
93
1
interested in these medications in the seventies,
2 and
actually, when I was a resident, I helped in
3
some of these studies.
4
These studies, at least the ones we did,
5
were very well done and I think, you know, as I
6
recall, there were very few side effects with these
7
different medications although some of these
8
things, it seemed like the vehicles were almost as
9
good as the medications.
10
So, I just want to say that you all are
11
lucky.
12
DR. CANTILENA: We are very
lucky. We
13
have an investigator here, as well as an advisory
14
committee member.
15
Dr. Whitmore.
16 DR. WHITMORE: With regard to contact
17
hypersensitivity and such, I think the chemicals
18
themselves are not big-time contact allergens by
19 any
means, and it would be more likely the
20
excipient agents.
21
DR. CANTILENA: Thank you very
much.
22
Our next FDA presenter is Dr. Shetty.
94
1
Topical Antifungal Drug Product Labeling
2
DR. SHETTY: My name is Daiva
Shetty. I
3 am
a medical officer in the Division of
4
Over-the-Counter Drug Products.
5
[Slide.]
6
My talk will consist of several different
7
topics. First, I will briefly present some
8
marketing and postmarketing safety data for topical
9 and
antifungal drug products. I will focus
more in
10
detail on labeling issues for this class of drugs
11 and
also provide some examples how we convey
12
efficacy information to consumers.
13
[Slide.]
14
First, I will start with the marketing
15
data.
16
[Slide.]
17
There are 11 active ingredients approved
18 for
tinea pedis indication through New Drug
19
Applications for prescription and over-the-counter
20
use. There are also, as mentioned
earlier, 7
21
monograph active ingredients that the Agency found
22 to
be generally recognized as safe and effective.
95
1
Both prescription and over-the-counter products are
2
widely used for the treatment of dermal fungal
3
infections.
4
[Slide.]
5
The Division of Surveillance analyze the
6
prescription and over-the-counter sales trends and
7
drug use patterns for topical antifungals.
8
Two IMS health databases were used to
9
gather this information, National Sales
10
Perspectives and National Disease and Therapeutic
11
Index.
12
[Slide.]
13
The first database, National Sales
14
Perspectives, measures the volume of drug products,
15
prescription and nonprescription, going from
16
manufacturers into a market in terms of eaches. An
17 each
is IMS's unit of measure for single items,
18
such as tubes, jars, or individual retail packages.
19
This database does not provide the
20
demographics of consumers purchasing the drugs. It
21
does not give the indication for use or the amount
22 of
drug actually used.
96
1
[Slide.]
2
This slide shows the National Sales
3
Perspectives data for topical antifungals in 2003.
4 Over-the-counter topical antifungal drug
products
5
accounted for over 20 million eaches, while
6
prescription products accounted for around 16
7
million eaches in 2003.
8
This is somewhat surprising to us given
9 that
over-the-counter products are freely available
10 to
consumers for their purchase and use.
Keep in
11
mind that the sales data are for topical antifungal
12
ingredients in general, and do not reflect the
13
tinea pedis indication.
14 [Slide.]
15
Here is the table from the same database
16
listing active ingredients, prescription and
17
nonprescription, approved for the treatment of
18
tinea pedis in terms of sales. We can see that
19
monograph ingredients highlighted on this slide in
20
yellow account for the highest volume sold.
21
[Slide.]
22
The second IMS health database, National
97
1 Disease
and Therapeutic Index, estimates the use of
2
drugs by collecting data on drug products
3
mentioned, but not necessarily prescribed, during
4
visits to a panel of approximately 2,000 to 3,000
5
office-based physicians.
6
These data are collected and
projected
7
nationally to reflect national prescribing
8
patterns. It may include profiles
and trends of
9
diagnoses, patients, and treatment patterns. It
10
does not, however, capture patients who
11
self-diagnose and purchase over-the-counter drugs.
12
[Slide.]
13
My final slide on marketing displays data
14
from National Disease and Therapeutic Index. The
15
vertical axis shows the numbers of users, and the
16
percentages of bar graphs reflect a fraction of all
17
drugs.
18
In 2003, the most common agents
19
recommended by a physician to treat tinea pedis
20
were those listed on this slide, and all of them
21
except for terbinafine are prescription products.
22
[Slide.]
98
1
In the second part of my talk, I will
2
briefly summarize findings from the FDA's Adverse
3
Event Reporting System. There is
a full review
4
included in your background packages.
