[Federal Register Volume 65, Number 168 (Tuesday, August 29, 2000)]
[Rules and Regulations]
[Pages 52302-52305]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-21896]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 333

[Docket No. 99N-1819]
RIN 0910-AA01


Topical Antifungal Drug Products for Over-the-Counter Human Use; 
Amendment of Final Monograph

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule 
amending the monograph for over-the-counter (OTC) topical antifungal 
drug products. The amendment makes a minor change in the indications 
for these drug products. This final rule is part of the ongoing review 
of OTC drug products conducted by FDA.

DATES: This regulation is effective May 16, 2002. The compliance date 
for products with annual sales less than $25,000 is May 16, 2003. The 
compliance date for all other OTC drug products is May 16, 2002.

FOR FURTHER INFORMATION CONTACT: Gerald M. Rachanow, Center for Drug 
Evaluation and Research (HFD-560), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2307.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of September 23, 1993 (58 FR 49890), FDA 
published a final monograph for OTC topical antifungal drug products in 
part 333 (21 CFR part 333), subpart C. That monograph includes labeling 
in Sec. 333.250. Section 333.250(b)(1) contains the following 
introductory language for the indications statement: (Select one of the 
following: ``Treats,'' ``For the treatment of,'' ``For effective 
treatment of,'' ``Cures,'' ``For the cure of,'' ``Clears up,'' or 
``Proven clinically effective in the treatment of''). Section 
333.250(b)(2) contains similar language for products labeled for the 
prevention of athlete's foot.
    In the Federal Register of July 22, 1999 (64 FR 39452), FDA 
published a proposed amendment of the monograph for OTC topical 
antifungal drug products to revise the indications in 
Sec. 333.250(b)(1)(i) and (b)(2)(i). The proposed revision added the 
word ``most'' after the introductory parenthetical ``Select one of the 
following'' choices and before the name

[[Page 52303]]

of the condition(s) for which the product is to be used. The agency 
also proposed to add the word ``most'' in Sec. 333.250(b)(2)(ii) after 
the word ``up'' and before ``athlete's foot.'' The agency explained 
that topical antifungal drug products will not cure or treat all 
conditions commonly thought by consumers to be athlete's foot or jock 
itch and that the revised labeling will more accurately inform 
consumers what they can expect from using these products. The agency 
stated that this approach is consistent with the current labeling 
approved for OTC vaginal antifungal drug products under new drug 
applications, which states ``cures most vaginal yeast infections.''
    Interested persons were invited to submit comments on the proposal 
and on the agency's economic impact determination by October 20, 1999. 
In response to the proposed monograph amendment, one trade association 
of OTC drug manufacturers submitted a comment, a copy of which is on 
public display in the Dockets Management Branch (HFA-305), Food and 
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    The agency has considered the comment in proceeding with this final 
rule. A summary of the comment with FDA's response follows.

II. Summary of the Comment Received

    The comment requested FDA to decide against the proposed amendment 
for several reasons:
    1. Scientific documentation is lacking to show that adding the 
qualifier ``most'' would meet an important consumer need or is 
important for safe and effective use of these products. The comment 
noted that in the tentative final monograph for OTC topical antifungal 
drug products (54 FR 51136 at 51154, December 12, 1989) the agency 
stated that the statement ``kills most athlete's foot fungi'' described 
the performance of the product and was not related in a significant way 
to the safe and effective use of antifungal drug products that are 
already labeled with the required information. The comment contended 
that FDA did not provide information showing that addition of the word 
``most'' relates in a significant way to the safe and effective use of 
OTC topical antifungal drug products or would have any value in 
assisting consumers to better use these products.
    2. The use of a qualified indication statement resulting from 
addition of the word ``most'' is unprecedented in the OTC drug review. 
The comment noted that no other OTC drug monograph requires a statement 
that qualifies the effect of a drug category and questioned why topical 
antifungal drug products are now an exception to this labeling policy 
that has consistently omitted effectiveness qualifiers.
    3. A qualified indications statement is potentially misleading, in 
that it implies inherent lack of efficacy of the active ingredient or 
questionable effectiveness of the drug product. The comment contended 
that this approach is inconsistent with the regulatory definition of 
effectiveness for OTC drug monograph products in Sec. 330.10(a)(4)(ii) 
(21 CFR 330.10(a)(4)(ii)), which states: ``Effectiveness means a 
reasonable expectation that, in a significant proportion of the target 
population, the pharmacological effect of the drug, when used under 
adequate directions for use and warnings against unsafe use, will 
provide clinically significant relief of the type claimed.'' The 
comment argued that the standard for effectiveness does not require 
that every user of an OTC topical antifungal drug product gets complete 
relief (or prevention) for the condition for which he or she chose the 
product. The comment added that the monograph already requires a 
warning statement to consult a doctor if the product is not effective 
within the recommended treatment period.
    4. Differences in labeling would occur between OTC drug products 
marketed under the monograph versus marketed under an approved 
application, resulting in consumer confusion. The comment noted that 
the amendment applies only to the monograph products and that FDA 
should coordinate label changes for all OTC products within a 
therapeutic category. The comment added that if monograph product 
labels are inconsistent with new drug application product labels for 
the same category of products, consumers could mistakenly believe that 
the monograph products are less effective because they are labeled to 
treat only ``most'' covered conditions.

