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
8
extremities. I am embarrassed to
do this because,
9 as
I am going to tell you in a little while, there
10 is
much more that we don't know than what we do
11
know about this particular subject.
12
What I am going to do is
start off with
13
some introductory remarks about the epidemiology
14 and
nature and clinical nature of cellulitis in
15
general, the problem of recurrent cellulitis and
16 its
control, and then go on to discuss in more
17
detail what data there are available on tinea pedis
18 and
cellulitis of the lower extremities.
19
Looking around this august group at the
20
table, I know that I am bringing coals to Newcastle
21 for
most of you, but I have to apologize for that.
22
[Slide.]
128
1
First of all, what is known about the
2
factors that predispose to lower extremity
3
cellulitis, because certainly, tinea pedis is not
4 the
only one, and there is sort of two groups of
5
factors that are known to predispose.
6
First, is anything causing cutaneous
7
disruption, trauma or surgery, burns or ulcers.
8 Varicella
is an interesting one, it is not limited
9 to
the lower extremities obviously, but
10
pediatricians have known and infectious disease
11
people have known for many years that children who
12 get
varicella may often get secondary cellulitis
13 and
even life-threatening bacteremias due to
14
streptococcal infection of the varicella, so it's a
15
good reason to have children immunized against
16
varicella.
17
Then, there is dermatophyte infections of
18 all
kinds, so cutaneous disruption is one issue,
19 and
then there are systemic factors that also
20
predispose to cellulitis including lymphedema and
21
venous insufficiency, obesity is a major risk
22
factor, as I will discuss, ischemia, IV drug abuse.
129
1
Obviously, we see lots of cellulitis in individuals
2 who
are parenteral drug abusers, both IV and skin
3
poppers, and then immunosuppression.
4 So, all of these are factors
predisposing
5 to
lower extremity cellulitis.
6
[Slide.]
7
This is a typical case of cellulitis.
I
8
don't know how well it shows here, but it is a
9
diffuse inflammatory process involving the skin and
10
subcutaneous tissues, and if this projects well
11
enough, which in this lighting it might not, those
12 of
you who may be able to see that it is occurring
13
along the site of a saphenous venectomy which was
14
performed for coronary artery bypass grafting.
15
[Slide.]
16
Erysipelas is a little bit different.
17
This is one of my patients with erysipelas, and it
18
involves the more superficial areas of the skin,
19 such that the lymphatics are greatly involved,
and
20
this leads to some of the special features of
21
erysipelas, namely, that it is raised above the
22
surrounding area, unlike the cellulitis that I
130
1
showed you in the last slide, and that unlike
2
cellulitis, there is a sharp demarcation between
3 the
involved and the uninvolved area.
4
[Slide.]
5
I just show this picture of classic facial
6
erysipelas, which isn't really pertinent to what we
7 are
discussing today, simply to mention that
8
nowadays, more and more, we don't see erysipelas in
9
that area, but we do see it in lower extremities,
10 as
shown by this patient.
11
You will have to accept my word, because
12 of
the lighting in here, that this is raised and
13
well demarcated, and it is a case of erysipelas of
14 the
lower extremities, also happens to be one of
15
those in the post-saphenous venectomy group.
16
[Slide.]
17
Sometimes this goes on to more extensive
18
problems. These bullae and vesicles with
19
dark-colored material in them don't necessarily
20
mean that there is going to be an adverse outcome,
21 but
they are very worrisome in terms of the
22
possibility, to me, they signify a lot of local
131
1
toxin production, and some patients with cellulitis
2 do
go on to have deeper tissue infection which can
3
even be life-threatening.
4
I have taken care of one patient recently
5 who
has had three episodes of cellulitis, an obese,
6
homeless patient with severe tinea pedis who had
7
been in the intensive care unit three times, twice
8 in
shock, because of this kind of a problem.
9
[Slide.]
10
Well, the microbial etiology of erysipelas
11 and
cellulitis differs a little bit in that classic
12
erysipelas, when you see the man that I showed you
13 in
the first slide, this is virtually always due to
14
beta-hemolytic strep, mostly Group A, but now
15
always.
16
But the terms cellulitis and erysipelas
17 are
often used interchangeably, particularly in the
18
European literature, so many of the studies that I
19
quote or that you will see talk about erysipelas,
20 and
they say erysipelas and cellulitis
21
interchangeably, and you can't really tell whether
22
they are talking about erysipelas or cellulitis.
132
1
In truth, that is not such a big deal
2
because many cases are not so clear-cut as the
3
examples that I have shown you, and it really is
4 not
always possible to classify it as one or
5
another.
6
The only reason I bring it up is because
7
although classic erysipelas is virtually always
8
beta-hemolytic strep, cellulitis can be due to a
9
wide variety of organisms. The
list of organisms
10
that can cause it is extremely long, but that is
11 for
another session.
12
But in most cases, nevertheless, the vast
13
majority of cases are due to beta-hemolytic strep
14 or
Staphylococcus aureus. When you see
typical
15
lower extremity cellulitis with diffuse spreading
16
erythema, and not localized pus, that is usually
17 not
staphylococcal, it is usually to beta-hemolytic
18
strep, but not necessarily Group A.
It can be A,
19 B,
C, or G.
20
[Slide.]
21
It is important for us to discuss
22
recurrent cellulitis because this is an important
133
1
issue in relationship to what we are going to be
2
talking about in terms of tinea pedis.
3
Many patients with episodes of cellulitis
4
experience recurrent attacks. The
percentage of
5
patients in whom this occurs is variable depending
6
upon the risk factors.
7
DeGodoy and associates did a study of a
8
large number of patients, and did lymphatic
9
scintigraphy on these patients and found that 77
10 percent
of such patients had abnormalities of
11
lymphatic drainage on scintigraphy, and it is
12
believed that lymphatic drainage is progressive
13
with recurrent episodes, thus exacerbating the
14
problem, so we would really like to prevent
15
recurrent cellulitis.
16
[Slide.]
17
I am going to show a couple of slides on
18
antimicrobial prophylaxis of recurrent cellulitis
19 for
a couple of reasons. The first is that
we will
20 get
some idea of the baseline rates of recurrence,
21 and
the second is that since control of tinea pedis
22 is
one of the things we are going to be discussing
134
1
today, that is only one method of preventing
2
recurrent cellulitis, and now you have taught me
3
this morning that most of these things don't work
4
anyway, so I have to look at alternative ways to
5 try
to prevent recurrent cellulitis.
6
It is generally written in the literature
7
that patients who have frequent episodes of
8
recurrent cellulitis should be put on continuous
9
antimicrobial therapy to prevent this.
Many of you
10 who
practice dermatology in this group may have run
11
into this issue, but it is surprising how little
12
real data there are and how marginally effective
13
such antimicrobial prophylaxis is.
14
For instance, in this study by Wang, et
15
al., 31 patients with definite or presumptive
16
streptococcal cellulitis of the lower extremities
17
were treated with monthly benzathine penicillin G
18
injections, and 70 patients who declined and 14 who
19
received incomplete prophylaxis served as controls.
20
The recurrence rate was 12.9
percent in
21 the
treated patients and 19 percent in the
22
controls, which wasn't statistically significant.
135
1
Interestingly enough, benzathine
2
penicillin G was spectacularly effective in
3
reducing recurrences in patients who didn't have
4 any
predisposing factors, but not in those with
5
predisposing factors.
6
I have a hard time interpreting this study
7
since the patients I see with recurrence all have
8
predisposing factors. One
predisposing factor they
9
didn't mention in the study, however, was tinea
10
pedis, and that may have been a major unrecognized
11
predisposing factor in this particular study.
12
[Slide.]
13
Here is another one of 40 patients with
14
venous insufficiency or "lymphatic congestion," who
15 had
suffered two or more episodes of erysipelas
16
during the previous three years.
17
Twenty patients received oral penicillin
18 or
erythro for a median of 15 months with two
19
recurrences versus 8 in 20 untreated controls.
20
That is 40 percent, that is pretty impressive to
21 me,
but the p-value is only 0.06, and the authors
22
themselves concluded that continuous prophylaxis is
136
1
indicated only in patient with a high recurrence
2
rate.
3
There are other things you can do in these
4
patients, such as giving them a prescription of
5
antibiotic to have in their pocket in case they
6
have the earliest signs at onset, they can
7
frequently truncate the attacks.
8
[Slide.]
9
With that introduction, let's talk about
10
tinea pedis and lower extremity cellulitis. Here,
11 I
am really on very shaky grounds, because I am an
12
infectious disease person, I am not a
13
dermatologist, and I am going to quote some
14
dermatologic literature, and it may or may not be
15
current, so you guys can please straighten me out
16 in
the discussion period.
17
I am quoting at least authority in the
18
person of Dr. Albert Kligman, who published back in
19 the
1970s the following: that the recovery
of
20
fungi decreases as athlete's foot becomes
21
progressively more severe; that aerobic microflora
22
expands as the disease becomes more and more
137
1
serious.
2
Athlete's foot represents a continuum from
3 a
relatively asymptomatic, scaling fungal eruption
4 to
a symptomatic, macerated, hyperkeratotic process
5 that results from the overgrowth of resident
6
organisms if the stratum corneum is damaged by
7
preexistent fungi.
8
Overgrowth of the same organisms in
9
normal, fungus-free interspaces does not produce
10
lesions.
11 [Slide.]
12
In a more recent review in the Clinics in
13
Podiatric Medical Surgery in 1996, the author made
14
many of the same points.
15
With progression of the process of
16
dermatophytosis, the normal protective skin barrier
17
becomes macerated and friable.
18
As the process continues, the skin becomes
19
debilitated and weakens as an effective barrier
20
against infection.
21
Fissures may occur, providing a portal of
22
entry for any opportunistic organism in the area,
138
1
resulting in cellulitis.
2
[Slide.]
3
Let's get on more specifically to tinea
4 pedis
and lower extremity cellulitis.
5
This really dates back to the earliest
6
studies that were published about saphenous
7
venectomy and coronary artery bypass grafts and
8
cellulitis.
9
The first of the two studies that were
10
published was that by Greenberg, et al., from Dr.
11
Roman Kasankosis' group, and my own study with Dr.
12
Larry Baddour, who was a fellow of mine, is now a
13
professor at the Mayo Clinic, in the Annals of
14
Internal Medicine in 1982. I am
not sure, sir, of
15 you
were the editor in 1982, but if you were, thank
16 you
for accepting the paper.
17
Anyway, the initial studies focused upon
18
patients who had undergone saphenous venectomy, and
19
many of these infections were due to non-Group A
20
beta-hemolytic streptococci, often B, C, or G, to
21 the
extent that you could get them. In most
cases
22 of
cellulitis, as you know, you don't get a
139
1
microbiologic diagnosis.
2
[Slide.]
3
Of these two studies, Greenberg, et al.,
4
really have precedence in terms of the tinea pedis
5
issue because they described 9 men, age 48 to 72
6
years, who developed cellulitis in the saphenous
7
venectomy extremity. Five of the
9 patients had
8
recurrent episodes.
9
The first infection was within 8 months
10
post-op in 8 patients, but one was 8 1/2 years
11
later. I should interject here
that actually, as
12 we
have had more experience with this, these things
13
happen frequently months and many years afterwards.
14 It
is something that the cardiovascular surgeons
15
never recognize because they don't see those
16
patients at that point.
17
Positive blood cultures in that study, in
18 one
patient, yielded beta-strep which weren't
19
further characterized.
20
All 9 had mild to severe tinea pedis of
21 the
involved leg, and they state there were no
22
recurrences after aggressive topical or oral
140
1
antifungal therapy. That is all
the information
2
that is given, so we don't know how long it was
3
given, how long it was followed, and that sort of
4
thing.
5
[Slide.]
6
Dr. Baddour and I went back to our
7
original studies and looked at our patients again,
8 and
we detailed 9 patients with post-CABG
9
cellulitis, 5 of whom experienced from 2 to more
10
than 20 recurrences.
11
At the time were reported this in the
12
1980s, it is amazing that clinicians were not
13
recognizing this as cellulitis.
They were
14
frequently thinking it was some sort of a deep
15
venous thrombosis, and people were anticoagulated
16 and
all kinds of other things were done to them, so
17
they ended up having many, many recurrences.
18 But anyway, 7 of these patients had
tinea
19
pedis, and in 2 instances, control of
20
dermatophytosis was associated with cessation of
21
attacks. I have to admit to you I
can't remember
22
now, 20 years later, how long we followed these
141
1
patients, and they are only 2, so I am guilty of
2 the
same thing that I critiqued the last study for.
3
[Slide.]
4
Now, more recently, Dr. Semel and Goldin
5
picked up on our work and did something very
6
interesting, and their paper I think is included in
7 the
packet that you have. They studied 20
patient
8
with lower extremity cellulitis, but they excluded
9 patients
with trauma or peripheral vascular disease
10 or
chronic leg ulcers. I am not sure why,
but I
11
suspect that those particular conditions are more
12
likely to be associated with staphylococcal than
13
with streptococcal infections.
14
Anyway, they found athlete's foot present
15 in
20 or 84 percent of the 24 episodes studied.
16
Beta strep were isolated from ipsilateral two web
17
spaces in 17 or 85 percent of the 20 cases.
18
Then, they took 30 controls seen in a
19
dermatologist's office for treatment of athlete's
20
foot, but without cellulitis, and not a single one
21 of
them were they able to recover beta strep.
So,
22
they concluded that only beta strep are recovered
142
1
more frequently from patients than controls
2
[Slide.]
3
Now, I am going to quote a few other
4
studies are less informative, but the literature is
5
spotty in this regard.
6
Thirty Venezuelan patients with erysipelas
7
were reported, who were in otherwise good health.
8
Forty-three percent of them had tinea pedis and in
9 7
of 30 or 23 percent tinea pedis was found to be
10 the
unique predisposing factor, but there were no
11
controls.
12
Again, I don't know what the base
13
prevalence of tinea pedis is in Venezuelan
14
patients, is it 43 percent or is it 10 percent. I
15
don't have that information.
16
[Slide.]
17
Koutkia, et al., did a prospective but
18
uncontrolled study of 62 hospitalized patients with
19
cellulitis, and they identified a large number of
20
possible predisposing factors here.
You can see
21
that tinea pedis was present in 32 percent. Again,
22
with the data that we have presented this morning
143
1
where the range of tinea pedis in normal
2 populations can be 15 to 40 percent, is that
a true
3
association or not? Again, it's
an uncontrolled
4
study.
5
Interestingly enough, fully a quarter of
6 the
patients in their study were studied as
7
post-CABG patients.
8
[Slide.]
9
The best study to date so far is the
10
Dupuy, et al., study, and this is a case-controlled
11
study of 167 patients hospitalized in 7 French
12
hospitals for lower extremity cellulitis, and they
13
compared it with 249 hospitalized controls.
14
In a multivariate analysis, significant
15
risk factors were disruption of the cutaneous
16
barrier, such as ulcer, wounds, or dermatosis,
17
lymphedema, venous insufficiency, leg edema and
18
overweight.
19
I should mention again obesity is a very
20
powerful risk factor. We just
completed now a
21
prospective case-controlled study of patient with
22
recurrent cellulitis in which we found BMI was a
144
1
highly strong predictor of cellulitis.
It was
2
statistically significant with recurrent
3
cellulitis.
4
But at any rate, in Dupuy's study, toe-web
5
intertrigo was present in 66 percent of patients
6 and
23 percent of controls, for an odds ratio of
7
6.6, and toe-web intertrigo was a strong risk
8
factor, an odds ratio of 13.9 with a population
9
attributable risk of 61 percent.
10
[Slide.]
11
I had a slide on the FDA adverse event
12
reports, but I am not going to beat this dead horse
13
since Dr. Schmidt has already woofed it to death,
14 so
I am not going to say any more about that.
15 [Slide.]
16
What are the unresolved issues that we
17
have to deal with? What is the
risk of normal
18
individuals with tinea pedis developing cellulitis
19 at
some time in their life? We don't have
any
20
information on this whatsoever that I am aware of.
21
Does the magnitude of risk justify a
22
warning? Certainly, if we don't
know the magnitude
145
1 of
risk, we really can't say whether it justifies a
2
warning, but I think the risk in normal individuals
3
with tinea pedis has got to be extremely low.
4
Again, we might have to stratify that as to what
5
kind of tinea pedis are we talking about, are we
6
talking about the kind of things we saw in the
7
first slides with minor scaling, are we talking
8
about really macerated toes, which I think may be
9 an
entirely different level of risk.
10
Are the beta-hemolytic strep strains
11
recovered from between the toes of patients with
12
tinea pedis and cellulitis, such as those by the
13
Semel and Goldin study, are those truly organisms
14
responsible for cellulitis? We
don't know that. I
15 am
unaware of reports of the same strain being
16
recovered from toe cultures in cellulitis during a
17
single attack of cellulitis, none in the literature
18
that I know of.
19
I personally have a case where I have
20
recovered strep over about 10 years, three times,
21
from a patient with tinea pedis and cellulitis, and
22
looked at the M proteins under PCR, and, indeed,
146
1
this is the same strain over and over, but was
2
never recovered during the time of his acute
3
illness. Usually, these patients
get whopped on
4
antibiotics as soon as they get in, and you don't
5 get
positive cultures often from between the toes,
6 so
that is an unresolved issue.
7
Another issue, unresolved issue, which I
8
didn't put on this slide, is do we really have any
9
idea whether treating tinea pedis will actually
10
prevent recurrences. I have given
you all the data
11 I
know, and there are a couple of articles with
12
observational data on a very small number of
13
patients.
14
Here is what we really need to do.
We
15
really need to have a controlled trial of patients
16
with athlete's foot to look at, in this controlled
17
fashion, those who are well treated and those who
18
aren't treated in terms of the incidence of
19
cellulitis.
20
But let's think about how you accomplish
21
that. Obviously, in the general population, the
22
incidence is so low that you would have to study
147
1
thousands and thousands of patients for months to
2
years, so you are not going to be able to do it.
3
So, the best one would be patients with
4
recurrent cellulitis. There, you
might have a
5
chance, particularly with people with frequently
6
recurrent cellulitis. Then, you
could have a
7
controlled trial of treating the tinea pedis of
8
patient with recurrent cellulitis and tinea pedis,
9 and
not treating it in another group of recurrent
10
cellulitis and tinea pedis.
11
You may have little problems with the
12
Human Utilization Committee, but even if you could
13 get
it through there, you would only be studying
14
probably one therapy or one therapeutic regimen.
15
Again, you people have told me that half the time
16 it
is not going to work anyway, so I don't know how
17 you
can study this problem in a really effective
18
manner, but certainly that is the kind of
19
information we need and we don't have.
20
[Slide.]
21
So, what are the issues for the committee
22 at
this point? Tinea pedis is only one of a
number
148
1 of
risk factors for the development of lower
2
extremity cellulitis, but one thing about it, it is
3 one
of the most modifiable of those factors, at
4
least I thought it was before I walked in this room
5
today.
6
Now, the committee might wish to add a
7
caution about the importance of eradication of
8
tinea pedis in patients with such risk factors as
9
lymphedema, venous insufficiency, edema of the
10
legs, marked obesity, saphenous venectomy, or for
11
CABG, or previous episodes of cellulitis.
12
So, I would say that if you are going to
13 do
anything at all, the best you could do, at least
14 in
my humble opinion, is to put In at least a
15
warning about the importance of assiduous treatment
16 of
tinea pedis in patients with these established
17
risk factors.
18
Thank you very much.
19 DR. CANTILENA: Thank you, Dr. Bisno.
20
Questions from the committee for Dr.
21
Bisno? Yes, Dr. Epps.
22
DR. EPPS: I don't know whether it
is more
149
1 of
a question or a comment. Within the
2
differential of a web space tinea pedis would be
3
erythrasma, which is actually a bacterial
4
infection.
5
DR. BISNO: Corynebacterium
minutissimum.
6
DR. EPPS: Right.
7
DR. BISNO: I recently had a
bacteremic
8
patient with that, interestingly enough.
9
DR. EPPS: I wondered whether some
of
10
these cases of cellulitis, whether, in fact, they
11 had
tinea, whether they had erythrasma, and perhaps
12
that could be an confounding issue.
13
DR. BISNO: I guess so, but look
at the
14
prevalence in the population of tinea pedis versus
15
erythrasma. I think there has got
to be a
16
magnitude of order difference. I
may be wrong
17
about that, again, I am not a dermatologist.
18
DR. CANTILENA: Dr. Schmidt.
19
DR. WHITMORE: Dr. Bisno, I had a
question
20 for
you regarding strep colonizing the skin.
It is
21 not
going to do that unless the integrity is
22
disrupted, is that correct?
150
1
DR. BISNO: I am sorry?
2
DR. WHITMORE: Strep is not going
to be
3
growing in the skin unless the integrity of the
4
skin is disrupted.
5
DR. BISNO: We used to think that,
but it
6 is
not entirely true, and the way that we know that
7 is
in studies of children, underprivileged children
8
with poor personal hygiene in areas where there is
9 a
lot of streptococcal pyoderma, and the studies by
10
Wannamaker and Digianni and their associates in
11
Minnesota many years ago showed that in those
12
circumstances, you do get colonization of the skin
13
with the pyoderma types of streptococci and then
14
presumably due to trauma, abrasions, or insect
15
bites, it gets converted into pyoderma.
16
So, at least in certain instances, it
17
could colonize normal skin, but generally, I think
18 in
general the answer is you wouldn't expect that
19 to
be part of the normal flora in a population of
20
people who weren't underprivileged or who were able
21 to
maintain normal hygiene.
22 DR. WHITMORE: The only reason I ask that
151
1 is
because if that were true, which apparently it
2 is
not, then, we could select out patients who have
3
disrupted skin, who are then actually put at risk
4 for
cellulitis because of their tinea, such as
5
cracking in the web space or vesicular bullous on
6 the
foot where there is disruption.
7
DR. BISNO: That is a
possibility. I mean
8 it
seems to me that even with those strictures, you
9 are
going to be treating an awful lot of people.
10 Of
course, you would be treating those patients
11
anyway, so I guess that would be fine, you would be
12
wanting to do that anyway.
13
DR. SCHMIDT: My clinical
impression is
14
that treating these things does help the tinea, but
15 the
biggest problem that we see clinically, at
16
least in Houston, is many of these people are these
17
massively obese female who are completely immobile,
18 and
I don't really think that these people who have
19
these recurrent cellulitises, at least in my
20
experience, really live that long, you know, that
21
there is something else that kills them, usually
22 the
obesity.
152
1
I have one other question. When
you said
2
obesity, you used the term--in Texas, we use TDF,
3 too
damn fat--but you said DMI.
4 DR. BISNO: Body mass index.
5
DR. SCHMIDT: Oh, that sounds a
lot
6
better. Thank you.
7
DR. CANTILENA: We should probably
strike
8
that from the transcript, just so we don't get in
9
trouble with Texas.
10
DR. BISNO: I think you have
identified
11 one
group, that is for sure, but there are lots of
12
other people who don't have those, particularly
13
saphenous venectomy group, people who have had,
14
let's say, nodal dissections for cancer and have
15
chronic lymphedema.
16
There are a number of other factors, and
17
another area that we are seeing a lot of problems
18
with, as I alluded to in one of the case
19
discussions is the homeless, because they are out
20
there, they can't really maintain good personal
21
hygiene, they have horrible feet, and they are at
22
risk for this, so I think that obese, and I
153
1
wouldn't necessarily--I don't know about the sexual
2
predilection for obesity, you know, we see obese
3
men, too--and I work at the VA a lot.
4
At any rate, I think obesity is certainly
5 a
major issue, but I don't think it's the only
6
issue.
7
DR. CANTILENA: Yes, Dr. Davidoff.
8
DR. DAVIDOFF: One of the
predisposing
9
factors that is not on your second slide is
10
diabetes, and yet, as a former diabetologist, I was
11 a little surprised because certainly one of
the
12
great concerns of diabetologists and podiatrists is
13
foot infection. Perhaps you could
comment on that.
14
DR. BISNO: Where something like
15
controlled studies have been done on this, as in
16 the
DuPuy study, and actually even in our
17
prospective case-controlled study, a lot of things
18 you
can't see in hospital records, but diabetes you
19
certainly can, and it hasn't emerged as an
20
independent risk factor.
21
So, yes, I agree, I am always worried
22
about diabetes, and I am always worried more
154
1
staphylococcal and streptococcal infections, but
2
nevertheless, I was careful not to say that because
3 I
don't have the data to back it up.
4
DR. CANTILENA: Go ahead, Dr.
Fincham.
5
DR. FINCHAM: I was also curious
about
6
that because you did reference the Koutkia article
7
that listed 50 percent diabetes.
8
DR. BISNO: That is the percentage
in the
9
general population. I mean yes, I
think we all
10
have a feeling, a gut feeling that diabetes is a
11 bad
thing for infection and for the feet, but in
12
terms of these kinds of infections, I don't have a
13
chapter and verse to be able to state that.
14
DR. CANTILENA: Thank you, Dr.
Bisno, a
15
very excellent presentation.
16
Our next speaker this morning would be Dr.
17
Ghannoum who is from Case Western Reserve
18
University talking about the microbiology aspect.
19
Microbiology and Dermatophyte Resistance
20
Related to the Treatment of Tinea Pedis
21
DR. GHANNOUM: Good morning, everybody,
22 and
thank you for inviting me to participate in
155
1
this session.
2
What I am going to try to talk to you
3
today is about really the knowledge we have as far
4 as
antifungal susceptibility is concerned.
Again,
5
this is really a new field, and I am going to
6
present to you a lot of the data which was
7
generated in the last, I would say five or so
8
years.
9
[Slide.]
10
I thought I would put my conflict of
11
interest at the beginning. I
direct the Center for
12
Medical Mycology and I would say the vast majority
13 of
companies that do work with antifungals, we work
14
with them as part of grants and contracts.
15
Also, I act sometimes as consultant and
16
speaker's bureau member for different companies, so
17 it
is not like one particular company, and I
18
thought I would point to some of the relevant
19
companies which we had grants, contracts, or
20
speaker's bureau listed here.
21
[Slide.]
22
Let's talk now about antifungal agents and
156
1
resistance. As you know, in
recent years, there
2 are
a number of compounds which have been
3
introduced to treat fungal infections, and these
4 are
quite efficacious compounds, they work very
5
well including the classes of allylamines and
6
azoles, and really this is very, very good news as
7 far
as treating superficial infections.
8
However, like with the introduction of any
9
antimicrobial, the likelihood or the potential of
10
resistance development is there.
11
This has been very clearly illustrated
12
when we look at systemic infections particularly
13
with Diflucan or fluconazole when it was
14
introduced.
15
[Slide.]
16
I did a literature search,
just to give
17 you
an idea when resistance usually occurs.
I did
18 a
Medline search when the drug is introduced, and
19
then a number of papers on resistance that came out
20
after an introduction of the drug.
You notice
21
like, for example, 5FC was introduced around here,
22
then, you see this is the total papers on
157
1
antifungal resistance increases.
2
The same, you put miconazole,
3
ketoconazole, again, you see the blips, and
4
fluconazole or terconazole, again, you can see I
5
would say resistance is reported about two years
6
after the introduction of new antifungal agents.
7
However, most of these
studies I focused
8 on
are systemic antifungals, because really we
9
don't have many papers, actually, we have nearly
10
none that address this issue.
11
[Slide.]
12
I want now to focus a little bit on the
13
dermatophytes. In spite of the
wide clinical use
14 of
topical antifungal agents, also agents to treat
15
dermatophytosis, very little data is available on
16 the
antifungal susceptibility, as I just alluded
17 to.
18
This is possibly due to the fact that we
19
really do not have a method, which is reference
20
method documented that can measure antifungal
21
susceptibility, and this is not a surprise. We had
22 the
same situation with systemic antifungal agents
158
1 for
30 or 35 years.
2
We only had amphotericin B, so you really
3
don't need to do this, however, when we start
4
seeing the new agents, then, there was a need for
5
developing a method, and the same thing is true
6
when we talk about the topical antifungals.
7
Griseofulvin was the one and now we have
8 the
classes of compounds that are also there.
9
Because of this, there is really a need to develop
10 a
method.
11
[Slide.]
12
With that in mind, what we did in my group
13 at
the Center for Medical Mycology in Cleveland, in
14
1998, we started to put a program to develop a
15
method for measuring antifungal susceptibility.
16
The compounds which we focused on are to
17
dermatophytes. These are the
compounds which we
18
focused on - terbinafine, griseofulvin,
19
intraconazole, and fluconazole.
20
[Slide.]
21
As a result of this program, we published
22 two
papers on them, Norris, et al., and Jessup, et
159
1
al. In these articles, we were
able to determine
2
that optimal conditions for doing antifungal
3
susceptibility. The method is
microdilution
4
method, what type of media used, the inoculum,
5
really all what you need if you want to do the
6
proper antifungal susceptibility as dermatophytes
7 are
concerned.
8
Once those papers are published, I am a
9
member of the NCCLS, the National Committee for
10
Clinical Laboratory Standards, I was asked to
11
really head the group to develop antifungal
12
susceptibility to the dermatophytes.
13
[Slide.]
14
Under the auspices of the NCCLS, we did a
15
number of studies. The first one
was a intra- and
16
inter-laboratory multicenter study to determine
17
whether the developed method is really reproducible
18 by
other people in a way to try to form a document
19 for
that.
20
Also, currently, we are conducting a
21
quality control study to define some organisms, so
22
that labs, when they want to do this, they have
160
1
their QC isolates and they will be able to really
2
know that the method they are performing is the
3
right one.
4
This is in preparation for our next
5
meeting in January 2005. That is
when the NCCLS
6 for
antifungal agents meet. We hope to have
all
7
this method approve and become part of the document
8
M38.
9
[Slide.]
10
Once the method was developed, we started
11
asking the question is there a resistance issue as
12 far
as dermatophytes are concerned. With
that, we,
13 at
the Center, we started really monitoring the
14
antifungal susceptibility of dermatophytes.
15
We had a number of dermatophytes.
We
16
collected isolates where they come from different
17
sources. We had a set of
isolates, sequential
18
isolates obtained from patient with onychomycosis.
19
They were enrolled in part of the clinical trial.
20
We had routine clinical specimens.
Our
21 lab
received specimens from about 400, 500
22
physicians, where we identified isolates through
161
1
KOH, and this sort of thing, so we collected those
2
also.
3
We were the central lab for clinical
4
trials for some topical agents, also those
5
organisms, and finally, we did a couple of
6
epidemiological studies, one on onychomycosis and
7 one
recently in tinea capitis, and we collected
8
also those isolates. These have
been published in
9 the
American Journal of Dermatology, and this one
10
also.
11
In total, we have over 2,000
isolates
12
which we tested.
13
[Slide.]
14
I am going to share with you some of the
15
data we collected over the last few years.
16
This is the dermatophytes which we
17
collected from epidemiological studies, the two
18
epidemiological studies that we mentioned. This is
19 the
organism, rubrum, mentagrophytes, tonsurans,
20 and
canis, and this is the number of each species,
21 in
total 117 isolates were collected.
22
This is the terbinafine susceptibility,
162
1 and
you can see this is the MIC in microgram per
2
ml. It went from less than 0.001
to 0.004, and you
3 can
see really 95 percent of the isolates were
4
inhibited by 0.002 micrograms per ml, so it is
5
quite good activity.
6
[Slide.]
7
This is the same isolates. We
looked at
8
fluconazole, who did it do. Again, you can see
9
this is a broader range really of MICs, but I would
10 say
the vast majority could be inhibited from here
11 to
here, 0.5 to 4 micrograms per ml.
12
A few isolates had I would say susceptible
13
dose dependent sort of MICs, two and four of them
14 had
16 or 32 micrograms per ml.
15
[Slide.]
16
We looked at itraconazole.
Itraconazole
17 did
I think the same, a good job. The vast
18
majority of organisms are inhibited within this
19
range. We had got 7 and like 8
isolates, 0.5 and
20 1,
which usually at least in the yeast area,
21
because we had developed breakpoints, you would say
22
maybe you suspect a little bit resistance, but this
163
1 is
a very, very big maybe, because we don't have
2
breakpoints developed for dermatophytes.
3
[Slide.]
4
Now, this is for griseofulvin.
Again,
5
these are from the epidemiological studies, and you
6 see
the vast majorities are quite susceptible and
7
they responded well.
8
[Slide.]
9
Now, I move into some isolates which we
10 got
from the clinical trials, so really some of
11
them saw patients, others did not see patients or
12 the
epidemiological part.
13
The same picture could be painted.
You
14 can
see here for terbinafine, again look at this.
15
Really, the vast majority are within what we
16
expect.
17
[Slide.]
18
This is fluconazole. Again, we
see the
19
same sort of susceptibility.
There is nothing that
20 is
up there.
21
[Slide.]
22
With itraconazole, the same story.
164
1
Remember I told you about 0.5 and 1, some isolates
2
tend to be a little bit high, but not too high.
3
[Slide.]
4
With griseofulvin, we saw something a
5
little bit more interesting, because unlike the
6
isolates which came from the epidemiological study,
7 we
see a number here 22 and 5 isolates with MIC,
8
which I would say higher than what we saw from
9
epidemiologic.
10
So, there is some feeling here that at
11
least griseofulvin, the MIC is going up a little
12
bit, and this had been observed by a colleague of
13
mine in his study from New York Labs, where he
14
showed that there is a little bit of increase in
15 MIC
against griseofulvin.
16
[Slide.]
17
Now, putting everything together for
18
terbinafine, 1,300 isolates, and you can see the
19
range of MIC, less than 0.001 to 0.25, and MIC50,
20
which is the minimum inhibitor concentration that
21
inhibited 50 percent of isolates, 0.002 and 0.015,
22 the
concentration that inhibited 90 percent of
165
1
isolates. So, in general, I would
say it is quite
2
active.
3
[Slide.]
4
This is the same story, but in a histogram
5
format, and I am showing you about fluconazole.
6
This is cumulative data, putting everything
7 together, and you can see T. rubrum, T.
8
mentagrophytes, and I would say here is where the
9
crux of the isolates, most of them are inhibited.
10
[Slide.]
11
Itraconazole, we saw those here at 0.5 and
12 1,
a little bit higher.
13
[Slide.]
14
Griseofulvin, the same thing.
These are
15
isolates which tend to be a little bit higher.
16
[Slide.]
17
To summarize this part of the talk, I
18
would say that all the antifungal agents we looked
19 at,
fluconazole, griseofulvin, itraconazole, and
20
terbinafine are active against the tested
21
organisms.
22
Really, no resistance to these drugs was
166
1
detected, a question mark about griseofulvin.
2
Now, terbinafine, when you compare
3
everything as far as the level of MIC, I would say
4
showed the most potent antifungal activity relative
5 to
the other agents.
6
Now, some clinical isolates I mentioned
7 had
a little bit of elevated MIC to griseofulvin.
8
[Slide.]
9
We then focused a little bit more on a
10
subset of isolates. Remember
those were about
11
1,300. We looked at the total
number, we continued
12
with terbinafine. What we found
is 99.4 percent of
13 the
isolates tested, they had an MIC listed as 0.06
14
micrograms per ml.
15
However, we detected a set of sequential
16
isolates. You remember I told you
we had some
17
isolates from the same patient over a period that
18 had
elevated MICs. Because of this, we
focused on
19
them and we wanted to try to understand.
20
[Slide.]
21
Now, these isolates came from a clinical
22
trial that has 1,500 patients.
They were treated
167
1 to
determine the efficacy and safety of oral
2 terbinafine.
The selection criteria for this was
3
culture positive at the initial visit.
In between,
4 it
could be at least in one or more visits, the
5
positive culture also, and then at the end of the
6
study, the culture was positive, as well, so
7
obviously, we did not get rid of the culture.
8
Now, in total, we had 38 patients positive
9 for
T. rubrum throughout the study. We again
10
focused on these and we looked at the number of
11
organisms. It was 140 sequential
isolates from
12
these 38 patients.
13
[Slide.]
14
Then, we wanted to know why are these
15
patients failing. The answer
could be one of these
16
three possibilities. It could be
due to decrease
17 in
antifungal susceptibility of the infecting
18
organism, MIC going higher.
19
It could be due to reinfection with a new
20
genetically unrelated strain, or it could host
21
factors.
22
[Slide.]
168
1
So, we started to answer each of these
2
questions.
