[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