5
[Slide.]
6
We requested the Office of Drug Safety to
7
review all the adverse event reports received
8
through the Adverse Event Reporting System for all
9
topical antifungal agents focusing on two issues:
10
lack of efficacy and cellulitis cases.
11
[Slide.]
12
There are certain limitations to these
13
data. There are no adverse event
reporting
14
requirements for monograph ingredients.
Therefore,
15
reporting for those drug products may be
16
significantly underrepresented.
17
The report gives only crude numbers for
18 the
active ingredients. That means that you
don't
19
have a denominator and cannot estimate the
20
incidence of each report. Some
ingredients are
21
marketed in multiple formulations for several
22
different indications which will not be reflected
99
1 in
the report.
2
Finally, causality of what is the primary
3
suspect drug in the report was not assessed.
4
[Slide.]
5
Given all the limitations, the search
6
found a total of 4,741 reports for 15 active
7
ingredients, of which the most common, 35 percent
8
reported a lack of efficacy.
9
This is a very high percentage.
In our
10
experience, we don't usually see that a third of
11 all
reports would be associated with a lack of
12
efficacy of the drug.
13
The majority of the lack of efficacy
14
reports in AERS database were associated with these
15
listed four ingredients, and the numbers in the
16 package
reflect year of approval of that particular
17
drug in the U.S.
18
Given this high number of low efficacy
19
reports, we worried if there are some consequences,
20
such as missed or mistreated diagnosis.
21
[Slide.]
22
What we could do is search our database
100
1 for
cellulitis reports. The Office of Drug
Safety
2
found 13 cases of cellulitis associated with those
3 15
topical antifungal agents.
4
Cellulitis in these 13 cases was reported
5 as
an adverse event, and was not a condition being
6
treated. Although more cases of
cellulitis were
7
reported for terbinafine and miconazole, based on
8
this small number of spontaneously submitted
9
adverse event reports, we are unable to say that
10
particular antifungal agents are associated with
11
more or less cellulitis cases than other agents.
12
[Slide.]
13
More on the issue of cellulitis, you will
14
hear later today presented by Dr. Bisno.
I will
15
summarize 13 AERS cases.
16
All 13 cases were diagnosed as cellulitis
17 and
were primarily of U.S. origin. The
patients
18
were using the antifungal agents for a variety of
19
reasons, but tinea pedis is the predominant reason.
20
Cellulitis symptoms typically started one
21 day
after application of the topical agent, and the
22
sites most often affected were the lower
101
1
extremities. One patient reported
having diabetes
2 and
seven patients reported hospitalization.
3
Of the seven hospitalization cases, one
4
patient was hospitalized for worsening Parkinson's
5
disease, and cellulitis in this patient was
6
diagnosed, but was not the reason for
7
hospitalization.
8
The six remaining cases were for
9
cellulitis, however, it was unclear in two cases
10
that the cellulitis occurred before or after the
11
administration of the antifungal agent.
12
[Slide.]
13
The last part of my presentation is
14
over-the-counter labeling issues.
15
[Slide.]
16
There are three types of labeling for
17
topical antifungal drug products:
prescription
18
labeling for prescription drug products and two
19
types of over-the-counter drug labeling for
20 monograph
and NDA drug products.
21
Given the efficacy rates for this class of
22
drugs and numerous consumer complaints on the lack
102
1 of
efficacy, it is apparent that consumers may not
2
understand that they may not achieve symptom relief
3 or
cure by the end of the treatment.
Current
4
labeling does not specifically communicate this
5
message.
6
[Slide.]
7
I will start with prescription labeling.
8
Information conveyed on prescription labeling is
9
targeted at health care providers.
It has detailed
10
information on drug pharmacology, microbiology,
11
preclinical and clinical data, indications,
12
contraindications, warnings, and dosage and
13
administration.
14
[Slide.]
15
This is an example of the indications and
16
usage section on prescription labeling for topical
17
antifungals drug products. The
point of this slide
18 is
to show that at it lists specific conditions,
19
that are in yellow and underlined, and specific
20
fungi that particular ingredient is effective
21
against.
22
[Slide.]
103
1
The Directions for Use Section in
2
Prescription Labeling gives the duration of use for
3 the
particular product, for example, two weeks for
4
tinea corporis or tinea cruris, and four weeks for
5
tinea pedis.
6
[Slide.]