3
First, is there a decrease in antifungal
4
susceptibility of the sequential isolates? We had
5 140
isolates. We did MIC for them, and what
we
6
found in all cases, the MIC of terbinafine from
7
each patient set were either identical or within
8 one
tube dilution. When there is one tube
9
dilution, really, there is no difference, so I
10
would say they are identical at least if you look
11 at
any of the MIC, that one to two tube dilutions
12 are
not considered significantly different.
13
The same results were obtained within each
14 set
against the other drugs, fluconazole,
15
itraconazole, and griseofulvin, showing you that
16
there is no cross-resistance. All of them were
17
actually susceptible.
18
One exception we noted was where one
19
organism, griseofulvin had a MIC 3-fold increase.
20
[Slide.]
21
Now, this is just to show you--I am not
22
going to give all the data--just a representative
169
1
example, and here we have MIC against flu, itra,
2
terb, and griseo. You can see low
and the same.
3 We
did not see an increase as these patients were
4
treated for the 12-week period.
5
[Slide.]
6
However, one patient had the sequential
7
isolate that had elevated MIC out of the 38. Look
8 at
this. This was published by my group in
9
Antimicrobial Agents and Chemotherapy last year.
10
These are the different isolates at
11
different visits, and here we put two isolates
12
which are really standard, just to make sure we, as
13 you
said, quality control and they are susceptible
14 to
terbinafine.
15
You can see here we used two different
16
methods, macrodilution method and microdilution
17
method, to measure the MIC. At
the very front, 4
18
microgram per ml, and remember most of the
19
isolates, really 99.4 percent of the isolates had
20 an
MIC of 0.002. So, this is a significant
21
increase in MIC.
22
When you look at using the microdilution
170
1
method, all the isolates had elevated MIC. Using
2
another method, the macrodilution, it made it even
3 more
interesting where at the beginning it was 4,
4 but
by the end of the study, the MIC microgram per
5 ml
was greater than 128, so it increased.
6
So, that really puzzled us, and we wanted
7 to
know more.
8
[Slide.]
9
But before I go into these, I just want to
10
conclude about the 38 patients.
Patient failure is
11 not
due to a decrease in antifungal susceptibility,
12
because MICs were very similar, only one exception
13
where all six isolates of T. rubrum were found to
14
have greatly reduced susceptibility.
These, we
15
analyzed them a little bit further.
16
[Slide.]
17
We wanted to know is there
18
cross-resistance to other classes of antifungals.
19
Suppose something happens and we have high MIC for
20
something, does it go across to other drugs. The
21
answer is really put simply no.
Here, we see at
22
least the azoles type of compound and griseofulvin.
171
1
Look at the MIC, the same sequential isolate. It
2 is
about the same irrespective of where it came
3
from.
4
[Slide.]
5
When you look at other compounds in the
6
same class, which is allylamine, we wanted to ask
7 the
question is there cross-resistance to other
8
squalene epoxidase inhibitors., and for this we
9
used again our control. This we
know is
10
susceptible to all these agents, 0.002, so it is
11
obviously susceptible, however, look at this.
12
The naftifine, butenafine, tolnaftate, and
13
tolciclate, they all had high numbers indicating
14
that there is a cross-resistance to squalene
15
epoxidase.
16
[Slide.]
17
Now, the question then, is it possible
18
that the patient got infected with another strain,
19
which was more resistant, so we looked at that. We
20
wanted to do genetically related studies to see
21
whether they are the same or not.
22
So, we performed RAPD analysis, which is
172
1
random amplified polymorphic DNA analysis.
2
[Slide.]
3 I am not going to bore you with the
4
method. This is standard
method. This is how you
5
extract the DNA. This is how you
do the analysis,
6 you
know, just to give you the cycle PCR, and this
7
sort of thing, so I am not going to go over that.
8
[Slide.]
9
I am going to just show you the results of
10
that.
11
This shows you, this is the letter, and
12
this is the standard ATCC just to make sure we have
13 T.
rubrum, and if you look at the other lanes, they
14 are
all very similar, indicating that the isolates
15
obtained at sequential visits represented a single
16 T.
rubrum isolate, so it is not something which
17
came new.
18
[Slide.]
19
The last possibility is, is it possible
20
that the patient failure is due to host-related
21
factors?
22
To do that, we know, as I told you, this
173
1 is
part of the clinical trial, so the clinical data
2 was
all available, it was reviewed, and for the 38
3
patients who failed, found the following points
4
which we thought could be really host related.
5
The first one, they had all these
6
patients, the 38, 53 percent of them have a history
7 of
prior use of antifungals, so they have been
8
using antifungals for a long time.
9
Family history of onychomycosis, 60
10
percent of patients had one or more member of their
11
family with history of onychomycosis.
Does it mean
12
that they are genetically predisposed?
I think a
13 lot
of people ask this question. I think
maybe
14
there is some truth to it, but unfortunately, we
15
don't have the study that proved it.
16
The last one, 70 percent were over 45
17
years old. I am not saying this
is old, I passed
18
that a long time ago, but in a study which we
19
published with Boni Elewski, what we did, we looked
20 at
patients who are 53 years old and compared them,
21 and
we found that people are more predisposed to
22
have onychomycosis if they are 53 years and older
174
1 compared to those 53 years and younger.
2
With that in mind, age is really a
3
contributing factor.
4
[Slide.]
5
Summary. Our data indicate that
the
6
failure of patients to clear onychomycosis is not
7
related to resistance development with one
8
exception, that patient which we analyzed. Not due
9 to
reinfection with a new T. rubrum strain, and may
10 be
attributed to host-related factors including
11
family history of onychomycosis, prior antifungal
12
treatment, an age.
13
So, now I am going to try to put
14
everything together is these last two slides.
15
[Slide.]
16
Where are we with dermatophyte
17
susceptibility? I can tell you a
method to measure
18
antifungal susceptibility is now established,
19
unlike before which we didn't have.
20
Only a few studies using this method have
21
addressed whether resistance existed or not, which
22 some
of it you just saw.
175
1
Based on these studies, the resistance, I
2
don't believe it is a problem, most compelling data
3 at
least for terbinafine, which I shared with you.
4
There is a lack of data concerning the
5
susceptibility profile of agents.
The method is
6
new, nobody used it and look at it.
We don't have
7
that.
8
For dermatophytes, unlike for yeasts, the
9 in
vitro-in vivo correlation is also lacking, like
10 we
need a lot of data from MIC and clinical data,
11 and
try to see is there a correlation with the in
12
vitro data and the in vivo. We did this for the
13
yeast, and it was published as part of the NCCLS.
14
There is no breakpoints established for
15 any
of the drugs, the breakpoints which can tell
16 you
let's say 60 microgram is resistant, less than
17
it's susceptible. We don't have
that for
18 dermatophytes. Obviously, the committee
19
established it for the yeast.
20
Now, information about the mechanism of
21
resistance is also not available.
These strains
22
which I talked to you obviously we did some
176
1
molecular studies, and we believe there is a
2
mutation in the squalene epoxidase.
This stuff is
3 not
published yet, but that's about the information
4 as
far as that is available for us on the mechanism
5 of
resistance.
6
[Slide.]
7
What needs to be done? This is
just me
8
sitting trying to think, okay, what do you think
9
should be done. Of course, it is
up to the
10
committee to decide what they want to do.
11
We need to establish baseline data
12
concerning antifungal agents, which will also allow
13 us
to observe trends. If we have a baseline
at
14
least for the compounds which are available, we
15
know what is now, we can look after two, three
16
years, and that could give us information whether
17
there is an increase in MIC or not.
18
Surveillance studies to determine the true
19
frequency of antifungal resistance also should be
20
implemented.
21
Studies to establish in vitro-in vivo
22
correlation should be undertaken.
Sometime this
177
1
could be done in animal models at the beginning
2
where you see there is strain with high MIC,
3
another strain with low MIC. You
infect animal,
4
treat them, and then see whether it worked or not
5
based on the susceptibility.
6
Data should be collected on both clinical
7 and
MIC from patients treated with various agents
8 in
an effort to establish breakpoints for different
9
agents.
10
Finally, I believe MIC data using the
11
developed method should be collected as part of the
12
drug approval study. At least we
know where the
13
agent is.
14
[Slide.]
15
These are the people in my lab who did the
16
work I just presented. Mary
Bradley, who did the
17 DNA
typing and followed the sequential.
Nancy
18
Isham, a lot of the data which I showed you, she
19 did
it. Steve Leidich is the molecular
biologist
20 who
really tried to understand the fact that we
21
have mutation at the squalene epoxidase.
Pranab
22
Mukherjee also was helpful in the biochemical
178
1
characterization of these isolates.
2
Thank you very much.
3
DR. CANTILENA: Thank you, Dr.
Ghannoum.
4 Any questions from the
committee? Dr.
5
Katz.
6 Committee Discussion
7
DR. KATZ: That's a very nice
8
presentation. I just have one
comment and one
9
question. The comment, as far as
patient failure
10 and
host susceptibility, and you question genetics,
11
there is work showing people, not with
12
onychomycosis, but with tinea pedis, with having
13
defective delayed hypersensitivity to Trichophyton
14
antigen in people who have familial tinea pedis,
15
clinically, right through four generations getting
16
tinea pedis.
17
So, that's in the literature some 20, 30
18
years ago.
19
DR. GHANNOUM: I just would
comment I
20
think Nadir Ziaz and Tozzi from Italy, yes, I
21
agree.
22
DR. KATZ: My question on page 13,
179
1
characterization of the sequential T. rubrum
2
isolates with elevated MICs, I wondered whether you
3
note any clinical correlation with those with high
4
MICs, treatment failures or anything different
5
clinically.
6
Was that done or was it a laboratory--
7
DR. GHANNOUM: What we did was
purely
8
laboratory, but then we went and looked at the
9
clinical data after this and tried to find a
10
correlation, and really, the only factors which we
11
found, as I said, age, and so on, but there was
12
nothing.
13 DR. KATZ: No correlation of failure?
14
DR. GHANNOUM: Not as much, no.
15
DR. CANTILENA: Thank you.
16
Dr. Wood.
17
DR. WOOD: I guess my questions
are
18
directed sort of where we may end up going towards
19
labeling. I have I suppose a
genetic resistance to
20
including stuff in labeling for which there is not
21
good data to support it.
22
So, I have a number of questions that
180
1
occurred to me in listening to this.
2
The first one is are there any data that
3
support a relationship between MIC or other
4
laboratory-measured resistance and outcome in terms
5 of efficacy in therapy. The reason I think that is
6
critical is that the data you show, shows most of
7
these isolates respond to less than 0.002
8
micrograms per ml, and this is a 1 percent topical
9
application, so even if you move one order of
10
magnitude, you are still vastly below the
11
concentrations that the organisms are exposed to.
12
So, the first question is are there data
13
that show a relationship between resistance and
14
outcome, and how rigorous is that given the
15
efficacy data that we saw earlier, which is not
16
terrific.
17
DR. GHANNOUM: I think this is a
good
18
question. The data as far as
dermatophytes are
19
concerned, I don't think they exist, as I said, but
20 we
have data where there is an in vitro-in vivo
21
correlation for Diflucan, for example, and
22
oropharyngeal candidiasis, and that was published
181
1 by
the NCCLS in Journal of Clinical Microbiology.
2
Based on that data, we had breakpoints.
3
This has not been done for dermatophytes, so
4
obviously, we need to have this collected, but that
5
data is robust, it was 600 patients.
It showed
6
that--I can give you an example with fluconazole.
7
If the MIC is less or equal to 8
8
micrograms per ml, then, you consider it
9
susceptible, and the success rate was 90 percent.
10 If
you go down in the MIC, let's say greater or
11
equal to 64, then, the outcome is about 60 percent
12
success rate.
13
Now, obviously, fungal infections, that is
14 one
which is very important for us to consider, the
15
disease of immunocompromise.
These patients, even
16
sometimes if you have a good correlation, it is not
17
necessarily that you are going to see success
18
because we have so many underlying factors which
19
need to be taken into consideration.
20
DR. WOOD: Well, 60 percent is still a lot
21
better than the outcome in the clinical trials on
22
Slide 19.
182
1
DR. GHANNOUM: Yes.
2
DR. WOOD: The second point
relates to my
3
fear that some of this might appear in labeling.
4
Most of the host factors that you cite sort of
5
relate to a potentially circular argument, so the
6
fact that you have treated yourself before with an
7
antifungal may reflect the fact you didn't respond
8 to
an antifungal before.
9
It may reflect even the fact that you
10
don't have a fungal infection, and you didn't
11
respond last time, and you don't respond this time,
12 and
so on. I mean I could go through it,
lots of
13
examples, but I think we have to be careful in
14
taking relationships that are not well documented
15 and
including these as host factors that may affect
16
response to therapy when these are not part of a
17
randomized trial or appropriately controlled for.
18
DR. GHANNOUM: First of all, I go
from the
19
back. I agree with you that it is
very important
20 to
do more of these and collect the data.
The data
21
which I showed you is really what is available, and
22
that is the best thing we could do because we had a
183
1 set
of isolates from patients who were enrolled in
2 clinical
trial, and we had the clinical data, so
3
that is the best case scenario.
4
Now, one thing is really clear.
In the
5
dermatology literature, really sometimes people
6
don't even do KOH or culture, and then they go and
7
treat, or they go sometimes and they say, look at
8
their feet, and we know, for example, although I
9
know we are talking about tinea pedis, but let's
10 say
onychomycosis, 50 percent of the time the cause
11 of
infection is nonfungal.
12
Again, here, I am sure there are some
13
other differential diagnosis which is included, but
14 if
the treating physicians don't do the
15
identification and the KOH, and then you are right,
16
maybe they don't have that, but at least with the
17
limited amount of data, that is what I can say.
18
DR. CANTILENA: Thank you.
19
Dr. Benowitz.
20
DR. BENOWITZ: To follow up on the
21
comments of Dr. Wood, it would seem to me, since
22 the
concentrations are so high topically, it should
184
1
never be a resistance issue, and one thing, I am
2 not
sure it was your presentation or someone
3 else's,
the question of just access, are these
4
topical preparations, is the drug getting to the
5
fungus, or is there some sort of barrier in the
6
skin or the keratin or something, why are we not
7
seeing 100 percent mycological cure in a week if
8 you
are giving such high concentrations to
9
susceptible fungi.
10
DR. GHANNOUM: I think, as far as
the
11
access is concerned, there are some studies where
12
they showed that there is skin level.
Let's say,
13 for
example, I know for at least two compounds,
14
itraconazole and terbinafine, there are some
15
studies by Fagerman where he showed they take, you
16
know, the skin shaving, and they were able to
17
isolate the drug, and the drug is there, so I think
18 it
is reaching there.
19
Now, why they are not doing it, is it the
20
patient compliance, is it the fact that there are
21
other underlying diseases? I
think this needs to
22 be
addressed, so I have no idea.
185
1
DR. CANTILENA: Thank you.
2
Dr. Wilkerson.
3
DR. WILKERSON: I think that was
an
4
excellent point. I mean we have
obviously learned
5
today that we treat many and cure few.
So, in this
6
situation, I don't think we really know the
7
pharmacokinetics.
8
We know that if we put 1 percent of
9
compound in a cream, that it works for a few
10 people,
and one of the paradoxes has always been,
11
extending over to onychomycosis, here, we have got
12
something sticking out on the outside of the body,
13 yet
to be treated effectively, you have to treat
14
someone orally instead of treating them topically.
15
My guess is that the nature of these
16
compounds is that we really don't reach very high
17
concentration effective levels.
Otherwise, this
18
data doesn't make any sense.
19
At 0.002 micrograms per milliliter, we
20
ought to be overwhelming these things, and
21
obviously, there is a drug availability issue here
22
which has not been addressed in the studies to
186
1
date, so there is a problem there in terms of yes,
2 the
drug is there, but it is not in a bioavailable
3
form, otherwise, it doesn't make any sense.
4
My second comment is that since we have
5
learned that we are not curing a whole lot of
6
people, I want to know what your feeling is if you
7
pulse treat someone with an antifungal versus
8
continually treating someone, knowing what we know
9
from the bacteriological literature that if you
10 exposed
organisms to sublethal amounts, are we, in
11
fact, going to grow numerous strains of resistant
12
organisms, and if we are looking at prophylaxis,
13
which may come into our labeling later on here, is
14 it
better to pulse someone with higher
15
concentrations and have holiday periods, or is it
16
better to treat them continuous.
17
Do we know that fungi and bacterial
18
resistance behave in the same way?
Along those
19
lines, do fungi lose their resistance over time if
20
they are no longer exposed to the drug, or do they
21
maintain it like bacteria do?
22
DR. GHANNOUM: I agree with you
with the
187
1
first one, but as far as pulse versus continuous--
2
DR. WILKERSON: I am speaking
strictly
3
topical, not oral therapy.
4
DR. GHANNOUM: Yes. I really believe when
5 you
have a fungal infection, it is better to treat
6 it
continuously, at least from our experience.
You
7
see, in dermatophytes, we don't have much
8
information, but our experience with the other
9
agents, again, like Diflucan, we noticed why did we
10
have resistance there develop? Because
they
11
underdose, they use to give 50 milligram.
12
So, definitely, it's a recipe for
13
resistance development, and we know in the lab if
14 you
take something, put it in some concentration,
15
after some time you see MIC climbing.
So, as a
16
microbiologist, I believe it is very important to
17
give continuous therapy to at least eliminate the
18
chance of the resistance development.
19
The last question was?
20
DR. WILKERSON: Over time, if you
have a
21
resistant organism, does it lose its resistance, or
22
does it maintain it like most bacteria do over a
188
1
period of time once a drug is no longer present?
2
DR. GHANNOUM: I think, again from
our
3
knowledge with the other agents, it keeps it. I
4
have a strain, for example, took from a patient.
5 The
baseline was susceptible. After 15
episodes,
6 its
resistant MIC is quite high, and we have been
7
using it for a long time now as controls, and it is
8
still there, so I don't think it loses it.
9
DR. WILKERSON: The obvious
implication
10 for
this is that we need to have regimens that lead
11 to
the highest rate of eradication as possible as
12
opposed to just maintaining the infectious state.
13
DR. GHANNOUM: Right.
14
DR. CANTILENA: Thank you.
15
We have a question from Dr. Whitmore.
16
DR. WHITMORE: What Mike was just
saying
17
about failure rates and why we have such high
18
failure rates, one of the things that is different
19
with topicals versus systemic is if somebody tells
20 you
they take a pill, you know they have swallowed
21
it. They might not absorb it
properly, but you
22
know at least they have swallowed it.
189
1
If somebody tells you they have put their
2
antifungal on their tinea pedis, they might have
3 put
it just right in that one crack, who know how
4
they are applying it.
5
DR. GHANNOUM: Also, a lot of time
we have
6 the
same shoes, I mean they use the same shoes, we
7
have the environment which is humid, and really,
8
there are many, many factors which you need to
9
address, and unfortunately, we really don't have
10
relative good data.
11
I mean I am new to the area of
12 dermatophytes,
my work, you know, time passes so
13
quickly, the last eight, nine years I have been
14
focusing a lot on dermatophytes, but before that,
15
when I came into it, I tried to look at, there
16
isn't relevant information. So, I
think it is very
17
important for us to have a better understanding of
18 the
pathophysiology of the disease.
19
DR. CANTILENA: Any further
questions?
20
Okay. If not, we will pause for
lunch now
21 and
return to start the open public hearing at 1
22
o'clock.
190
1
[Whereupon, at 11:40 a.m., the proceedings
2
were recessed, to be resumed at 1:00 p.m.]
191
1
A F T E R N O O N P R O C E E D I
N G S
2
[1:00 p.m.]
3
DR. CANTILENA: Before we begin
the open
4
public hearing, the following statement is read
5
from the Food and Drug Administration.
6
Both the Food and Drug Administration and
7 the
public believe in a transparent process for
8
information gathering and decisionmaking. To
9
ensure such transparency at the open public hearing
10
session of the advisory committee meeting, FDA
11
believes that it is important to understand the
12
context of an individual's presentation.
13
For this reason, FDA encourages you, the
14
open public hearing speaker, at the beginning of
15
your statement, to advise the committee of any
16
financial relationship that you have in terms of
17 the
content, any financial relationship that you
18 may
have with any company or any group that is
19
likely to be impacted by the topic of the meeting.
20
For example, the financial information can
21
include a company or a group's payment of your
22
travel, lodging, or other expenses in connection
192
1
with your attendance at the meeting.
Likewise, FDA
2
encourages you at the beginning of your statement
3 to
advise the committee if you do not have any such
4
financial relationships.
5
If you choose not to address this issue of
6
financial relationships at the beginning, it will
7 not
stop you from speaking at the meeting.
8
Now that that is in the record, I think if
9 you
look at the open public hearing, who is
10
scheduled, I think that we probably won't have a
11
hard time with the conflict of interest, but it is
12
something we have to do anyway.
13
I will ask the committee actually to hold
14 your questions until the end of the entire
session
15 and
then we will have time for questions and
16
answers at the end of the time period.
17
The first group in the open public hearing
18 is
the Consumer Healthcare Products Association who
19
will lead off and then I will ask you to then
20
introduce the other speakers for the open public
21
hearing.
22
Thank you.
193
1 Open Public Hearing
2
Consumer Healthcare Products Association
3 Doug Bierer, Ph.D.
4
DR. BIERER: Good Afternoon. My name is
5
Doug Bierer. I am the Vice
President of Regulatory
6 and
Scientific Affairs for the Consumer Healthcare
7
Products Association.
8
CHPA represents the vast majority of the
9
distributors and manufacturers of topical
10
antifungal products which are used for the
11
treatment of tinea pedis.
12
Our presentation today from industry will
13
consist of three parts. In the
first part of our
14
presentation, Dr. Boni Elewski, who is a well-known
15
clinical dermatologist and expert in the field of
16 topical
fungal diseases, will talk about clinical
17
endpoints, resistance, and safety.
18
I will provide a few comments about the
19
reported lack of efficacy, as well as some
20
suggestions for enhanced labeling for OTC
21
antifungal drug products.
22
The second portion will be turned over to
194
1
Schering-Plough Consumer HealthCare products, and
2 the
third portion will be Novartis Consumer Health,
3 and
they will make their separate presentations.
4
Dr. Boni Elewski, as I mentioned before,
5 has
considerable experience both as a practicing
6
dermatologist, as well as clinical researcher, for
7
fungal infections. She is very
widely published
8
about cutaneous fungal infection and shared
9
guidelines of Care Committee for the treatment of
10
tinea pedis for the American Academy of
11
Dermatology.
12 Boni E. Elewski, M.D.
13
DR. ELEWSKI: Good afternoon,
everyone,
14 Mr.
Chairman, ladies and gentlemen. It is my
15
pleasure to talk to you today about one of my
16
favorite topics, tinea pedis.
17
Before I begin my discussion, I want to
18 add
that I am a consultant under this capacity,
19
working with CHPA, and I have also have been, and
20 am,
a consultant for many of the companies whose
21
products will be discussed today, including both
22
Novartis, who will be discussing today, and
195
1
Schering-Plough.
2
[Slide.]
3
So, I am going to spend some time
4
reviewing the scope of the problem, and then we
5
will look at strategic issues regarding this
6
problem.
7
Tinea pedis is a common fungal infection
8
caused by the dermatophyte fungi.
The most common
9 is
Trichophyton rubrum. I happen to really
like
10
Trichophyton rubrum. Its first
case in the United
11
States, interestingly enough, was in Birmingham,
12
Alabama, in 1922. I happen to
live in Birmingham,
13
Alabama, and so I tell my patients that we live in
14 the
fungus capital of the world, and I believe that
15
actually.
16
It is an infectious disease that affects
17 the
interdigital spaces and contiguous skin and has
18
been mentioned this morning, it affects up to 70
19
percent of the population.
20
Dr. Rappon, in his textbook, wrote that
21 our
lifetime risk factor of getting tinea pedis
22
living here in the United States is 70 percent, and
196
1
it's more likely to get it if you do certain
2
habits, such as you go to swimming pools or gyms or
3
health spas, and there have been a lot of data
4
coming from large studies and surveys looking at
5 how
common it is among swimmers, among people who
6 go
to gyms, and so forth, but must of the data from
7
swimmers is very compelling, and people who go to
8
swimming pools at any age have a very high risk of
9
getting tinea pedis, which again confirms that it
10 is
an infectious disease.
11
[Slide.]
12
Well, what does it look like?
What we see
13 is
generally a dry, scaling process in the toe
14
webs, most common between the third and fourth, and
15
fourth and fifth web space.
16
As you see here, this is a typical patient
17
with interdigital tinea pedis.
Keep in mind that
18
interdigital tinea pedis is what we are talking
19
about today, not moccasin tinea pedis, but
20
particularly interdigital tinea pedis.
21
I would like to say as a
sidebar that if
22
this patient came into my office with a simple
197
1
scaling process like you see, and this scale in
2
between the toe webs, the treatment of choice would
3 be
a topical antifungal.
4
A topical antifungal would be my
5
preference, much better over an oral antifungal
6
because it will be applied directly to the
7
infection, as I will be addressing later. I would
8 not
recommend an oral antifungal for treating this
9
simple scaling process
10
[Slide.]
11
So, interdigital tinea pedis is very
12
easily recognized by the consumer.
It is common.
13
People who have it often have friends and relatives
14 who
have it. They go to the gym, and their
15
colleagues at the gym, friends at the gym, friends
16 at
the swimming pool had it, so they know what it
17
looks like.
18
It also has consistent symptoms, itching
19 and
burning in the toe webs. There is also
20
consistent signs - erythema or redness, scaling,
21
hyperkeratosis, and fissures or cracking, and these
22 are
also the same signs that we capture when we do
198
1 a
study.
2
[Slide.]
3
So, what do we do for treating tinea pedis
4
over the counter? Well, first of
all, I am happy
5 to
say that there is a large selection of effective
6
over-the-counter antifungal drugs available for
7
treating tinea pedis, some of which are
8
monographed, and some are NDA switches at the full
9
prescription strength.
10
I would like to add that because they are
11
both prescription and over the counter for some of
12
these drugs, over the counter is as effective as
13 the
prescription topical antifungal and as safe as
14 the
prescription topical antifungal.
15
[Slide.]
16
So, how do we treat tinea pedis over the
17
counter? Well, number one, you apply the antifungal
18 to
the affected area and to the adjacent skin once
19 or
twice a day as recommended by the manufacturer.
20 You
also treat for one or four weeks as recommended
21 on
the OTC label.
22
Keep in mind that the signs and symptoms
199
1
generally improve during or shortly after the
2 treatment course. That is a point I will come back
3 to,
because I think it was a very important point
4 to
address this morning.
5
[Slide.]
6
What is the real purpose to treat this
7
infectious process? Well, the
real objective is to
8
eliminate the dermatophyte, to eliminate the
9
fungus. The fungus resides, in
this particular
10
process, it's a superficial fungal infection and it
11
resides in the outer layers of the stratum corneum,
12 as
you see here.
13
I don't have a pointer, but it's these
14
blue little dots that you see in the outer layer of
15 the
skin. The red part here is the stratum
16
corneum, and then you are getting into the
17
epidermis and dermis, the lower part of the
18
epidermis and the dermis here, below there.
19
So, the very outer layer of the stratum
20
corneum is where the infection resides, and because
21 it
is in the outer layer of the stratum corneum,
22
when you apply topical antifungal, it is going to
200
1
exceed the MIC of the dermatophyte.
It will reach
2 the
area.
3
You won't have to worry about it getting
4
there, because it will get there because you are
5
applying it right on top of where the fungus is
6
residing, so it is getting to the area and easily
7
will exceed the MIC of the organism. This is not an
8
issue.
9
It may be an issue, however,
if you use an
10
oral agent, because if you take an oral agent to
11
treat this, you have to get it absorbed, it may
12
have to be metabolized, and then has to get into
13 the
skin.
14
It is either going to get into the skin
15
through passive diffusion, through excretion
16
through the sweat, or through excretion through the
17
sebum, which is why a drug like amphotericin B,
18
which is, of course, a very potent drug for
19 treating systemic infection, does not work at
all
20 for
interdigital tinea pedis, because it will not
21 get
into the superficial layer of the stratum
22
corneum at high enough levels to kill the
201
1
dermatophyte.
2
So, many patients at our institution who
3
come in with a systemic infection and are given a
4
drug, such as amphotericin B, may still have
5
dermatophytosis.
6
[Slide.]
7
So, topical antifungals, the message is,
8 are
very effective applied to these superficial
9
infections. So, what happens
after you apply the
10
topical antifungal during and after the course of
11
treatment?
12 From my experience seeing patients,
and I
13 see
patients almost every day, I am in the medical
14
dermatology trenches, and I have been doing this
15 for
close to 25 years, itching and burning and
16
generally alleviated very early in the therapy.
17
Fortunately, for patients who suffer with itching,
18
shortly after you start applying it, the itching
19 and
burning seem to go away.
20
As mentioned however this morning, some
21
clinical signs may take longer to resolve, and in
22
some instances, from my experience, may not fully
202
1
resolve at all. There may be
erythema or
2
inflammation, scaling and hyperkeratosis, and the
3
fissures and cracking.
4
[Slide.]
5
So, let's explore these healing dynamics
6 and
why one process may resolve faster and one
7
takes longer to resolve, and what might be
8
underlying risk factors that cause one person to
9
heal at a different rate than another person.
10
First, the erythema. Erythema
again is
11
redness. Erythema is inflammation in the skin, and,
12 of
course, it's a response to the infection of the
13 dermatophyte in the stratum corneum. As the
14
dermatophyte is eliminated erythema is improved.
15
One of the speakers this morning showed
16 the
erythema going away, and it generally goes away
17
fairly quickly, but now always.
Occasionally, you
18
have erythema at the end of treatment, and I will
19
address those points later.
20
[Slide.]
21
Scaling and hyperkeratosis is also caused
22 by
the dermatophyte living happily in the stratum
203
1
corneum, but occasionally, scaling and
2
hyperkeratosis may not completely resolve after the
3
dermatophyte is eliminated.
4
One, patients may have an anatomic
5
occlusion, they may have a hammertoe, they may have
6 toe
overlap. They may have arthritis where
two
7
toes are rubbing against each other, causing some
8
friction or causing some scale or a callus from the
9
anatomy of the patient or the deformity of the
10
foot.
11
We also may have pre-existing skin
12
diseases, and one may have psoriasis.
Someone else
13 may
have atopic eczema, and as a sidebar, people
14 who
are atopic or have an atopic diaphysis have the
15
highest rate of getting tinea pedis to begin with,
16 and
these people may also have underlying atopic
17
dermatitis, which could be some reason why they may
18
have some scale and hyperkeratosis.
19
Some people I like to refer to also as
20
fast healers. Remember we have to
wait until the
21
skin turns over, which can take four weeks and some
22
patients even longer.
204
1 Other people are faster healers, and
since
2 we
are arbitrarily assessing this data at one given
3
point in time, it may vary from person to person,
4
because we are all people, we are all different,
5 and
no two people do anything exactly the same.
6
So, from my experience, residual scaling
7 and
hyperkeratosis is not uncommon after the
8
elimination of the dermatophyte.
Most always it
9
eventually goes away, but occasionally, you still
10
have some that may be totally unrelated to the
11
dermatophyte.
12
It may be that they had a soft corn, it
13 may
be that they had a hammertoe, it may be that
14
they have something else. So,
these studies may
15 not
take all this data into account, they are just
16
taking in the dry data, scale, is there a flake, is
17
there some redness, and we will come back to that
18
point in a few moments.
19
[Slide.]
20
Next, fissures or cracking. Again,
this
21 may
occur due to the presence of a dermatophyte in
22 the
stratum corneum, although you can have fissures
205
1 and
cracking due to other reasons, too, if someone
2 has
a hammertoe or someone has a toe overlap or
3
some other anatomical occlusion, they may have
4
fissures for other reasons.
5
But resolution of fissures generally is
6
fairly reliable except some fissures are very deep,
7 and
then it may take longer for them to resolve, or
8
someone may have other confounding factors that may
9
delay healing, such as they have peripheral
10
vascular disease, and so forth, and that is not all
11
excluded in patient studies or in your real
12
practice, of course.
13
So, from my experience, occasionally, you
14 see
fissures and cracking after the elimination of
15 the
dermatophyte, but from my experience, it is
16
much less common to see than simple scaling after
17 the
elimination of the dermatophyte.
18
[Slide.]
19
So, we have to have a system of evaluating
20 all
this in our practice, but more importantly,
21
since the issues is studies, in our studies.
22
Study methodology are twofold.
One, the
206
1
microbiology parameters, microbiological
2
parameters, and, two, clinical efficacy parameters.
3
[Slide.]
4
Well, what are microbiological parameters?
5 We
addressed this, let me recap. First, we
have
6 the
KOH. A KOH shows the presence or absence
of
7
fungal elements. It does not
capture, however,
8
whether the fungal elements are dead or whether
9
they are alive. You don't
know. You just know
10
that the fungus is there or that it's not there.
11
That is an important point, we will come back to
12
that.
13
We also a fungal culture which identifies
14 the
organism by the genus and by the species.
It
15
also tells you whether there is viable fungi there.
16 So,
sometimes you can use the positive or negative
17
fungal culture and correlate it with the KOH to see
18
whether they are viable or nonviable, but again, we
19
don't have a lot of data to look at that, but the
20
main objective is mycological cure.
21
Mycological cure, by the definition that
22 we
live by is negative KOH and negative culture.
207
1 In
most studies, from looking at the data presented
2
this morning, it appeared that more than half the
3
people in the studies had a mycological cure of
4
about 80 percent or higher.
5
That doesn't surprise me, and I would
6
predict that those who are not mycologically cured
7
probably had some persistent scale, and the
8
persistent scale had some nonviable fungal
9 elements, and the nonviable fungal elements
made
10 the
mycological cure falsely low.
11
So, what I am getting at it is in my
12
experience, I think we can cure a lot of patients
13
with interdigital tinea pedis, it depends on how we
14
define cure, and we are going to hit that again in
15
just a moment.
16
[Slide.]
17
So, we have the microbiological
18
parameters. Now, let's look at
the clinical
19
efficacy parameters. Here, we
have two. Complete
20
cure, that means mycological cure plus absolutely
21 no
sign and absolutely no symptom.
Effective
22
treatment. Effective treatment is
mycological
208
1 cure,
so negative KOH, negative culture, plus no
2
more than mild signs or mild symptoms.
3
Again, in a study, most studies are
4
generally looking at this in a 4-point scale, zero
5
being absent, 1 mild, 2 moderate, 3 severe. So,
6
when the patient or the subject was enrolled in the
7
study, they were moderate to severe in one of the
8
parameters, and at the end of the study they may
9 end
up as mild.
10
That can be very frustrating to me as an
11
investigator, especially when I have a patient who
12 is
totally clear clinically, not a flake to be
13
found, not a fissure to be seen, no erythema
14
lurking in the toe webs, yet, they murmur "but it
15
itches" or "I think it itches." Then, I have to say
16
perhaps mild itching, so they would be a failure,
17 it
can be very frustrating.
18
It also might be frustrating if I see
19
something, such as erythema, but my gut feeling is
20
that the erythema or the flakes of scale I see, or
21 a
little callus I see is not due to the tinea
22
pedis, but it is due to a toe overlap or due to an
209
1
anatomic occlusion.
2
Nonetheless, it is there, it
may be better
3
because we got rid of the dermatophyte, but the
4
fact that it is there, I will have to tick "mild,"
5
which will bring the whole results of the data
6
down. So, keep all that in mind.
7 [Slide.]
8
Which brings me to the point, when we say
9
cure, what do we mean by cure, what is meaningful?
10 How
I do this in my practice and how I do this when
11 I
look at the data from a study, if I am evaluating
12 a
drug, what are my personal objectives?
13
Well, objective number one is you want to
14
eliminate the dermatophyte. After
all, it is an
15
infection, and that is how we define these to begin
16
with. They are dermatophytosis,
so you want to
17
eliminate the dermatophyte. So, by the definition
18 we
are using, we would have to say mycological
19
cure.
20
Also, for practical purposes, no more than
21
mild signs and symptoms, and I am going to stick
22
with that, because there are frequently a patient
210
1 at
the point of time that the study ends, their
2
symptoms are on the way down, and they went from
3 severe
to moderate, and now there is a flake of
4
scale or a speck of erythema, and they are still
5
improved, but not 100 percent, or they may have
6
some underlying process that causes this.
7
[Slide.]