III. The Agency's Response to the Comment and Final Conclusions

    The agency disagrees with the comment's request to decide against 
the proposed amendment and is responding to the comment's reasons in 
the order in which they appear in section II of this document.
    1. As stated in the proposed amendment (64 FR 39452), the agency 
believes that addition of the qualifier ``most'' to the indications for 
OTC antifungal drug products would more accurately inform consumers 
what they can expect from using these products. When it proposed this 
labeling revision, the agency was aware of previous labeling claims it 
had discussed in the tentative final monograph (54 FR 51136 at 51154), 
as noted by the comment. The agency stated, at that time, that the 
claim ``kills most athlete's foot fungi'' was one of a number of claims 
that did not relate in a significant way to the safe and effective use 
of antifungal drug products that are labeled with the required 
information.
    The agency notes that the Advisory Review Panel on OTC 
Antimicrobial (II) Drug Products (the Panel) discussed this claim in 
its report (47 FR 12480 at 12511, March 23, 1982). The Panel stated 
that ``Many claims would appear to be acceptable; however, certain 
modifying words can make these claims unclear or even imprecise. For 
this reason, modifiers such as `most' or `fast' are not allowed.'' The 
Panel then listed the claim ``kills most athlete's foot fungi'' as 
unacceptable.
    As noted in the proposed amendment (64 FR 39452), the word ``most'' 
is currently used in the labeling of OTC vaginal antifungal drug 
products, which are marketed under new drug applications. This labeling 
has been in effect since late 1990 when these products were initially 
approved for OTC marketing. In making its decision to include the word 
``most'' in the labeling of these products, the agency disagreed with 
the Panel and its previous position stated in the tentative final 
monograph for OTC antifungal drug products. The agency now considers it 
imprecise not to state in the labeling of all OTC antifungal drug 
products that they treat or cure or prevent ``most'' athlete's foot 
[and the other treatment claims listed in the monograph]. As discussed 
in the proposal (64 FR 39452), topical antifungal drug products will 
not cure or treat all conditions commonly thought by consumers to be 
athlete's foot or jock itch. In addition, data reviewed by the Panel 
for the various monograph ingredients showed that varying percentages 
of subjects were clinically and mycologically ``cured.'' The agency, 
therefore, concludes that inclusion of the word ``most'' in the 
labeling of these products is related to their effective use and will 
assist consumers in knowing better what to expect from using these 
products.
    2. The agency disagrees with the comment's assertion that it is the 
agency's policy to omit effectiveness qualifiers. In addition, the use 
of a qualified indication statement resulting from addition of the word 
``most'' is not unprecedented in the OTC drug review. The final 
monograph for OTC topical acne drug products contains the following 
indication statement in

[[Page 52304]]

