MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN
SERVICES
PUBLIC
HEALTH SERVICE
FOOD
AND DRUG ADMINISTRATION
CENTER
FOR DRUG EVALUATION AND RESEARCH
DATE:
FROM: Houda
Mahayni, Ph.D., Interdisciplinary Scientist
Division
of Over-the-Counter Drug Products, HFD-560
SUBJECT: HISTORY AND OVERVIEW OF OTC MONOGRAPH FOR
TOPICAL ANTIFUNGAL DRUG PRODUCTS
______________________________________________________________________
Introduction
Over-the-counter (OTC) drug products can be marketed under
two regulatory mechanisms:
(1) a new drug application (NDA)
(2) OTC drug monograph system
This discussion
will focus on the OTC drug monograph system.
More specifically, the OTC drug monograph for topical antifungal
products will be discussed, with emphasis on those products used to treat
athlete’s foot (tinea pedis).
OTC Drug Monograph System
The OTC drug review began in 1972 as a review of the safety
and effectiveness of OTC drugs on the market at the time. This marked the beginning of the OTC drug
monograph system. FDA (we) initiated the
OTC drug review by identifying a number of therapeutic categories for which we
would establish OTC drug monographs. The
OTC drug monograph system gives manufacturers a mechanism to market OTC drug
products without needing a new drug application (NDA). Unlike OTC drug products marketed under an
NDA, products marketed under an OTC drug monograph do not need pre-approval
from FDA. OTC drug monographs list the
conditions of use under which a drug product is generally recognized as safe
and effective (GRASE). The conditions of
use include active ingredients (single or in combination), dosage strength,
dosage form (in some cases), indications, warnings, directions for use, and, in
some cases, final formulation testing.
The OTC drug review is a four step public rulemaking process:
(1)
Advisory Review Panel: The Panel is a group of experts in a
particular OTC drug category. The Panel
reviews data for OTC drug products marketed prior to December 1975 and
recommends GRASE conditions for an OTC drug monograph.
(2)
Advance Notice of Proposed Rulemaking (ANPR): FDA publishes the
ANPR in the Federal Register to
announce its intention of creating an OTC drug monograph. The ANPR also contains the Panel’s report,
which lists the recommended GRASE conditions.
Following publication of the ANPR, interested persons may submit
comments and additional data regarding the Panel’s recommendations during a
90-day comment period.
(3)
Tentative Final Monograph (TFM): FDA publishes the TFM, or
proposed rule, in the Federal Register
as its preliminary position regarding the safety and effectiveness of each
active ingredient in a therapeutic category.
The TFM is based on FDA’s interpretation of data provided to the Panel,
the Panel’s recommendations, and any new data submitted in response to the
ANPR. Following publication of the TFM,
there is a 90-day comment period.
(4) Final Monograph (FM):
FDA reviews all comments and data submitted during the TFM comment
period and amends the TFM to create the FM, or final rule, which is published
in the Federal Register. The monograph is a set regulations included
in the Code of Federal Regulations. The
FM includes an effective date, after which drug products marketed under the
monograph must comply with the conditions of use described in the monograph.
Each step in
the process builds upon and is a continuation of the previous step. Although the FM is the final step in this OTC
drug review process, FDA can amend the FM to include additional GRASE
conditions (e.g., add a new active
ingredient).
History of OTC Topical Antifungal Monograph
Advanced Notice of Proposed Rulemaking
The ANPR was published on
The Panel expressed concerns about the ingredients only mitigating
the symptoms rather than curing the condition, as apparent by the statement
that, in order to best serve all consumers, “an OTC product must provide more
than temporary symptomatic relief of athlete’s foot, jock itch, and ringworm” (Ref.
1, page 12489). The Panel required at
least one well-designed clinical study demonstrating that an active ingredient treats
athlete’s foot as evidence of effectiveness. In reviewing the clinical trials, the Panel
defined a well-controlled study as one that met the following six criteria (Ref.
1, pages 12491-92):
(1) double-blinded and randomized
(2) vehicle-controlled
(3) test groups of adequate size
(4) entry criteria based on clinical
sign and symptoms with diagnosis verified by positive potassium hydroxide (KOH)
preparation and positive culture (confirming the presence of fungus)
(5) standardized dosing regimen (i.e., at least four week treatment for
athlete’s foot)
(6) follow-up examinations performed
at the end of treatment and final evaluation of clinical results corroborated by
negative KOH and negative culture two weeks after therapy ends
The Panel
recommended an ingredient as GRASE for the treatment of athlete’s foot if it
was significantly more effective than vehicle.