8
So, when I say "mild," the mild could be
9 due
to the fact that they have an underlying
10
dermatosis, they have psoriasis which we are not
11
capturing, they have eczema, they have xerosis.
12
We talked about this morning that people
13 who
have dry feet, also often have fungal
14
infections, but you can't say that everyone with a
15 dry
foot has fungal infections, and if you think
16
that, we will look at everyone's feet here, we can
17 do
cultures and see how many of you have fungal
18
infections if you have dry feet.
I doubt that we
19
would correlate that with a very high figure.
20
Also, keep in mind that treating tinea
21
pedis with an antifungal cream will certainly not
22
make the skin better than it was prior to the
211
1
infection, it can't be done, so all we can do is
2
restore the skin to the baseline status it was
3
before the patient acquired the infection.
4
[Slide.]
5
So, what I think is the most meaningful
6
datapoint that I like to hold my hat on is
7
effective treatment. Effective
treatment means the
8
dermatophyte is eliminated and we have improved the
9
patient significantly, down to just a trivial
10
point, which may be and probably is unrelated to
11 the
process, or if it is related, it is going down
12 a
slower slope than other patients.
13
[Slide.]
14
So, clinical insights that I
have built up
15
now. Current over-the-counter antifungal drugs, in
16 my
opinion, deliver very safe and effective
17
treatment especially since we are treating an
18
infection that is in the very superficial layers of
19 the
skin. When you apply an antifungal to
this
20
area, you are getting it onto the infective
21
organism and killing organism.
22
In my opinion, the clinical meaningful
212
1
endpoint is effective treatment.
Because of this,
2 I
don't think dose response studies are needed,
3
because topical antifungals easily reach the
4
dermatophytes in excess of the MICs.
5
[Slide.]
6
Likewise, as Dr. Ghannoum so eloquently
7
pointed out today, there is really no concern about
8
dermatophyte antifungal resistance, and even if
9
there were organisms that had a borderline
10
resistant issue, because you are applying it in
11
such a high amount, it will readily exceed the MIC
12 of
the dermatophyte living in the very superficial
13
layers of the skin.
14
This is not the same situation as we have
15
with oral drugs where you have to worry about them
16
getting there in high enough numbers, and there are
17 so
many factors that can confound that from
18
happening, whether the patient absorbed it
19
correctly, whether there is any other process that
20 might
have impaired the drug from getting to the
21
target point of infection.
22
So, in my experience, when used as
213
1
directed, topical antifungals are very effective at
2
eliminating the fungus.
3
[Slide.]
4
There are a couple of other issues I want
5 to
address. One came up this morning as
secondary
6
bacterial infections. As we have
discussed, there
7 are
rare reports of secondary bacterial infections,
8
i.e., cellulitis associated with tinea pedis.
9
In my 25 years of being out in the
10
trenches, seeing patients, I have never seen a
11
patient with interdigital tinea pedis or moccasin
12
tinea pedis developing a bacterial cellulitis. I
13
have never seen it. I know it has
been reported, I
14 am
aware of the literature.
15
The explanation for this the authors have
16
postulated is that the presence of the dermatophyte
17
damages the stratum corneum, causing loss of
18
barrier function, resulting in microfissures or
19
obvious fissures that serve as portals of entry for
20
secondary bacterial infection.
21
Having said that, it would make even more
22
sense to state that prompt and effective treatment
214
1 is
clearly essential, and therefore,
2
over-the-counter topical antifungals are important
3 because they eliminate the dermatophyte to
allow
4 the
skin to naturally replace itself and restore
5 its
barrier function.
6
I will leave you back with Doug.
7 Doug Bierer, Ph.D.
8
DR. BIERER: I would like to
provide some
9
perspective on lack of efficacy reports that have
10
been reported by FDA.
11
[Slide.]
12
FDA reported that 35 percent of all
13
adverse events of topical antifungal agents were
14 due
to lack of efficacy. This is from their AERS
15
database. The database actually
goes back in the
16
late sixties and encompasses about 30 years. It
17
includes reports of both OTC, as well as Rx drugs.
18
In those reports, it is unclear whether
19 the
reports of lack of efficacy were specifically
20
related to tinea pedis or perhaps one of the other
21
labeled indications, or actually may have been used
22 for
another disorder all together.
215
1
In order to help put these lack of
2
efficacy reports into perspective, CHPA looked at
3
lack of efficacy reported for OTC topical
4
antifungals related to the number of units sold.
5
[Slide.]
6
CHPA collected the number of lack of
7
efficacy reports from seven OTC manufacturers, who
8
actually distribute probably the vast majority of
9 OTC
antifungal products used to treat tinea pedis,
10 and
we looked at the years from 1999 to the year
11
2003, over a four-year period.
12
We saw or found that there was 1,468
13
reports of lack of efficacy, but during that same
14
period of time, greater than 180 million units were
15
sold and used by consumers. If
you translate this
16
out, this calculates into less than 9 lack of
17
efficacy reports per million units sold.
18
Even if these are underreported, as people
19
have commented this morning, it still is a very low
20
rate of lack of efficacy reports for such a drug.
21
One of the other areas that we wanted to
22
talk about was that we believe that some of the
216
1
concerns raised by the FDA perhaps can be handled
2
through enhanced labeling of OTS antifungal
3
products, and I would like to take you through a
4
couple of our suggestions that we have.
5
We believe that these should be applied to
6 not
only OTC monograph products, but also OTC
7
products which are regulated under new drug
8
applications or NDA.
9
[Slide.]
10
As we talked a little bit earlier this
11
morning, and I just mention lack of efficacy,
12
actually could be due to some consumers stopping
13
treatment prematurely, not completing the full
14
course of therapy.
15
FDA had suggested that we may want to look
16 at different devices for showing consumers
what
17
could be expected, and one of the suggestions was
18
perhaps looking at GRASE or tables on package
19
labels. We believe that these are
quite confusing
20 to
consumers since most consumers cannot understand
21
data or tables, and overwhelming consumers with
22
complicated data should be avoided.
However, we
217
1
believe that consumers do need simple and concise
2
label statements of how to use the products in
3
order to achieve the maximum benefit from the
4
products.
5
[Slide.]
6
Therefore, we are proposing that we add
7 the
statement under directions for all OTC
8
products, which is use daily as directed for the
9
full treatment time even if symptoms improve.
10
[Slide.]
11
Also, along directions, the FDA asked
12
whether labeling should convey lag time between the
13
completion of treatment and the resolution of
14
symptoms, and we believe it is also helpful to
15
educate consumers on what can be expected under use
16
conditions.
17
[Slide.]
18
Therefore, we are proposing to add another
19
statement for directions for one-week use products,
20
that symptoms may continue to improve after one
21
week of treatment as the skin naturally replaces
22
itself.
218
1
As you heard this morning, the use of
2
one-week products, there is an increase in efficacy
3 and
clinical cure, as well as effective treatment,
4 as
time progresses beyond the one week, so we
5
believe this statement would be important for
6
one-week products.
7
[Slide.]
8
Lastly, we believe that to address the
9
FDA's concern about secondary bacterial infection,
10
that is, cellulitis, we propose adding labeling
11
information about when to see a doctor.
12
[Slide.]
13
We would propose to add a new statement,
14
which is new symptoms develop or condition worsens,
15 and
this statement would be added after the phrase,
16
"Stop use and ask a doctor if--the warning part,
17
which is currently on OTC product labeling--so, the
18
statement would read, "Stop use and ask a doctor
19
if"--bullet point--"new symptoms develop or
20
conditions worsen."
21
[Slide.]
22
This slide just reviews the three proposed
219
1
label additions that we would recommend to enhance
2
labeling for OTS drug products, and we believe that
3
these will not only reinforce consumer compliance,
4 but
also further decrease the potential of serious
5
adverse events.
6
DR. ELEWSKI: Let me conclude with
some
7 key
points.
8
[Slide.]
9
First, clinical cure, as I
mentioned, I
10
feel should be defined as effective treatment.
11
Dose response studies are not needed because
12
topical antifungals easily reach dermatophytes in
13
excess of MICs.
14
Dermatophyte resistance is not a concern.
15 The
risk of secondary bacterial infections is very
16
low. OTC antifungals play an
important role by
17
restoring the barrier function of the skin and
18
allowing the skin to naturally replace itself.
19
[Slide.]
20
The proposed enhanced labeling will
21
reinforce consumer compliance and decrease
22
potential serious adverse events.
Current OTC
220
1 products
are safe and provide effective treatment
2
when used as directed.
3
Now, we are going to take a few questions
4 if
you have any now.
5
DR. CANTILENA: Actually, I think
we are
6
going to hold questions, and we will have all three
7
groups go ahead and speak, and then we will do
8
questions at the end.
9
DR. ELEWSKI: Okay.
10 Schering-Plough
11 John Clayton, M.D.
12
DR. CLAYTON: Good afternoon. I am John
13
Clayton, Senior Vice President, Scientific and
14
Regulatory Affairs for Schering-Plough HealthCare
15
products.
16
I think the conflict of interest is
17
obvious. My paycheck comes from
there.
18
I certainly welcome the opportunity to
19
share with you Schering-Plough's experience and
20
views over a number of years of marketing
21
over-the-counter OTC products for treating topical
22
fungal infections, as well as Rx products.
221
1
[Slide.]
2
Our agenda for the afternoon, for my
3
presentation, is to share with you based on our
4
marketing history, our clinical experience,
5
consumer experience, some consumer research, our
6
recommendations and conclusions that hopefully will
7 be
helpful to you in your deliberations.
8
[Slide.]
9
By way of background, Schering-Plough has
10
been a leader in research and marketing of Rx and
11 OTC
topical antifungals for the treatment of tinea
12
pedis for more than 40 years.
13
[Slide.]
14
We began marketing tolnaftate in the
15 sixties and actually developed tolnaftate in
this
16
country, as well as clotrimazole in this country,
17 for
tinea pedis.
18
Products currently that Schering-Plough
19
markets OTC represent about 44 percent of the units
20 sold
in the U.S., and the brands include those
21
listed on this slide, some of which you hopefully
22 are
familiar with, and the antifungal agents used
222
1 in
these products are betenafine hydrochloride,
2
clotrimazole, tolnaftate, or miconazole nitrate.
3 All
of these ingredients have marketing history Rx
4 and
were approved under NDAs originally.
5
[Slide.]
6
In terms of clinical experience,
7
obviously, the ages of these products is different,
8 as
was suggested in presentations this morning.
9
Therefore, the clinical endpoints, the designs of
10
clinical trials, while state of the art in their
11
day, vary, but overall, the clinical trials through
12 a
variety of designs have demonstrated the safety
13 and
efficacy of these products at the current
14
dosing levels.
15
Even though the study endpoints have
16
changed dramatically over these past four decades,
17
significant clinical efficacy has consistently been
18
demonstrated for all of these ingredients through
19
various types of clinical trials.
20
[Slide.]
21
I certainly concur, the company certainly
22
concurs with the presentation and recommendation of
223
1
CHPA presented through Dr. Elewski, that complete
2
cure endpoint definition is an unrealistic
3 parameter of efficacy based on the natural
course
4 of
healing. That is, it truly understates
the
5
efficacy of these products.
6
We believe that it is a more appropriate
7
indicator, the effective treatment, which is
8 defined as negative mycology, both culture
and KOH,
9 and
minimal erythema and scaling is a more
10
appropriate descriptor of efficacy.
11
[Slide.]
12
In our consumer experience, just looking
13 at
the data that we have collected over the past
14 12,
13 years of more than 230 million units sold of
15 our
various antifungal ingredients, that extensive
16
patient and consumer experience confirms that these
17
products are very effective.
18
In our experience, the
complaint rates
19
regarding lack of efficacy have been extremely low,
20 2
per million calculating over the past 5 years,
21
which I think is the most meaningful data that we
22
have.
224
1
The consumer letters that we received
2
unsolicited, surprisingly enough, almost achieve
3 the
same level, indicating to us the success that
4
they have had with a variety of products, anecdotal
5 for
certain, but the fact is the consumers appear
6 to
be satisfied with the products.
7
[Slide.]
8
One of the more quantitative and
9
structured ways that we have used to achieve
10
information about consumers that use these products
11 is
through a consumer tracking study. We
have
12
conducting the study annually over the past 10
13
years to get the views and practices that consumers
14
will share with us.
15
These are consumers that actually suffer
16
athlete's foot, have suffered athlete's foot within
17 the
preceding 12 months. The most recent
tracking
18
study that we completed was in October of last year
19
that included 350 consumers between the ages of 18
20 and
64 years of age.
21
As I said, they reported they had suffered
22
from athlete's foot within the previous 12 months,
225
1 and
distribution was 70 percent male and 30 percent
2
female, which in the variety of studies we have
3
done, this seems to be about the--I will say
4
incidence, but in terms of usage of products to
5
treat--it is about 70 percent male, 30 percent
6
female.
7
This particular research study was done by
8 way
of the internet.
9
[Slide.]
10
A number of interesting observations out
11 of
the study. Consumers purchase the OTC
topical
12
antifungals driven by the need for symptom relief.
13
Universally, consumers that suffer the
14
itching an burning of athlete's foot will
15
self-treat, 95 percent of the time they will seek
16
some type of therapeutic agent to treat their
17
condition. Approximately, 80
percent purchase
18
4-week products, and approximately 20 percent
19
purchase products, I have less than or equal to
20
4-week.
21
As was noted this morning, one product has
22
labeling for 1 week, another product has labeling
226
1 for
1 or for 4 weeks, an optional dosing regimen,
2 the
difference being two times per day for the
3
1-week treatment versus one time per day for the
4
4-week treatment.
5
Again, intense itching and burning are the
6
primary drivers, and 69 percent rate the symptoms
7 as
bothersome or very bothersome.
8
[Slide.]
9
Consumers tell us that relief begins
10
within a matter of a few days following initiation
11 of
treatment. I am sure we are talking
about the
12
bothersome symptoms that drove them to buy the
13
product in the first place, so 60 percent say that
14
these products, in their opinion, provide fast
15
relief of their symptoms.
16
Consumers also tend to discontinue use of
17
these products despite the labeling upon achieving
18
relief of their symptoms.
19
We found in our survey in September of
20
last year that the average treatment period was 7.3
21
days.
22
[Slide.]
227
1
You may say that probably has been
2
influenced by newer products that offer alternative
3
dosing regimens, but looking back at our 1997
4
study, similar design, consumers reported an
5
average treatment time of 8.8 days at that point in
6
time, so none of the shorter course therapy
7
products were labeled for shorter use back in 1997
8
OTC.
9
Interesting, too, is that only 6 percent
10
report that they treat greater than 14 days, again
11
driven by relief of symptoms, discontinuation of
12 use
of product.
13
More than 50 percent treat 5 days or less
14 on
average.
15
Despite that, the consumer satisfaction
16
with OTC antifungals was extremely strong.
17
One point that is not on target with the
18
treatment time, but interesting, that I wanted to
19
share with you, is that 42 percent of the
20
individuals in our most recent study indicated that
21
they are experiencing athlete's foot less often now
22
than they were 2 years ago.
228
1
We don't have a reason for that, we can
2
speculate that it is a change in footwear,
3
improvement of the hygiene, I am not sure what it
4 might be, but it was interesting to note that
they
5 are
complaining less frequently.
6
[Slide.]
7
Our conclusions from the consumer research
8
data are that consumers are highly satisfied with
9 the
performance of currently marketed OTC products.
10
Consumers consistently experience fast
11
relief of symptoms, as was noted that more than 60
12
percent have reported that.
Therefore, most
13
consumers do not use the product for the entire
14
label treatment period, yet, are driven by the
15
symptom relief that they get from the products.
16
[Slide.]
17
As a result of this, while the information
18
that we have on lack of efficacy in our experience
19 is
that it is reported infrequently, we still
20
believe that based on the consumer research
21
learnings, that there is a likelihood that we could
22
improve the efficacy rate for consumers by
229
1
reinforcing the need to apply these products
2
throughout the entire directed labeled treatment
3
period.
4
We do think that therapeutic success can
5 be
enhanced, and similar to what CHPA presented, we
6
recommend that the Direction Section of the label
7
include a statement to remind the consumer to use
8
daily, as directed, for the full treatment period
9
even as their symptoms improve.
10
[Slide.]
11 Dr. Bisno gave us a lecture this
morning
12 and
education on the complications of tinea pedis
13 and
particularly as it relates to cellulitis or the
14
potential for cellulitis to develop.
15
In our experience, it is extremely rare,
16 and
I won't rehash the discussion of the morning.
17
[Slide.]
18
Despite that, we believe that because of
19
concerns of other infections that may occur either
20
through improper usage of the product, that is,
21
using the product for a short duration of period,
22 or
because they have mischaracterized their
230
1
condition, that an additional warning statement
2
should be added to products, that if there is no
3
improvement, stop use and ask a doctor if there is
4 no
improvement within a matter of days, and I am
5 not
sure that 14 is the right number of days, but
6
within some reasonable period of time, or if the
7
condition worsens.
8
[Slide.]
9
Our conclusions are that the current
10
products are very effective in treating tinea pedis
11 as
demonstrated through a variety of clinical
12
trials and through our consumer satisfaction
13
testing.
14
Products are extremely safe based on
15
extensive marketing history.
16
We believe that the effective treatment is
17 the
appropriate clinical endpoint for making
18
decisions about efficacy of product, and that we
19
support the enhancement of existing product
20
labeling to improve consumer compliance, as well as
21
treatment success.
22
Thanks very much.
231
1
DR. CANTILENA: Thank you.
2
Our final presentation in the open public
3
hearing is from Novartis.
4 Novartis
5 Helmut H. Albrecht, M.D., M.S.,
FFPM
6
DR. ALBRECHT: Good afternoon, Dr.
7
Cantilena, members of the Committee, Drs. Wilkin
8 and
Ganley, FDA staff.
9
[Slide.]
10
I am Dr. Helmut Albrecht, Vice President
11 of
Clinical and Medical Development at Novartis
12
Consumer Health.
13
As a leader and innovator in the topical
14
antifungal category, we are here to discuss how
15
terbinafine fits into today's dialogue,
16
specifically, addressing the issues outlined by the
17
Agency including efficacy, safety, and labeling.
18
We have extensive experience in the
19
category. Novartis markets
terbinafine in a
20
variety of forms including an Rx table and topical
21 OTC
products introduced through an NDA.
22
We also market monograph products in this
232
1
category. We understand the
terbinafine compounds
2 and
how consumers use the product based on years of
3
market availability and millions of usage
4
occasions.
5
We have heard what the FDA has to say and
6
agree with much of it, an we will discuss our
7
position on how antifungals can be used more
8 appropriately
by consumers to maximize their full
9
potential.
10
We look forward to the committee's input
11 to
help us enhance our label, to guide future
12
development in the interests of improving public
13
health.
14 [Slide.]
15
I will provide context and commentary for
16 the
committee's considerations. First, we
concur
17
with the Agency that labeling could be enhanced to
18
improve compliance. This will
optimize treatment
19 benefits,
reduce the incidence of lack of
20
effectiveness reports, and minimize the possibility
21 of
adverse events.
22
[Slide.]
233
1
Next, we will show how our compound
2
terbinafine offers unique properties that should be
3
communicated to consumers through labeling, and we
4
will comment on the need for appropriate clinical
5
endpoints to guide product development, consumer
6 expectations, and labeling.
7
[Slide.]
8
Here, we see a presentation of
9
interdigital tinea pedis or athlete's foot as it is
10
seen clinically with signs and symptoms.
Doctors
11 and
consumers may perceive this condition
12
differently. Doctors appreciate
that it is an
13
infectious disease, and they understand that some
14
signs and symptoms may persist for weeks even after
15 the
causative fungus has been killed.
16
In contrast, consumers have a different
17
understanding of athlete's foot.
Our market
18
research indicates that they start and stop
19
treatment primarily based on the onset and
20
resolution of the most troublesome symptoms,
21
including itching and burning.
These symptoms
22
often last for a week or less.
234
1
[Slide.]
2
On this slide, we show the natural history
3 of
the athlete's foot condition and its treatment.
4 The
mycology is shown in the green, symptoms shown
5 in
yellow, and signs as shown in red.
6
As you can see, the signs of the
7
condition, such as mild erythema and scaling, can
8
often persist for sometime beyond resolution of the
9
symptoms and after the fungus has been eliminated.
10
The actual repair and healing of the skin
11
progresses at its own rate, and there is no need
12 for
further treatment.
13
This healing process reflects
the time it
14
takes for the skin to heal and it is influenced by
15
several factors including individual skin types,
16
foot condition, and healing rates.
17
As you would agree, the primary goal of
18
therapy is to effectively eliminate the fungus.
19
Once the fungus is eliminated, there is nothing
20
more you can do with an antifungal product.
21
We conducted a market research study
22
involving more than 300 consumers.
Our findings
235
1
demonstrate that consumers initiate treatment based
2 on
symptoms, such as itching and burning, and
3
discontinue treatment based on resolution of these
4
symptoms, which commonly resolve within one week or
5
less.
6
If a consumer treats for only 1 week, even
7 if
the product is recommended for 4 weeks, this has
8
significant implications for those products that
9 require
4 weeks of treatment.
10
These findings provide a rationale for our
11
belief that effective treatment is the appropriate
12
clinical endpoint for guiding consumer expectations
13 and
labeling.
14
Effective treatment reflects resolution of
15
both mycology, here in the green, and symptoms,
16
here in the yellow.
17
[Slide.]
18
Now, I would like to turn your attention
19 to
terbinafine, which we market under the brand
20
name Lamisil AT. Terbinafine is a
synthetic
21
antifungal of the allylamine class.
It has broad
22
spectrum fungicidal activity including the
236
1
dermatophytes that cause the athlete's foot.
2
This property is based on the compound's
3
unique mechanism of action which involves specific
4
inhibition of squalene epoxidase, a key enzyme in
5
ergosterol biosynthesis of fungi.
6
As such, the fungicidal activity of
7
terbinafine is distinct from the fungistatic
8
activity of the azole compounds in this category.
9
Terbinafine offers proven efficacy with
10
only 1 week of treatment, with no need for
11 additional
therapy. Terbinafine was introduced in
12
1992 and switched to OTC status in 1999.
13
Since then, there have been more than 200
14
million exposures to the compound with no
15
identification of safety issues, trends, or
16
development of significant persistence.
17
It is worth noting that terbinafine is the
18
only active ingredient in the Lamisil AT line, and
19
therefore has consistent labeling and dosing
20
instructions, reducing the likelihood for consumer
21
confusion.
22
[Slide.]
237
1
Let us now focus on the efficacy of
2
terbinafine. This morning, we heard a lot about the
3 clinical
effectiveness from pooled data. Please
4
allow me to show you the actual efficacy results
5
from the terbinafine pivotal studies for the cream
6
product.
7
[Slide.]
8
First, I show in vitro and in vivo
9 evidence of the activity of terbinafine
where it is
10
needed to kill the fungus.
Minimum inhibitory
11
concentrations or MIC values show a high degree of
12
antifungal activity at very low concentrations,
13
providing antidermatophyte potential that is 100
14
times more effective than Butenafine and 1,000-fold
15
more potent that clotrimazole.
16
In contrast to what you may have heard
17
this morning, terbinafine does indeed reach the
18
site where it is needed. After 1
week of topical
19
application, concentrations in the skin are 1,000
20
times the MIC. Seven days
post-therapy,
21
concentrations in the skin are still 100 times the
22
MIC. In fact, therapeutic values
remain in the
238
1
skin 5 weeks post-dosing.
2
[Slide.]
3
Terbinafine has been extensively studied
4 and
safety and efficacy have been clearly
5
demonstrated in 15 well-controlled clinical
6
studies. This shows from a
representative pivotal
7
study in tinea pedis from the NDA filing for the
8 OTC
switch of Lamisil AT 1 percent cream.
9
The y axis shows for each of the three
10
clinical endpoints the percentage of subjects who
11
successfully achieved them. The
red bars represent
12
terbinafine and the green bars represent placebo.
13
The two columns on the left show the
14
result of mycological cure. This
is, of course,
15 the
prerequisite for the other endpoints -
16
effective treatment and complete cure. So,
17
effective treatment results are shown in the
18
middle, and the bars on the right show complete
19
cure.
20
It is important to note that all three
21
endpoints represent the same patient experience.
22 The
differences in the values simply represent the
239
1
different clinical parameters.
2
As mentioned previously, complete cure is
3
heavily weighted by signs of the condition, and
4
therefore is always found at a lower rate.
5
These next two slides represent data from
6 one
of our studies comparing terbinafine and
7
clotrimazole at 6 weeks post-baseline.
8
[Slide.]
9
We are showing you 1-week data because
10
this is how we understand consumers to use these
11
products. As you can see, at this
point in time,
12
terbinafine is highly effective and far superior to
13
clotrimazole on each of the three endpoints.
14
[Slide.]
15
These are results from the same study
16
showing efficacy at 6 weeks post-baseline following
17 4
weeks of treatment with the two products.
You
18 can
see that 4 weeks of treatment with terbinafine
19
produces no additional benefit over the 1-week data
20
shown in the last slide.
21
After 1 or 4 weeks of treatment,
22
terbinafine has essentially equivalent efficacy for
240
1 all
three endpoints. This is not the case
with
2
clotrimazole even if it is used for the full 4
3
weeks as it is currently labeled.
4
[Slide.]
5
This slide demonstrates the impact of
6
these different treatment outcomes at 12 weeks. As
7 you
can see, only 9 percent of patients go on to
8
have relapse on terbinafine with 1 week of
9
treatment, and 11 percent with 4 weeks of
10
treatment, compared to higher rates with
11
clotrimazole of 47 and 30 percent, respectively.
12
This reflects the potency and sensitivity
13 of
terbinafine.
14 [Slide.]
15
This slide shows the same data just viewed
16 now
in a line format to allow us to look at the
17
time course of the effect on mycology over the 12
18
weeks evaluation.
19
As you can see, the red lines which
20
represent terbinafine treatment, there is no
21
difference between the 1 week and 4 week treatment.
22
There is, in contrast, clotrimazole, in the yellow,
241
1
where the 4-week treatment shows a remarkable
2
difference from the 1-week treatment, highlighting
3 the
potential impact on treatment outcomes in those
4 who
do not complete the 4-week treatment course.
5
[Slide.]
6 This shows the same depiction for
signs
7 and
symptoms for the 12-week assessment period.
8
This slide also serves as a nice overview of the
9
effectiveness of terbinafine. As
you can see, it
10
produced comparable efficacy at 1 and 4 weeks.
11
Within days of initiating treatment, signs
12 and
symptoms are reduced. However, after
about 6
13
weeks, you can see a plateau in the effect,
14
demonstrating that some signs persist over an
15
extended period of time.
16
The clotrimazole data demonstrate that
17
when used for a full 4 weeks course, favorable
18
resolution of signs and symptoms comparable to
19
terbinafine can be achieved.
However, when used
20 for
only 1 week, as consumers often do, the results
21 are
significantly less favorable.
22
This confirms what Dr. Elewski presented
242
1
earlier from the clinical experience in her
2
patients.
3
Now, in response to FDA's questions, I
4
would like to present our perspective on new
5
product development requirements.
6
[Slide.]
7
There are two different types of
8
development approaches in this category involving
9
either new chemical entity or an NDA line extension
10 of
a currently available compound.
11
All new developments, whether NCEs or line
12
extensions, should require a statistically
13
significant separation from placebo using the
14
complete cure endpoint to demonstrate efficacy as
15
required for Rx drugs, where NCE studies may also
16 be
required to define the appropriate dose.
17
With respect to line extensions, where the
18
dose of the active has already been effectively
19
established, the dermal pharmacokinetics and MIC
20
values for the new formulation of the known drug
21
should guide dose decisionmaking.
22
Based on this approach, line extensions
243
1
would require clinical evaluations to establish the
2
appropriate frequency and duration, but would not
3
necessitate dose ranging studies.
4
[Slide.]
5
Having established the effectiveness of
6
terbinafine and provided our perspective on new
7
product development, I would like to spend a few
8
moments of my presentation responding to the
9
questions regarding safety and labeling raised by
10 the
Agency.
11
[Slide.]
12
Starting with the lack of effectiveness or
13 LOE
reports, the Agency has noted that there has
14
been an increasing number of these reports in their
15
AERS database. In fact, overall, the number of
16
adverse reports we receive for topical Lamisil is
17
quite small.
18
LOE reports are captured as part of the
19
adverse event reporting. As you
see in the middle
20 row
at the bottom of this chart, it represents the
21
absolute number of LOE reports received for topical
22
Lamisil.
244
1
Below that, we see the number of units
2
sold during the same time frame.
Consequently, the
3
graph gives you the ratio of these numbers and
4
demonstrates a declining rate of LOE reports as a
5
percentage of product purchases since the launch of
6 the
OTC product.
7
[Slide.]
8
In the interest of understanding whether
9
effectiveness has changed over time, we compared
10
studies conducted over the last decade and found no
11
difference in efficacy.
12
Other analyses have confirmed that the
13
species of dermatophytes in our studies that cause
14
athlete's foot are the same over time.
They
15
continue to be fully susceptible to terbinafine.
16
[Slide.]
17
The Agency also raised the questions of
18
whether the risk of cellulitis is increased in
19
inadequately treated tinea pedis.
It is well
20
understood that cellulitis is rare, and is not
21
related to the drug per se. In
fact, it could even
22 be
misdiagnosed, as we heard this morning.
245
1
In the AERS database, a review of all 15
2
topical antifungals, there were only cases of
3
collection since 1965. Since 1993, cases have been
4
reported in connection with Lamisil.
The
5
relationship between cellulitis and drug treatment
6 in
these cases is unclear.
7
There also does not appear to be an
8
increase in cellulitis reports over time. However,
9
inadequately treated tinea pedis may make
10
individuals more prone to this infection.
11
The data indicate that certain
12
subpopulations, such as people with diabetes, may
13 be
at the higher risk of cellulitis, but that the
14
risk may actually be reduced by effective
15
antifungal treatment.
16
Our recommended label changes would
17
include a warning for people with diabetes and
18
other identified risks.
19
[Slide.]
20
Regarding other labeling changes, we have
21
given great consideration to the issues raised by
22 the
FDA, and are pleased to share our labeling
246
1 recommendations,
which are intended to optimize the
2
consumer benefit with terbinafine, and what do we
3
know about the patient experience.
4
We know they are equally satisfied whether
5
they achieve the effective treatment or complete
6
cure endpoints.
7
[Slide.]
8
As you can see in this chart, the
9
comparison evaluates patient global assessment
10
scores from the analysis of one of our clinical
11
trials. Patients who achieve either
effective
12
treatment or complete cure were selected and had
13
equivalent findings on the global assessment scale.
14
Based on clinical and consumer experience,
15 we
conclude that effective treatment should be the
16 basis
for setting consumer expectations for product
17
performance, and therefore be reflected in
18
labeling.
19
[Slide.]
20
If this committee recommends that new
21
label be developed for NDA products to set consumer
22
expectations about treatment outcomes, we recommend
247
1
that effective treatment be the guide.
These
2
improvements will set appropriate expectations,
3
enhance compliance, optimize treatment outcomes,
4 and
provide stronger safety guidance.
5
Consequently, monograph products should
6 add
similar language indicating the required
7
duration of treatment and indicate if no reliable
8 clinical data are available. We would like to take
9 you
through our current thinking on propose
10
labeling changes for the class using terbinafine as
11 an
example.
12
We agree that there is potential confusing
13
language in the current PDP or primary display
14
panel of the packages.
15
[Slide.]
16
We recommend removing "Cures most
17
athlete's foot" and replacing that language with
18
"Athlete's foot treatment."
19
To enhance compliance, we also recommend
20
making treatment duration prominent in this primary
21
display panel. For example, we would replace
22
current language with information that helps
248
1
consumers understand they are treating an
2
infection, and for the full course of treatment.
3
This is the most important language to
4
communicate in the label. All
products in this
5
category should clearly delineate the required
6
duration of treatment.
7
In the case of Lamisil, the statement
8
would be, "Must be used twice daily for full 7 days
9 to
eliminate fungal infection."
10
We also recommend moving the language on
11
"Relieves itching and burning" to the Drug Facts.
12
[Slide.]
13
Here, we remind the consumer about
14
completing the full course of treatment even if
15
symptoms resolve. What we want to
do is help
16
consumers manage the expectations toward treating
17
symptoms and signs.
18
This copy may read, "Many get relief from
19
their symptoms (itching and burning) after 1 week
20 of
treatment. Signs such as redness will
last
21
longer until the outer layer of skin naturally
22
replaces itself."
249
1
Additionally, we recommend strengthening
2 the
warnings specific to diabetics. For
example,
3
that language would read, "Stop use and ask a
4
doctor if condition worsens or new symptoms
5
develop; this is especially important if you have
6
diabetes."
7
In short, these changes will improve
8
health outcomes for the millions of consumers with
9
athlete's foot who count on these safe and
10
effective treatments.
11
We intend to test, refine, and implement
12
enhanced labeling that will more clearly guide
13
those who use our antifungal products, so that
14
their expectations are well met and their outcomes
15
improved.
16
[Slide.]
17
In conclusion, we have provided data from
18 a
variety of sources that confirm the safety,
19 effectiveness,
and unique benefits of terbinafine
20
when used for 1 week with no evidence of increased
21
lack of effectiveness or resistance development.
22
While we recognize complete cure as the
250
1
appropriate endpoint for the approval of OTS
2
topical antifungals, effective treatment is the
3
most meaningful endpoint for communicating efficacy
4
information in labeling.
5
We have provided commentary on how future
6
products might be developed and have highlighted
7 the
rationale by which new chemical entities should
8 be
held to a higher standard than line extensions
9
based on separation from placebo.
10 Finally, we share the goal of improving
11
consumer health outcomes. We have
presented our
12
proposed labeling and delineated its clear purpose.
13
We thank the committee for your time and
14
interest and look forward to your input and
15
guidance, as well, to further collaboration with
16 FDA
to bring label improvements that maximize the
17
safety and effectiveness of these important
18
therapies.
19
I will be glad to address any questions
20 you
may have.
21
Thank you very much.
22
DR. CANTILENA: Thank you, Dr.
Albrecht.
251
1
I will actually ask all the speakers from
2 the
open public hearing to come up to the podium
3 and
we will open this up to questions from the
4
committee members. You can just
identify who you
5 are
asking, if you know, and we will start with Dr.
6
Fincham.
7
DR. FINCHAM: I have a question
for Dr.
8
Albrecht. You presented data from two studies,
9
2506-01 and 2508-01. In the
2506-01, you listed
10 the
sample size as 67. Was that in both
treatment
11
arms or was that total patients?
12
DR. ALBRECHT: No, that is total, that is
13
total patients, one of our pivotal studies in the
14
NDA.
15
DR. FINCHAM: So, approximately 35
in
16
each.
17
DR. ALBRECHT: Yes.
18
DR. FINCHAM: In the second study,
on one
19
slide, you said the sample size was 97.
20
DR. ALBRECHT: Yes.
21
DR. FINCHAM: And in the other
slide it
22 was
listed as 193.
252
1
DR. ALBRECHT: Yes. Actually, the total
2
size is 193. In fact, these data
were presented
3
this morning by the FDA, as well.
The 97 relates
4 to
two treatment groups I showed in that chart,
5
which is the 1 week and the 4 week, so we have
6
broken that up. It is 97 for the
1 week and 96 for
7 the
4 weeks, so it adds up to the 193. That
was
8 the
total study size, 4 treatment legs, 1 week
9
terbinafine, 1 week clotrimazole, 4 weeks
10
clotrimazole, and 4 weeks terbinafine.
11
DR. FINCHAM: Just a follow-up
question,
12 if
I might, sir. How were the subjects
chosen to
13 be
in each of those arms?
14
DR. ALBRECHT: They were randomly
assigned
15 to
the treatments.
16
DR. CANTILENA: Other questions on
the
17
committee? Dr. Davidoff.
18
DR. DAVIDOFF: I have a comment
and a
19
question.
20
The comment relates to the apparent close
21 tie
between changes in symptoms, or appearance of
22
symptoms, or disappearance of symptoms, to where
253
1 the
people start or stop therapy, because I was
2
noticing, looking back at the data that Dr. Fritsch
3
presented this morning, that the vehicle actually
4 in
the first week appears to be responsible for
5
eliminating the symptom of pruritus--that is page
6 12
of her slides--and for a sizable portion of the
7
relief of pruritus even in the 4-week treatment
8
with Drug Product F.