Sec. 333.350(b)(2)(ii): ``Penetrates pores to'' (select one of the 
following: ``eliminate most,'' ``control,'' ``clear most,'' or ``reduce 
the number of'') (select one or more of the following: ``acne 
blemishes,'' ``acne pimples,'' ``blackheads,'' or ``whiteheads''). The 
agency notes that both acne and antifungal drug products are included 
in the same part 333 of the Code of Federal Regulations, entitled 
``topical antimicrobial drug products for over-the-counter human use.'' 
As discussed above, the agency concludes that the qualifier ``most'' 
will assist consumers in knowing better what to expect from using these 
products.
    3. The agency disagrees that a qualified indications statement is 
potentially misleading or that it implies inherent lack of efficacy of 
the active ingredient or questionable effectiveness of the drug 
product. The regulatory definition of effectiveness in 
Sec. 330.10(a)(4)(ii) (see section II.3 of this document) provides 
sufficient latitude for the word ``most'' in describing the 
pharmacological effect of the drug and relief of the type claimed. Many 
indications in OTC drug monographs contain qualifiers of one kind or 
another, e.g., ``helps,'' ``reduces,'' ``occasional,'' ``temporarily,'' 
``temporary relief.'' Even with this qualifier in the indications 
statement, these OTC drug products also contain a warning statement to 
consult a doctor if relief is not obtained, just as the topical 
antifungal drug products do. The agency concludes that the presence of 
such a warning statement in the product's labeling is not a sufficient 
basis not to have a qualified indications statement.
    4. The agency does not intend for labeling differences to occur 
between topical antifungal drug products marketed under the monograph 
or an approved application. While the amendment applies only to the 
monograph products, the agency intends to notify all holders of 
approved new drug applications for OTC topical antifungal drug products 
to revise their product labeling in accord with the monograph by the 
effective date of the amendment. Thus, the labeling changes will have a 
coordinated effective date, and consumer confusion should not occur.
    In conclusion, the agency is finalizing its proposal to amend the 
monograph indications statements by inserting the word ``most'' between 
the introductory phrase and the name of the condition(s) for which the 
OTC topical antifungal drug product is to be used. Accordingly, the 
agency is revising the indications in Sec. 333.250(b)(1)(i) and 
(b)(2)(i) to add the word ``most'' after the introductory parenthetical 
``Select one of the following'' choices and in Sec. 333.250(b)(2)(ii) 
to add the word ``most'' after the word ``up.'' This ``treats most'' or 
``cures most'' language must also be used whenever the alternative 
labeling approach allowed by Sec. 330.1(c)(2) (21 CFR 330.1(c)(2)) is 
used or whenever a general statement containing this information 
appears in the labeling of the product (e.g., on the principal display 
panel).

IV. Analysis of Impacts

    FDA has examined the impacts of this final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501et seq.). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Under the Regulatory 
Flexibility Act, if a rule has a significant economic impact on a 
substantial number of small entities, an agency must analyze regulatory 
options that would minimize any significant impact of the rule on small 
entities. Section 202(a) of the Unfunded Mandates Reform Act requires 
that agencies prepare a written statement and economic analysis before 
proposing any rule that may result in an expenditure in any one year by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100 million (adjusted annually for inflation).
    The agency believes that this final rule is consistent with the 
regulatory philosophy and principles identified in the Executive Order. 
In addition, the final rule is not a significant regulatory action as 
defined by the Executive Order and so is not subject to review under 
the Executive Order.
    The purpose of this final rule is to make a minor revision in the 
indications for OTC topical antifungal drug products. This revision 
should improve consumers' self use of these products by better 
informing them about what they can expect from using the products.
    The agency stated in the proposal that manufacturers of these 
products will incur minor costs to relabel their products to revise the 
indications statement and, in some cases, other statements that appear 
in product labeling (64 FR 39452 at 39453). The agency indicated that 
relabeling costs of the type required by this rule generally average 
about $2,000 to $3,000 per stockkeeping unit (SKU) (individual 
products, packages, and sizes). In determining this cost, the agency 
did not believe that manufacturers would need to increase the package 
size to make this minor labeling revision. Almost all of these products 
are marketed in an outer carton which should have adequate space for 
the minor labeling revision. The agency noted that approximately 50 
manufacturers produce about 200 SKU's of OTC topical antifungal drug 
products marketed under the monograph. There may be a few additional 
small manufacturers or products in the marketplace that are not 
identified in the sources FDA reviewed. Assuming that there are about 
200 affected OTC SKU's in the marketplace, FDA estimated that the rule 
would impose total one-time compliance costs on industry for relabeling 
of about $400,000 to $600,000. The agency did not receive any comments 
on these estimates.
    The agency believes the actual cost could be lower for several 
reasons. First, most of the label changes will be made by private label 
small manufacturers that tend to use simpler and less expensive 
labeling. However, the final rule will not require any new reporting 
and recordkeeping activities. Therefore, no additional professional 
skills are needed. Second, the agency has made the compliance dates for 
this final rule the same as the dates for these monographed products to 
be in compliance with the new standardized format and standardized 
content requirements for the labeling of OTC drug products (21 CFR 
201.66), which are now May 16, 2002 (and May 16, 2003, for products 
with annual sales less than $25,000). Thus, all required labeling 
changes can be made at the same time, thereby reducing the labeling 
cost of this final rule.
    The agency considered but rejected several labeling alternatives: 
(1) A shorter or longer implementation period, and (2) an exemption 
from coverage for small entities. While the agency believes that 
consumers would benefit from having this new labeling in place as soon 
as possible, the agency also acknowledges that coordination of this 
labeling change with implementation of the new OTC ``Drug Facts'' 
labeling may significantly reduce the cost of this final rule. Both a 
shorter and a longer time period for this rule may cost more if firms 
would have to undertake two successive labeling revisions. In addition, 
a longer time period would unnecessarily delay the benefit of the new 
labeling to consumers who self-medicate with these OTC