7
Expectations of treatment are also
8
specified in Prescription Labeling.
Sample of such
9 a
labeling is shown on this slide. If a
patient
10
shows no clinical improvement after four weeks of
11
treatment, the diagnosis should be reviewed.
12
This information does not appear on
13
patients' container labeling, and it is very
14
dependent on a physician who is prescribing and
15
giving instructions to the patient.
16
[Slide.]
17
The second type is labeling for
18
over-the-counter monograph products.
19
[Slide.]
20
This is an example of over-the-counter
21
drug facts labeling format, which appears on the
22
carton of each over-the-counter drug.
Labeling of
104
1 OTC
monograph ingredients conveys indication in the
2
Uses Section, which follows Active Ingredient
3
Section.
4
There are two statements in the Uses
5
Section on all monograph antifungal products.
6
The first is a required statement, and it
7
states, "Treats or cures most athlete's foot."
8
The second is an optional
statement, and
9
states relieves or for relief of a list of
10
symptoms, such as itching, burning, cracking, and
11
scaling.
12
[Slide.]
13
Labeling for monograph ingredients
14
specifies four week duration of treatment and
15
directs the consumer to seek medical advice if
16
symptoms persist at the end of the treatment.
17
Under the Directions Section, it states,
18
"Use daily for four weeks, and if condition
19
persists longer, ask a doctor."
20
[Slide.]
21
Also, the Warning Section states, "Stop
22 use
and ask a doctor if irritation occurs or if
105
1 there
is no improvement within four weeks," which
2 is
the label duration of treatment.
3
[Slide.]
4
The third type of labeling is for
5
over-the-counter NDA drug products.
There are a
6 few
differences between the labeling of monograph
7
ingredients and products marketed under NDAs.
8
[Slide.]
9
The Uses Section of NDA nonprescription
10
product labeling is usually consistent with the
11
Uses Section of the products marketed under the
12
monograph except when conditions studied in
13
clinical trials are somehow different.
14
For instance, if patients enrolled into
15
clinical trials get only interdigital tinea pedis,
16
this will be reflected in the Uses Section, as is
17
shown on this slide, "Cures most athlete's foot
18
between the toes, and effectiveness on bottom or
19
side of foot is unknown."
20
The second bullet is also similar to
21
optional indication statements as monograph
22
ingredients.
106
1
[Slide.]
2
The Directions Section on the
3
over-the-counter NDA drug labeling also reflects
4 the
treatment regimen studied in clinical trials.
5 We
have two types of over-the-counter antifungal
6
drug products for tinea pedis approved under NDAs.
7
This is an example of product that is
8
approved for four-week duration of treatment.
9
[Slide.]
10
This is an example of the labeling for
11
product that is approved for one-week duration of
12
treatment.
13
[Slide.]
14
The main difference between NDA and
15
monograph product labeling is that NDA labeling
16
does not specifically inform consumer about the
17
time of expected outcome. The
warning simply
18
states, "Stop use and ask a doctor if too much
19
irritation occurs or gets worse."
There is no
20
specific information on expected efficacy.
21
[Slide.]
22
Talking about efficacy, I would like to
107
1
show a few examples of over-the-counter labeling,
2 how
we convey this information to consumers.
3
[Slide.]
4
Most of over-the-counter products are
5
indicated for acute symptom relief.
Few have a lag
6
time between the treatment initiation and
7 completion,
and the expected results. Efficacy
8
rates usually are not presented on over-the-counter
9
labeling, which few products have.
If this
10
information is present, it is presented in Drug
11
Facts on the carton or in the package insert.
12
[Slide.]
13
One example is one of the newly-approved
14
over-the-counter products that has a lag time
15
between the initiation of treatment and complete
16
response is omeprazole. The Uses
Section and the
17
Direction Section both state that it may take one
18 to
four days for full effect.
19
This information is included on the carton
20
label, so consumers can read this statement when
21
considering to purchase the product. The same
22
information is included in the package insert.
108
1
[Slide.]
2
The next example is an over-the-counter
3
product with the efficacy information is labeling
4 for
minoxidil. The following warning
statement on
5 the
carton label is also available to consumers at
6 the
time of purchase.
7
Under the section When Using this Product,
8 it
states, "It takes time to regrow hair.
Results
9 may
occur at two months with twice-a-day usage, and
10 for
some it may take four months to see results."
11 The
same information is included in the package
12
insert.