9
I suppose that argues for being especially
10
cautious about having patients stop treatment
11
prematurely, because the treatment decision may be
12
based on something that has nothing to do with the
13
active drug. That was just really
a comment, and I
14
would be curious whether you have any thoughts on
15
that.
16
The question had to do with the proposed
17
statement of encouraging patients to be sure to
18
take the full number of prescribed days of
19
treatment, which I think everybody in medicine
20
would agree with it in general that undertreatment
21 and
partial treatment is a bad thing particularly
22 in
light of potential emergence of resistant
254
1
strains in bacteriological infections.
2
However, it seems to me that it is quite
3
possible, given some other data, that even a
4
shorter period of treatment than 7 days might
5
actually be as for, say, terbinafine, may be as
6
effective as 7 days.
7
My question is, are there data on that,
8
because the drug apparently is there in such large
9
quantities and persists even after you stop using
10 it,
that it is possible the organism is effectively
11
eliminated on Day 2, so it would be a little hard
12 to
justify that statement, if that is the case.
13
DR. ALBRECHT: Thank you for the
question.
14
Perhaps to the first question you had, which was,
15 of
course, the drug product works as a composite.
16 It
is the drug in the composition and the vehicle.
17 Of
course, if you have a very good emollient
18
vehicle, it will help to heal the condition.
19
In the case of our product, it is very
20
clear that terbinafine is such powerful fungicidal
21
agent that it certainly kills the fungus, and then
22 is
symptoms persist, that is just the dynamics of
255
1 the
disease, as I showed.
2
Now, in response to your other question,
3 we
actually have clinical data from controlled
4 studies
that show that terbinafine is effective in
5
eradicating the fungal disease and eliminating the
6
symptoms after 5 days. We have
the studies both
7
with 7 days and 5 days in the same study leg.
8
There also is, it's not on the market,
9
terbinafine Rx derm gel preparation, which is
10
effective both in 7 days and 5 days with a single
11 day
application.
12
So, again, I think the potency of the
13
antifungal compound is extremely important.
14
DR. DAVIDOFF: So, then, it isn't
entirely
15
justified to recommend treatment for the full 7
16
days on the basis of the data.
17
DR. ALBRECHT: Well, we have a
labeling
18 for
7 days, we have not pursued a shorter treatment
19
period, but I think if your patient should tell you
20
they only treated for 6 days, you should probably
21
feel quite comfortable that at least the fungus is
22
being killed.
256
1
DR. CANTILENA: We have a comment
over
2
here from Dr. Wilkin.
3
DR. WILKIN: I would be interested
if you
4 are
aware of any literature that speaks to
5
allylamines, and I am actually blocking which ones
6
were tested, but I thought they had modest
7
cyclooxygenase inhibitor reactivity, some
8
anti-inflammatory activity.
9
Dr. Elewski seems to know that part.
10
DR. ELEWSKI: I know that. There was a
11
study done by I believe Ted Rosen in Texas, and he
12
looked at that in sunburns. I think he actually did
13 a
study where he burned red skin from a sunburn to
14 see
what gets rid of the erythema the fastest, and
15
judging what gets rid of erythema from a sunburn,
16 he
was looking at an allylamine with a trade name
17
Naftifine. It actually was a
fairly good
18
eliminator of inflammation.
19
Consequently, some other drugs have been
20
look at it this same fashion, Ciclopirox, which was
21
mentioned this morning, is one of the more common
22
prescription products, and so forth.
257
1
So, I don't think it is a function of
2
allylamines only, because Ciclopirox had it, and
3
ketoconazole, I think had something similar, but it
4 was
done in a different way, but the paper was Ted
5
Rosen, and it was looking at burns, if that helps.
6 DR. WILKIN: But the moiety we are talking
7
about now is an allylamine.
8
DR. ELEWSKI: Right, Naftifine is
an
9
allylamine.
10
DR. WILKIN: And also terbinafine.
11
DR. ELEWSKI: Right.
12 DR. CANTILENA: Dr. Katz.
13
DR. KATZ: I have a question for
Dr.
14
Clayton concerning the consumer research data that
15 you
referred to, done on internet.
16
How did you locate those patients in the
17 first
place and what was the percent of people who
18
responded to that survey?
19
DR. CLAYTON: The patients or the
20
consumers are identified through screeners of
21
symptoms that they complain of, so it is done
22
through a variety of signs.
258
1
DR. KATZ: How do you get the
names to
2
contact them on the internet?
3
DR. CLAYTON: I can't tell
you. A firm is
4
employed that is skilled at surveying by internet.
5
DR. KATZ: Do you know the
percentage of
6
response?
7
DR. CLAYTON: I don't know the
percentage
8 of
response.
9
DR. KATZ: We need to know. Provides fast
10
relief, 60 percent of the respondents, so how do we
11
know that is not 6 percent of the respondents, the
12
others didn't bother responding?
13
DR. CLAYTON: These are 350 that
actually
14
completed the survey.
15 DR. KATZ: But maybe 3,000 were surveyed.
16 I
mean we have no idea of this data that is being
17
presented.
18
DR. CLAYTON: I apologize for the
fact
19
that it wasn't complete. This
survey that I
20
reported today is very consistent with the others
21 we
have done for the past 10 years. Some of
them
22
have been one by mail panels, some of them have
259
1
been done by internet.
2
This particular most recent
one was done
3
that way, but it is done through a statistical
4
model that is used to validate the representation.
5 I
apologize for not having that information for you
6
today.
7
DR. GANLEY: Could I comment on
that, too?
8
DR. CANTILENA: Go ahead.
9
DR. GANLEY: We have seen some of
these
10
before, and there are internet sites where you can
11
sign up and fill out a questionnaire and give some
12
history about yourself. They create a database.
13
For example, if you have a history of
14
athlete's foot, they may ask you that question, and
15
then when someone comes in for a survey, they will
16
send out to all the respondents, you know, they may
17
have several hundred thousand respondents and
18
10,000 or 50,000 say that they have a history of
19
athlete's foot, and then they will go out and send
20
e-mails to all of those people, asking them if they
21 are
interested in participating in a survey.
22
A certain percentage will come back and
260
1 say
yes. Now, the one thing about these sites is
2
that you collect points by the more surveys that
3 you
fill out, and if you collect enough points, you
4
will get some type of gift.
5
DR. KATZ: That is the point of my
6
question.
7
DR. GANLEY: John, you can correct
me if I
8 am wrong.
9
DR. CLAYTON: As Dr. Ganley said,
some are
10
that way. I, unfortunately don't
have that
11
information today. Again, it has been done by a
12
variety of different methods over these 10 years,
13 the
data have been extremely consistent throughout
14
except for the trends that we have noted.
15
DR. KATZ: But that type of survey
would
16 be
highly questionable as far as the validity of
17 who
is responding to the internet and getting
18
points and getting prizes for responding. I think
19 you
would have to agree that the scientific
20
validity of such a survey would be subject to
21
question.
22
DR. CLAYTON: There have been
standards
261
1 set
for these types of surveys as a general
2
statement. I am not addressing
all that are out on
3 the
internet, but particularly the firms that we
4
employ to do these types of things, they are
5
validated against a certain model.
Unfortunately,
6 as
I said, that was done by a market research
7
group, and I apologize for not having that
8
information.
9
DR. CANTILENA: I think we can
move on.
10 Dr. Ringel.
11
DR. RINGEL: I think this question
is best
12
addressed to Dr. Elewski because she has had so
13
much experience, breadth of experience with many
14
different products.
15
We have heard that most cases of tinea
16
pedis, in fact, are moccasin style tinea pedis,
17
whereas, I believe most of the studies have been
18
done with interdigital tinea pedis.
19
I was wondering if you or the companies
20
that you have consulted for have data about the
21
cure rates, mycological and clinical, for patients
22
both with moccasin style and/or interdigital,
262
1
first, and secondly, with patients who have
2
onychomycosis along with their interdigital tinea
3
pedis since probably those are the majority of
4
patients who are going to be treated.
5
DR. ELEWSKI: The most common type
of
6
tinea pedis that we see is the interdigital. The
7
interdigital is by far the most common, much more
8
common than moccasin. The
interdigital is when the
9 toe
webs, you know, that we went over, the web
10
spaces are infected, and the prime organism is
11
Trichophyton rubrum.
12
By the time someone has actually gone on
13 to
get the moccasin type tinea pedis, many of these
14
people, if not all, have some form of onychomycosis
15 by
that point, so treatment with a topical
16
antifungal poses some challenges because if you use
17 a
topical antifungal for moccasin, you probably
18
could eventually eradicate the dermatophyte from
19 the
bottom of the foot, but the problem is you
20
still have dermatophytosis in the nail, which will
21
eventually--what I teach our residents are the
22
fungi are greedy and they want to continue to grow,
263
1 and
if you get rid of it from the bottom of the
2 foot,
the plantar surface, it may eventually come
3
back from the nail.
4
So, unless you eradicate the fungus in the
5
nail, then, you probably will have recurrence down
6 the
road, but interdigital tinea pedis can occur
7 without onychomycosis, in fact, it generally
does
8
especially in the epidemics that you see from
9
swimming pools, gyms, and health spas, and so
10
forth.
11
The interdigital, simple and complicated,
12 is
a simple scaling process, and these people don't
13
have onychomycosis.
14
DR. RINGEL: Perhaps someone at
the FDA
15
could help me. I believe in the
package that we
16 got
before the meeting, moccasin style tinea pedis
17 was
about 50 percent, isn't that correct?
18
At any rate, do you have data for
19
clearance of moccasin style tinea pedis?
20
DR. ELEWSKI: Well, for
moccasin--the
21
antifungals we are talking about now, that are OTC,
22 are
for interdigital tinea pedis--for moccasin
264
1
tinea pedis, there have been studies looking at it
2 for
topical antifungals, and it has to be done
3
longer.
4
For example, and I could probably defer to
5
Novartis, because there has been a study looking at
6 it,
and it is 1 week for interdigital, I understand
7 it
would it would be 4 weeks for moccasin tinea
8
pedis.
9
DR. ALBRECHT: It's 2 weeks.
10
DR. ELEWSKI: Oh, it's 2 weeks.
11
DR. ALBRECHT: The Lamisil AT
cream is
12
labeled for 2 weeks of treatment for moccasin.
13
DR. RINGEL: So, do you think that
should
14 be
on the labeling what kind of tinea pedis is
15
being treated?
16
DR. ALBRECHT: It is on the
labeling. If
17 you
look at our labeling, in fact, there is even
18
images for interdigital foot as opposed to another
19
image for the sides of the foot, which indicates to
20 the
consumer the plantar form. So, there are
two
21
indications on the label, and they are differently
22
instructed in terms of duration of treatment and
265
1 the
imagery, how to apply the product.
2
DR. WHITMORE: I don't think we
saw
3
efficacy data on that, and I think Dr. Ringel and I
4
would also like to know the effectiveness, the
5
efficacy of the study with the plantar for 2 weeks
6 as
indicated on the label.
7
DR. ALBRECHT: Right. Again, the meeting
8 was
focused on interdigital, so I didn't put the
9
data into my presentation. Do we
have them handy?
10
DR. CANTILENA: You could have
life-line,
11 if
you would like, and call home, or we can poll
12 the
audience, that's right.
13
[Laughter.]
14
DR. CANTILENA: Dr. Whitmore.
15
DR. WHITMORE: Are there different
studies
16
done with each of the different vehicles, for
17
instance, Lotramin Ultra Cream versus Lotramin
18
Antifungal Cream and also with Lamisil Spray versus
19
Cream? Is there a superior
vehicle that produces
20
better clearance, or why the different vehicles?
21
DR. ALBRECHT: Different vehicles
because
22 the
consumers actually like variety. In
fact,
266
1
consumers are very form loyal, if consumers like a
2
cream or consumers like a spray or a powder, so we
3 do
separate studies on the cream, and we have
4
separate studies in our solution, and the efficacy
5 of
both vehicles is quite comparable.
6
DR. WHITMORE: Is the same true
for
7
Lotramin Ultra Cream?
8
DR. CLAYTON: Actually, Lotramin
Ultra
9
Cream is only in cream form, so it is the only
10
dosage form, but comparative studies against other
11
active ingredients, I don't believe they have been
12
done. There may be a few out
there, but not
13
pivotal type, large-scale studies.
14
DR. WHITMORE: Do you use anything
to
15
direct consumers to which they should purchase?
16
DR. CLAYTON: Other than through
17
advertising, not directly. I mean
the labeling
18
certainly describes the treatment regimens
19
specifically, but only through those means of
20
communication.
21
DR. CANTILENA: Thank you.
22 Dr. Benowitz.
267
1
DR. BENOWITZ: I have two
questions. Dr.
2
Elewski would probably be the one to address them.
3
The first is you made the point that you
4
think effective therapy is equivalent to cure by
5 the
criteria we heard this morning. I am
just
6
wondering, do you know of any data on relapse using
7
those two criteria, or may recurrence or long-term
8
outcomes?
9
DR. ELEWSKI: I don't have data on
that,
10 but
let me expound a little bit on what you said
11 for
effective therapy, because one thing I didn't
12 use
as an analogy is acne. You know, it is
hard to
13
evaluate skin studies, and if you are treating, for
14
example, something like acne, what do you say is
15 the
endpoint, is it getting rid of the comedones,
16 is
it getting rid of the pustules, is it getting
17 rid
of the papules or nodules or cysts, of is it
18
getting rid of the scarring or the oil?
19
So, at the end of the study, if you still
20
have scarring or you still have oil, does that mean
21 you
still have acne? No. Likewise, that is what I
22 was
getting at for effective treatment, if you have
268
1 a
little bit of erythema, a little it of scale that
2 may
be unrelated, it could be effective treatment.
3
As for data, probably the best study was
4 the
study that was alluded to this morning looking
5 at
Lamisil/Terbinafine 1 week versus 4 weeks, and
6
looked at it after--I wrote this many years ago, so
7 it
is hard to remember--I think it was 48 percent
8 in
those who used it for a month, and it was 42
9
percent in those who used it for a week, had no
10
recurrence at 1 year or longer.
11
Of those that recurred, one-third actually
12 had
a new organism, implying that they didn't
13
really recur, they got a new infection.
So, that
14 is
probably the best study looking at that, that I
15
know of, unless any of the industry colleagues want
16 to
add to that.
17
DR. BENOWITZ: I was just trying
to be
18
sure that the finding of mild symptoms really means
19 the
same thing as a cure in terms of recurrence
20
rates, because the efficacy or efficient, whatever
21 the
term is, shows about 80 percent outcome for
22
that endpoint, but yet there is about a 40 percent
269
1
recurrence rate.
2
I am just trying to figure out can we
3
really be sure that what you are saying in terms of
4
effective outcome is the same as cure.
5
DR. ELEWSKI: The issue, I think,
is the
6
word "recurrence," because how do you define
7
recurrence? Is it recurrence
meaning you never got
8 rid
of the infection in the first place, so the
9 infection
recurred? Or is recurrence that they got
10 rid
of the infection, but they put their feet back
11 in
their fungal-ridden shoes, as someone mentioned
12
already? You have fungus in your
shoes, as Dr.
13
Wilkin mentioned, and they got a new infection.
14
So, it is very hard to sort this out.
I
15
know Dr. Ghannoum and I at one point were looking
16 at
doing molecular strain types on initial
17
infections to see if someone got a new infection,
18
which we could call a recurrence, if you wish,
19
whether it was really a recurrence or whether it
20 was
a new infection.
21
You could do this if you found the
22
molecular strain of infection A, and then six
270
1
months down the road, they get a new infection,
2
what is the molecular strain type of that new
3
infection, you know, looking at the DNA pattern of
4 the
organism.
5
We have never done that. I don't
know if
6 you
have.
7
DR. GHANNOUM: Actually, you know,
we were
8
trying to do that. At that time,
there was no
9
method which allows differentiation of different
10
strains, that allows you to differentiate rubrum
11
from mentagrophytes, but not between rubrum.
12
Now, the good news is there is a method
13
that allows people to differentiate between two
14
different strains for T. rubrum, for example, or
15
mentagrophytes, and I think maybe pretty soon we
16
will be able to have some sequential isolates to
17
follow that.
18
DR. BENOWITZ: I understand
that. That is
19 not
really my point. I think there are
probably no
20
data.
21 My point is just however you look at
22
recurrence, do we know it is the same for someone
271
1 who
has a complete cure by the definition we heard
2
this morning, versus effective treatment.
3
DR. ELEWSKI: I can tell you from
my own
4
practice, from my own patients, when I have a
5
patient and they finish their treatment, and I see
6
them a month later, and the majority of their
7 symptoms
and signs are resolved, and they may have
8
just a wee it of something left, and I follow them
9
again, for other reasons, they come in for problem
10 A
or B or C down the road, they generally are still
11
free of fungus.
12 Some of them will go on to get something
13
new. I am particularly interested
in this, so I
14
like to do cultures. I am out
there doing cultures
15
where many people don't. Often it
is a different
16
organism. I just like to do that
for academic
17
interest, but I have never published that.
18
No, there is no data that I am aware of.
19
DR. BENOWITZ: The second question
that I
20 had
is you made a statement and supplied some
21
evidence for why you thought there was no need to
22 do
dose responses.
272
1
My question is, why was the particular
2
dose chosen, has been chosen for the various drug,
3 and
without doing a dose response, how can you be
4
sure that you don't need to do a dose response?
5
DR. ELEWSKI: I think I should
defer that
6 to
the companies who have the drugs.
7
Do you want to comment on that?
8
DR. ALBRECHT: I can offer
comment. I
9
think I showed the data that we, based on the MIC
10
values, and then based on the availability of the
11
drug in the skin, it was determined that we had an
12
effective dose at a low level, and therefore, no
13
safety issue involved, pursued that further for
14
clinical development.
15
DR. CLAYTON: I would give a
similar
16
response except that there are also some studies
17
that have been done with some of the drugs using
18
guinea pig models, infected guinea pig models to
19
determine various concentrations, and differences
20 in
outcomes on those.
21
I am not aware of many, if any, clinical
22
trials that are comparing true dose response.
273
1
DR. ELEWSKI: The objective is to
exceed
2 the
MIC of the fungus and eradicate the organism.
3 I
think we are doing that with the antifungals
4
available for superficial cutaneous fungal
5
infections, which is the issue on the table.
6
DR. BENOWITZ: So, can we be as
sure for
7
concentrations in the skin? I
know for blood it's
8
simpler because there is organism in the blood and
9 we
get a concentration of an antibiotic in the
10
blood, and we can sort of make sense out of the
11
MIC, but can we extrapolate that to skin
12
concentrations versus MIC acting on fungus in the
13
skin?
14 DR. ELEWSKI: I can't really comment on
15
that. I don't know if anyone else
wants to.
16
DR. CANTILENA: Okay. No one is going to
17
move on that. Is there a
comment? You had your
18
hand up, Dr. Wilkin.
19 DR. WILKIN: I think Dr. Benowitz asked a
20
really key question, and that is what is the gold
21
standard for cure. I think that
is what you were
22
going after. Dr. Elewski has
obviously thought a
274
1 lot
about this, and many of the things that you
2
have thought about, our dermatology group at FDA,
3 you
know, I have to say that we think in many of
4 the
details along the same line. I think
that may
5 be
a general dermatology perspective.
6
One of the difficulties that we have had
7 to
wrestle with is since we are looking at just the
8
three things, one is the KOH, that is, you scrape
9 and
you look and see if there is any evidence of
10 the
hyphae present.
11
There is an enormous sampling error
12
difficulty. One of the exercises
that a first year
13
resident gets to do, or a fourth year medical
14
student rotating on Dermatology, is you have them
15
scrape the foot and do a KOH.
They can't find it
16 the
first time, and you have them do it again, and
17
they can't find it.
18
Finally, on the third time, they may
19
locate it. So, it's not the easiest thing to do
20
even in the hands of a skilled investigator,
21
sometimes there is one small area.
So, I think
22
there are enormous sampling errors with the KOH.
275
1
The culture may be the
same. We do
2
actually have some information that helps us
3
understand the culture. The entry
criteria for the
4
kinds of studies that we are discussing today are
5
patients who have a positive KOH, and they look to
6 the
clinician as though they have the presentation
7 of
tinea pedis. That is what gets the
patient into
8 the
study.
9
So, that patient would be in the
10
intent-to-treat group. They also
get a culture at
11
baseline, and then three weeks later, either a
12
dermatophyte grows out or it doesn't, and it
13
doesn't grow out one-third of the time, so the MITT
14
group is typically on the order of 65 percent of
15 the
ITT group.
16
That tells me that there is that
same
17
problem with the culture, is that when it is
18
negative, it may have less informative value, that
19
there can be enormous sampling errors.
20
Nonetheless, we are willing to take
21 mycological
negativity, if you will, negative KOH,
22
negative culture, and then look at the skin signs,
276
1 and
I think as Dr. Elewski has pointed out, the
2
skin has a very limited repertoire in response to
3 any
kind of noxious agent, be it atopic dermatitis,
4
contact dermatitis, or tinea pedis, or the
5
dermatophyte.
6
I mean it can scale, it can get red.
It
7
doesn't really have many other things in its
8
vocabulary. So, there is some
confusion when you
9 get
down to the 1-plus erythema and 1-plus scale.
10 It
is probably true that some of those patients
11
represent a cure and some of them don't. I think it
12 may
go both ways.
13
It may be too high a hurdle on the foot to
14
actually demand zero clinical signs and symptoms,
15 but
we like looking at that because it is such a
16
pristine group. I mean it's a
nice comparator from
17 one
product to the next, especially when we are
18
comparing against the placebo, so we didn't really
19
prepare that part for the discussion today, but I
20 am
glad Dr. Benowitz brought it up.
21
There is no gold standard. It would
22
really require people who got new shoes, maybe went
277
1 to
the International Space Station where there is
2 no
dermatophytes on the floor, and they were
3
watched over an entire year to see whether or not
4 the
fungus came back. So, that is a little
on the
5
epistemology, if you will, of what we really do
6
know.
7
The second part, I would like to say is
8
about do antifungals get to the site of action. I
9
think it is true that you can scrape skin, you can
10
lift it off with tape strips, and you can find that
11 the
active is there, but we all know that it needs
12 to
be in solution before it is really going to be
13
active.
14
The other thing is Robert Jackson has got
15 a
really nice paper, and Dr. Elewski probably knows
16 the
exact citation, but it is the one where
17
dermatophytes move in a centrifugal manner, I mean
18
they move out, so that the leading edge, when you
19
were looking at the very nice picture of between
20 the
fourth and fifth toe, that center part that
21
everyone was focused on, that is probably
22
gram-negative bacteria in that location.
278
1
The actual dermatophyte is out in what
2
looks like normal-appearing skin out at the edge,
3 and
I think it is really very difficult to get
4
these large chemicals to that location down through
5
that very thick stratum corneum, so I don't think
6 we
have seen at FDA really good data to tell us
7
that these products are in solution at the site of
8
action, at that location, and it is a 1 to 1
9
relationship.
10
I guess I will stop at that.
11
DR. CANTILENA: Thank you.
12
Did you have a comment on this question,
13 Dr.
Ghannoum?
14
DR. GHANNOUM: Which question?
15
DR. CANTILENA: On the comment that was
16
raised over here by Dr. Benowitz.
17
DR. GHANNOUM: I just wanted to
comment
18
about a couple of things. Number
one is about how
19
really do we determine the vehicle or the dose. A
20 lot
of the time, I know our Center gets studies in
21
guinea pig model, which was mentioned, and that
22
guinea pig model we look at different vehicles and
279
1 say
which one, let's say, caused this erythema, and
2 the
same applies for the doses. We really
do,
3
let's say, three, four doses, and then select the
4
best one.
5
I think industry at that time, then, they
6
take it, that's one thing.
7
I want also to comment about the
8
International Space Station. In
actual fact, there
9 is
Trichophyton there, they found.
10
[Laughter.]
11
DR. GHANNOUM: There was a study,
and it
12 was
there. So, I don't know where it came
from,
13 but
it was there.
14
The last point is about the calcofluor and
15 the
KOH, the difficulty in that. I think
really it
16 is
very important to use, not just regular KOH, use
17 the
calcofluor, because you can improve the
18
sensitivity because this dye is specific for it,
19 and
I think a lot of the studies, like from 53
20
percent, you can improve it up to 80 percent.
21
DR. CANTILENA: Thank you.
22
Dr. Wilkerson.
280
1
DR. WILKERSON: Dr. Elewski, one
question.
2
There has been a lot of talk over the years about
3
yeast and bacteria, and I haven't heard much about
4
that today. Some of these
compounds are more
5
effective from what I understand from what people
6
say, which isn't always true.
7
Overall, do yeast and gram-negative
8
bacteria, one thing and another, play, and how
9
important is it that the agents that you are
10
treating with have activity against those also?
11
DR. ELEWSKI: That would be
called, if you
12 had
a yeast or bacteria in the toe web, we could
13
call that toe-web intertrigo. It
could have
14
started with a dermatophyte. I
think one of the
15
speakers talked about how Dr. Layden and Kligman
16
described this, and they described it as a syndrome
17 of
dermatophytosis complex, where the dermatophyte,
18
which is able to digest the keratin, damages the
19
keratin, destroys the barrier function, and allow
20
bacteria to enter.
21
Then, you may get a weeping, macerated toe
22 web
in that scenario. I actually did a study
281
1
looking at this, and we found that topical azole
2
family category, and we were using Econazole cream
3 as
an example, and we published this and found that
4 it
had a lot of antibacterial activity, because we
5
culture people beforehand and treated them with
6
Econazole, and they did very well.
7
We can extrapolate from that and from
8
others who have written about this that the azole
9
family Econazole, clotrimazole, and so forth, have
10
some antibacterial activity, and also anti-yeast
11
activity.
12
Now, candida can also be a pathogen in the
13 toe
web, but it is extremely rare, and it generally
14
would be a secondary problem, and probably I would
15
think if it is there, it probably came riding on
16 the
back of a dermatophyte, so if you killed the
17
dermatophyte, then, you would eradicate everything
18
that was there because of the dermatophyte, and the
19
same thing you could also say with this
20
dermatophytosis complex. If you
kill the
21
dermatophyte, well, the dermatophyte was the way
22
that the bacteria could get a hold in the foot, so
282
1 if
you kill it, there is nothing left for the
2
bacteria to do but leave.
3
DR. WILKERSON: Well, I think
where this
4 is
important is particularly when we are talking
5
about diabetics and other immunocompromised
6
situations where it may be more important. My
7
understanding is that allylamines do not have much
8 of
this activity towards yeast, and I don't know
9
what their activity towards bacteria is.
10
DR. ELEWSKI: The allylamines have
less
11
activity for yeast and less activity for bacteria
12
than the azoles, however, we are talking about now
13 a
topical antifungal, so if you were to take a
14
drug, such as oral terbinafine orally, it is not
15
going to be very effective for cutaneous candida,
16
again because terbinafine would have to get
17
absorbed, get into the skin, and it wouldn't get
18
into the skin in high enough concentration to kill
19
Candida albicans.
20
It might kill Candida parapsilosis, but
21 not
Candida albicans, but applying it topically, it
22 is
a very effective drug for Candida.
283
1
Another example could be another yeast
2
Pityrosporon. Terbinafine doesn't
get into the
3
skin in high enough concentrations orally to kill
4
Pityrosporon, but you can apply it topically to
5
kill Pityrosporon, because it is exceeding the
6
yeast.
7
So, when using these drugs topically, they
8
generally, because you are applying to the skin in
9
high enough levels, are going to exceed the MICs of
10 the
dermatophytes, of Candida, and of some, but not
11
all, bacteria.
12
The bacteria that I still see a problem in
13 my
patients who have bacterial infections, some of
14
which are diabetic, most of whom, though, have an
15
anatomical occlusion causing a deformity, which
16
leads to maceration because of the deformity, and
17
they may have pseudomonas, and that can be a
18
problem.
19
I have seen a few, a handful of patients
20
with chronic pseudomonas in the toe web, that the
21 only thing that I have been able to do to
eradicate
22
that is topical gentamicin, garamycin product or
284
1
oral products that are appropriate, but that is
2
very, very rare, but nonetheless, I have seen.
3
DR. CANTILENA: Thank you.
4
DR. WILKERSON: One other part of
my
5
question was to the Schering-Plough
6
representatives. My understanding
is Lotramin
7
Ultra is a different compound than Lotramin AF, is
8
that correct?
9
DR. CLAYTON: Yes, Lotramin Ultra
uses
10
butenafine hydrochloride, whereas, Lotramin AF is
11
clotrimazole.
12
DR. WILKERSON: Outside of playing
on
13
brand names, don't you consider that to be really
14
confusing to consumers?
15
DR. CLAYTON: We have tried to
communicate
16 the
difference. We have tried to communicate
it
17
both through packaging and advertising, and we have
18 been
challenged by Dr. Ganley and his Division to
19
test this with consumers, which we have done
20
through actual label comprehension and
21
understanding, but we have tried to make them
22
happy, quite different in appearance and the
285
1
communication piece also.
2
DR. WILKERSON: It was obviously
done to
3
play off of your brand name, correct?
4
DR. CLAYTON: It was done to
establish
5
credibility that existed in the marketplace, but
6
there was the full intent to make sure that
7
consumers could distinguish between the two.
8
DR. CANTILENA: That was a very
good
9
answer, by the way.
10
Dr. Fincham.
11
DR. FINCHAM: I have a question
for Doug
12
Bierer.
13
You mentioned in one of your slides, three
14
hoped-for additions to labeling, and you mentioned
15 a
hope for increase in compliance. I was
just
16
curious from your data, what is the baseline rate
17 of
compliance and what do you hope to gain as far
18 as
an increase in compliance by your proposal?
19
DR. BIERER: I don't actually have
data on
20 the
baseline for compliance with these products.
21
That would depend upon the individual product. We
22
don't collect that as an association.
I think you
286
1
would have to talk with the individual companies.
2
But I hope that we would see consumers
3
understanding from this proposed labeling, which I
4
think you have heard from both companies that they
5
would understand that they should complete the full
6 course
of therapy even if their symptoms improve.
7 I
think that is the message that we want to
8
communicate to consumers.
9
DR. FINCHAM: But nowhere did I
hear
10
anybody talk about specific compliance rates,
11
unless I missed it.
12
DR. BIERER: No.
13
DR. CLAYTON: The only thing we
had was
14
consumer survey, which indicated that they were
15
using it on average 7.3 days, and a high percentage
16 was
using it less--
17
DR. FINCHAM: I guess I am talking about
18
both duration, as well as intensity, and nobody
19
talked about specific intensity, just the duration.
20
DR. CLAYTON: You mean numbers of
21
applications per day? Some of the
products are
22
once-a-day application, some of them are twice a
287
1
day.
2
DR. CANTILENA: Final
question. Dr. Wood.
3
DR. WOOD: I have two comments rather
than
4
questions. The first one is the
techniques, the
5
laboratory techniques that are used to establish
6 the
diagnosis. We are here to give advice,
and it
7
seems to me that the techniques that are being used
8 are
antiquated.
9
We no longer use cultures to identify
10
tuberculosis for lots of good reasons.
There are
11
much better molecular biology techniques that could
12 be
used to identify these organisms. The
fact that
13 we
are still using KOH seems to me just
14
mind-boggling, so I would recommend that if we are
15
going to start thinking about how we identify the
16
organisms in the future, we ought to use the 21st
17
century techniques, and not techniques from I guess
18
almost the 19th century.
19
The second part is I think it shouldn't go
20
unchallenged that concentrations in skin are
21
necessarily higher by topical administration than
22 by
systemic administration, and I haven't heard
288
1
data to support that, nor have I heard data that
2 say
what these concentrations need to be at the
3
site that kills the organism, because presumably,
4 the
site that kills the organism is not necessarily
5 the
one that you are sampling from when you scrape
6 the
skin.
7
So, I think we need to be careful about
8
that. I am particularly concerned
with the way
9
that has been offered given that the data seem to
10
suggest that systemic administration is at least,
11 and
probably substantially more, effective in terms
12 of
a cure rate than topical administration, so the
13
assumption that the topical administration gives
14 you
higher concentrations and, hence, greater
15
efficacy, doesn't seem to be borne out by the
16
facts.
17
DR. CANTILENA: Any comments from
the
18
speakers to Dr. Wood?
19
DR. ELEWSKI: I don't have a
comment on
20
that, but we did do once a tape stripping study
21
with an antifungal called Econazole, and did find
22
that it was viable in the skin doing it
289
1
sequentially over a long period of time after
2
someone applied it and tape stripping it off to see
3 if
you could still get fungus.
4
It was an in vivo kind of test, but I am
5 not
aware of any other data on that.
6
DR. ALBRECHT: I might just add to
the
7
study I referred to in my presentation.
We did a
8
skin stripping study using the nesmith [ph] method,
9 and
five weeks after initiation of treatment, you
10
could still find drug at effective levels, you
11
know, representing superpotent MIC values, if you
12
will. I don't know whether that
satisfied you.
13
DR. WOOD: Oral administration?
14
DR. ALBRECHT: We haven't done
oral
15
administration.
16 DR. CANTILENA: Dr. Ganley has one comment
17 and
then we will go to a break.
18
DR. GANLEY: I just wanted to
follow up on
19
something that Dr. Benowitz asked, and I am going
20 to
direct it to Dr. Elewski, because you had made
21 the
recommendation that there not be dose response
22
studies done.
290
1
I think from a regulatory point of view, I
2
think when we look at the data for the negative
3
mycology, that Dr. Fritsch reported on today, it
4 was
her Slide 15, if you look at the negative
5
mycology, at the primary timepoint, it runs from 55
6
percent to 88 percent.
7
If you look at her Slide 17, where you
8
actually look at effective treatment, the effective
9
treatment is 38 to 69 percent.
So, it seems that
10
there is a lot of room for improvement there.
11
In a slide that Dr. Albrecht showed, which
12 was
his Slide 13, which showed that there is a
13
1-week treatment of clotrimazole and a 4-week
14
treatment of clotrimazole, there seemed to be
15
difference. It may not have been
powered to show a
16
difference, there seems to be a difference on the
17
treatment in obtaining a negative mycology.
18
So, I would like some information on how
19 you
could recommend that there not be a dose
20
response, or that we shouldn't request that because
21 our
situation is we have folks coming in wanting to
22 do
3-day treatments and 1-day treatments just to
291
1
establish that they beat placebo.
It seems that if
2 you
come in with the right chemical, you can beat
3
placebo, but then that may not be the best
4
treatment for someone.
5
It would be concentration or numbers of
6
applications per day or duration.
Your statement
7 is
a very important statement if that is your
8
position, and I would like to understand, because
9 in
my discussions with industry, when I have asked
10 for
data on a study where it has looked at multiple
11
different regimens or doses within the same study,
12
there is not much data.
13
I mean it is very important from a
14
regulatory point of view as to what the hurdle is
15
that someone has to get over, because otherwise you
16
will see 3-day and 1-day treatment simply because
17
they have beaten placebo.
18
DR. ELEWSKI: I guess I am not
totally
19
sure what you want, but I know with terbinafine,
20
there have been data showing that 1 week of
21
treatment may be as effective as 4 weeks of
22
treatment for tinea pedis, so that dose response
292
1 has
already been done.
2
DR. GANLEY: Within the same
study.
3
DR. ELEWSKI: Within the same
study.
4
DR. GANLEY: But I am thinking as
a
5
blanket statement, you know, you are saying that
6
there is not a need for it, and that has a profound
7
impact.
8
DR. ELEWSKI: I guess I was
getting at
9
that we have drugs that are effective, that are
10
working to kill the dermatophyte, and I wasn't sure
11
that further gathering more data is going to help
12 the
patient.
13
DR. GANLEY: But if someone comes
in a 70
14
percent mycologic cure rate and an effective
15
treatment rate of 50 percent, there is a lot of
16
room there for improvement, it seems.
I mean your
17
blanket statement is--
18
DR. ELEWSKI: I don't have her
slides in
19
front of me, but 70 percent mycological cure, it
20
probably isn't higher because there is some
21
persistent scale there, which is causing the KOH to
22 be
positive. I think that is part of the
problem
293
1 with
that.
2
DR. ALBRECHT: May I comment on
that?
3
DR. CANTILENA: Yes, one quick
comment,
4
please.