[[Page 52305]]

antifungal drug products. The agency rejected an exemption for small 
entities because the new labeling information is also needed by 
consumers who purchase products marketed by those entities.
    Under the Unfunded Mandates Reform Act, FDA is not required to 
prepare a statement of costs and benefits for this final rule because 
this final rule is not expected to result in any one-year expenditure 
that would exceed $100 million adjusted for inflation.
    This analysis shows that the agency has considered the burden to 
small entities. Thus, this economic analysis, together with other 
relevant sections of this document, serves as the agency's final 
regulatory flexibility analysis, as required under the Regulatory 
Flexibility Act.

V. Paperwork Reduction Act of 1995

    FDA concludes that the labeling requirements in this final rule are 
not subject to review by the Office of Management and Budget because 
they do not constitute a ``collection of information'' under the 
Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). Rather, the 
indications statements are a ``public disclosure of information 
originally supplied by the Federal Government to the recipient for the 
purpose of disclosure to the public'' (5 CFR 1320.3(c)(2)).

VI. Environmental Impact

    The agency has determined under 21 CFR 25.31(a) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

List of Subjects in 21 CFR Part 333

    Labeling, Over-the-counter drugs.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
333 is amended as follows:

PART 333--TOPICAL ANTIMICROBIAL DRUG PRODUCTS FOR OVER-THE-COUNTER 
HUMAN USE

    1. The authority citation for 21 CFR part 333 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
    2. Section 333.250 is amended by revising paragraphs (b)(1)(i) 
introductory text, (b)(2)(i) introductory text, and (b)(2)(ii) to read 
as follows:


Sec. 333.250  Labeling of antifungal drug products.

* * * * *
    (b) * * *
    (1) * * * (i) (Select one of the following: ``Treats,'' ``For the 
treatment of,'' ``For effective treatment of,'' ``Cures,'' ``For the 
cure of,'' ``Clears up,'' or ``Proven clinically effective in the 
treatment of'') ``most'' (select one condition from any one or more of 
the following groups of conditions:
* * * * *
    (2) * * * (i) (Select one of the following: ``Clinically proven to 
prevent,'' ``Prevents,'' ``Proven effective in the prevention of,'' 
``Helps prevent,'' ``For the prevention of,'' ``For the prophylaxis 
(prevention) of,'' ``Guards against,'' or ``Prevents the recurrence 
of'') ``most'' (select one of the following: ``Athlete's foot,'' 
``athlete's foot (dermatophytosis),'' ``athlete's foot (tinea 
pedis),''' or ``tinea pedis (athlete's foot)'') ``with daily use.''
    (ii) In addition to the information identified in paragraph 
(b)(2)(i) of this section, the labeling of the product may contain the 
following statement: ``Clears up most athlete's foot infection and with 
daily use helps keep it from coming back.''
* * * * *

    Dated: August 15, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-21896 Filed 8-28-00; 8:45 am]
BILLING CODE 4160-01-F