13
[Slide.]
14
The last example is labeling for
15
famotidine, which includes information about the
16
efficacy rate of the product in the package insert.
17 Two
bar graphs demonstrate heartburn relief,
18
prevention, or reduction for the drug product
19 relative to placebo.
20
Because this information is in the package
21
insert, it is not available to consumers at the
22
time of purchase, and we don't know if consumers
109
1
reach this information at all.
2
[Slide.]
3
Today, we are seeking your advice.
Should
4 the
following be in the over-the-counter topical
5
antifungal drug label? Efficacy
rates, time to
6
symptom relief, expected time to cure, when to see
7 a
doctor, and whether ancillary measures to prevent
8
tinea pedis, such as changing socks, wearing
9
well-fitting, ventilated shoes, or cleaning showers
10
should be emphasized on the label.
11
This concludes my talk.
12
DR. CANTILENA: Thank you, Dr.
Shetty.
13
We have time for questions from the
14
committee. Dr. Lam.
15
DR. LAM: I want to go back to the
Adverse
16
Event Reporting System data that you presented,
17
specifically regarding the 35 percent lack of
18
efficacy data.
19
Do you have information whether that was
20
mostly associated with the one-week regimen, or the
21
four-week regimen, or a combination of both?
22
DR. SHETTY: This is all,
combination of
110
1
all.
2
DR. LAM: Okay. So, we don't even have a
3
sense whether it is primary one week, because the
4
data clearly showed that one week--
5
DR. SHETTY: We have more reports
for
6
one-week products. Maybe the
reviewer for the
7
database will answer your question.
8
DR. CANTILENA: Yes, there is a
comment
9
over here?
10
DR. PITTS: My name is Marilyn
Pitts.
11
Actually, for the lack of efficacy reports, because
12 of
the extreme volume, we were unable to look at
13
those reports individually, so we don't know the
14
duration of treatment. We don't
know if's a
15
one-week or four-week or three-week, or even if the
16
patient used it once a day or twice a day. So, we
17
don't have that information.
18
DR. LAM: I will say that if there
is a
19 way
that we can get a sense, it will be important
20 for
us to consider some of the issues either this
21
afternoon or tomorrow. There is
no way to do that?
22
DR. CANTILENA: There probably are
111
1
thousands, right?
2
DR. PITTS: There are thousands,
there is
3
almost 1,700 reports. It takes a
long time to even
4
pull the images and then to go through and
5 categorize
and get that information. It is
6
extremely time-consuming and difficult to get that.
7
DR. CANTILENA: You know, we have
really
8
about three hours before we come back after lunch.
9
[Laughter.]
10 DR. CANTILENA: There is a lot of FDA
11
employees. It is not going to
happen, Dr. Lam.
12
DR. LAM: Are we going to consider
the
13
question whether--in your executive summary, you
14
indicated that some of the manufacturers are
15
considering developing products of less than
16
one-week treatment duration--so, are we going to
17
consider that at all today or not?
18
DR. GANLEY: I think it is done in
the
19
context of understanding what the cure rates are or
20
effective treatments that we see, and the lack of
21
dose-response information.
22
In that context, if someone did a study
112
1
that showed three days of treatment was as good as
2 one
month of treatment, and they figured out what
3 the
correct concentration is, well, that is pretty
4
good, I think.
5
The issue I think is we don't get that
6
information. It is really what
beats vehicle and
7
what kind of study is done, and I think that is
8
where the committee has to start addressing, you
9
know, from a dose-response, and one of the
10
questions actually addresses that.
11
I think that is the context, but I have no
12
objection to have a one-day or a three, and we have
13 had
inquiries about a one-day treatment product.
14 So,
it is what is the bar that we want to set here,
15 is
it just that you beat vehicle or is it that we
16 try
to maximize the efficacy for consumers.
17
DR. CANTILENA: We have Clapp,
Raimer,
18
Schmidt, and Katz.
19
DR. CLAPP: This is just a
question really
20
based on curiosity. Because of
the sheer volume of
21
complaints you have had, or consumer complaints,
22
what is the method by which a consumer's concern of
113
1
lack of efficacy gets to the FDA?
2
DR. MAHAYNI: Well, they just
report like
3 any
other adverse event. It is actually a
4
complaint, but they call to Adverse Event Reporting
5
System.
6
DR. CLAPP: But how does the
consumer get
7 to
the Adverse Event Reporting System? I
don't
8
think many physicians do it on this level.