5
DR. ALBRECHT: I think Dr. Elewski
made
6 the
point 1 and 4 weeks, there is no difference,
7 established
dose differences, there is lack of dose
8
differences for this compound.
9
Another study that we have done, and I
10
can't say a whole lot, because it's a developmental
11
project, but we have actually done a study, a
12
properly designed, adequately well controlled,
13
randomized, placebo-controlled study with three
14
different concentrations, 1, 5, and 10 percent for
15 a
proper treatment course of tinea pedis.
We did
16 not
find any difference in the response.
17
So, again, I think dose ranging doesn't
18
seem, with these kind of compounds, doesn't seem to
19
really gain a whole lot once you have established
20
enough drug in the skin. That is
really the point
21 I
was trying to make before.
22
DR. GANLEY: The other question I
have for
294
1
you, Dr. Albrecht, is you achieve approximately, I
2
think 88 percent negative mycologic cultures, so
3
that seems to suggest that the 12 percent or so
4
would have had positive cultures.
5
DR. ALBRECHT: Not so, Dr. Ganley,
because
6
mind you, mycological response is the combination
7 of
culture negative and KOH negative, and I think
8 we
just discussed that KOH is a very fickle, if I
9 may
so, kind of instrument, so we may have had--I
10
don't know the number right now--but we may have
11 had
95 percent negative cultures, but the people
12
failed because the KOH was positive, and that just
13
means nonviable structures may have been found in
14 the
skin.
15
DR. GANLEY: So, you have 100
percent of
16 the
cultures are negative, is that what you are
17 saying?
18
DR. ALBRECHT: I am not saying
that, and I
19
would have to look that up, but I submit to you,
20 and
I think even as we heard earlier from the FDA
21
statistician, that a number of cases fail based on
22
positive KOH.
295
1
DR. GANLEY: My question is has
anyone
2
ever looked at those where the culture has failed
3 to
see, are those the MICs for the organism growing
4
there different from what we have seen throughout
5
today, is it something that that is a resistant
6
organism, or it just turns out that this is a
7
compliance issue possibly with the individual.
8
I am directing it, are there outlier
9
organisms there that require higher MICs.
10
DR. ALBRECHT: I can't speak to
that, but
11 may
be Dr. Ghannoum or Dr. Elewski.
12
DR. ELEWSKI: Dr. Ghannoum and I
did a
13
study two years ago looking at onychomycosis. It
14 was
a huge study to see--and we did MICs on the
15
organism against all the antifungals, and there was
16
really no issue of resistance including people who
17
failed, which made you wonder, and this data has
18
been published, what does failure mean and why does
19
someone fail. It's a very
complicated process. It
20 may
be compliance issues, it may be the extent of
21 the
infection, and it may very likely be the
22
patient's immune system may be doing something.
296
1
DR. CANTILENA: Are there
questions for
2 the
speakers? We had a show of hands over
here,
3 Dr.
Benowitz, Dr. Whitmore, and Dr. Wilkin.
Are
4 they
for the speakers or are they general comments?
5
DR. WILKIN: Mine is actually just
a
6
response to Dr. Wood's query this morning on the
7
effectiveness of systemic agents.
8
DR. CANTILENA: How about if we
hold that
9
until after the break.
10
Dr. Benowitz, do you have a comment or a
11
question?
12
DR. BENOWITZ: I wanted to ask Dr.
13
Ghannoum, who made the comment that he had done
14
some animal studies on dose response, which I think
15
would be quite interesting to know what the nature
16 of
the dose response is, do they really flatten out
17 and
do they flatten out at the same concentrations
18 as
these products are used clinically in people.
19
DR. GHANNOUM: We have an animal
model
20
which is coming out, also published, for
21
dermatophytosis, and we use this model for
22
different biotech companies, as well as pharma, to
297
1
look at the different concentration.
Once you see
2
something works in OIC, then, we say, look, does it
3
work in vivo. So, we move into
this animal model
4 and
to find the appropriate concentration, we
5 always
use at least three different groups, 1, 5,
6
and, let's say, 10 percent.
7
When we look at that model, we look at
8
efficacy as well as is there a clinical, let's say,
9
redness to see whether there is irritation with
10
higher concentrations and whatever.
11
Based on this, you will recommend or you
12
call and suggest to the manufacturer, look, this is
13 the
concentration which is efficacious, as well as
14 we
don't see redness, scaling, and this sort of
15
thing in that animal model.
16
Then, the manufacturer will sometimes take
17
that concentration and try other vehicles because
18
again to know, to improve it, will it improve or
19
not, and then after that, they plan their clinical
20
trial.
21
We found, at least with Lamisil, I know at
22 an
early time when they were trying to test it,
298
1
that 1, 5, and 10, there is really no difference, I
2
mean they reached the maximum with 1, at least in
3
that class of compounds.
4
DR. WOOD: What about duration of
effect?
5
DR. GHANNOUM: Because the animal
model
6
itself, it is really self-healing, so you have only
7
about 10 days where you can look, and we look only
8 a
1-week treatment, but in that 1-week treatment,
9 we
compare once a day or twice a day, but only 1
10
week, and then we do after that, 9 days, we do the
11
evaluation.
12
DR. CANTILENA: Dr. Whitmore, did
you have
13 a
question or a comment?
14
DR. WHITMORE: Are we going to be
talking
15
about the consumer educational brochure for
16
patients in the packaging?
17
DR. CANTILENA: Yes, that will be
actually
18
part of our discussion at the end of the day on
19
labeling.
20
Any more questions or comments?
21
Let's go ahead and take a 15-minute break
22 and
return at 3:05.
299
1
[Break.]
2 Committee Discussion
3
DR. CANTILENA: The plan for the
rest of
4
this afternoon and possibly tomorrow morning,
5
depending on time, is to discuss the issues before
6 the
committee. They are outlined for you,
some in
7 the
form of questions, in the handout that you were
8
given.
9
What I have done on this PowerPoint is to
10
sort of partition our discussion, if you will, so
11
that we are on track, by topic.
We are first going
12 to
talk about the issues that actually come up in
13
Questions 4 and 5 with microbiology.
14
We will have that discussion, we will
15
focus on those issues, and then we will actually go
16
through Questions 4 and 5. After
that, drug
17
development issues will be discussed, you know,
18
dose response issues, lowest acceptable cure rate,
19 et cetera, as outlined.
20
For that discussion, we will answer
21
Question 2, and we will give our comments as
22
requested in Issue No. 1, so we will comment on
300
1
Issue 1 and answer yes/no Question 2 under drug
2
development, under the broad category of drug
3
development.
4
Finally, under labeling issues, we will
5
talk about the existing label and then the possible
6
modifications or additions, deletions to the future
7
labels. In that discussion, we
will answer
8
Question 6, as well as Questions 3(a) and 3(b).
9
So, that is the plan. If you can
click on
10
Clinical Microbiology, what I would like to do is
11 try
to focus the discussion sort of as requested by
12
FDA, drug resistance issues and also the use of
13
MICs in drug development.
14
I will just start by saying that what I
15
heard this morning and also this afternoon was
16
resistance is really a rare finding and does not
17
seem to be an issue. What I
thought possibly for
18
MICs, and I would obviously love to hear
19
everybody's comment on this, is that perhaps in the
20
case of treatment failures, that could be part of
21 the
drug application file.
22
So, those are sort of my initial thoughts,
301
1 but
I would like to open it up to the committee,
2
again sort of in this topic, and let's hear what
3 you
all think about this, clinical microbiology
4
issues as they relate to Items 4 and 5.
5
General discussion. One is we ran
out of
6
coffee and people are sagging, or the other is that
7
there are no issue.
8
Go ahead, Dr. Wilkerson.
9
DR. WILKERSON: To assume that
drug
10
resistance is not going to occur, or is going to
11
occur infrequently is probably relatively naive. I
12
think part of the problem is we don't look for it,
13 we
don't have laboratory methods at least on a
14
clinical level to evaluate for drug resistance.
15
If someone is treated with a topical or
16
oral course of antifungal, and it doesn't work, the
17
decision of the clinician is to just move forward
18
generally with another drug or tell the patient to
19
live with it.
20
So, I am not sure that we don't have drug
21
resistance here already. It may
be just the fact
22
that we don't recognize it because we don't have
302
1 any
means for screening for it like we do bacterial
2
resistance, and we don't look for it.
The
3
techniques that were described this morning aren't
4
available on a clinical basis for general use.
5
As far as the MICs, I am assuming we are
6
talking about new drugs, new chemical compounds. I
7
mean I would think that would be essential for any
8 NDA
type of application, that we need to know the
9
pharmacology, we need to know when we put it into a
10
particular vehicle or incipient, does it, in fact,
11
deliver the compound, or does it sit there, you
12
know, what are the pharmacodynamics that drive the
13
compound out of the incipient and into the target
14
organism or cell.
15
Just assuming that a 1 percent
16
concentration does this and that we can strip it
17 off
the tape later, you know, for all we know, you
18
know, the compound is sitting on top of the stratum
19
corneum and doing absolutely nothing, yet, by the
20
crude tape stripping methods that we use to
21
evaluate this, one thing and another, it would
22
still show up in the chemical analysis.
303
1
I think, going forward, you know, since
2
these techniques are available, these are things
3 that
should be looked at for new compounds, new
4
applications.
5
DR. CANTILENA: Thank you.
6
Any other comments in general?
Dr.
7
Benowitz.
8
DR. BENOWITZ: It seems to me we
still
9
have a lot to learn about mechanisms of fungal
10
resistance. It looked pretty
convincing from what
11 I
heard today that there is not much of a problem
12
with the current drugs, and the question is with
13 new
drugs, would resistance be different. We
need
14 to
know more about how the fungus works.
15
I think laboratory in the U.S., like is
16
being done now, should follow this, but I don't
17
know yet that it needs to be done as part of every
18 new
drug evaluation. It is just a big vacuum
in
19
terms of mechanisms.
20
DR. CANTILENA: Dr. Ghannoum.
21
DR. GHANNOUM: Just a comment
about this
22
number. I think I agree with you
if we think
304
1
resistance is not going to develop, it's not right,
2
which could be rare I agree, because we already saw
3 at
least one patient, which is very well
4
characterized, so I think it will happen.
5
The fact that the method is
just
6
developed, we have the paper coming out in July
7
issue of Journal of Clinical Microbiology, and the
8
method will be adopted and available to the other
9
laboratories in January of 2005.
So, we are there
10 as
far as availability.
11
As far as measuring the MIC, from the
12
clinical point of view, I think if we look at how
13 we
use MICs in the systemic agents, where we have
14
methods available, what we do, we don't do it
15
routinely, we do it for patients who fail therapy,
16 and
then you do it, and they say, okay, this is
17
resistant, so you can switch drugs.
18
That is well documented and it is one of
19 the
IDSA guidelines, Infectious Disease Society of
20
America, that it should be for those who fail
21
therapy.
22
Now, as far as part of drug development, I
305
1
think it is very important that we have a baseline,
2 I
mean otherwise how are you going to know whether
3 a
drug works, not work, and once you have that
4
available, it is going to help you in the long run
5
whether there will be a change in MIC or not as you
6 are
monitoring patients, so that is what I can say.
7
DR. CANTILENA: Thank you.
8
Other comments? Okay. If there are no
9
objections and no further discussion on this topic,
10 why
don't we actually go to Question 4.
11
Given the efficacy rates observed in the
12
clinical trials, should antifungal drug resistance
13 be
a concern?
14
Actually, what I would like to do, Dr.
15
Ganley and Dr. Wilkin, if this is acceptable, is to
16 do
this as a yes/no vote and then ask the
17
individual to say what the concern is, so that you
18
will know what is going on.
19
Why don't we start voting over on this
20
side. Actually, before we start
the voting, I
21
would like to ask the non-voting members if they
22
would like to comment on Question 4, first of all,
306
1 so
I don't omit that as I have done in the past.
2
So, I will start over here, Mr. Kresel,
3 and
then Dr. Alfano.
4
MR. KRESEL: Based on the data
that we saw
5
this morning, I agree, as a microbiologist, that
6
ultimately, you will see some resistance, but based
7 on
the tons of these products literally that are
8
used every year, and for the number of years they
9
have been used, I don't see that it creates a
10
concern, the difference between whether it will
11
happen and whether it's a concern.
12 So, yes, I agree it will happen, but,
no,
13 I
don't think it is really a concern at this point.
14
DR. CANTILENA: Dr. Alfano.
15
DR. ALFANO: I agree that I don't
think it
16 is
a concern. It is difficult when the
efficacy
17
rates are linked to resistance, because in this
18
particular condition, as we have heard, the
19
efficacy can be playing off of other parameters,
20
i.e., the anatomical deformities, and so forth,
21
that exist, but I didn't hear any data of any
22
significance that drug resistance is a problem.
307
1
DR. CANTILENA: Thank you.
2
Why don't we continue here and we will
3
just go around this way.
4
Dr. Ten Have.
5
DR. TEN HAVE: You want a yes/no
to what
6
question?
7
DR. CANTILENA: Question No. 4,
yes/no,
8 and
if you are concerned, if you can explain your
9 concerns.
10
DR. TEN HAVE: Given I have no
knowledge
11 in
this area, I am going to approach it from a
12
slightly different point of view.
I agree that the
13
efficacy rates probably could be higher, but, of
14
course, there are other reasons in addition to the
15
other parameters that Dr. Alfano just mentioned.
16
We haven't really looked at other factors,
17
such as non-adherence, which could be a big factor
18 in
the lack of efficacy, if there is a lack of
19
efficacy, so I would say given my lack of knowledge
20 in
this area, no.
21
DR. CANTILENA: Thank you.
22
Dr. Wood.
308
1
DR. WOOD: No, but, of course, our
tense
2 is
in some way future tense, and there is no way of
3
telling that for drugs that are under development
4 or
might appear in the future.
5
DR. CANTILENA: We are not going
to let
6 you
two vote.
7
Dr. Bisno.
8
DR. BISNO: No. In a word.
9
DR. CANTILENA: That was Dr.
Bisno. In a
10
word, he said no.
11
Yes, Dr. Ghannoum.
12
DR. GHANNOUM: No.
13
DR. CANTILENA: Dr. Katz.
14
DR. KATZ: No.
15
DR. SCHMIDT: No.
16
DR. CANTILENA: That was Dr.
Schmidt.
17
Dr. Davidoff.
18
DR. DAVIDOFF: I am not entirely
clear
19
what we are voting on, because it seems to me there
20 are
two concerns. One of them is a
biological
21
concern, and the other one is a regulatory concern,
22 and
I am not sure which one this is really
309
1
referring to.
2
DR. CANTILENA: You can answer it
actually
3
both ways.
4
DR. DAVIDOFF: I think that there
is a
5
biological concern. I mean it
took many years
6
before the pneumococcus became resistant to
7
penicillin, 30, 40 years of exposure.
So, I think
8
that there could very well be biological and
9
clinical concerns over time for resistance with
10
these organisms, so I would vote yes, that is a
11
clinical concern.
12
Is it a regulatory concern? I
would say
13 no.
14
DR. CANTILENA: Thank you.
15
Dr. Whitmore.
16
DR. WHITMORE: No.
17
DR. CANTILENA: Dr. Fincham.
18
DR. FINCHAM: It is difficult to answer
19 yes
or no, everybody knows that, but I think it is
20 a
concern. I guess my concern relates to I
don't
21
think we really know, as Dr. Benowitz pointed out,
22 a
lot about a lot of things here, one of which is
310
1 how
many of these infections, so to speak, are
2
repeat infections, multiple, multiple, multiple
3
cases, time after time after time, and is that due
4 to
non-adherence, is it due to misunderstanding of
5
what the drug is, is it related to something else.
6
So, I think it is a concern.
7
DR. CANTILENA: Dr. Ringel.
8
DR. RINGEL: Basically, no for
now, yes
9 for
eventually. I do think that it would
make
10
sense for new NDAs to include minimal inhibitory
11
concentrations because you really don't know how to
12
interpret the future if you don't know what is
13
there in the present.
14
DR. CANTILENA: That is actually
Question
15 5,
so you will have an opportunity to say that
16
again in a minute.
17
Dr. Lam.
18
DR. LAM: I agree. Right now based on the
19
data that has been presented today, I don't think
20 it
is a concern at this moment, but we know fungus
21 are
pretty smart and it may be a concern down the
22
road.
311
1
DR. CANTILENA: Dr. Patten.
2
DR. PATTEN: I join Dr. Davidoff
in a
3
split vote. I will vote no from a
regulatory point
4 of
view, but yes in terms of the future. I
mean
5
theoretically, yes, it is going to happen. Fungi
6
have been around for a long time, undergoing
7
natural selective pressures, no reason to think
8
they won't respond to this.
9
DR. CANTILENA: Dr. Wilkerson.
10
DR. WILKERSON: As far as for the
present,
11 no,
but looking forward, so we don't get the
12
flesh-eating Tinea rubrum, and be blamed 15 years
13
from now that we didn't stop the epidemic when we
14
could have, I think we need to be aware and
15
monitoring for that, but it is not an issue with
16 the
current drugs.
17
DR. CANTILENA: Dr. Raimer.
18
DR. RAIMER: I agree, no for now,
but
19
possibly yes in the future.
20
DR. CANTILENA: Dr. Epps.
21
DR. EPPS: I concur on no at this
time. I
22
guess a comment about some of my patients.
312
1
Certainly, a lot of them, as a subspecialist, have
2
already used products when they come, and I
3
certainly have faith that quite a few of them are
4
compliant. As a parent who
applies medication to
5
their child, I think a lot of them do.
I guess the
6
difficulty is proving the resistance.
7
DR. CANTILENA: Dr. Clapp.
8
DR. CLAPP: No for now, yes for a
concern
9 for
the future.
10
DR. CANTILENA: Dr. Benowitz.
11
DR. BENOWITZ: I sort of have a
split
12
vote, but my concern is actually regulatory for new
13
drugs. I would say no for the
current classes of
14
antifungal drugs because resistance is rare, but I
15
think when there are new drugs that come out, there
16 are
going to be new mechanisms of resistance, and I
17
think that we should look at the potential for
18
developing resistance when there are new classes of
19
drugs that are introduced.
20
DR. CANTILENA: Thank you.
21
Ms. Knudson.
22
MS. KNUDSON: My vote is exactly
the same,
313
1 no
for right now, but yes for the future.
2
DR. CANTILENA: Thank you.
3
My vote is from a regulatory standpoint,
4 no,
at this time; from a clinical standpoint, yes.
5 Now that we have given you all
those
6
options, Dornette is going to give us the vote
7
tally.
8
LCDR SPELL-LeSANE: 18 no and 1
yes.
9
DR. CANTILENA: With all the
10
qualifications that are fortunately on the
11
transcript. Okay. Very good.
12
Let's go to Question 5. Should
antifungal
13
MICs be determined for clinical isolates during
14
drug development and submitted with the NDA?
15
I think we have some of your answers, but
16 we
have to have anyway for the transcript, so let's
17
start on this side over here.
18
Ms. Knudson.
19
MS. KNUDSON: I will have to
pass. I
20
can't answer that.
21
DR. CANTILENA: Okay. Dr. Benowitz.
22
DR. BENOWITZ: I would say yes,
now that
314
1 we
can do this, I don't see any reason why we
2
shouldn't do it, and it might be very informative.
3 I
would say yes.
4
DR. CANTILENA: Dr. Clapp.
5
DR. CLAPP: I would say. I think that
6
helps address our concern about the resistance for
7 the
future drugs.
8
DR. CANTILENA: Dr. Epps.
9
DR. EPPS: I certainly think it
could be
10
helpful and informative. I have
met some
11
infectious disease people who wonder about MICs and
12 the
relevance, and that sort of thing, but perhaps
13 it
would help us look forward to know with more
14
data what is pertinent and whether it's relevant.
15
DR. CANTILENA: Dr. Raimer.
16
DR. RAIMER: Yes.
17
DR. CANTILENA: Dr. Wilkerson.
18
DR. WILKERSON: I am assuming this
was
19
referring to in vitro or in vivo MICs?
20
DR. CANTILENA: In vitro on the
isolates.
21
DR. WILKERSON: In vitro?
22
DR. CANTILENA: On the isolates.
315
1
DR. WILKERSON: I think it is part
of an
2
investigative process, it is absolutely essential.
3
DR. CANTILENA: Dr. Patten.
4
DR. PATTEN: I vote yes.
5
DR. CANTILENA: Dr. Lam.
6
DR. LAM: Yes, and it would allow
us to
7
learn more about may drug resistance and fungal
8
resistance, and help us to devise strategies to
9
prevent them down the road.
10
DR. CANTILENA: Thank you.
11
Dr. Ringel.
12
DR. RINGEL: Yes.
13
DR. CANTILENA: Dr. Fincham.
14
DR. FINCHAM: Yes.
15
DR. CANTILENA: Dr. Whitmore.
16
DR. WHITMORE: Yes.
17
DR. CANTILENA: Dr. Davidoff.
18
DR. DAVIDOFF: Yes, although I
assume that
19
it's not just the drug developers who are going to
20 be
studying MICs, it's clearly a wider problem.
21
DR. SCHMIDT: Yes.
22
DR. CANTILENA: That was Dr.
Schmidt.
316
1
Dr. Katz is yes?
2
DR. KATZ: Yes.
3
DR. CANTILENA: Dr. Ghannoum, yes.
4
Dr. Bisno?
5 DR. BISNO: First, to go back to 4 for
6
just a second, we didn't discuss really in any
7
detail what the reasons are for the lower efficacy
8
rates when using drugs that are obviously very
9
potent.
10
Some things came up about hammertoes and
11
local factors and everything, but it seems to me
12
that there needs to be more emphasis on what the
13
factors are that make failure when you are using
14
highly potent drugs, because if we don't identify
15
those, then, we are going to be doomed to wasting
16 all
these drugs, because we will be doomed to fail.
17
So, I would like to see more interest in
18
that anyway.
19
Now, to go on to 5, yes, it is true that,
20 as
an infectious disease person, we do believe in
21
MICs, but we don't believe in them absolutely, but
22 I
think the fact is that if someone presented an
317
1 NDA
that showed a tremendous clinical potency for a
2
particular drug against particular isolates, and
3 yet
it was resistant by MICs, we would all scratch
4 our
heads and have to go back to the drawing boards
5 a
bit, so I definitely think this should be part of
6
drug development and submitted with the NDA.
7
DR. CANTILENA: Thank you.
8
Dr. Wood.
9
DR. WOOD: Yes.
10
DR. CANTILENA: Dr. Ten Have.
11
DR. TEN HAVE: Yes.
12
DR. CANTILENA: Comments from Dr.
Alfano
13 and
Mr. Kresel.
14
MR. KRESEL: I agree and I think
in order
15 for
that to be meaningful, you would also want to
16 do
MICs on clinical failures, because you want to
17 see
if there has been any change in the MIC.
If
18 you
start out susceptible and end up resistant,
19
which is highly unlikely given the data that we saw
20
today, but nevertheless, an MIC at the beginning
21 and
a failure at the end is really not very
22
compelling data.
318
1
DR. CANTILENA: Thank you.
2
I also vote yes. I think it would
be
3
especially helpful in explaining treatment failures
4 if
they should occur.
5
I am sorry, have you commented? I
thought
6 you
passed, Dr. Alfano.
7
DR. ALFANO: Pass.
8
DR. CANTILENA: So, you did pass.
9
DR. ALFANO: Yes.
10
DR. CANTILENA: You have
sensitized me now
11
forever for skipping you, so I am going to ask you
12 at
least five times every vote.
13
We will go to the next slide which changes
14
topics now. Now, we are actually
specifically
15
talking about drug development.
Basically, I would
16
like to center the initial discussion on, first,
17
Question 2, which has to do with drug response.
18
Dose response studies are not conducted in
19 the
development programs of antifungal products for
20 the
treatment of tinea pedis. Given the
efficacy
21 of
products currently marketed, should they include
22
dose response, you know, specifically, they
319
1
evaluate safety and efficacy at different
2
concentrations, dosing durations, and dosing
3
frequencies?
4
Let's initially sort of focus our
5
discussion, if you will, on the whole issue of
6
including exposure response type of information in
7
drug development for new antifungals for this
8
indication.
9
I guess we will just open up the floor.
10
Dr. Wilkin.
11
DR. WILKIN: Would you still want
the
12
efficacy information on the systemic agent that Dr.
13
Wood requested?
14
DR. CANTILENA: Yes, we do. We have to
15
have that because that was a homework assignment
16
that we gave you.
17
DR. WILKIN: That was a homework
18
assignment. The systemic
antifungals are in a
19
different division, so it took us a few moments to
20
find out, and I will describe--and this ought to be
21
available through Freedom of Information, and I
22
assume this is so old, this is the ketoconazole
320
1
oral.
2
Protocol 009, patients were eligible if
3
they had dermatophyte infections:
one, which had
4 been resistant to prior topical antifungals;
two,
5 if
topical treatment were contraindicated due to
6 the
extent of the fungal infection; three, if the
7
infection had failed to respond or had recurred
8
after griseofulvin therapy; or, four, if patients
9
requiring griseofulvin could not tolerate the drug.
10 So,
those are the entry criteria.
11
There were 47 evaluable subjects.
There
12
were 3 separate study centers.
The patients who
13
were in the negative KOH and culture group, that
14 was
70 percent. We call that the
mycologically
15
negative. You have also earlier
heard the phrase
16
"mycological cure."
17
Then, the clinical and mycological cure
18 was
62 percent, and that is above, well above
19
actually, the rates that we saw in the topicals
20
earlier.
21
DR. CANTILENA: And that was what
dose of
22
ketoconazole, and how long was the treatment?
321
1
DR. WILKIN: Patients were treated
with
2
either 200 or 400 milligrams a day for a minimum of
3 28
days and a maximum of 60 days.
4
DR. WOOD: Just for clarification,
that
5
would be the equivalent of Slide 19 in Dr.
6
Fritsch's presentation, is that what we are saying?
7 The
clinical and mycological cure would be the
8
equivalent of a complete cure on her slide, is that
9
right?
10
DR. WILKIN: No, this is an older
review,
11 and
it is really not that clear whether this would
12 fit
most with effective treatment and allow for
13
some or not, because they say global clinical
14
assessment was recorded as cured, markedly
15
improved, moderately or slightly improved,
16
unchanged, or deteriorated, and, as healed, mild,
17
residual lesion or considerable residual lesion,
18
unchanged or deteriorated in 9, and 9 is the one we
19 are
talking about.
20
So, it is not quite clear as I read this
21
whether it fits with one or the other.
22
DR. WOOD: But the 62 percent is
that
322
1
clinical endpoint plus mycological cure?
2 DR. WILKIN: Exactly so.
3
DR. CANTILENA: Thank you. That was the
4
fastest Freedom of Information response I have ever
5
heard of. Same day service. Thank you very much.
6
Comments, concerns looking at dose
7
response, safety and efficacy at various sort of
8
exposure responses for drug development of future
9
agents? Dr. Katz.
10
DR. KATZ: I am a bit
confused. Are we
11
talking about issues for the committee now?
12
DR. CANTILENA: Yes, this is sort
of like
13
Issue No. 2 for the committee as it relates to drug
14
development programs.
15
Should sponsors be doing exposure response
16 for
dried development for new products for
17
over-the-counter? I think you
have heard earlier
18
about the exposures in either changing the
19
concentrations or the application frequency or the
20
length of application, and that is really what we
21 are
talking about.
22 Comment, Dr. Whitmore?
323
1
DR. WHITMORE: I guess we can't
ask
2
Novartis to do this, so this would of their own
3
accord. It would be nice, as has
been said here,
4 to
know if 3 days of therapy is the same as 7 days
5 of
therapy, but for future companies coming forth
6
with the antifungals, it would be nice to have
7
comparator days of dosing.
8
I think, more importantly, at least with
9 the
antifungal chemicals that we know of right now,
10 in
that the MICs are such that you are going to be
11
killing them, you are above the MIC and everything
12
else, but with those drugs, as far as different
13
dosing regimens, if they could come up with a
14
dosing regimen that has whatever acceptable percent
15
clearance, we are talking about 70 or 80 percent or
16
whatever of clearance, and then have a level of
17
dosing somewhere below that where it's a lesser
18
clearance rate.
19
Thus, to kind of restate that, when they
20 are
doing studies, come up with a dose response
21
based on the number of days of dosing, so we know
22 we
are at the minimum number of days to get 80
324
1
percent clearance or whatever.
2
DR. CANTILENA: Very good.
3
Dr. Schmidt.
4
DR. SCHMIDT: Don't the drug
companies do
5 this
already? I mean this seems awful simple,
you
6
know, that even before they would even approach or
7
when they come to the committee or the FDA, they
8
would have some evaluation of, say, different
9
concentrations or some idea of the dosing and
10
dosing frequencies.
11
Maybe I just don't understand how we are
12
supposed to present this to them.
This just seems
13
like it's a given.
14
DR. WHITMORE: Can I just say it's
kind of
15 a
new area because we have just gotten down to 7
16
days of dosing, and we have never talked about
17
anything less than that to clear up tinea pedis, so
18
that is kind of a new thing as far as asking drug
19
companies to look at 2 days and 3 days.
20
DR. CANTILENA: I think I could
say that I
21
have heard that in terms of dose response, there
22 are
some companies that had animal data that we
325
1
have heard about, but I think what I have heard
2
from FDA is in terms of clinical studies, you know,
3
it's almost unheard of.
4
So, it isn't available from the actual
5
studies, and they are asking us if we think it is a
6 good
idea for that to be included in the NDA.
7
DR. SCHMIDT: Well, I think
definitely, it
8 is
a good idea, but it just seems like a no-brainer
9 in
the sense that the people would do it from the
10
start to present that data. It is
just a point of
11
order of how these studies are done, but no, I
12
agree definitely we should.
13
DR. CANTILENA: Comments from FDA
to help
14
clarify the issue?
15
DR. WILKIN: If I could just make
a
16 comment
on the guinea pig model, I mean that is one
17
where, quite literally, you have to hurry up and
18
treat it before it goes away. I
mean it is going
19 to
go away on its own, so there are limited days.
20 I
am not sure that the skin of the guinea pig
21
really reflects the skin between the toes or on the
22
plantar surface of the foot. So,
there are many
326
1
relevant aspects of that model that really would be
2
dissimilar and maybe not predictive.
3
DR. GHANNOUM: If I might comment
on this.
4 I
agree with you, we are not guinea pigs, so we are
5 not
going to have the same data you will see in a
6
patient exactly, but I can tell you from our
7
experience with all the different classes of
8
compounds that are now, whether topical or oral,
9
that the guinea pig can predict whether the drug
10
works or not.
11
You can see, for example, we have--not to
12
bias, to be on anybody's side--but we have a
13
positive control in the guinea pig, and it works
14
beautifully, and when you compare it to other
15
drugs, which does not work as well, although it is
16
marketed, you will see the same.
17
I agree with you, the caveats which you
18
mentioned are very important, because if you leave
19 it
up to 17 days, then, it is not good, but if you
20
have that window of 9 days to do the whole
21
experiment, then, I think it's predictive. The
22
drugs that have been approved were tested in this
327
1 in
the preclinical setting, and I really believe it
2 is
a very useful way to tell you whether, when you
3
move from the in vitro to the in vivo, that things
4 are
going to work, number one, and number two, you
5 can
see the dosing also predictive, but eventually,
6 you
have to go into patients obviously.
7
DR. CANTILENA: Dr. Wilkin.
8
DR. WILKIN: Dr. Ganley earlier
mentioned
9 the
"cures most" and the thinking that went into
10
those words and how the original hope was that most
11
would qualify the cure in a positive direction.
12
Perhaps one of the unintended consequences of that
13 is
it is actually this incentivized competition for
14
more effective products.
15
If that is going to be on the labeling for
16
virtually all these over-the-counter topical
17
antifungals, then, when the marketing groups at the
18
different industries try to decide whether there is
19 a
place where they can make a profit with the new
20
medication, and incidentally, that is how we get
21 all
the new and important drugs that are helpful to
22 the
public health, is someone, somewhere is going
328
1 to
make some money.
2
I mean that is the American way, and I
3
think it has a lot of positive aspects to it, so I
4 am
certainly not going to give any negative side.
5
But the one place that currently I think,
6 if
they look at these products and look at the
7
labeling, is make it quicker, make it less time.
8
I walked by the microwave the other day.
9 We
have a microwave at FDA out at the corporate,
10 and
I was going in there to do something, and
11
someone was standing by the microwave going "hurry
12 up,
hurry up," and I think that is one of the great
13
things that patients want with products also, is
14
they want something that is faster.
15
So, that is where the incentive today is,
16 and
maybe part of this plays into the labeling,
17
maybe it cures most. If that gets
modified, we can
18
then encourage sort of moving towards higher
19
concentrations, maybe somewhat longer durations in
20 an
effort to get better efficacy.
21
DR. CANTILENA: Thank you.
22
Dr. Wood.
329
1
DR. WOOD: Seeing that just came
up, the
2
most again, I don't think the Agency should allow
3
labels that say "most," unless it is based on
4
comparison. "Most" is a
word that has a clear
5
meaning. It means that it cures
more than any
6
other something. You know, it is
not more, it is
7 not
a comparison, it is most, so it implies that
8
this is better than anything else, and that is
9
clearly not true, so it shouldn't be on the label.
10
But that wasn't what I wanted to say.
It
11
seems to me that you should insist on exposure
12
response, and that is better I think than dose
13
response, because my fear would be that somebody
14
will do a study that beats placebo with one dose,
15 and
that doesn't mean that 7 days wouldn't have
16
cured a lot more people.
17
Consumers will assume that the drug has
18
been evaluated in a way that tested it and gave
19
them the most--I will use that word--effective
20
therapy, and not just any old therapy.
21
So, I think there is a real need to ensure
22
that exposure is evaluated, to make sure that you
330
1 are
not forced constantly into the least effective
2
dose, even if it only cures, you know, fill in the
3
percentage.
4
So, I think it is absolutely essentially
5
that you know where you are on the exposure
6
response, not the dose response, and that you have
7
some understanding that you are at the plateau
8
level of what is being produced and before you
9 approve
it.
10
DR. CANTILENA: Yes, Dr. Ten Have.
11
DR. TEN HAVE: Following up on Dr.
Wood's
12
comment, and I think I am interpreting it
13
correctly, but correct me if I am wrong, so with
14
exposure, you are talking about duration times
15
dose, the total.
16
DR. WOOD: Correct, or some
combination,
17
yes, and it might be number of times per day or
18
some variable.
19
DR. TEN HAVE: So, following up on
that
20
comment and also Dr. Wilkin's comment about
21
increasing dose, but shortening the duration, it
22
seems to me that the companies are interested in
331
1
shortening duration, but not necessarily increasing
2
dose, and I may have that wrong, too, but
3
increasing dose obviously increases efficacy, but
4 may
work against safety, so you have two competing
5
criteria there.
6
I presume that the interest in increasing
7
dose is to get at the non-responders.
I know in
8
other areas of medicine, there is sort of a
9
stepped-up approach where if you don't respond at a
10
certain dose, you step up the dose if you don't
11
respond, so you can get a higher response rate for
12 the
non-responders.
13
I am wondering if that is feasible in this
14
situation, or is it just not clinically feasible?
15
DR. CANTILENA: Dr Whitmore.
16
DR. WHITMORE: Pass.
17
DR. CANTILENA: Mr. Kresel.
18
MR. KRESEL: I was just going to
comment
19 on
the classic anti-infective drug development
20
paradigm as it relates to this, because what we
21
usually look at as we are determining the dose is
22 the
half-life, the area under the curve, MICs when
332
1
they are available, bioavailability of the
2
formulation, and tolerability to the patient.
3 So, I think that there is not
likely to be
4 the
need to test multiple concentrations when you
5
have done that preliminary work.
Then, you get to
6
dosing frequency, and dosing frequency has a very
7
limited number of options, as I think somebody
8
commented on earlier.
9
You can do once a day, you can do twice a
10
day, patients are going to carry their medication
11
with them to work and take their shoes and socks
12 off
in the middle of the day and do another dose.
13
So, you can dose something three times a
14
day, and you can get labeling for three times a
15
day, but you won't get any compliance to three
16
times a day, so that it becomes kind of a moot
17 point.
18
So, I think dosing duration becomes the
19 one
that probably ought to be thought about, and I
20
think that FDA probably should determine what the
21
"gold standard" is.