The Panel also reviewed clinical studies meeting this criterion that
demonstrated tolnaftate is effective in the prevention of athlete’s foot and
recommended the prevention claim for this ingredient.
A relatively small percentage of the studies submitted to FDA
actually met these criteria. There was
considerable variability in the study protocols. Enrollment for most of the clinical studies submitted
to the Panel was based on diagnosis of tinea pedis by a physician. In a third of the studies that included
physician diagnosis, the diagnosis was confirmed by positive KOH and
culture. Treatment duration varied
between 2 to 6 weeks with the treatment duration being 4 weeks in the majority
of studies. These studies also assessed
efficacy at different time points and used different criteria for cure. All of these factors make it difficult to compare
the cure rates of the monograph products to those of the NDA products because
of differences in the design of the clinical
studies.
In addition, the Panel proposed the idea of simple and
concise labeling that “should enable the consumers to clearly understand the
results that can be anticipated from the use of the product” (Ref. 1, page 12490). Examples of indications recommended by the
Panel included the following (Ref. 1, page 12565):
· “treats athlete’s foot”
· “for the treatment of athlete’s
foot and for the relief of itching”
Labeling
for products used for the treatment of athlete’s foot should include the
following warning (Ref. 1, page 12565):
“If irritation occurs or if there is
no improvement within 4 weeks, discontinue use and consult a doctor or
pharmacist”.
Furthermore,
the Panel stated that “the directions for use should be clear and direct. They should provide the user with sufficient
information to enable safe and effective use of the product” (Ref. 1, page 12490).
Based on the clinical studies, which generally involved four
weeks of treatment, the Panel determined that OTC topical antifungal drug
products are most effective in treating athlete’s foot with application twice per
day for 4 weeks. The Panel recommended that six active
ingredients be classified as GRASE based on their review of the studies.
Tentative Final Monograph
The TFM, or proposed rule, was published on December 12, 1989
(Ref. 2). In the TFM, we discussed 25
clinical studies submitted following publication of the ANPR. Six of the 25 studies addressed athlete’s
foot. Based on these studies, we agreed
with the Panel’s recommended conditions of use except with regard to two active
ingredients. we disagreed with the Panel
and did not propose nystatin as GRASE. we
also proposed to include povidone-iodine as GRASE based on clinical studies.
Final Monograph
The FM, or final rule, was published on
· clioquinol
3%
· haloprogin
1%
· miconazole
nitrate 2%
· povidone-iodine
10%
· tolnaftate
1%
· undecylenic
acid and its salts (calcium, copper, and zinc) for a total undecylenate
concentration of 10-25%
We found all
other ingredients considered in this rulemaking not to be GRASE for use in an
OTC topical antifungal drug product. In
addition, the FM includes labeling similar to that recommended by the Panel in
the ANPR. All of the active ingredients are
indicated for the treatment of athlete’s foot as well as the relief of symptoms
due to athlete’s foot. One active
ingredient, tolfaftate, is indicated for the prevention of athlete’s foot. In addition, the active ingredients are
indicated for the treatment of ringworm (tinea corporis) and jock itch (tinea
cruris).
Final Monograph Amendment: “cures
most” indication
Following
publication of the FM, we published a proposed rule and a final rule on July
22, 1999, and August 29, 2000, respectively, to modify labeling of OTC topical
antifungal drug products (Refs. 4 and 5).
The amendment added the word “most” to the indication statement between
the introductory phrase and the name of the condition(s) for which the product
is to be used (e.g., “cures most
athlete’s foot”). We recognized that OTC
topical antifungal drug products do not cure or treat all conditions commonly
thought by consumers to be athlete’s foot or jock itch. We also noted that varying percentages of
subjects were clinically and mycologically cured of athlete’s foot
infection. Inserting a qualifying word (i.e., “most”) into the indication
statement would help inform consumers about what they can expect from these
products. We pointed out that this
amended label is consistent with current labeling approved for OTC vaginal
antifungal drug products marketed under NDAs.
The OTC vaginal antifungal drug product labeling states that the product
“cures most vaginal yeast infections.”
Final Monograph Amendment: Addition
of clotrimazole as an ingredient
In addition to this amendment, on