9
DR. MAHAYNI: Maybe they call the
number
10 on
the package and then it comes. I don't
know
11
they come to us.
12
MR. KRESEL: Can I comment because
13
pharmacovigilance is part of my department, as
14
well? They call the number that
is on the bottle,
15 and
then we are required to report it to FDA.
16
DR. CANTILENA: And then FDA holds
an
17
advisory committee.
18 Yes. Did you have a comment about it?
19
DR. PITTS: Right, the Med Watch
form is
20
also available via the internet.
There is also a
21
1-800 number. But I recognize that patients have to
22
recognize that there is a system in place, and I
114
1
don't think the carton actually has that
2
information specifically, because even for health
3
care providers, to recognize there is a system in
4
place where if you have a complaint about a
5
product, then, you should call.
6
DR. CANTILENA: Thank you.
7
Dr. Raimer.
8
DR. RAIMER: I was just going to
mention
9
that most of the complaints were against agents
10
that you could over the counter, so a lot of the
11
patients probably had psoriasis or probably had
12
eczema or probably did not have tinea in the first
13
place, so there is no way to really judge whether
14 the
patient even had tinea to start with.
15
So, a lot of the complaints, they have
16
similar symptoms, so it would be difficult to know
17
what the patient really had in the first place.
18
DR. CANTILENA: So, you are saying
there
19 is
a problem in the setting of an OTC, you know,
20
self-diagnosis?
21
DR. RAIMER: Yes.
22
DR. CANTILENA: Well, that is
another
115
1 issue that is not on our list of issues.
2
DR. PITTS: I am sorry, could I
make a
3
clarification? Actually, we
believe that the
4
reports for the over-the-counter products are
5
underrepresented. If you look at
the number of
6
reports, the topical terbinafine and topical
7
miconazole, those were previously prescription
8
products, and if we were to probably look at that,
9 we
probably would see that most of those or some of
10
those occurred more during the prescription process
11 as
opposed to the OTC process, so I don't have any
12
idea.
13
DR. RAIMER: Even then, a lot of
14
physicians do not do the mycology, they don't the
15
KOH, they judge just clinically, so even then, I
16
think a lot of those probably don't really
17
represent tinea.
18
DR. CANTILENA: Dr. Schmidt.
19
DR. SCHMIDT: Before too long, I
would
20
like to address this about the cellulitis issue and
21 get
this on the table.
22
These case reports are real dogs, you
116
1
know, as far as cellulitis. I
don't think any of
2
these people had really an adverse reaction to any
3 of
these medications, and I don't think they were
4
cellulitis. I think they were
contact dermatitis.
5
There was one patient that had TEN
6
probably from Enbrel, and I think to put this down
7 as
these 13 cases of cellulitis, this really needs
8 to
be brought up and discussed.
9
DR. CANTILENA: I am not sure what
that
10 is,
but there is an opportunity right after our
11
next speaker, we will be actually talking about the
12
complications.
13
DR. PITTS: Can I respond to that?
14
Actually, the prescriber or the reporter identified
15 the
cases as cellulitis, we did not make any
16
judgment call in terms of whether they were
17
cellulitis or not, but this was what was actually
18
reported by the health care practitioner that
19
submitted the report for those cases.
20
We are not making any judgment call as to
21
whether or not they are good cases or bad cases.
22
These are just the cases that were reported.
117
1
DR. SCHMIDT: Woof, woof, woof.
2
DR. CANTILENA: I think Dr.
Schmidt has
3
just made a judgment call.
4
[Laughter.]
5
DR. CANTILENA: Dr. Katz.
6
DR. KATZ: I wanted to reemphasize
that we
7
should keep in mind the likelihood that the reports
8 of
lack of efficacy must represent a minuscule,
9
tiny minuscule portion of people who have lack of
10
efficacy, because the average folks out there are
11
going to use this for what they perceive to be, as
12 Dr.
Raimer said, tinea pedis, and it doesn't work.
13
They think it says it should relieve symptoms, it
14
doesn't work in two or three applications, so they
15
stop using it, and they take it as a loss.
16
So, I wouldn't be surprised, if a survey
17 was
done at the 0.1 percent of reports you are
18
getting.
19
DR. CANTILENA: Dr. Benowitz and
then Dr.
20
Alfano.