That is, if four weeks is the
22
gold standard, then, people should have to compare
333
1 to
four weeks, are you better than or worse than
2
four weeks, or as good as four weeks, you know, are
3 you
as good at three days as you are at four weeks,
4 or
if the gold standard is one week, then, the
5
comparison should be that, but I don't know that
6
there is a lot of value to be gained at looking at
7
multiple concentrations if the preclinical work is
8
done adequately, and certainly I don't think dosing
9
frequency helps.
10
DR. CANTILENA: Dr. Davidoff.
11
DR. DAVIDOFF: I agree with and
extend a
12
little bit what has just been said.
It seems to me
13
that the assumption that has been expressed a
14
number of times is that the concentrations that are
15
generally implemented are high enough, so that they
16 are
essentially nuking the bugs in terms of the
17
concentration.
18
The issue, though, does seem to be
19
primarily duration of exposure.
Judging from the
20
data on clotrimazole, there was a fairly clear
21
difference between one week and four weeks of
22
exposure, minimal or maybe zero difference between
334
1 one
and four weeks for terbinafine, so I think it
2 is
not a fair assumption that one week is as good
3 as
four weeks for all drugs, and it does seem
4
entirely reasonable to look for exposure-response
5
relationship.
6
Otherwise, both the committees, the
7
Agency, and clinicians are essentially flying
8
blind, and five years from now or 10 years from
9
now, they will still be in the dark as to how to
10
make the decisions if they don't have the data.
11
DR. CANTILENA: Dr. Lam.
12
DR. LAM: I actually concur with
Dr.
13
Schmidt in that I thought dose-response studies are
14
given in drug development, and I was surprised to
15 see
that this group of drugs is not required to do
16
that.
17
Given the difference in response rate
18
between one-week regimen and four-week regimen, I
19
would imagine that there has to be some sort of an
20
exposure-response relationship, and I would like to
21
kind of turn the question into the opposite
22
direction in terms of is there any historical
335
1 reason
or scientific reason that this group of
2
drugs should be exempt from doing that.
3
DR. CANTILENA: Historically, you
heard
4
sort of how they got here, but I think in terms of
5 the
Rx to OTC switches, I don't have that history.
6
Would you like to comment on that, Dr.
7
Wilkin?
8
DR. WILKIN: Well, actually,
requesting
9
dose-response studies, you know, the Code of
10
Federal Regulations is pretty good in giving us
11
information on how to seek efficacy and safety
12
information, but it is somewhat edentulous when it
13
comes to going after dose ranging, and there is a
14
ICHE.4 document that talks about dose ranging and
15
exposure response, and interestingly enough, the
16
last part of that is devoted to Phase IV dose
17
ranging.
18
When I first heard that, I thought, you
19
know, that might be some regulatory humor, but it
20
really does exist, you know, that you can look for
21
this after something has already been approved, and
22
generally, that is in the circumstance of where
336
1
there is a safety issue and one might be trying to
2
find a lower dose that might be just as effective.
3
But, no, we really are often at the mercy
4 of
the sponsors to whether they find it something
5
that they want to do.
6
DR. CANTILENA: Dr. Ringel.
7
DR. RINGEL: Many of these
antifungals
8
have been around, I don't know, I can't imagine,
9
probably since the turn of the century, 1920, some
10 of
the older ones like heliprogen [ph], I think it
11 is
high time that we stop testing these drugs
12
against placebo and start testing them against the
13
known drugs, the drugs that we have that we know
14
work, that at least another monograph system have
15
been approved since 1982.
16
If you think about it, the competition
17
right now is how infrequent and how short a
18
duration can you give these medications and still
19
have them work. Theoretically,
you could have a
20
drug that has a very steep response curve, so that
21 you
could get a maximal response in a very short
22
duration, but the ultimate cure rate could still be
337
1
very low.
2
I mean you could get to a 20 percent cure
3
rate very quickly, but maybe all you will get is a
4 20
percent cure rate, and if you are only going to
5
test them against placebos, you may actually be
6
approving drugs that are less efficacious than the
7
ones that are already out there.
8
So, I think at this point,
you know, 2004,
9 I
think it's time that we stop testing against
10
placebo and start testing against known agents.
11
DR. CANTILENA: Thank you.
12
Dr. Katz.
13
DR. KATZ: The point of necessity
of new
14
drugs getting dose-response studies, as brought out
15 by
Mr. Kresel's comment of comparing to gold
16
standard, the problem is we have no gold standard.
17 I
mean our gold standard is, over placebo, 30
18
percent efficacy, or if you see Dr. Fritsch's page
19 9,
page 10 cure rates of 20 percent over placebo,
20 so
we do need dose response.
21
There may be drugs that we know with the
22
oral antifungals, they can use one week a month and
338
1 get
equal effect, so it may be topical preparations
2
would be in development that have to be used much
3
less frequently or better cure rates if they use
4 more frequently, so dose response I think
would be
5
very important because we have no gold standard.
6
DR. CANTILENA: Thank you.
7
Dr. Wilkerson.
8
DR. WILKERSON: I just wanted to
say I did
9 my
homework before I came, and went to the grocery
10
store, you know, a drugstore, and looked at the
11
over-the-counter antifungal products that were
12
there. Even as someone who I
think is relatively
13
sophisticated as far as these things, I was
14
confused by everything that was out there.
15
I thought part of the gist or thrust to
16
this was to maybe bring some comparative value for
17 the
consumer to the table, such that the consumer
18
could be guided on something beyond packaging and
19
advertising claims as to which agent to pick,
20
because when you go in there to look, I like the
21
question a while ago, even using the same brand
22
name, you are talking about two totally different
339
1
antifungal agents, it is very, very confusing.
2
My recommendation would be a simple analog
3
scale, much like what we have done with the
4
psoriasis drugs with the biologic compounds, is
5
that we set a minimal efficacy level and allow that
6 to
be used as the standard, whatever it be, 60
7
percent or whatever, so that consumers can actually
8
compare between different products.
9
If I pay X dollars for this,
I will get
10
this level of potential cure versus paying $3.00
11 for
this generic that will give me this potential
12
level of cure.
13
I think there has to be some, you know,
14 and
even amongst physicians, most physicians'
15
choices are based upon who the last rep was that
16 was
in their office, that they remember their name.
17
There is very little science that goes into picking
18
these antifungals on the consumer or on the
19
physician level.
20
As far as the basic pharmacology, to me,
21
this is just a slam dunk. I mean
if you are going
22 to
put a drug on the market, you need to know the
340
1
pharmacology of it.
2
DR. CANTILENA: Dr. Benowitz.
3
DR. BENOWITZ: I would say first
that I am
4
sympathetic to the idea that if you have a good
5
animal model, and you know pharmacokinetics and
6
mechanism of action, that you can simplify the
7
process and reduce the need to do dose response
8
studies.
9
However, I don't think we are there, but I
10
think we should try to get there.
So, some of the
11 things
that I would suggest, for example, is that
12
guinea pig data really be analyzed in a systematic
13 way
and brought to FDA to see how predictive it
14
really is based on what we know from a whole
15
variety of current agents, and see how good that
16
test is.
17
I think we need PK data including things
18
like both concentrations in skin and also
19
persistence. It was of interest
to me that
20
terbinafine, I guess is the one persistent in the
21
skin for up to 5 weeks after the end of
22
administration. I think that is
what I heard, and
341
1
other drugs don't do that, and that obviously is a
2 key
factor when you are dosing something, how long
3 it
stays in the skin.
4
It is going to influence what level you
5
build up. So, I think it's a
potential in the
6
future, if we really got good PK data, good skin
7
concentration data, good persistence data, and good
8
animal model, but until we do that, I think we need
9 to
have dose response data.
10
DR. CANTILENA: Dr. Wood.
11
DR. WOOD: Could I just add to
Neal's
12
comment, and I think we need to be pretty careful
13 of
the animal model. The animal model, from
what I
14
have heard, is, by definition, fundamentally
15
different from the human model.
16
The animal model is self-curing, the human
17
model is not, so mechanisms of action that might be
18
effective in the animal model, that would
19
accelerate the self-cure, and would probably not be
20
effective in humans, so I think the confidence in
21 the
animal model is, from what I have heard,
22
grossly overstated right now.
342
1
We know that it does not reproduce what we
2 see
in humans, and that is something we need to be
3
careful about.
4
DR. CANTILENA: Dr. Davidoff.
5
DR. DAVIDOFF: That really needs a
point
6 of
clarification, and that is, are we talking about
7
clinical dose ranging studies or animal dose
8
ranging studies, or both.
9
DR. CANTILENA: Clinical.
10
DR. DAVIDOFF: Okay.
11
DR. CANTILENA: Dr. Bisno.
12
DR. BISNO: Help me out as a
13
non-dermatologist, because I am not sure what we
14 are
talking about in terms of the endpoints here.
15 Are
we talking about negative mycology, effective
16
treatment, or complete cure?
17
Particularly, I don't understand complete
18
cure when you have eradicated the fungus, you have
19
effectively improved the patient's symptomatology,
20 and
there is a tremendous gap between that and
21
complete cure, what is in that area, are those just
22
some residual scaling and flaking, and things like
343
1
that, that are maybe of no clinical significance at
2
all.
3
So, if some of my dermatologic colleagues,
4 who
understand this a lot better than I, can
5
explain what that big gap is and is it worthwhile
6 to
shoot for complete cure when even the best stuff
7
that we have now is getting 20 percent cure, and we
8
seem to be curing it mycologically and in terms of
9
symptomatology, is that a reasonable standard to
10
set.
11
DR. CANTILENA: Comments from the
12
dermatologists?
13
DR. KATZ: Well, simply the
difference
14
there is clinically improved, in plain English,
15
improved, or completely clear, and improved is very
16
subjective and it is less of an endpoint, because
17 it
is subject to the investigator, who may be
18
biased since he is doing the study for the drug
19
company, and it is compared to placebo, which is a
20
necessity, but in plain English, what they call
21
"effective" is improved, which is important, and it
22 may
be important enough to some people.
344
1
In fact, in real life, I check patients
2
back, and, well, how is that doing, that topical
3
treatment doing, oh, that is fine, that cleared me
4 up,
and to go along with what Dr. Elewski said, I
5
said, well, let's have a look, and you look and
6
it's 50 percent better. I
wouldn't have thought it
7 was
that great. So, that is the difference.
8
DR. CANTILENA: Dr. Schmidt.
9
DR. SCHMIDT: I think that these
funguses
10
itch like the devil, and they are almost like an
11
insect bite, like a mosquito bite, and most people,
12 and
I think these medications work very, very well
13 and
very, very fast for the most part, and most of
14 my
patients, I don't want to see them back and look
15 at
their feet again.
16
So, what I do is I usually tell them to
17 use
one of these things, and when I see them again,
18
what they do is use it for four or five days and
19
then they stop, but I don't even wish to cure them,
20 I
don't think I can. I think that every
six
21
months, or when it gets hot every summer, I tell
22
them you are going to have to use this stuff again.
345
1
So, I think it's a pipedream, you know,
2
that basically, at least in Houston and the Gulf
3
Coast, you know, maybe up here in Yankeeland, you
4
know, that you are going to do it, but I don't
5
think so down where we come from.
6
DR. CANTILENA: Thanks for
clarifying
7
that.
8
DR. GHANNOUM: I just would like
to
9
clarify something of the animal model and put it
10
into perspective. I think what
our colleague said
11 is
very true. It is a good idea to bring
all the
12
data together and see how predictive is this model,
13
number one.
14
Number two is this is not a model which is
15
going to replace any clinical data.
It is a part
16 of
the puzzle. A lot of the time, in the
17
preclinical stage, you take a compound, you test it
18 in
vitro. It works great.
19
You go move into the animal model, whether
20 it
is for systemic infections or whether it is
21
superficial infections, and the drug does not do
22
anything. So, I think it is a
method of another
346
1
stage for screening of the compound to determine
2
whether it works or not.
3
Now, once that is clarified, and then also
4 it
is going to help the manufacturers to test a
5
number of things, to allow them to have some basis
6 for
moving into humans. Once they move into humans,
7
obviously, they have to look at, you know, again, a
8 lot
of the drugs fail once you move from animals to
9
human, so that is really where I would like to
10
clarify.
11
DR. CANTILENA: All right. Dr. Epps.
12
DR. EPPS: I think it would be
useful, not
13
only for dose response, but also for efficacy, to
14
have that kind of information. I
like the
15
head-to-head studies, I think that is interesting
16 to
compare drugs. I agree there is no real
17
standard, and I think individual response can vary.
18
As far as guinea pigs, you know, we are
19 not
talking about IV or oral medication, we are
20
talking about cream on feet, and I think it is
21
pretty straightforward and easy.
Obviously, we go
22
through the phases that we should, but I think the
347
1
hazards are fewer when we are talking about feet.
2
DR. CANTILENA: Comments? Over here, Dr.
3
Alfano.
4
DR. ALFANO: I think Dr. Bisno hit
on one
5 of
the key issues, maybe the pivotal issue, and
6
that is what are we expecting in complete cure. I
7
think it is, in some ways artificial and
8
potentially misleading.
9
As I think through OTC categories and try
10 to
design what would be a complete cure, you think
11 of
acne, you think of psoriasis, gingivitis,
12
dandruff. You know, for the most
part, we don't
13
achieve complete cures in any of those conditions--
14
DR. CANTILENA: How about
headache?
15 DR. ALFANO: --whether they are managed Rx
16 or
OTC. So, it seems to be an artificial
17
constraint that is compromised, his point about,
18 you
know, if the symptoms are mitigated and the
19
organism is gone, what are we talking about.
20
I think there should be a more appropriate
21 way
to view how we see this category going forward.
22
The second comment I had is actually a
348
1
question to the dermatologists. I
mean is there
2
something in between an animal model and to full in
3
vivo use studies. I am thinking
going back to the
4
Layden chambers or even organ culture in which skin
5 can
be obtained in cultured foreskin, for example,
6
which would be perhaps a more relevant model and
7
allow for some of the type of analysis that FDA is
8
looking for to help with the dose ranging, and so
9
forth.
10
I haven't heard it mentioned at all today,
11 and
I don't know if it has fallen into disfavor or
12
whatever, but there was a time when I mean you can
13 do
permeability studies and find out about dermis
14
penetration.
15
I know, for example, a cadaver skin
16
actually behaves very much like live human skin, so
17
there do seem to be other mechanisms that could be
18
brought to bear on this problem.
19
DR. CANTILENA: Any comments from
the
20
dermatologists? Dr. Wilkin, do
you have any
21
experience with those other models?
22
DR. WILKIN: I think this bears on
the
349
1
notion of bioavailability for topical products and
2
bioequivalence. When one is doing
a comparison of
3
bioavailability of, say, a new product versus a
4
reference listed product in the setting of a 505(j)
5
Ananda [ph], a generic, or perhaps a 505(b)(2), the
6
relevant part of our regs is 320.24(b)(4), which
7
says that it is a topical trial, that is, it is a
8
regular clinical trial, and you look at regular
9
clinical endpoints.
10
The rationale for why that is different
11
from the drugs that are given systemically is there
12 you
have systemically, you have the blood, which
13 may
not be perfectly mixed, but is, if you will,
14
well mixed, and it's in equilibrium at some point
15
with the organ site.
16
There is no comparable sampling site, no
17
compartment, if you will, in the skin, and often
18 the
way the drug is extracted from different levels
19 in
the stratum corneum, it is not even clear
20
whether it was in solution at the time it was
21
extracted, and we know that drugs are not active
22
unless they actually are in solution.
350
1
So, we haven't figured out a really good
2
way, but when we do, that is going to dramatically
3
lower the current burden that is out there right
4 now
for all the generic topical drug products.
So,
5 we
are keen on hearing a good way to approach that.
6
DR. CANTILENA: Thank you.
7
Mr. Kresel.
8
MR. KRESEL: I just wanted to
comment on
9 Dr.
Katz's comment about bias, because for one
10
thing, we really don't encourage bias, we are quite
11
adamant about not wanting bias, and there really
12
isn't an incentive on the part of an investigator
13 to
be biased, financially or otherwise, since they
14 get
paid whether the study fails or not.
15
However, it is one of the reasons why we
16 do
placebo-controlled studies, because they are
17 double-blind and placebo controlled, and if
18
everybody gets better, then, in fact, you didn't
19
beat placebo and your drug just failed.
20
So, I think it is one of the reasons why
21 we
don't like to introduce active controls, because
22 if,
in fact, your control is active and everybody
351
1
gets better, then, your drug does get approved.
2
DR. KATZ: I didn't mean that in a
3
pejorative way. We are all biased.
I just mean
4
that in a normal way, that is why we have placebos
5 in
the first place.
6
DR. KRESEL: If everybody gets
better,
7
then, you didn't beat placebo, your study fails
8
anyway, your product doesn't get approved.
9
DR. KATZ: I understand that, but
that is
10 why
we have placebos in the first place, and my
11
comment was only in response to the fact that this
12
intermediate state of effective can mean different
13
things to different people, so if we have placebos,
14
like we do, we can see the true effectiveness of
15 the
medication. I was just meaning that in
16
contrast to complete cure. I
didn't mean it in a
17
negative manner.
18
DR. CANTILENA: Yes.
19
DR. WILKIN: I was going to make a
comment
20
about the active comparator.
There is also a
21
document signed by President Clinton, Vice
22
President Gore, 1997. It is
called Reinventing
352
1
Government.
2
There is a section regarding drugs. On
3
page 27 of that, it points out those circumstances
4
where we would use an active comparator, and that
5
would be for indications which are severely
6
debilitating or life-threatening.
So, that would
7 be
the setting.
8
In other settings, it is clear-cut.
It
9
said generally in other settings, an active
10
comparator would not have to be in the mix.
11
DR. CANTILENA: And that is on
what page
12
again? No. All right.
It's very impressive.
13
Why don't we go to Item No. 2 then, Issue
14 2,
in the form of a question for the committee
15
then, under Clinical Efficacy.
16
Given the efficacy of products currently
17
marketed, should topical antifungal drug
18
development programs for tinea pedis evaluate
19
safety and efficacy at different concentrations,
20
dosing durations, and dosing frequencies?
21
Basically, exposure, you know, response,
22
which is what we have been talking about.
353
1
We will start over here if non-voting
2
members would like to comment, and then we will
3
head around, and if you can justify your answer or
4
just yes or no, and I voted that way because, that
5
would be fine.
6
MR. KRESEL: In order to be
consistent
7
with what I have said before, dosing duration I
8
think is the one area that we could probably look
9 at
and get some data that would be useful to
10
clinicians, so I would vote yes for dosing
11
duration, but not dosing frequency or dosing
12
concentration.
13
DR. CANTILENA: Dr. Alfano.
14
DR. ALFANO: I don't vote. I would
15
certainly agree with the comment, and I am glad Dr.
16
Wilkin clarified, because I was sitting here all
17
morning wondering why FDA can't get this
18
information that they are asking for.
19
Many years ago, when I used to be in the
20
industry, it seemed to me FDA got whatever they
21
wanted, so I now understand why some of this data
22 is
not available to you.
354
1
DR. CANTILENA: Dr Ten Have.
2
DR. TEN HAVE: Yes, especially
with
3
respect to non-responders.
4 DR. CANTILENA: Dr. Wood.
5
DR. WOOD: Yes.
6
DR. CANTILENA: Dr. Bisno.
7
DR. BISNO: Yes.
8
DR. CANTILENA: Dr. Ghannoum.
9
DR. GHANNOUM: I agree with dose
duration.
10
DR. CANTILENA: Dr. Katz.
11
DR. KATZ: Yes.
12
DR. CANTILENA: Dr. Schmidt.
13
DR. SCHMIDT: Yes with the dose
duration.
14
DR. CANTILENA: Dr. Davidoff.
15
DR. DAVIDOFF: Also yes, and also
with the
16
main focus on duration.
17
DR. CANTILENA: Dr. Whitmore.
18
DR. WHITMORE: Yes with the dose
duration
19 and
frequency, and with regard to concentrations,
20 if
we are requiring MICs to be done, I guess we
21
don't need the different concentrations, like, for
22
instance, if something like tea tree oil gets
355
1
proposed for a treatment, I think in that case, you
2
would need if they came up with it, I don't know,
3 but
I think with products that are not established
4
antifungal chemicals like the current ones we have,
5 you
would need different testing with different
6
concentrations.
7
DR. CANTILENA: Thank you.
8
Dr. Fincham.
9
DR. FINCHAM: Yes for all, and
while I
10
have the mike, it's a naive question or statement,
11 but
when you talk about these FDA regulations, and
12 you throw out these numbers and the letters, I
13
don't have a clue what you are talking about. You
14 are
intimately involved with this on a day-to-day
15
basis, but if you could just give us a simple
16
explanation of what those are, it would help me
17
immensely, and thank you very much for allowing me
18 to
say that.
19
DR. CANTILENA: Well, actually,
you didn't
20 ask
me if you could say that.
21
[Laughter.]
22
DR. CANTILENA: That was actually
in the
356
1
orientation packet that you got for the advisory
2
committee, it's all the regulations and all the
3
numbers.
4
DR. WHITMORE: I think all the
numbers
5
were just citations of the locations.
They don't
6
mean anything to us, but they are just citations of
7
where this is.
8
DR. FINCHAM: My comment still
stands.
9
DR. WILKIN: I may have said
CFR. It is
10
true, we tend to talk in a lot of alphabets. Code
11 of
Federal Regulations is basically what Congress
12 has
given us, how to actually interpret the '38
13
Act, and it does have a lot of interesting nuggets.
14
It is available electronically
on the FDA
15 web
site. If you jot those down or I could
mention
16
them to you afterwards, there are some good places
17 to
look, because the exact wording is pivotal to
18
industry. I know they really read
those lines very
19
carefully, and we do, as well, and they have
20
enormous constraints ultimately on the information
21 set
that comes into FDA, so they are not trivial.
22
ICH, I may not have mentioned that, I
357
1
think it is International Conference on
2
Harmonisation. It is
Harmonisation with an "s" at
3 the
end, so it's not totally harmonized with
4
American English, but it is Japan and Europe, and I
5
think Canada is involved, and it involved
6
academics, government regulators, and industry all
7
coming to the table and deciding what were some of
8 the
common ways that everyone can look at it in
9
different geographic regions with the idea that
10
someday we might be able to have NDAs that are
11
submitted simultaneously in different countries, so
12 I
think it is a positive sort of step, and I
13
apologize.
14
DR. CANTILENA: Dr. Ringel.
15
DR. RINGEL: I would say yes. Just one
16
further comment that if, in fact, we can't get an
17
active control group when doing these studies, I
18
would think that at the very least we should be
19
able to have some minimal standard of efficacy.
20
Perhaps that would be allowed by the regulations.
21 I
think it's CFR 43.154.
22
[Laughter.]
358
1
DR. CANTILENA: I think you just
quoted
2 the
Drug Enforcement Agency, but I am not sure.
3
Dr. Lam.
4
DR. LAM: Yes for duration and
frequency.
5
DR. CANTILENA: Dr. Patten.
6
DR. PATTEN: Yes for all three.
7
DR. CANTILENA: Dr. Wilkerson.
8
DR. WILKERSON: Yes.
9
DR. CANTILENA: For all three?
10
DR. WILKERSON: For all three.
11
DR. CANTILENA: Dr. Raimer.
12
DR. RAIMER: I wouldn't care too
much
13
about concentrations as long as we had good,
14
reliable MICs. I think dosing
duration is very
15
important. Dosing frequencies, I
agree, it is
16
probably going to be once or twice a day unless the
17 company
wanted to go for something like once a week
18 for
a month or thought they had something they
19
could market. I don't think it
matters whether you
20 put
it on once or twice a day to most patients.
21
DR. CANTILENA: Dr. Epps.
22
DR. EPPS: Yes for all three, and
I guess
359
1 as
a point of information, and thanks to CDER,
2
under Tab 6 are some of the CFR and definitions.
3
DR. CANTILENA: Dr. Clapp.
4
DR. CLAPP: Yes for all, but my
concern is
5
about standardization of efficacy.
6
DR. CANTILENA: Dr. Benowitz.
7
DR. BENOWITZ: Yes for all three,
but I
8
would just emphasize that the concentration issue,
9
which many members felt did not have to be tested,
10 I
think in theory, that could be defended, but I am
11 not
convinced that the data presented to date
12
adequately defend not testing different
13
concentrations.
14
I think it is possible, but I don't think
15 it
is done, and I think it is the obligation of a
16
sponsor to do that before we accept not testing
17
different doses.
18
DR. CANTILENA: Thank you.
19
Ms. Knudson.
20
MS. KNUDSON: I will say yes to
all three,
21 and
I would like to say that as a consumer, I would
22
certainly like to see comparative trials done, and
360
1 I
don't care whether a tube of this medication only
2
cost $8.00, to some people, that is really a very
3
important figure.
4
DR. CANTILENA: Thank you.
5
My vote is yes to all three. I
think
6
exposure response is important, and it just
7
improves the overall use of the product.
8
The tally, please?
9
LCDR SPELL-LeSANE: To Question
No. 2, 19
10
yes, all yes, no "no."
11
DR. CANTILENA: Thank you.
12
I think really what I would like to do is
13 you
didn't ask us a question per se for clinical
14
efficacy, lowest acceptable rate of care, so what I
15
would like to do is just open this for discussion
16 and
see if we can drive toward a consensus.
If
17
not, then, we can do a vote on this, but this would
18 be
Item No. 1, where we are looking for the lowest
19
acceptable rate of cure, clinically meaningful, for
20 a
topical OTC drug product for the treatment of
21
tinea pedis, using the complete clinical and
22
mycological clearance as definition of "cure."
361
1
Really, what is the lowest that you would
2 be
comfortable with for a cure rate, you have
3
something that is effective.
4
I will just open it up for discussion.
5
Dr. Lam.
6
DR. LAM: Are we lumping 1-week
regimen
7 and
4-week regimen together into our consideration
8 and
deliberation?
9
DR. CANTILENA: I was, but we will
ask Dr.
10
Ganley or Dr. Wilkin, can we lump the 1- and the
11
4-week for acceptable cure rate?
Are you looking
12 for
a cure rate irregardless of duration of
13
treatment? Yes, okay, so we are
lumping.
14
So, what is a number that meets your
15
definition of an acceptable cure rate in this
16
setting? Dr. Wood.
17
DR. WOOD: I am not going to give
you a
18
number, but let me raise an issue that came up from
19 the
homework.
20
It seems to me that if you are a consumer
21 and
you are about to make the decision as to
22
whether you should buy a product to treat some
362
1
disease, you want to know what the likelihood that
2 you
are going to respond is, but you also want to
3
know what other options are out there.
4
Now, in an Rx situation, you expect your
5
physician to do that, you expect your physician to
6
look at you, make the diagnosis, and decide what
7 the
optimal therapy is.
8
In an over-the-counter situation, it seems
9 to
me that the consumer ought to have information
10 on
the cure rates which are substantially higher,
11 and
with systemic therapy that are available with
12
these.
13
I think that should be in the package
14
labeling, because that seems to me a critical piece
15 of
information that people ought to know.
16
Somebody said a minute ago, you know, if
17 you
are buying $8.00 tubes of something, and you
18 are
getting nowhere, for many patients, the
19
decision to go to a dermatologist would be a huge
20
decision for them, and their loins would be girded
21 if
they knew that there was a likelihood that the
22
doctor could provide the therapy that would be more
363
1
effective.
2
DR. CANTILENA: Dr. Bisno.
3
DR. BISNO: Again, i want to make
sure
4
that I understand what we are discussing here. Are
5 we
discussing the complete cure for which the
6
general data are about 20 percent, because it says
7
"complete clinical and mycologic cure," so you are
8
asking what is the lowest acceptable rate for
9
complete cure in which the general data are about
10 20
percent?
11 DR. CANTILENA: I think that is what they
12 are
asking, yes.
13
DR. BISNO: I am a little bit
blown away
14 by
that, because the only colleagues I have that
15
think that 20 percent is a great rate are my
16
oncologic colleagues, who really have to deal with
17
some very, very life-threatening infections.
18
If the best we can do is 20 percent, I am
19 not
sure that we should be sitting around here in
20
this room, I am not sure what we are accomplishing.
21 My
personal view, and again I am reluctant to
22
express this, since I don't have the requisite
364
1
dermatologic expertise, but I do see a lot of
2 inflammatory
conditions and I know that after you
3
have cured the infection, and after you have
4
eradicated the organism, it takes a long time for
5 the
physical manifestations of inflammation to go
6
away.
7
Therefore, I wonder, you know, if somebody
8
came up with something that was a combination of
9
terbinafine and then used the last week, steroids,
10
that he might really get a much higher clinical
11
cure rate because would inflammation would subside
12 and
it would look great, but I am not sure it is
13
something we would want to be doing on a routine
14
basis, maybe we would.
15
Anyway, I just have difficulty with
16
setting a lowest acceptable range for complete cure
17
when we know that the bar right now is set at only
18 20
percent, and is it possible that we can talk
19
about lowest acceptable cure rate for mycologically
20 and
symptomatically improved, or is that not an
21
acceptable thing to be discussing?
22
DR. CANTILENA: I will ask Dr.
Wilkin
365
1
because it's advice for him and Dr. Ganley.
2
DR. WILKIN: I think it can be
approached
3 in
multiple ways. The truth is that we do
not know
4
which patients who are effective treatment meaning
5
KOH-negative and culture-negative, but having a
6
1-plus erythema or 1-plus scale, or maybe both of
7
those, how many of those really that scale and
8
erythema is due to residual tinea and how much is
9 due
to some other condition, maybe just inadequate
10
epidermal turnover.
11
Our thought was that while it may be
12
conservative, and I think it is conservative,
13
looking at the complete cure population, it still
14 may
not be complete cure, because there may be some
15
KOH's that they couldn't find it, and some cultures
16
that they couldn't find it, so people still get
17
into the complete cure, and still have--I mean
18
these are all very imperfect ways of looking at it,
19 but
I think Dr. Bisno makes an important point.
20 You
probably wouldn't want to be going for 100
21
percent.
22
I think that is the essential point, is
366
1 100
percent is not the target, because it is
2
probably going to be hard to get there.
Another
3
example of what you are describing is if you look 3
4
weeks after treating a pneumonia, at the chest
5
x-ray, you would still see, you know, maybe what it
6
looked like at the beginning.
7
So, I think that is the way it is with the
8
foot, the epidermis is not going to turn over, but
9 the
idea of the complete cure at least is something
10
that is--it is somewhat artificial, but it is a
11
very clear endpoint.
12
DR. BISNO: First of all, just
finding
13
mycologic elements, again, I mean the clinical
14
situation may have been completely resolved, but,
15 you
know, fungi are universal and it may be
16
difficult to completely eradicate even if you have
17
eradicated a clinical--but I am getting beyond my
18 own
area of expertise by far.
19
But what I am saying is if we set 25
20
percent or 30 percent as an acceptable cure rate,
21
then, we don't have anything on the market right
22 now
that meets our executive cure rate, is that
367
1
correct?
2
DR. WILKIN: Well, you have Dr.
Fritsch's
3
example. What page is that on?
4
DR. CANTILENA: It's Tab 4, page
2, for
5 the
complete cure rates.
6
DR. WILKIN: The complete cure at
the
7
time. This is now, again, Week 6
to 9, so in 6
8
weeks it has allowed for substantial epidermal
9
turnover. This is like waiting
for many months
10
before you get the chest x-ray.
11
DR. WHITMORE: I have a
question. This
12
addresses labeling, and not what we are saying the
13 FDA
should be approving, right?
14
DR. CANTILENA: I think actually
we have
15 on
sort of the next category, we will be talking
16
about the labeling. Here, I think they are asking
17 for
really, you know, in terms of a complete cure
18
rate, what is something that is meaningful from our
19
standpoint for an approvable drug.
20
So, like if you had a new drug under
21
development, what would you like to see, and I
22
think the ideas earlier about the active control
368
1 are
important.
2
I think that sort of gives you a
3
reference, you can have vehicle only and an active
4
control, and that really sort of tells you exactly
5
where you are, but are you able to ask for those,
6
active control, and placebo, is that something that
7 is feasible, or is that advice that really
couldn't
8 be
followed?
9
DR. WILKIN: Again, if it's for an
10
indication that is not life-threatening or severe
11
debilitating, typically, it's against the vehicle
12 or
the placebo, and not against an active.
I mean
13
that just has been the standard.
14
I think I missed a response to one of Dr.
15
Bisno's points, and that is, you know, what should
16 the
committee be looking at. It would be I
think
17
acceptable to look at maybe something that is less
18
conservative, the effective treatment, realizing
19
that some of the people who have effective
20
treatment are clearly going to have some fungus
21
remaining.
22
None of these are perfect ways of
looking
369
1 at
it, but if the committee felt more comfortable
2
characterizing the endpoint, the lowest acceptable
3 in
terms of effective treatment, we would be happy
4 to
hear it either way.
5
DR. BISNO: Well, I would
certainly bow to
6 the
expertise of my dermatologic colleagues on this
7
one. I am out of my depth.
8
DR. CANTILENA: We actually have a
list
9
going here. We have Epps, Katz,
Fincham, Wood, and
10
Davidoff.
11
Dr. Epps.
12
DR. EPPS: I guess speaking
clinically,
13 the
patients, we don't see the ones who do well,
14 the
ones who go to the drugstore, they get the
15
cream, they are treated, and it works well. The
16
ones who are referred to me, and when we say
17
"fail," I mean it looks like baseline. It is still
18
raw, it is still macerated, they are still
19 fissuring,
it is not like it is just a little pink,
20
otherwise, they wouldn't come to the dermatologist.
21
If it is getting better with the
22
over-the-counter, they keep using it, oh, it's
370
1
getting better, I am just going to keep going. How
2
long that is varies by the patient.
3
Percentagewise, I tell a lot of people it's zero or
4
100, it works or it doesn't. I
mean ideally,
5
across the board, I guess I tend to be tough, like
6 I
would like 75, 80 percent, I mean we want it to
7
work, that is what I would call most.
8
I don't think "most" is equivalent to
9
better, because we are not comparing drug to drug,
10 but
certainly it should be better than vehicle, it
11
should be better than placebo, obviously, that is
12
proven.
13
As far as culturing, by the time we get to
14 the
subspecialist, you know, they are partially
15 treated,
it's not very useful, you may still get a
16
KOH, sometimes that can be helpful, but a lot of
17 the
ones that don't work tend to be weeded out.
18
I mean you use if three or four times, it
19 is
not working, you just don't use that drug
20
anymore, and fortunately, we have a lot of options,
21 but
a lot of the patients, if you ask them--and I
22
guess that goes to reporting--what was the cream
371
1
that you used before, well, it was white, and
2
that's all you can get. They
don't remember the
3
name, they don't remember, you know, well, it was
4 my
friend's, you know, you get a lot of answers, so
5
that clearly affects the reporting of failures, as
6
well.
7
DR. CANTILENA: Dr. Katz.
8
DR. KATZ: Well, the question is
what
9
should we accept as the lowest acceptable rate.
10
Now, it was my understanding from a previous
11
meeting at the FDA that the FDA approves medication
12 if
the safety profile was such that it shows some
13
effectiveness, even the slightest statistically
14
significant effectiveness in the face of pretty
15
complete safety.
16
If that is the case, and you can correct
17 me,
Dr. Wilkin, if that is not correct, that is why
18
things like Penlac, which is almost tantamount to
19
useless, but it is completely safe, and it did show
20 a
slight, after a year, 15 percent of people got
21
better, so that is why it was approved.
I wasn't
22
involved in that. So that was my
understanding.
372
1
Now, if that is the case, then, the answer
2 to
this question should be the lowest acceptable
3
rate in the face of pretty complete safety, should
4 be
good effect over placebo even if it's 20
5
percent.
6
That, seeming somewhat ludicrous, we get
7
into the situation, which we are not answering the
8
question on labeling now, but in answer to Dr.
9
Wood's comment, I don't know that we have to set a
10
certain percentage here if there is truth in
11
labeling.
12
That is going to be another issue, but
13
rather than arbitrarily set the lowest acceptable
14
rate, if something is on the label that says 15
15
percent of patients can expect complete clearing,
16 but
that 50 percent of patients can expect
17
significant improvement, that tells the consumer
18
quite a bit.
19
I know you don't want to get into
20
labeling, but that would be my argument against
21
setting a lowest acceptable rate, if my feeling of
22 the
charge at the FDA is correct.
373
1
DR. CANTILENA: Yes, Dr. Bull.
2
DR. BULL: I would like to bring
your
3
attention to the other part of that statement,
4
which is that the lowest acceptable rate of cure
5
that is clinically meaningful, and I think
6
certainly we want to be in the business on behalf
7 of
public health of approving drugs that provide
8
something clinically meaningful for the patients,
9 who
are either prescribed a drug or the ones for
10
over-the-counter products, purchase them on the
11
basis of self-diagnosis and self-management.
12
So, I think it is very important to attend
13 to
the qualifier that is part of this Question 1,
14
which is what is clinically meaningful, and that
15
what we want your input on is to attend to what is
16 the
lowest acceptable rate that addresses this
17
concern of what is clinically meaningful and
18 patients
having a reasonable expectation of having
19 a
positive effect, a benefit relative to the risk
20 for
their condition.
21
DR. KATZ: Then, perhaps on the
basis of
22
that and Dr. Bisno's comments, this question should
374
1 be
altered, rather than saying our definition of
2
cure, rather that we should use the definition of
3
effectiveness, which means significant clinical
4
improvement and mycologic cure.
Maybe the question
5
should be changed.
6
DR. CANTILENA: As we go around,
you can
7
qualify your answer in that way.
I think that is
8
perfectly reasonable.
9
Dr. Fincham.
10
DR. FINCHAM: I guess just looking
at this
11
from a consumers' perspective, if you have
12
something on the label that says "cures most," I
13
think it would behoove everybody involved, and
14
certainly people are making excellent points about
15
definitions and rates and whatnot, but I think we
16
need to be specific or suggest that it be specific
17 as
far as what those words mean, so the consumer
18 can
make an informed decision in order to be
19
empowered about his or her health.
20
To get to what Dr. Epps said, you know, we
21 saw
slide, several times curiously, from different
22
people, about presentation of interdigital tinea
375
1
pedis, and it looked one way on the screen, but if
2 you
look at the photo, page 4 of the Novartis
3
handout, I would doubt that this patient just
4
appeared at the pharmacy to get this fixed.
5
I mean I would say that there are some
6
serious involvement here. It
looks like there is
7
some nail involvement. What I am
trying to say is
8 a
person like this or a person with a less severe
9
case of tinea pedis should have an informed ability
10 to empower
themselves to make a decision based upon
11
what the labeling says relative to "cures most,"
12
what does cure mean, what does most mean.
13
Again, we are back to semantics.
We are
14
back probably to 3(b), but it is hard to separate
15
these out and look at them one question at a time,
16 and
I just think that the more specific that you
17 can
be, the better it is going to be for the most
18
important person in this whole equation.
It is not
19 us
in the room, it's the patient that is going to
20 use
it or try to use it to get better.
21
DR. CANTILENA: Dr. Wood.
22
DR. WOOD: Well, I am a great
believer in
376
1
letting the marketplace shake these things out. I
2
mean I think the way to handle this is to have
3
people put on the label the efficacy found from
4
that product, defined in whatever common way you
5
want to define that, and that should have on the
6
label and the comparison that can be achieved from
7 an
Rx product.
8
The reason I like that is going back to
9 the
comment that was just made, is what is the
10
minimally clinically significant effect is a moving
11
target. You know, the minimally
clinically
12
significant effect for a diuretic was different
13
when it was a mercurial diuretic from when
14
furosemide came along.
15
So, as therapy improves, what is minimally
16
acceptable, and hopefully improves with it,
17
minimally acceptable, to me, seems different today
18
with systemic and the drugs that have been given
19
systemically produce 70 percent cure in patients
20 who
have been defined as resistant to treatment.
21
So, I agree with what was just said by
22
Jack, I mean I think the consumer should know what
377
1
they are likely to see with the efficacy, and that
2
when Dr. Whitmore, or whoever it was, goes into the
3
pharmacy and picks up these packets and looks at
4
them, he should be able to see the different
5
response rates for the different products, and have
6 some
concept of how that fits with alternatives.
7
DR. DAVIDOFF: I want to be sure I
am
8
clear on exactly why this question is being asked.
9 I
mean I am assuming that it is being asked because
10 the
Agency is trying to decide whether they should
11 set
a threshold level before a drug is approved.
12 Am
I correct? That makes some difference as
to the
13 way
I would answer the question.
14
DR. CANTILENA: Dr. Wilkin, would
you like
15 to
answer?
16
DR. WILKIN: Again, I think there
is a
17
marketing pressure for faster, and faster may mean
18 it
still beats vehicle, but there may be a drop in
19 the
efficacy whether you look at it as complete
20
cure or effective treatment.
21
We are wondering if there ought to be some
22
base rate below which even if you have a product
378
1
that has no major safety issues in the safety
2
profile, whether still there should be that
3
baseline.
4
DR. DAVIDOFF: So, it is an
approval
5
decision question. My thoughts in
that connection
6 are
that if it is an approval question, it seems to
7 me
it would be difficult to justify accepting a new
8
product unless the efficacy rate, whether it is
9
defined on the basis of complete cure or effective
10
cure, that is less than what is on the market.
11
That just seems reasonable to me.
I
12 realize the marketplace maybe speaks
otherwise, but
13 in
terms of regulatory decisions, that seems
14
reasonable.
15
I also recognize, though, that there are
16
other approaches to making the decision.
I mean
17 one
would be to look at what is the absolute risk
18
reduction for other drugs or other classes that is
19
considered acceptable, sometimes expressed as
20
number needed to treat, and number needed to treats
21 in
the range of 5, which is what I understand the
22
complete cure rate here would translate into, are
379
1
considered terrific. I mean a lot
of drugs on the
2
market that have NNTs of 100 or whatever.
3
So, I think that you could
take that
4
approach and say that at least it ought to be doing
5 as
well as most other drugs in terms of NNT, and it
6
clearly would be, I think.
7
The final thought in connection with
8 rationale
would be that I agree with Alastair Wood
9
that it is hard to give a single answer, because a
10 lot
depends on the seriousness of the underlying
11
condition.
12
I think you would accept efficacy of maybe
13 1
percent absolute risk reduction for something
14
that was a fatal disease. I mean
I would be happy
15 to
have a 1 percent chance of being protected or
16
cured if I was otherwise going to die, but if I
17
took the drug, I would have a small chance of
18
survival.
19
If it is a matter of clearing up a rash on
20 my
feet, I might see it differently. I
might be
21
interested in complete cure rates that were In a
22
different ballpark than maybe would have to be
380
1
higher--
2
DR. CANTILENA: But that is the
question,
3
Frank, is higher.
4
DR. DAVIDOFF: Yes, I understand,
and I
5
think that that is a reasonable way to go if the
6
condition that you are treating is less than fatal.
7
DR. CANTILENA: We have Dr.
Ringel.
8
DR. RINGEL: I have two
comments. The
9
first one addresses what everyone is talking about
10 here. Basically, I kind of disagree. I think that
11 the
FDA should use as a standard mycologic cure
12
rather than complete cure or even effective cure,
13 and
the reasons are threefold.
14
First, because at the very least, I think
15 you
should be able to say that you should kill the
16
fungus to an optimal level.
Whether or not the
17
person gets better, I don't know, but at the very
18
least, we should be able to say that the fungus
19
dies. That is number one.
20
The second is that perhaps it is not quite
21 as
straightforward as complete cure, but it is
22
certainly more straightforward than effective cure.
381
1 At
least you can measure it, you could do a KOH,
2 you
could do a culture. I know they are not
3
perfect, but it's doable.
4
The third reason is that I don't know any
5
other antimicrobial agent that is being held to the
6
standards that we are holding tinea pedis. When I
7
treat a patient for scabies, the scabies' mites
8
will be dead the next day or two days perhaps, but
9 I
tell the patient he is going to itch for another
10 two
weeks, and I don't call that ineffective
11
treatment.
12
When someone has pneumonia, they cough for
13
another month. That doesn't mean
that they still
14
have pneumococcus. When they have meningitis, they
15 are
going to feel lousy for the next two months.
16 It
doesn't mean that their CNS is still infected.
17
I think that for those reasons, mycologic
18
cure is actually the better standard here, and I am
19
going to go a little bit out on the limb.
20
I would say that if we are going to choose
21 an
efficacy level, I would choose that of the first
22
modern antifungal, which at least in my mind has
382
1
always been miconazole, and that is very
2
subjective, I realize, but, you know, trained when
3 I
did, I thought of the old antifungals and the new
4
antifungals.
5
I have always thought of the new
6
antifungals as starting with miconazole, so I would
7 say
that the efficacy for mycologic cure should be
8 at
least that of miconazole, and I supposed we
9
could look that up. I know it is
arbitrary, but
10
that is what I would do. That is
the first
11
comment.
12
The second comment is I guess
this is
13
addressing Dr. Wood about whether or not we need to
14
compare topical antifungals to oral antifungals,
15 and
I would I think argue against that for two
16
reasons.
17
First of all, I think most normal
18
consumers would assume that over-the-counter
19
medications are not as effective as prescription
20
medications. It may or may not be
true, but I
21
think that is what people assume.
22
For example, if they get an
383
1
over-the-counter antitopical, antibiotic that is
2 not
helping, they will go to their doctor and say,
3
gee, that didn't help, what else do you have,
4
assuming the doctor is going to have something that
5 is
stronger and better.
6
The other issue is that I think that you
7
can't assume that the safety of a topical
8
antibiotic is going to be the same as the safety of
9 a
systemic antibiotic.
10
I don't think that people should assume,
11
well, I can just go the doctor and do better,
12
because the systemic antibiotics have black box
13
warnings for liver toxicity, for congestive heart
14 failure,
and also have significant hematologic
15
toxicity, so I really don't want my patients going
16 to
the drugstore and say, hey, well, I can just get
17
Sporonox.
18
I don't think that is good. I
would
19
rather have them approach it the way I think most
20
people do, when you are first looking at
21
over-the-counter, if that doesn't help, then, going
22 to
their physician for a prescription.
384
1
DR. CANTILENA: Dr. Schmidt.
2
DR. SCHMIDT: Looking at the data
that has
3
been presented today and thinking about skin
4
diseases just in general, when I have patients come
5 in
with a lot of these skin diseases, like acne, I
6
usually consider a good improvement, say, for acne,
7 at
about 20 percent per month, and usually, someone
8
after about 3 months, I like to see about, say, 75
9 to
85 percent clearing.
10
To me, I think these antifungal agents are
11
much more effective than some of the medications
12
that we use for acne, so in looking at these
13
graphs, I would say that what I would put down for
14
this, if you want some hard data, is between 20 and
15 30
percent improvement in a week or two, and then I
16
think the bar should be about 75 percent after a
17
month for all these topical antifungals.
18
I think that, to me, you know, 75 percent,
19
that is a magic number in my mind, maybe more in
20
acne, eczema, but if you had to say from what you
21 see
in these studies, you know, with the 20 to 30
22
percent, and then it bounces up with some of the
385
1
others, that that is the bar that I would say if we
2 are
looking for numbers.
3
DR. BISNO: Do you mean
symptomatic in
4
mycologic, but not complete?
5
DR. SCHMIDT: Yes.
6
DR. CANTILENA: Dr. Ghannoum.
7
DR. GHANNOUM: I think the way,
let's say,
8 we
look at other antifungals, like it was suggested
9 it
would be good to have a comparator,
10
non-inferiority sort of cases. We
don't have that
11
because we don't have gold standard.
12
But I think we have what is available in
13 the
market, and I think that should be for complete
14
cure, and if say like "assume," it is
15
non-inferiority, it should be between 20 to 30
16 percent.
17
If we go into the effective cure, even if
18 you
look at the oral stuff, let's say Lamisil
19
compared to Sporonox when they are compared for
20
onychomycosis, it was 65 percent sort of cure, so I
21
think that is reasonable for the effective cure.
22
DR. CANTILENA: Thank you.
386
1
Dr. Wood.
2
DR. WOOD: I think we should
answer this
3
question the way we are doing it.
I think I
4
understand now what Dr. Wilkin is asking us, and it
5
seems to me that the question we are being asked is
6 how
we evaluate products, and everybody rushing to
7 the
bottom, and that everybody moves to the bottom
8 of
the pack and finds the lowest dose that they can
9
give for the shortest period of time, anything that
10
beats placebo.
11
Now, I think we answered that already, and
12 I
think we said that we should see exposure
13
ranging, and I think you should only approve drugs,
14
assuming they have no toxicity, that are given at
15 the
exposure that produces the maximum effect.
16
That gets you off the hook for the rush to
17 the
bottom, which is what I am hearing here, and
18
having said that, maybe surprisingly, I am very
19
opposed to introducing new hurdles that drugs have
20 to
leap to get approved.
21
So, the hurdle is you beat placebo right
22
now, and the idea that we are going to sit around
387
1
here and kind of chew on our thumbs and come up
2
with some arbitrary number that you have to beat to
3 get
approved is very disturbing to me, because that
4
creates all kinds of issues for other drugs, as
5
well, you know, what is it in heart failure, what
6 is
it in Alzheimer's, for God's sake, I mean the
7
effects there are pretty trivial for most of the
8
drugs on the market.
9
So, I think the answer to your problem is
10 I
am telling you that we should look at exposure
11
ranging. I would expect that you
would only
12
approve a drug, assuming the drug has minimal
13
toxicity, as these topical agents do, that you
14
would approve the drug at the dose or exposure of
15 the
drug that produces the drug's maximum effect.
16
As a consumer, that is what I would think
17
when I was standing in the drugstore.
If you do
18
that, then, you are not in this position of this
19
rush to the bottom, because I think that is a very
20
dangerous step to get into.
21
DR. CANTILENA: But how about if
the drug
22
overall is not very effective, it has just barely
388
1
beaten placebo?
2
DR. WOOD: Well, if the drug
overall is
3 not
very effective, I think we should tell people
4
what the efficacy is, and I think if you are
5
standing in the drugstore and you have got three
6
packets in front of you, and one says this is 20
7
percent effective, one says this is 60 percent
8
effective, and one says it is something else, let
9
people choose.
10
I mean if they like the prettier packet
11
that's 20 percent effective or maybe it will be
12
cheaper.
13
DR. CANTILENA: Dr. Epps.
14
DR. EPPS: Brief comments. Certainly when
15
there is a discussion about the movement to
16
decrease the duration, certainly, if we were
17
talking about antibiotics, we would be certainly
18
concerned about resistance. Does
it apply to
19
antifungals? I don't know.
20
Although tinea pedis may not be life or
21
death, certainly, there are quality of life issues.
22 I
have patients who can't walk, they can't go to
389
1
work, they can't go to school because it is so
2
severe. So, I certainly don't
think it is trivial,
3 but
it is certainly not fatal and certainly, to
4
piggyback on what Ms. Knudson said, I think if we
5 are
going to move to approve drugs or have
6
antifungals approved, they should work.
7
Certainly, whether it's $8.00 or $15.00,
8 or
whatever the co-pay is, there should be some
9
reasonable expectation that they are going to
10
benefit from it.
11
DR. CANTILENA: Thank you.
12
I think what I would like to do is for
13
anyone who has not expressed their opinion on this,
14 I
will give you an opportunity yet to do so, but I
15
think we have heard from probably 90 percent, which
16 is
clinically significant, I believe, by anyone's
17
definition.
18
Is there anyone else who would like to add
19 to
the discussion?
20
DR. TEN HAVE: Could we hear from
the
21
consumer representatives on what the consumers
22
would think?
390
1
DR. CANTILENA: Good. We have Dr. Patten
2 and
Ms. Knudson.
3
MS. KNUDSON: I have an
unrealistic
4
expectation that we should have 100 percent
5
effectiveness on anything that is on a shelf. I
6
realize that is unrealistic.
However, I do want to
7 see
some comparisons between anything that is on
8 the
shelf as to what the effectiveness rate is for
9 most
people.
10
DR. CANTILENA: Are you able to do
that in
11
terms of the current regulations, can you put
12
efficacy rates, comparison to like other things
13
that are generic?
14
DR. GANLEY: You wouldn't
necessarily
15
compare something else. You could
be able to put
16 in
cure rates or efficacy rates. The
company who
17
does want to do two comparative studies, comparing
18 it
to another regimen of another drug, and show
19
that they are better than them, they could achieve
20
labeling by doing that.
21
I think that we would have to talk about
22 it
internally, there is some difficulties, because
391
1 we
don't have, particularly for the monograph
2
products, we don't have the consistent types of
3
efficacy endpoints that we have for the NDA
4
products, at least the most recent approvals.
5
DR. TEN HAVE: Then, how can you
set a
6
standard?
7
DR. GANLEY: We would have to go
back and
8
look at the data that was collected.
Nothing is
9
perfect here.
10
DR. TEN HAVE: In terms of
defining the
11
minimum rate, if the efficacy definitions differ
12
across studies--
13
DR. GANLEY: Well, that is the
potential
14
down side, and that goes back to what Dr. Fritsch
15 had
said, is that in some of these studies, they
16 may
have included patients with onychomycosis, for
17
example, which may lead to a lower efficacy rate.
18
So, it is like comparing apples and
19
oranges in some cases. But it may
be that you
20
create categories of efficacy or something, I don't
21
know, I think we would have to talk about it.
22
DR. TEN HAVE: So, is the
implication,
392
1
though, that we need different thresholds,
2
different minimum acceptable thresholds for
3
different categories for these different
4
definitions?
5
DR. GANLEY: No, I don't think so,
but I
6
think that it is what we do with the products we
7
have now and what we decide we are going to do for
8 the
future, so I think that is where we have to
9
really start from, and then set the standard of
10
what we would like to do for the future and see
11
what we can do for the other products that are on
12 the
market right now.
13
Nothing is going to be perfect here,
14
because of that.
15
DR. CANTILENA: I think we also
want to
16
hear from Dr. Patten.
17
DR. PATTEN: I am going to agree
with Dr.
18
Ringel. I would say that, at a
minimum, there
19
needs to be negative mycology. If
anything comes
20 in
without that, then, it seems to me it's an
21
application for something that will manage the
22
condition or decrease severity of symptoms, and the
393
1
concept of cure would be inappropriate.
2
My understanding of this is that this is
3 the
agent that causes the condition. If the
agent
4 is
still there, the condition may recur, will
5
recur.
6
DR. CANTILENA: Thank you.
7
Let's move to the last broad topic area,
8
which has to do with the label.
Actually, I would
9
like to start with the safety issue, which is
10
Question 6, and then we will do Question 3, (a) and
11
(b).
12
I think what I heard this morning, and I
13
apologize, Dr Bisno, if I didn't hear you
14
correctly, but that with regard to safety, it
15
really didn't seem to be a large problem, and from
16 the
AERS database, it doesn't show up in terms of
17
cellulitis.
18
So, I think what the Question 6(a)
19
basically talks about subpopulations, which I would
20
like to hear from everyone. I am
sure we all have
21 an
opinion on if there are specific subpopulations,
22
because if so, then, we will sort of meld that into
394
1 the
labeling.
2
I will open it up for general comments and
3
talk about the risk of secondary infections, and
4
then if there are any subpopulations who are at
5
higher risk, and, if so, should that be in the
6
label.
7
Yes, Dr. Bisno.
8
DR. BISNO: If I may say, I think
the
9
study that needs to be done, probably should be
10
done, is to look at patients who have cellulitis
11 and
particularly those who have recurrent
12
cellulitis, and to grade them on two different
13
factors.
14 One is the severity of their tinea
pedis,
15 and
the other is their coexistent comorbidities.
I
16
think if that study were ever done, we would see
17
that there is probably a small subsegment of people
18
with severe tinea and comorbidities who are
19
probably at much risk of cellulitis and that the
20
general population is not.
21
Lacking those data, my suggestion would
22 be,
what I had in my last slide, although I would
395
1
expand it just a little, I said tinea pedis is only
2 one
of a number of risk factors for the development
3 of
lower extremity cellulitis, but it is one of the
4
most modifiable of such factors.
5
The committee might wish to add a caution
6
about the importance of eradication of tinea pedis
7 in
patients with such risk factors as lymphedema,
8
venous insufficiency, edema of the legs, marked
9
obesity, saphenous venectomy for coronary artery
10
bypass graft, or previous episodes of cellulitis.
11
It might be worthwhile to add
12
immunosuppression there, too, immunosuppressed
13
patients, and although the data on diabetes are not
14
clear-cut, I wouldn't object if you wanted to add
15
diabetes, too.
16
That would be my suggestion, to just have
17
something on there that says that tinea pedis is a
18
risk factor for cellulitis particularly in this
19
group of patients, and they should take particular
20
care to eradicate their condition.
21
DR. CANTILENA: Thank you.
22
Other comments? Dr. Benowitz.
396
1
DR. BENOWITZ: I think we need a
2
clarification of what the issue is here.
One
3
issue, if tinea infection predisposes to
4
cellulitis, then, we should treat them.
5
The question would be if you are at high
6
risk of cellulitis, should you use oral instead of
7
topical, because it is more effective.
I mean that
8
would be one question.
9
Or is there a concern that if you have
10
cellulitis, you are not being treated for
11
cellulitis adequately, because you think it's
12
tinea, and you are being treated for that instead.
13
So. those are the problems, but I am not
14
sure what the intent is of special labeling. We
15
should effectively treat someone if they are
16
infected, right?
17
So, my question is what is the purpose of
18 the
special label?
19
DR. BISNO: The question that was
raised
20 by
the committee and to me specifically is what
21
recommendation I could make regarding the issue of
22
cellulitis and tinea pedis, and my feeling was that
397
1
there are certain subgroups of people who are at
2
higher risk, and that it would be prudent and
3
feasible to identify those.
4
We are not telling anybody not to treat
5
tinea pedis, but we also know tinea pedis is
6
extremely common and in many cases, go untreated
7
unless they are highly symptomatic.
8 DR. BENOWITZ: I understand that, but in
9
terms of the labeling for a product to treat tinea,
10 the
question is if you have this, make sure you
11
take this product?
12
DR. WHITMORE: I think this is not
a
13 consumer information product. I think this is a
14
physician education product, and those patients who
15 do
have these risk factors are being seen by a
16
physician, so it actually is the responsibility of
17 the
physician to look for tinea pedis.
18
You can bet that the majority of the
19
people with those predisposing factors probably
20
have fungus on their feet, too.
21
DR. CANTILENA: Dr. Alfano.
22
DR. ALFANO: I am concerned about
changing
398
1 the
label for a potential effect that has occurred
2 at
such a low, ultra-low rate. I mean we
learned
3
this morning that we are really now talking about
4 hundreds of million of doses, of treatments,
and we
5
have 13 cases reported, and as Dr. Bisno pointed
6 out
this morning when he reviewed those cases, most
7 of
them didn't seem to him to be cellulitis in any
8
case, they seemed to be allergic reactions.
9
We have seen the industry propose to add
10
some labeling that would encourage people to seek
11 the
advice of a physician if the condition worsens
12 or
changes in any way, which would be sort of the
13 preamble to cellulitis, so there already is
sort of
14
a--I don't think we need a fix--but there already
15 is
I think a good one that has been proposed.
16
I am very concerned that as we make the
17
label more complicated, it becomes less
18
understandable and more intimidating, and we could
19
actually be discouraging people from using this
20
product, and it could have the unintended effect of
21
decreasing use and increasing risk.
22
So, in the absence of any consumer
399
1
comprehension studies, label comprehension studies,
2 I
just wouldn't go near this particular one for
3
such a seemingly inconsequential risk.
4
DR. CANTILENA: Dr. Schmidt.
5
DR. SCHMIDT: We are seeing more
cardiac
6
surgery and we are seeing a lot more stasis
7
dermatitis, and a lot more lipodermatosclerosis,
8 and
I think even though these cellulitises of the
9
lower extremities, I don't think they are rare, and
10 I
think that the cases that they presented were not
11
cellulitis, they were contact dermatitis, but I
12
would be interested to hear from the consumer reps
13
because, to me, this does sound like a good idea,
14 you
know, we are doing something for these people.
15
A lot of these people just kind of bang
16
around and then they finally come in with problems,
17
and, to me, to have this on the labeling where
18
someone comes in and they have a fungus, and they
19
read this and they say wait a minute, I do have--I
20 am
wearing my support hose and I did have, you
21
know, they have harvested my veins and now my legs
22 are
messed up, and I am going to start putting this
400
1 on,
because it is a treatment that we can do
2
something about it, whereas, this other stuff, it
3
just happens.
4
So, I vote for this.
5
DR. CANTILENA: Dr. Wood.
6
DR. WOOD: I want to agree with
what Neal
7 and
Dr. Alfano said. We can bog the label
down
8
with so much stuff, and I don't understand the
9
problem we are addressing here. There is no
10
evidence that these drugs produce cellulitis. This
11 is
not hepatic toxicity or some side effect we are
12
trying to identify and tell people to go their
13
doctor about.
14
These people are also at risk for having a
15
heart attack. Why don't we put in
the label, you
16
know, if you get chest pain, be sure to go to see
17
your doctor. These people are in
danger of having
18 a
DVT, if you get calf pain, go and see your doctor
19 and
particularly if you get short of breath. I mean
20
there is no end to this.
21
Unless there is some association between
22 the
drug and some adverse outcome, and that
401
1
informing the consumer will help prevent that
2
adverse outcome, I don't think we should burden the
3
label with a bunch of stuff, that I don't see that
4 it
helps them very much.
5
Maybe I am missing something here, but I
6
have not heard some reason to believe that going to
7
your drugstore, buying an antifungal, it makes you
8
more at risk for cellulitis than you were five
9
minutes before you did that.
10
DR. CANTILENA: It is just the
11
complications if it is unsuccessfully treated, and
12 I
think that is what we don't know.
13
Dr. Davidoff.
14
DR. DAVIDOFF: I understand the
kind of
15
concerns that Alastair and others have had about
16
unduly complicating things. The
problem I have is
17 not
so much the concern of whether or not the drug
18 is
causing the infection, and so on, which it
19
clearly isn't, the problem I have is that patients
20 who
are not clear whether they have a beginning
21
cellulitis or tinea pedis, and if they have decided
22
that it's tinea pedis and start treating it, when,
402
1 in
fact, it really was cellulitis, and the continue
2
treating it because they think if I wait 7 days or
3 4
weeks, or whatever, I am going to be okay, those
4 are
the people I am concerned about.
5
So, I think that the notion of adding some
6
wording about if the condition worsens or if
7
irritation occurs, and so on, it is more than
8
reasonable, because of the issue of difficulty in
9
people's minds in distinguishing what is going on
10 in
their foot, so that is my view on that
11
particular subquestion.
12
I had some comments on some of the other
13
subquestions, too. One of them
was on this issue
14 of
cure rate, because it seems to me that the
15
notion of adding data about cure rates for the
16
different products--
17
DR. CANTILENA: Actually, that is
going to
18 be
coming up.
19
DR. DAVIDOFF: I am sorry, okay, I
will
20
save it.
21
DR. CANTILENA: Dr Bisno.
22
DR. BISNO: I would like to say,
first of
403
1
all, that I am not advocating for this change. I
2 was
asked to make a suggestion for the committee as
3
what could be done about this very difficult and
4
complex issue on which there is not a lot of data,
5 and
this was the best suggestion I could come up
6
with. I am not advocating it one
way or another.
7
But I would disagree, Dr. Wood, with your
8
analysis or your comparison with other kinds of
9
illnesses, because these are illnesses that are
10
distinct risks for these cases of cellulitis, and
11
some of these cases are severe and, at times, even
12
life-threatening, and they are directly related, at
13
least in part, not in total, but in part to the
14
tinea pedis.
15
What is missing is we don't have
16
tremendous great data to indicate--you said topical
17 or
oral--we don't have tremendous data to indicate
18
that either of those would be actually effective in
19
preventing it. It is only an
assumption that if we
20 are
treating with something that is effective
21
against the t. pedis, that we are going to
22
therefore not be having a nidus for the bacteria,
404
1 and
therefore we won't have the cellulitis, but
2
that is a lot of speculation based on no firm data.
3
So, anyway, just to conclude, I am not
4
advocating one way or another, I was asked to
5
suggest what could possibly be said about this, and
6
this is the best I could come up with.
7
DR. CANTILENA: We will have a
comment
8
here from FDA, and then we will actually go around
9 the
table with the vote.
10
DR. WILKIN: One of the things we
learn in
11
advisory committees is how to construct questions
12
better. I think this has been
expanded in a very
13
useful way. I mean I think we
have heard about
14
some other areas other than what our original
15
intent was, but I thought I would just share with
16 you
what the original intent was.
17
We did think that it would be helpful to
18
have Dr. Bisno's experience given his writings in
19 the
literature, and, in part, we saw this paper by
20
Morton Schwartz, Cellulitis. It
is the Clinical
21
Practice section in the New England Journal of
22
Medicine.
405
1
He goes on to say the things to do in the
2
management. You can imagine that
the large part is
3
devoted to antimicrobial therapy, but then when you
4 get
down under Ancillary Measures, he talks about
5 the
local care.
6
The second sentence is, "Interdigital
7
dermatophytic infections should be treated with a
8
topical antifungal agent until they have been
9
cleared. Such lesions may provide
ingress for
10
infecting bacteria"--and then he goes on.
11
"Observational data suggest that after the
12
successful treatment of such dermatophytic
13
infections, the subsequent prompt use of topical
14
antifungal agents at the earliest evidence of
15
recurrence or prophylaxis application once or twice
16 per
week will reduce the risk of recurrences of
17
cellulitis."
18
That was the genesis of the question.
19
DR. CANTILENA: Would you have any
20
objection if we slightly modify this to say, "Would
21 you
recommend that the current labeling be modified
22 for
subpopulations at risk for secondary
406
1
infections, yes or no, and if yes, which ones would
2 you
highlight?" Is that acceptable to
you? Okay.
3
Is it a burning question, Dr. Benowitz?
4
DR. BENOWITZ: Yes, because there
is still
5 two
things that are totally different that I don't
6
understand what we are labeling.
7
One is a misdiagnosis question, so make
8
sure that you don't have cellulitis before you take
9
this stuff and it gets worse, and the second thing
10 is
if you have a predisposition to this, you should
11 be
treated more promptly. I don't see how either
12 one
is really relevant to the label, or the first
13 one
might be to diagnosis, but I still don't
14
understand what you really want out of the label.
15
DR. CANTILENA: In that case, then, your
16
answer would be no, because of those reasons, but
17 if
you have subpopulations, if you are concerned
18
about the diabetics, for example, who would use the
19
product, and it would fail for them, they would
20
have a secondary infection that they still think is
21 the
slowly healing fungus, then, that is another
22
issue.
407
1
DR. BENOWITZ: I guess I just need
to know
2
what specific label are you talking about, is it a
3
diagnosis label or is it a treatment label? I just
4
don't understand what the label would be.
5
DR. BISNO: Are you addressing
that to me?
6 The
first issue that you raised was, let's see, it
7 has
nothing to do with if you have cellulitis, you
8
should do something. That is not relevant.
9
The second issue is maybe it's not an
10
appropriate place to put on a label, I am not
11
saying it is, I am saying this is the best I can
12
come up with if you want to give a caution to
13
patients as part of the label as to what people are
14 at
particular risk of getting cellulitis related to
15 t.
pedis, and it may or may not be an appropriate
16
thing to go on a label, that is for the committee
17 to
decide.
18
DR. CANTILENA: Would you like to
vote yes
19 or
no on should we modify the label for
20
subpopulations at risk for secondary infections
21
like cellulitis? That would be a
yes/no.
22
DR. GANLEY: Lou, I would just
interject
408
1
here. I think it is probably
better just to get
2 comments
from people, because there is a lot of
3
caveats that have been thrown into this, and I
4
think we can try to sort it out.
5
There is numerous ways to do things.
6
Clearly, if we thought, for example, that people
7 with
lymphedema or venous insufficiency shouldn't
8
even be starting a therapy on their own, you could
9
include something in the label, such as ask a
10
doctor before use if you have these conditions.
11
If there is no data here to support that,
12
then, your answer would be no. Or
you could decide
13
that maybe we should put some package insert in
14
there and include some information on some
15
conditions that if you are not getting better, you
16
should get better in this period of time, if you
17 are
not getting better, you should see a doctor
18
immediately if you have these underlying
19
conditions, and I think that is what Dr. Bisno was
20
getting at.
21
I think there is a lot of ways to do it,
22 and
I think it is probably more fruitful to have
409
1
just a discussion as what people's biases are.
2
DR. CANTILENA: Okay.
3
DR. BISNO: Let me just say that one thing
4 we
wouldn't want to do is say go to your doctor
5
before starting to treat this. I
mean we don't
6
want to discourage people with these risk factors
7
from starting self-treatment.
8 DR. WOOD: But you want to encourage them
9
surely.
10
DR. GANLEY: I think it comes out
more in
11 a
discussion than in a vote.
12
DR. CANTILENA: How about if we
just start
13
over here, just go around the table and comment on
14
your thoughts on this.
15
We will start over here. Ms.
Knudson.
16
MS. KNUDSON: It seems to me that
if
17
diabetics are at higher risk for secondary
18
infection or those who are immunocompromised, and
19
certainly AIDS patients must get tinea pedis in
20
great numbers, but I would like to see something in
21 the
label that indicates that if you have these
22
conditions and you are not responding to the drug,
410
1
please see your physician or we recommend that you
2 see
your physician.
3
DR. CANTILENA: Dr. Benowitz.
4
DR. BENOWITZ: I would certainly
agree
5 with
that as a label, and I think what the
6
manufacturers suggested seemed like a reasonable
7
label. If you want to do just
extra education
8
about people at risk of cellulitis, if there is
9
room on the label, that's fine.
10
DR. CANTILENA: Dr. Clapp.
11
DR. CLAPP: It seems like the
addition of
12 a
cautionary note on the outside of the box, that
13
states if this is not getting better or gets worse,
14 and
give a specific time frame, that could be a
15
clear general warning to anyone, and therefore give
16
information that would make people stop and take
17
note without giving a tedious list that might not
18 be
all-encompassing of the types of people who are
19 at
increased risk for problems secondary to
20
cellulitis following or associated with the tinea
21
pedis infection.
22
DR. CANTILENA: Thank you.
411
1
Dr. Epps.
2
DR. EPPS: Perhaps on both ends,
one, you
3
could say for uncomplicated cases of, you know,
4
tinea pedis, interdigital, that sort of thing, and
5
then follow with a sentence about if you X, Y, Z
6
conditions, you consider asking your doctor about
7
use.
8
DR. CANTILENA: Dr. Raimer.
9
DR. RAIMER: Logically, it does
seem like
10
people with lymphedema and obesity, and that sort
11 of
thing, certainly would have a higher risk of
12
getting cellulitis if they did have a nidus or
13
infection, so it seems logically like a reasonable
14
thing to do, but I don't know if we should actually
15
label, put things in labels when we don't have any
16
scientific proof at this point in time.
17
So, I would like to see it done just
18
because my opinion is that it is kind of logical
19
that it would happen, but maybe it's too early,
20
maybe we shouldn't do it without any real proof
21
that it is happening.
22
DR. CANTILENA: Thank you.
412
1
Dr. Wilkerson.
2
DR. WILKERSON: I like the
labeling that
3
Novartis came up with. I think this
is reasonable
4 for
consumer packaging. I think if you put
too
5
many things in there, list all these conditions, it
6
just causes confusion.
7
I agree with Dr. Raimer.
Teleologically,
8 we
believe that we are right about treating tinea
9
pedis, but as far as I know, no one has done a
10
large-scale study to show that if you put the stuff
11 on
once a day, twice a week, whatever, that we
12
actually affect the outcome that we think we are
13
going to affect here.
14
I think keep it simple, and their wording
15
seems very good to me.
16
DR. CANTILENA: Dr. Patten.
17
DR. PATTEN: I would support
indicating on
18 the
label if condition does not improve, condition
19
worsens, or new symptoms develop, see your doctor.
20 I
would not support naming specific conditions.
21
If there is evidence to support increased
22
risk of any kind coming from these conditions,
413
1
then, perhaps in insert, but not on the label.
2
DR. CANTILENA: Dr. Lam.
3
DR. LAM: I definitely agree with
what Dr.
4
Patten said, to make it simple.
5 DR. CANTILENA: Dr. Ringel.
6
DR. RINGEL: I would recommend
putting a
7
caution on the outside of the box, but simply have
8 it
refer to the medication guide inside the box, in
9
other words, to say, you know, please see Caution
10
Section of package insert or whatever, and then in
11 the
medication guide, then, have a discussion of
12
specific issues.