21
DR. BENOWITZ: It was striking to
me that
22
there was almost as many prescriptions by
118
1
physicians for topical antifungals as OTC uses, and
2 my
question is, is this for insurance purposes, or
3 is
there some evidence that the antifungals that
4 are
available by prescription only work better or
5 why
is this the case? It is very striking to
me
6
that there is such a huge volume of prescriptions.
7
I guess that question might be to my
8
dermatology colleagues about why that is occurring.
9
DR. CANTILENA: Anyone? Comments from the
10
Dermatology Committee?
11
MR. KATZ: Might it be that some
of them
12
were prescribed prior to its becoming OTC, for
13
instance, clotrimazole has been OTC probably for,
14
what, five or eight years, so maybe a lot of those
15
reports were when it was prescription?
16
DR. BENOWITZ: This was 2003.
17
MR. KATZ: 2003. I would be very
18
surprised because in recent years, we don't write
19
prescriptions for that. We just
write it for the
20
patients to get it at the drugstore.
We may write
21 it
down on a prescription, but without its being a
22
signed prescription.
119
1
DR. SHETTY: Maybe the physicians
are
2
still used to prescribe or advice to use products
3
that were prescription recently.
4
DR. SCHMIDT: May I comment just a
minute?
5 I
think a lot of this, I don't really write for
6
prescription topical antifungals anymore. You
7
know, the majority of them, they may have a funny
8
name, but they will have the medication that is a
9
prescription, but I think a lot of this is
10
marketing by some of the drug companies.
11
I think, to me, there are a lot of people
12 who
will still write prescriptions for things, and
13 I
think a lot of it is a marketing effort by the
14
drug companies.
15
DR. CANTILENA: Other comments?
16
DR. WOOD: As I understand this,
we don't
17
know that this is OTC, do we? I
mean the Rx's may
18
well be for systemic antifungals for this
19
indication.
20
DR. SHETTY: Only topical
antifungals.
21
DR. WOOD: Are you sure? Are you sure of
22
that?
120
1
DR. SHETTY: Yes. We took out the
2
systemic and we took out some ketoconazole.
3
DR. WOOD: So, the 15.7 million
4
prescription were eaches for itches, that were all
5
topical, is that right?
6
DR. SHETTY: Yes.
7
DR. GANLEY: I think that it was
pointed
8 out
that we can't separate out, particularly for
9 the
prescription, which ones were for other
10
conditions other than tinea pedis, and even for the
11
OTCs, there is other claims. I
think tinea pedis,
12 of
the three that are over the counter, is probably
13 the
most common, but that is the difficulty.
14
But is it a little surprising I think when
15 you
see the percentages here or the number of
16
eaches for each. I think what is
interesting, too,
17 is
if you look at the National Sales Perspective,
18
which was Slide 8, the Clotrimazole and
19
betamethasone was the highest there in the number
20 of
eaches.
21
But if you look at Slide 10, only 12
22
percent of those prescriptions accounted for tinea
121
1
pedis, so the 90 percent of those, you would have
2 to
assume then were related to other conditions
3
where if someone saw a rash, didn't know if it
4
required an antifungal or a steroid, so they gave
5
them the combination product.
6
So, it is difficult data to look at, but
7 it
is the best that we can do with it.
8
DR. CANTILENA: Thank you.
9
Did you have a comment, Dr. Whitmore, on
10
this topic?
11
DR. WHITMORE: I was going to
agree with
12 Dr.
Schmidt as far as why prescriptions are written
13 for
prescription antifungals. Marketing
definitely
14 is
a big one, and the pharmaceuticals will come out
15
with studies where they have certain efficacy rates
16 in
their control study or whatever, which is better
17
than X drug.
18
Also, oftentimes patients will have used
19
their clotrimazole for two or three days or
20
whatever, a short period of time, come in to the
21
physician and say I am not better, so a
22
prescription is written for something else.
122
1
DR. CANTILENA: Dr. Alfano.
2
DR. ALFANO: Dr. Shetty, your
Slide 12,
3 you
said you searched the AERS data as of March
4
16th. What is the start date on
that data?
5
DR. SHETTY: All the reports that
were
6
received.
7
DR. ALFANO: So, this is all
reports like
8 in the history of man? I guess my point is so we
9 saw
20 million eaches, whatever that translates to
10 in
terms of treatments, just for the year of 2003,
11 so
we are talking about tens of millions, if not
12
hundreds of millions, of doses, treatments in this
13
database for a condition for which the previous
14
data presented said 40 percent of people who
15
present to hospitals have the condition and 15 to
16 70
percent of free-living Americans have the
17
condition.