13
I would think things on the label should
14
have more to do with whether a person would buy the
15
product or not, does he need to know that
16
information at the time of purchase or does he not.
17 I
would say no, you don't need it at the time of
18
purchase, you need to know it as you are using it.
19
So, I think it could go inside on the
20
medication guide.
21
There is another issue that perhaps should
22 be
addressed, as well, having to do with diabetes,
414
1 not
only as a risk factor possibly for cellulitis,
2 but
also in terms of poor wound healing.
People
3
with diabetes and peripheral vascular disease get
4
ulcers on their feet if they are scratching at them
5 all
the time.
6
There are a number of issues
that may come
7 up
that you might want to reference, and you can't
8
possibly put all of that on the package.
9
DR. CANTILENA: Dr. Fincham.
10
DR. FINCHAM: I would vote to have
the
11
packaging be as inclusive as possible, and
12
specifically because we are looking at a
13
self-diagnosis in many cases and relying on the
14
patient to make a decision without input from a
15
health professional, so I think it needs to be
16
inclusive.
17
I don't see this as any different than
18
some of the things that are on pseudoephedrine
19
labeling relative to hyperthyroidism, hypertension,
20
prostate disorders, et cetera. I
think the more
21 inclusive
you can be, you just give consumers a
22
better chance to be better informed.
415
1
DR. CANTILENA: Dr. Whitmore.
2
DR. WHITMORE: I think the proposed
3
packaging with back label information on the box by
4
Novartis is good, and I think that is adequate.
5
DR. CANTILENA: Dr. Davidoff.
6
DR. DAVIDOFF: I would tend to the
more
7
conservative side, that is, trying to avoid
8
overcrowding an already crowded label, on top of
9
which I think it would kind of lead to endless
10
discussions about what conditions should be and
11
what shouldn't be on that complicating list.
12
I do like the notion of including
13
information about those conditions or whatever
14
subset in the package insert, however.
15
DR. CANTILENA: Dr. Schmidt.
16
DR. SCHMIDT: I agree with Dr.
Raimer and
17 Dr.
Davidoff. I think it sounds good, that
it
18
makes sense to be inclusive with some of these
19
things, but it is going to crowd this package
20
insert, and until we really know just how many
21
times we have, you know, these cellulitises, I
22 think
it probably is best left out.
416
1
I agree, I think that the package insert
2
that Novartis, they have pretty well covered
3
everything.
4
DR. CANTILENA: Dr. Katz.
5
DR. KATZ: I would say no to the
6
overinclusive listing of each subpopulation, and
7
just a general comment if you don't get better, see
8
your doctor, which I assume is on all the other
9
over-the-counter things, so one sentence would be
10
fine without listing all of the other
11
subpopulations.
12
DR. CANTILENA: Dr. Ghannoum.
13
DR. GHANNOUM: I think make it
simple, and
14 I
agree with the other members that just provide
15
information as mentioned by Novartis.
16
DR. CANTILENA: Dr. Bisno.
17
DR. BISNO: I think after
listening to the
18
discussion, I would agree that this is probably
19
inappropriate to put on the package label, and
20
don't think it should be put on.
21
If there is a decision to add such a
22
caution anywhere else, on the box or anywhere else,
417
1 I
would advocate that the conditions that I
2
mentioned in my slide be put on, because they are
3
established risk factors, and I would diabetes on
4
general grounds and also immunosuppression, which
5 is
also an established risk factor, if there is a
6
decision to do that, but I would certain agree that
7 it
doesn't belong on the package labeling.
8
DR. CANTILENA: Dr. Wood.
9
DR. WOOD: I agree with what was
just said
10
about presumably, every over-the-counter product
11
should probably have some disclaimer that says if
12 you
are not getting better or you are getting
13
worse, see your doctor.
14
I am comfortable with putting lists on the
15
label that are actually lists of things that should
16
encourage you to take the drug rather than lists of
17
things that can go wrong when you take the drug,
18 and
these are very different issues. I think
most
19
consumers would interpret a list on the label as
20
something that should encourage them to avoid
21
taking the drug rather than the other way around.
22
In fact, in Dr. Bisno's risk factors, it
418
1
would seem to me to be indications for rushing out
2
today and buying these drugs, and the idea that
3
consumers will read this label and be discouraged
4
from taking it seems to me a major public health
5
hazard actually.
6
DR. CANTILENA: Thank you.
7
Dr. Ten Have.
8
DR. TEN HAVE: Support a simple
general
9
statement, cautionary statement.
10
DR. CANTILENA: Dr. Alfano.
11
DR. ALFANO: Same comment I made
earlier,
12 simple
statement as has been propose by both
13
Novartis and CHPA, essentially, the same statement.
14
DR. CANTILENA: Thank you.
15
Mr. Kresel.
16
MR. KRESEL: I support a simple
statement.
17 I
think the first rule of label writing is keep it
18
simple. People don't read beyond
that, or they
19
just get so confused they give up.
20
DR. CANTILENA: I would agree with
21
generally what has been said, that we should not
22 add
specifics at this point until we have the data
419
1 to
support that, but we do need to strengthen the
2
other warnings, which have already been talked
3
about, and I would support those changes.
4
Okay. I think we have all talked about the
5
shortcomings of the existing label, so I am
6
confident that this group can go right to 3(b), are
7
there claims on the current labeling that may
8
mislead consumers to have greater expectations.
9
We can start here and we will do an actual
10 yes
or no on this. If there are claims,
then, if
11 you
would specify which ones trouble you the most
12
about misleading consumers.
13 Tab 7, Table 2 tells you the choices
for
14 the
monograph, and Table 3 has some samples of
15
information from some of the OTC NDA drugs. We had
16
sort of touched on these earlier today.
17
Some people have significant trouble with
18
some of the wording and whatnot, and the qualifiers
19 or
lack thereof, so I think maybe we can just say
20
whether or not you do have a problem with the
21
existing label in terms of it being misleading to
22
consumers, and if you do, which are the things that
420
1
trouble you the most.
2
Go ahead, Mr. Kresel.
3
MR. KRESEL: I think the one that
we have
4
talked about the most is "cures most," which I
5
don't think anybody really had any understanding of
6
anyway, it doesn't seem to have any meaning, so it
7
ought to go away. I think
"cures most" being
8
replaced with "treats" makes a lot of sense to me.
9
DR. CANTILENA: Dr. Alfano.
10
DR. ALFANO: I think back to what
Dr. Bull
11
said, what is clinically meaningful to the
12
consumer, and if you think of the data that was
13
presented by Schering-Plough, most consumers buy
14
these products for sort of symptomatic relief, they
15 are
not treating hyperkeratosis.
16
So, under that basis, just to clear up the
17
issue on cures, I would agree that "treats" would
18 be
a better word as proposed by Novartis.
19
DR. CANTILENA: Dr. Ten Have.
20
DR. TEN HAVE: I agree that
"treats" is
21
better.
22
DR. CANTILENA: How about in terms
of the
421
1
other items in the current OTC labeling?
Let me
2
find a good example of that.
Attachment 2?
3
DR. FINCHAM: It is Tab 7,
Attachment 2,
4 not
Table 2.
5
DR. CANTILENA: Attachment 2 in Tab
7.
6
Yes, we are going to go all the way around.
7
Dr. Wood. I think I know what
your most
8
important concern is.
9
DR. WOOD: My biggest concern is
most, but
10
seriously, I think there are other questions that
11 are
in here that we should address, on page 6, for
12
example, that are specifically addressed, at least
13 I
imagine are specifically addressed to the
14
committee.
15
I like the idea on page 5 of including
16 specific
efficacy data, which would not have to
17
rely on comparative studies. Does
that make sense?
18 So,
the data that came from the studies, if that
19
exists; if it doesn't exist, then, tough luck. I
20
mean if it doesn't exist, you don't get to put
21
anything on, and people should draw their own
22
conclusions from that. Maybe you
should say there
422
1 are
no data to say how effective this is, if that
2 is what it is, and if the other products
that says
3 it
is X percent effective--
4
DR. CANTILENA: I think perhaps
you are
5
crossing over into 3(a) with additions.
I am
6
actually sort of looking for problems that you have
7
with the current label.
8
DR. WOOD: Then, I will pass.
9
DR. CANTILENA: We will have an
10
opportunity to come back to all the items that we
11
would like to add.
12
Dr. Bisno.
13
DR. BISNO: I don't have any comment.
14
DR. CANTILENA: Dr. Ghannoum.
15
DR. GHANNOUM: I agree
"treat" is better.
16
DR. CANTILENA: Dr. Katz, any
problems
17
with the current label?
18
DR. KATZ: There is a lot of
problems here
19
because as Dr. Wood said initially, "cures most,"
20 it
clearly doesn't cure most, so that is wrong, it
21 is
deceptive. It is not even effective in
most, so
22
using that word is very deceptive.
The effective
423
1
treatment in Dr. Fritsch's discussion on page 8,
2
Table 16, even effective treatment, if you subtract
3 the
effective improvement from the placebo, in none
4 of
them does it even reach 50 percent. That
is not
5
considering cure, it is just effective.
6
So, using that word, I agree with Dr. Wood
7
adamantly that that is deceptive.
Even treating
8
most, what does that mean, "treating most?" I
9
don't understand that. If I am a
consumer and I go
10 to
the store, and I see it "treats most," what does
11
that mean, that it helps most?
So, that is another
12
word that shouldn't be there.
13
The most clear-cut situation would be
14
clear symptoms in whatever the number that the FDA
15 and
company agree upon improves symptoms in 48
16
percent of patients, or if you take a few studies,
17 in
anywhere between 35 and 48 percent of patients.
18
That means something. Most
consumers know what
19
that percentage means.
20
So, I would be very specific with that
21
without getting too tedious, and that should be for
22
each drug.
424
1
That's all the comments I had.
2
DR. CANTILENA: Dr. Schmidt. Problems
3
with the existing label.
4
DR. SCHMIDT: I agree. I think put
"treats
5
athlete's foot," and then I agree with Dr. Wood
6
that there should be some percentage, if it's
7
available.
8
DR. CANTILENA: Dr. Davidoff.
9
DR. DAVIDOFF: I also have a
concern with
10 the
"cures most," phrasing, but for a somewhat
11
different reason. It seemed to me that we have been
12
looking at this from a rather narrow point of view,
13
namely, sort of a bug in the skin, and it seems to
14 me
that the actual situation is more complicated
15
than that in the sense that there is bugs in the
16
skin and in the surrounding environment, and that
17
unless you take that ecological view, it's I think
18 not
fair to be talking about cure, because unless
19 you
treat all parts of the situation, you are not
20
really dealing with the whole situation.
21
It would be a little bit like talking
22
about preventing surgical infections because you
425
1
have given pre-op antibiotics, but surgeons don't
2
have to wash their hands. I mean
the ecological
3
view would include the surgeons' hands.
4
So, having said that, I think it is also
5
fair to say that the word "cure" is appropriate for
6
many patients. The organism is eliminated, the
7
symptoms either disappear or get much better, and
8
what is residual may not be related to the
9
infection. So, I think
"cure" actually is not an
10
unreasonable term.
11 So, putting that all together, it
seems to
12 me
that the word "cure" might be appropriately
13
retained, that the word "most" should go, agree,
14 but
I think there are other words that could be
15
used, for example, I know you may not want to get
16
into wordsmithing, but even saying "cures many"
17
would be not be unreasonable.
That is not I think
18
false advertising.
19
Finally, if you take the ecological point
20 of
view, you might want to include a word like
21
"helps," so "helps cure many tinea pedis
22
infections" might be useful in the same sense that
426
1
fluoride in toothpaste, the claim for it is
2
included in the context, you know, the ADA's
3
statement about fluoride is that fluoride helps
4
prevent cavities as part of a program.
5
I wondered if from the dermatologists'
6
point of view, having a word like "helps" might be
7
useful in the sense that it would allow or
8
encourage patients to at least find out what else
9
they could be doing like the other things that
10
dermatologists do talk to their patients about,
11
like how they should deal with their socks and
12
shoes and their shower, their avoidance of swimming
13
pools, or whatever else.
14
So, I would summarize it by suggesting
15
that "helps cure many" might be the way to go.
16
DR. CANTILENA: Dr. Whitmore.
17
DR. WHITMORE: I agree with what
has been
18
said about the current labeling and then if I could
19 say
something about the proposed label. On
the
20
front of the Lamisil box, they talk about
21
"eliminating fungal infection," and I would not say
22
that, I would say "treat fungal infection." The
427
1
same is true for the Desenex.
2
DR. CANTILENA: We will talk about
the
3 additions
that you would like in the next question,
4 but
thank you.
5
Dr. Fincham.
6
DR. FINCHAM: I have troubles with
the
7
wording of "cures" and "most," and an appropriate
8
replacement needs to be made. One
of the problems
9
with advisory committees is they give you advice,
10 and
I appreciate your patience listening to us
11
today.
12
DR. CANTILENA: Dr. Ringel.
13
DR. RINGEL: I think that the
label should
14 reflect
exactly what the product does, and I think
15
what this product does is that it kills athlete's
16
foot fungus, and I think that the label should say
17
"kills most athlete's foot fungus." If, then, the
18
symptoms don't go away, the person should have
19
assumed that either he has persistent inflammation
20 or
some other disease that is not athlete's foot,
21 or
perhaps a resistant organism, but that is as
22
honest as I can think of, it kills athlete's foot
428
1
fungus.
2
DR. CANTILENA: Dr. Lam.
3
DR. LAM: I actually think that
the word
4
"most" should go just because it's misleading, and
5
leave out "cure athlete's foot." To me, the
6
consumer will actually think that it takes care of
7 the
problem, and when you look at the response
8
rate, it doesn't.
9
So, I think it should just state what it
10 is
supposed to be used for, which is treatment of
11
athlete's foot, and that, in a sense, make an
12
implication that there is not guarantee that it
13
will take care of that condition in every single
14
patient.
15
DR. CANTILENA: Dr. Patten.
16
DR. PATTEN: Certainly, the word
"most"
17
should go, and I even wonder about the word
18
"treatment." I wonder
if, in the general usage of
19
that word, or the way it is conceptualized,
20
treatment does not imply the goal of cure.
21
I just raise that question. I am operating
22 on
the assumption that it does, so I would favor
429
1
information that tells people that it improves
2 symptoms
or alleviates symptoms, or something like
3
this.
4
Also, I am looking farther back in this
5
Section 7, and I am seeing some samples on
6
prescription drug labels, and I am seeing the word
7
dermatologic and dermal crop up several places, and
8 I
think when that is for consumption of the
9
purchasing public, the word "skin" should be used
10
rather than dermal or dermatologic.
11
DR. CANTILENA: Thank you.
12
Dr. Wilkerson.
13
DR. WILKERSON: The only thing I
have to
14
add, I have seen on some packaging, there is a
15
warning on there to the effect of do not use on
16
nails, and I don't see that in any of our
17
materials. I just wondered if Dr. Ganley could--I
18
mean many times we don't want to treat patients
19
with systemic antifungals, and we tell them to go
20 get
something, and they read this warning on the
21 box
not to use this on their nails, thinking that
22
some harm is going to come to them outside of the
430
1
fact that it may not work.
2
Dr. Ganley, I was wondering, it is not in
3 our
materials, but I know it is on consumer items,
4 I
have seen it in the last few weeks.
Maybe it is
5 in
there.
6
DR. CANTILENA: Dr. Ganley, do you
know?
7
DR. GANLEY: Yes, I am looking on
page 18
8 of
Tab 7. Do not use on nails or scalp.
9 DR. WILKERSON: A lot of people interpret
10
that to mean that--I mean is this the standard
11
wording every time, or are there variations on this
12
wording?
13
DR. CANTILENA: This is for the
NDA
14
version, right?
15
DR. GANLEY: It's on some of the
products,
16 I
believe, not all of them.
17
DR. WILKERSON: Would there be
other
18
wording that would actually warn against using it
19 on
hair or nails?
20
DR. GANLEY: I think the point
would be is
21
whether this would be effective in treating a nail
22
infection like onychomycosis, and it may be that it
431
1 may
have to be stated differently, but I think it
2 is
a point well taken.
3
DR. WHITMORE: I think it might be
helpful
4 to
say do not use to treat infection of the scalp
5 or
nails, because patients will come in and say I
6 got
some on my nails, am I going to die.
7
DR. CANTILENA: So, you have a
problem
8
with that in the NDA version.
9
Dr. Raimer.
10
DR. RAIMER: I don't really have
much to
11 add
either. I don't like the most cures
obviously,
12 as
everyone else has stated, but what we should
13
replace it with exactly, I think we have had
14
several good suggestions, I don't have any strong
15
feelings about any of them.
16
DR. CANTILENA: Dr. Epps.
17 DR. EPPS: Well, if someone wanted to use
18
cures, that would be a nice time to put in your
19
percentage cures, or a little asterisk referring to
20 the
bottom, in our trials 50 percent or 20 percent
21 or
60 percent or whatever, that might be helpful.
22
Are we commenting on all the label or just
432
1
that part? I like relieves, for
relief of, as
2
well.
3
DR. CANTILENA: Dr. Clapp,
problems with
4 the
existing label and what you don't like.
5
DR. CLAPP: Problems with the
existing
6
label certainly are "cures most," because I haven't
7
seen any evidence of that.
"Most" and "cures" is a
8 standard
that I don't think most of them can live
9 up
to within the time frame that is expected.
I
10
think if we take it out to 6 to 9 weeks, then, we
11 see
more relationship to actual cure.
12
But I think that the efficacy endpoint are
13
interesting, and negative mycology certainly would
14 be
among our standards for expectation with
15
patients, but I think the patients are more
16
interested in a symptomatic cure or to symptomatic
17
relief, so I like the concept of effective
18
treatment as being the standard for us to consider
19 as
opposed to actual cure, complete cure, but I
20
think it could also be something that consumers
21
could conceptualize better than cure, and that if
22 they
have a relapse or recrudescence or just
433
1
incomplete treatment, they can say, well, it didn't
2 say
it was going to cure me and just didn't
3
effectively treat me.
4 Perhaps that is a middle ground
that makes
5
patients more willing to try again.
6
The other things on the label that I am
7
concerned about are the warnings for children,
8
because I am not sure--I know that this is getting
9
into a different scope, but I think we have to
10
consider always reasons that we are limiting use
11 for
children under 2 if there is not a legitimate
12
reason, or whether or not there is.
13
Also, we are talking about the monograph
14
labels, are we?
15
DR. CANTILENA: Actually, either
one.
16
There is NDA, OTC, and the monograph.
17
DR. CLAPP: Some say don't use in
children
18
under 2, some say use only in children over 12, and
19 I
think we have to have a good reason for the use
20
specific to the medications that are being used.
21
The other interesting thing that I find ,
22 the
Novartis label is interesting, the graphics are
434
1
nice, but I am concerned about the claim that is
2
must be used twice daily for full 7 days to
3
eliminate fungal infection, when, in fact, on the
4
indications that we have for usage was the moccasin
5
type tinea pedis, is that it must be used for 2
6
weeks, so there is an ambiguity here that I think
7
perhaps patients are not, when they grab the box
8 and
read it, and if they think that they have
9
tinea, and it is the moccasin type, I don't think
10
they are distinguishing between moccasin versus
11
intertriginous, and they would perhaps expect,
12
leave with the expectation that they are fully
13
cured in one week, so I think that ambiguity should
14 be
addressed.
15
The other part that I see in some of these
16
labels are where we are demanding of the patient to
17
make the diagnosis of not only tinea, but
18
intertriginous versus moccasin type, and I think it
19
puts quite burden on the patient, and when you read
20 the
attached labels, some of the labels you have
21 say
cures between the toes, and others say but not
22 on
the bottom of the feet or only for use between
435
1 the
toes, and I want to make sure there is some
2
consistency between the use and indication, and the
3
actual reality of whether or not patients should
4
then think that they should not use it if they have
5 it
on their feet or whether they can only use it if
6 it
is between the toes.
7
The instructions to the patient has to be
8
consistent with the type of tinea that we are
9
advising them or the location of the tinea that we
10 are
advising that they could treat.
11
Oh, and one last thing about the Novartis.
12 If
we are talking about the last question about
13
indications or warnings for patients, many stated
14
that they liked their label in terms of the
15
warnings to ask a doctor if the symptoms worsen or
16 new
symptoms develop, but then it also has a
17
precautionary note especially if you have diabetes,
18 and
I haven't heard that we have a clear link
19
between diabetes as being worse than anything else.
20 I
like the caution, but not specifying diabetes and
21 not
listing lymphedema and CABG patients and
22
everything else.
436
1
DR. CANTILENA: Thank you.
2
Dr. Benowitz.
3
DR. BENOWITZ: For the first part,
I am
4
happy to say "treats athlete's foot." One thing
5
which I just noticed in this Novartis ad which is a
6
problem because it's not true, although it is not a
7 bad
idea to encourage people, but it says, "Must be
8
used to eliminate."
9
According to these guidelines, to
10
eliminate fungal infection, that's not true. Most
11 people don't use it according to the way it
is
12
supposed to be used, and in many cases, it still
13
works. I think we should
encourage people, but not
14 say
that it must be used according to guidelines in
15
order to kill fungi.
16 DR. CANTILENA: Ms. Knudson.
17
MS. KNUDSON: Well, everything I
was going
18 to
say has been said. I really do not like
the
19
word "most," I don't like the word "cure," and I am
20 not
crazy about the word "treatment" either.
21
I like Dr. Ringel's idea about "kills
22
athlete's foot fungus." I
think that is a pretty
437
1
clear statement and there is enough information to
2 back that up.
3
I would also like to see something that
4
says something about when you could expect your
5
symptoms to clear.
6
DR. CANTILENA: Well, that will be
coming
7 up
actually. We will make it unanimous in
terms of
8
nobody likes "cures most," and I think you should
9
obviously fix that, and then strengthening the
10
warnings is something that we will talk about now.
11
That was unanimous for 3(b).
12
Let's conclude. I don't think you
all
13
want to come back tomorrow morning just for one
14
part of one question, so although we are past the
15
hour, I apologize, but I think we will be finished.
16
3(a) is the last thing we need to deal
17
with, and basically, in addition to what has
18
already been said, I would like to get everyone's
19
opinions, and we will go around the room this way
20
looking for specific additions that should be made
21
with regard to the three things that were
22
suggested. Cure rate, should that
be there.
438
1
Expectation of symptom relief, you know, delay in
2
response, and anything else that you need, that you
3
think should be added to the label to help
4
consumers select this and use this class of
5
products.
6
Ms. Knudson, would you like to talk about
7
things that you would like to see added to the
8
label of existing and future?
9
MS. KNUDSON: I would like to see
what the
10
effective treatment rate is. I
think that is more
11
important for consumers than cure rate, because
12
they are going to think that it is has really gone
13
forever.
14
I would like to see certainly expectation
15 of
symptom relief. That is something that I
think
16 is
terribly important. I think that since
it has
17
been pointed out repeatedly in the material that we
18
have received, that there is a delay in response.
19 I
think that should be noted, so that consumers can
20
expect that and will continue with the drug or wait
21 to
see what happens for the full 7 days or however
22
many days it's appropriate.
439
1
DR. CANTILENA: Thank you.
2
Dr. Benowitz.
3
DR. BENOWITZ: I agree with
Paula's
4
comments.
5
DR. CANTILENA: So, everything
that was in
6 the
question, you are in favor of.
7
DR. BENOWITZ: Yes.
8
DR. CANTILENA: Dr. Clapp.
9
DR. CLAPP: Oops, I think I gave
my answer
10
already.
11
DR. CANTILENA: Well, that's all
right. I
12
just wanted to come back to see if you had any
13
additional comments. You were on
such a roll
14
there, I didn't want to interrupt you.
15
Dr. Epps.
16
DR. EPPS: Yes, I agree with 3(a)
and all
17 its
parts.
18
DR. CANTILENA: Dr. Raimer.
19
DR. RAIMER: I like the idea of
effective
20
treatment rates also rather than cure rates.
21
DR. CANTILENA: Dr. Wilkerson.
22
DR. WILKERSON: I like effective
rates,
440
1
too, much like what we are doing with psoriasis.
2
Instead of calling this the PASI index, we are
3
going to call it the FASI index. That's the Fungal
4
Area Severity Index, and we will put a 12-week
5
marker, at which time they have to be mycologically
6
negative culture, after a course of therapy,
7
develop a score, and then classify it on an easy
8
scheme.
9
I think this is something we need
to cross
10 all
drugs right now for comparability is we don't
11
have standards to really compare whatever we are
12
comparing to each other.
13
DR. CANTILENA: So, how would you
express
14 that
information on a label for consumers?
15
DR. WILKERSON: I would develop a
very
16
short analog scale 1 to 4 or some kind of
17
classification, very effective or ultra effective,
18 or
something, but behind the scenes, we would score
19
these to some standard, 75 percent mycologic cure
20 at
12 weeks or whatever our standard.
21
This thing about the erythema and the
22
scaling, and all that, I agree is nothing, and what
441
1
really counts in the end is once you are treated,
2
does your infection come back, and there is a lot
3 of
reasons to have red feet and one thing and
4
another, but in the end, at a reasonable period of
5
time, 3 months out, it could be arbitrary, is your
6
infection still gone, or are your symptoms of your
7
infection still gone.
8
If it is, then, as a consumer, I would
9
probably be very happy. I think
we need some
10
standardized scoring, something that is
11
standardized, easily scored, and to give consumers
12 an
idea of which one of these, because as a
13
physician, I have no objective evidence outside of
14
clinical experience to tell me which one I think
15
works better.
16
DR. CANTILENA: Dr. Patten,
specific
17
additions to the label.
18
DR. PATTEN: I support all
three. I think
19
telling the consumers something about effective
20
treatment is particularly important, but I think
21 you
also need to tell the consumer what effective
22
treatment means, so they don't conflate it or
442
1
confuse it with complete cure.
2
DR. CANTILENA: Dr. Lam.
3
DR. LAM: Some sort of a measure
of
4
effective treatment by whatever means that we agree
5
later. I think definitely, the
consumer should be
6
notified on the label regarding the time course of
7
response relative to the duration of treatment, as
8
well as the time course of resolution of symptoms,
9 so
that they know that they have to continuously
10
take the medication as directed.
11
DR. CANTILENA: Dr Ringel.
12
DR. RINGEL: I agree that there
should be
13
labeling that addresses all three of these issues,
14
however, I think it needs to be pretty general
15
unless we can do one head-to-head study of every
16
antifungal on the market and then update that study
17
every time a new antifungal comes on the market,
18
there is going to be unrealistic competition and
19
unrealistic claims for every product that comes
20
along.
21
So, I think what you need to do is stay
22
pretty general and say something like resolution of
443
1
symptoms may take weeks, not all symptoms may
2
resolve, you know, reinfection is possible, and
3
just leave it at that.
4
DR. CANTILENA: Dr. Fincham.
5
DR. FINCHAM: I think to reduce
costs on
6 the
part of the sponsor, which, in turn, will
7
reduce costs for patients hopefully, I think we
8 need to be general relative to the effective
9
treatment and what that means, but I think
10
something needs to be referenced to that point, and
11 I
think expectation of symptom relief, as well as
12
delay in response are perfectly appropriate to have
13 on
there.
14
DR. CANTILENA: Dr. Whitmore.
15
DR. WHITMORE: I second all that,
and I
16
wonder if you could cut down on physician visits
17 for
tinea pedis not responding to topicals by
18 adding
to the labeling that if after one month, you
19
still have some symptoms, you can repeat it, but
20
that is another issue.
21
DR. CANTILENA: You would probably
have to
22
study that in order to put that in your label.
444
1
Dr. Davidoff.
2
DR. DAVIDOFF: Yes, I agree that
Nos. 2
3 and
3, there should be additional information about
4 the
delay in response, and so on. No. 1, I
am not
5
comfortable with, the notion of putting cure rates
6 for
several reasons, one being that there aren't
7
head-to-head studies and therefore if you are
8
asking consumers to compare one box to another,
9
they are really comparing data that is not very
10
comparable, and I don't think that is fair or
11
appropriate, on top of which, we can't even decide,
12 I
think for good reasons, whether cure rate or
13
effective treatment is the appropriate endpoint to
14 be
talking about.
15
Finally, Tom Ten Have and his colleagues
16
have convinced me that relying on point estimates
17 as
a way of conveying information alone is very
18
chancy, and I think that putting down cure rates
19
doesn't take into account the measures of
20
uncertainty of the data, and without that, it is
21
actually misleading.
22
DR. CANTILENA: So, how would you
445
1 communicate that information to the consumer?
2
DR. DAVIDOFF: I wouldn't try to
3
quantitate it.
4
DR. CANTILENA: Dr. Schmidt.
5
DR. SCHMIDT: I agree. The one thing I
6
would mention, though, as putting information on
7 the
labeling, and it is already on this one on page
8 19,
is about proper foot care. I think that
is
9
very important.
10
DR. CANTILENA: Dr. Katz.
11
DR. KATZ: I think it would be
more
12
informative for the consumer to know whether it's
13
effective in 20 percent or 40 percent or 90
14
percent, and a range. It wouldn't
be head-to-head
15
comparison if it was just comparison against
16
placebo.
17
I think also it is very important when you
18 say
80 percent clear, that the consumer know that
19 50
percent of the placebo may be clear in that
20
study, so the effective clearing rate is really 30
21
percent, so I think it is important that we not be
22
deceptive in that degree, but it is more specific
446
1 to
let somebody know when they are picking up a
2
tube of medication whether they have a 30 percent
3 chance
of stopping itching or 90 percent.
4
I would say also as an aside, that when
5
people say that it's negative mycology completely
6 in
90 percent of patients, things of that sort on
7
page 7, Dr. Fritsch's comment, even negative
8
mycology, if you subtract placebo, you are talking
9
about 23 percent to 67 percent with different drugs
10
giving clearing KOH and culture.
That is on page
11 7.
12
DR. CANTILENA: Thank you.
13
Dr. Ghannoum.
14
DR. GHANNOUM: Although I agree
with Dr.
15
Davidoff about really it is no comparative, I think
16 it
will be helpful to add for the effective
17
treatment, the percentage, clarifying that is
18
relative to the placebo, and I agree with the other
19 two
that we should add information as far as
20
symptom relief, that the response may take longer,
21 may
be delayed.
22
DR. CANTILENA: Dr. Bisno.
447
1
DR. BISNO: No additional
comments.
2
DR. CANTILENA: Dr. Wood.
3
DR. WOOD: I think we should add
efficacy
4
data and although I am very sympathetic to Frank's
5
comments about point estimates, and so on, I think
6 one
of the issues here is that we want to encourage
7
people to develop more effective therapy, and the
8
only way we are going to do that is to give them
9 the
right to promote on that.
10 So, I think allowing people to put
11
efficacy data on the label encourages better and
12
more effective therapy to be developed, because
13
people will have a commercial advantage.
14
I am very much against putting wording on
15 the
label that requires interpretation, like very
16
effective, partially effective, and so on, because
17 the
FDA will end up in interminable arguments about
18
where these cutpoints are, and they will appear to
19
have credibility that don't exist, so I mean if you
20 are
going to put it on, you put it on the way the
21
studies came out, and you don't try and squeeze
22
them into boxes, because everybody will be trying
448
1 to
move the box line to catch their product.
2
DR. CANTILENA: Dr. Ten Have.
3
DR. TEN HAVE: As a statistician,
I would
4
take Dr. Davidoff's bait and say confidence
5
intervals, of course, but as a consumer with
6
athlete's foot, I can understand both sides of the
7
issue in terms of whether or not you report, say,
8
effective treatment rates.
9
It's a difficult issue and as a scientist,
10 I
would say yes, even though the rates are based on
11
different types of responses, it is still the more
12
information and caveat emptor, so, I would have to
13 say
report confidence intervals, but I know that is
14 not
plausible.
15
DR. CANTILENA: The comprehension
study on
16
that would be interesting.
17
Dr. Alfano.
18
DR. ALFANO: I would agree with
(a) ii and
19
iii, and I think there have been adequate proposals
20
from the industry to enrich those two claim areas.
21
I strongly disagree with any specific
22
statement of cure rates or effective treatment
449
1
rates or whatever. Dr. Ringel
just said it
2
brilliantly, I think. I mean we
will have
3
initiated an insane horsepower race that will only
4
confuse the consumers. The
studies are done at
5
different times in different ways.
6
The newer studies could be penalized
7
because they have more rigorous controls and the
8
response rates might not look as good, and we have
9
already seen how this becomes a slippery slope. We
10 now
have charts, now we are talking about
11
confidence intervals on some package labels. The
12
consumers are going to need Ph.D.'s to understand
13
these things.
14
I thought we were going the other way.
I
15
thought we were going to simple icons to make it
16
easier for people to do this, and you apply this to
17
other categories, analgesics. Do
you put on
18
headaches, do you put on toothaches, third molar
19
extraction, episiotomy? I mean
it's insane.
20
I understand we want to inform the
21
consumers, but this is I think wasteful information
22
that will only confuse them.
450
1
DR. CANTILENA: Thank you.
2
Mr. Kresel.
3
MR. KRESEL: I think meaningful
data is
4 the
only thing that helps the consumer, and I
5
absolutely agree with Dr. Ringel and Dr. Davidoff.
6 You
are just comparing apples and oranges, studies
7
that were done over a 40-year period, conducted
8
different ways, and try to compare them to today's
9
standards.
10
I don't think that gives any meaningful
11
data to consumers. We here today
couldn't agree on
12
whether it should be a complete cure and effective
13
treatment, so we don't even know where that number
14
would start.
15
I think what the consumer really wants to
16
know is when can I expect to start to feel relief,
17 so
onset of activity is really important for a
18
consumer, and the fact that after I stop treatment,
19 can
I expect to continue improvement and for how
20
long.
21
So, I think those are things that
22
consumers really want to know, need to know, and I
451
1
think it really helps them.
2
DR. CANTILENA: Dr. Alfano, did
you want
3 to
add one thing?
4
DR. ALFANO: One follow-up
comment. I
5
think it's a justifiable concern that the Agency
6 has about improving drugs in this therapy,
so I can
7
understand the concern, but there is a mechanism,
8 Dr.
Ganley pointed out earlier, and that is, two,
9
well-controlled trials will get you a claim.
10
You can advertise that claim, and you can
11
drive sales in that fashion, and I think that is
12 the
mechanism that will drive this category to
13
further improvements. We have
seen it driven that
14 way
already without all these other tools brought
15 to
bear.
16
DR. CANTILENA: I would just like
to add
17
that I certainly understand what has been said and
18 the
concerns about confidence intervals and
19
flooding the label, but I think as it stands now,
20 the
consumer is not given enough information for
21
them to select the most efficacious product.
22
There obviously is information available
452
1
because we have seen it today and we will hear the
2
Code in our closed session tomorrow in terms of who
3 is
A, B, C, and D. So, at least you, as a
4
committee member, will be able to go buy the most
5
effective treatment for athlete's foot.
6
So, Tom, if you can just hold on another
7
day, relief is on the way.
8
But I think the other things, what is on
9 the
slide, I think would inform the consumer.
I
10
think the current label is inadequate in those
11
areas and I agree with what has been suggested as
12
possible additions. I don't know
the right way to
13
handle the effect of treatment, but you have to
14
give them some information that is quantitative in
15
some respects.
16
So, having almost the last word, we have
17 an
issue for tomorrow. Since we basically
18
accomplished the morning agenda for tomorrow this
19
afternoon, we will start the closed session--the
20
Nonprescription Advisory Committee will meet here
21 at 8 o'clock.
Everyone will meet here and we will
22
split up.
453
1
DR. GANLEY: Jon and I talked and
I think
2 we
could probably meet here at 8:30. We
have to
3 have the Open Session at 11 o'clock. I think both
4 of
us have probably two hours' worth of information
5 to
go over with the committees.
6
DR. CANTILENA: Just to summarize
for
7
those of you who didn't hear all that, all of us
8
back here at 8:30 tomorrow morning.
The other
9
committee is escorted over to the Parklawn. We
10
will have another class outing with your chaperons.
11
Then we are all back here together for the Open
12
Public Hearing at 11 o'clock.
13
With that, we will close today's meeting.
14
Thank you very much, members of the committee and
15
members of FDA.
16
(Whereupon, at 6:00 p.m., the meeting was
17
recessed to be resumed at 8:30 a.m., Friday, May 7,
18
2004.)
19 - - -