18
So, I guess the trouble I am having is,
19 you
know, the perception that this is such a large
20
database, it actually seems to be a very tiny
21
database relative to the number of individuals who
22
have the condition and who have treated the
123
1
condition.
2
DR. PITTS: If I can respond, the
AERS
3
database, this is all reports in the database for
4
those agents, for the topical agents, and we know
5
that there is a significant amount of
6
underreporting that occurs between recognizing that
7
there is an adverse event and then having that
8
person report it.
9
With the topical agents, I would suspect
10
that there is even less of a reason for people to
11
draw a correlation, but there is a different time
12
period where they came on the market, so it is
13
really for all the ones that we have for the life
14
that we have, but these are two different databases
15
between the drug use data and the adverse event
16
databases. Those are different
databases.
17
DR. CANTILENA: Dr. Katz.
18
DR. KATZ: I just want to clarify
19
something. What was mentioned,
the
20
over-the-counter products are being prescribed,
21
were you referring to page 5 of this last
22
presentation, where in 2003, most physicians
124
1
recommended antifungals for tinea pedis, is that
2
what you were referring to?
3
DR. BENOWITZ: No, what I was
referring to
4 was
actually Slide 7, just showing the volume.
5
DR. KATZ: What page is that?
6 DR. BENOWITZ: Page 4, I was just
7
referring to the volume of prescribed topicals.
8
DR. KATZ: That doesn't mean
prescribed,
9
number one.
10
DR. SHETTY: No, this is all in
terms of
11
eaches, whatever goes from manufacturer into the
12
marketplace.
13
DR. KATZ: That is not prescribed.
14
DR. SHETTY: That is not
prescribed.
15
DR. KATZ: And on page 5, where it
says
16
"National Disease and Therapeutic Index 2003"--
17
DR. SHETTY: This is a different
database.
18
DR. KATZ: That is physician
recommended.
19
DR. SHETTY: That physician
mentioned
20
during the visit.
21
DR. KATZ: That doesn't physician
22
prescribed.
125
1
DR. SHETTY: No, that doesn't.
2
DR. KATZ: So, we should have that
3
straight, because frequently, we will write--not
4
frequently--always we will write if we want patient
5 for
tinea pedis to use clotrimazole, miconazole, we
6
will write on the prescription, for patient to
7
remember, so we will write on the prescription
8
without signing it, without the patient's name on
9 the
top, just so they remember.
10
That is physician recommended.
That
11
includes not OTC, because
12
Clotrimazole/betamethasone is not OTC, I don't know
13
what Naftifine is, so I think that may have been
14 the
source of confusion.
15
DR. GANLEY: I just want to
clarify, on
16
that Slide 10, for the National Disease and
17
Therapeutic Index, that could have been OTC or
18
prescription.
19
DR. SHETTY: Right, Butenafine is
20
nonprescription.
21
DR. GANLEY: Right, so it does
suggest
22
that the Ciclopirox, which I think is the Rx drug,
126
1 is
the most prescribed for tinea pedis. You
would
2
have to think that if that is a prescription drug,
3 and
that is the most recommended, that they
4
actually prescribed it. That's
the only thing I
5 can
take away from it.
6
DR. CANTILENA: We have a final
comment
7
over here from Mr. Kresel.
8
MR. KRESEL: I was just going to
comment
9 on
the AERS database again and that is what then
10 you
look at a class of drugs that doesn't have a
11
significant serious adverse event profile, it is
12 not
uncommon then to see that the most common
13
consumer complaint would be lack of efficacy.
14
My experience in getting consumer
15
complaints is that consumers learn early on that if
16 they
call the sponsor and complain that their
17
product didn't work, they will get a refund.
18
DR. CANTILENA: That certainly is
an
19
incentive, and I think we all have an incentive to
20
take a break. We will return at
10:30.
21
[Break.]
22
DR. CANTILENA: Our first speaker
for
127
1
after the break here will be Dr. Alan Bisno from
2 the
University of Miami, School of Medicine,
3
infectious disease complications of tinea pedis.
4
Infectious Disease Complications of Tinea Pedis
5
DR. BISNO: Good morning. My assignment
6
this morning has been to discuss the relationship
7 of
tinea pedis and cellulitis of the lower