[Federal Register Volume 66, Number 103 (Tuesday, May 29, 2001)]
[Proposed Rules]
[Pages 29059-29064]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-13299]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

 21 CFR Part 333

[Docket No. 96P-0460]
RIN 0910-AA01


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a proposed 
rule that would amend the final monograph for over-the-counter (OTC) 
topical antifungal drug products to add the ingredient clotrimazole as 
generally recognized as safe and effective for the treatment of 
athlete's foot, jock itch, and ringworm. This proposal is part of FDA's 
ongoing review of OTC drug products.

DATES: Submit written comments by August 27, 2001. Submit written 
comments on the agency's economic impact determination by August 27, 
2001. See section IX of this document for the effective date of any 
final rule that may publish based on this proposal.

ADDRESSES:  Submit written comments to the Docket Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

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 six 
antifungal active ingredients used for the treatment of athlete's foot, 
jock itch, and ringworm and one ingredient used for the prevention of 
athlete's foot. The monograph provides that two ingredients may contain 
professional labeling (may be provided to health professionals but not 
to the general public) for the treatment of superficial infections 
caused by yeast (Candida albicans). A manufacturer submitted a citizen 
petition (Refs. 1 through 4) to include the antifungal ingredient 
clotrimazole in the monograph for both the OTC and professional 
labeling treatment claims. Subsequently, the manufacturer withdrew its 
request to include clotrimazole in the monograph for the professional 
labeling treatment claim (Ref. 5).

II. The Agency's Evaluation of the Citizen Petition

A. General Background

    Clotrimazole is a member of the imidazole class of antifungal drugs 
and is recognized in the U.S. Pharmacopeia (Ref. 6). Clotrimazole has 
been marketed as a topical antifungal at a 1-percent concentration in 
the United States as a prescription product since 1975 and as an OTC 
product since 1989 under new drug applications (NDAs) in cream, lotion, 
and solution dosage forms. The agency notes that clotrimazole has also 
been marketed OTC in a number of other countries, the first marketing 
occurring in 1980. Distribution figures (Ref. 1) indicate a significant 
amount of the drug has been marketed OTC in the United States and other 
countries since 1990. Miconazole nitrate, a related member of the 
imidazole class of antifungal drugs, is currently included as an active 
ingredient in Sec. 333.210(c) of the final monograph for OTC topical 
antifungal drug products.

B. Safety

    The toxicity of clotrimazole has been well-studied (Refs. 1 and 2). 
Acute

[[Page 29060]]

toxicity has been studied in a variety of animal species. When 
administered intraperitoneally, the LD50 was approximately 500 
milligrams/kilogram (mg/kg) for mice and 1,200 mg/kg for rats. Subacute 
dermal toxicity studies in rabbits (comparing clotrimazole cream or 
solution to its vehicle) did not reveal any significant dermal or 
systemic changes. Other dermal tolerance studies showed minimal 
irritation from clotrimazole, and they showed that skin reactions on 
rabbits were essentially the same for the drug and the vehicle cream, 
solution, or lotion. Ocular tolerance studies in rabbits showed slight 
conjunctival reddening and mild irritation for both clotrimazole cream 
or solution and its vehicle, which subsided 48 to 72 hours after 
instillation.
    Studies have shown clotrimazole is very poorly absorbed following 
dermal application. Duhm et al. (Ref. 7) reported that topical 
administration of radiolabeled 1-percent clotrimazole cream or solution 
to normal skin resulted in less than 0.5 percent of the activity 
excreted in the urine up to 5 days after application of the cream and 
less than 0.05 percent up to 4 days after application of the solution. 
When the solution was applied to acutely inflamed skin, 0.15 percent of 
the activity was excreted in the urine. This amount was slightly higher 
than after applying the solution to normal skin. In all subjects, 
urinary excretion was largely completed 2 to 3 days after application. 
No definitely measurable amounts of radioactivity were found in the 
serum of any of the subjects in whom the radiolabeled clotrimazole 
cream or solution was applied to intact or inflamed skin until 48 hours 
after application. The equivalent clotrimazole concentrations were 
below the detection limit of 0.001 microgram of clotrimazole per 
milliliter (mL) of serum.
    Reproduction studies in animals showed, in general, that 
clotrimazole was well tolerated and had no teratogenic effect. All 
reproduction studies (Ref. 1) were done with oral dosing, 25 to 200 mg/
kg in mice and rats and 60 to 180 mg/kg in rabbits. The only adverse 
effects noted were: (1) Lower fetal weights and more resorptions in 
rats given 100 mg/kg, and (2) clotrimazole at 200 mg/kg was lethal to 
pregnant rats. Mutagenic studies in Chinese hamsters showed that 
clotrimazole had no mutagenic effect. An 18-month oral dosing study of 
clotrimazole in rats did not show any carcinogenic effect.
    Clotrimazole has an excellent safety record during its 24-year 
history of marketing as a prescription and OTC topical antifungal drug 
in the United States. The manufacturer has reported 555 adverse drug 
events (ADEs) from March 1975 through March 1996. Of these, 240 (43 
percent) are reports of ``therapeutic response decrease'' (lack of 
effectiveness) with topical antifungal treatment. The majority of the 
ADEs were topical and nonserious in nature. Pruritis (itching), rashes, 
erythema (abnormal redness of the skin), and paresthesia (abnormal 
sensation of the skin, such as burning, stinging, or tingling) were the 
most common events reported and are common to all topical antifungal 
drugs. Rarely, individuals experienced a systemic allergic reaction. 
The number and nature of reported ADEs is similar before and after 
clotrimazole OTC marketing in the United States began in 1989.
    The contact sensitization potential of 1-percent clotrimazole cream 
was determined using the Maximization Test (26 subjects) and the Draize 
Repeat Insult Test (207 subjects) (Ref. 2). No sensitization occurred 
in either test. There are no known drug interactions, abuse potential, 
or overdose potential associated with clotrimazole when applied 
topically to the skin for antifungal use. There have been infrequent 
reports of consumers mistaking the solution (10 mL container) product 
for eye drops and instilling it in their eyes. All eye effects reported 
have been minor and transient and were completely relieved by flushing 
the eye with water or the passing of a short period of time. Although 
these effects have been minor, Sec. 333.250(c)(1)(iii) of the monograph 
for OTC topical antifungal drug products includes the warning: ``Avoid 
contact with the eyes.''

C. Effectiveness

    Clotrimazole has been shown in a number of controlled studies to be 
an effective OTC topical treatment for tinea pedis (athlete's foot), 
tinea cruris (jock itch), and tinea corporis (ringworm). The causative 
organisms in these studies were primarily the same organisms for which 
clotrimazole is indicated: Trichophyton rubrum (T. rubrum), 
Trichophyton mentagrophytes (T. mentagrophytes), and Epidermophyton 
floccosum (E. floccosum).
    Knox, Zaias, and Battistini (Refs. 2 and 3, Delbay 004) compared 
the antifungal effectiveness of 1-percent topical clotrimazole with its 
vehicle in 71 subjects (61 subsequently acceptable for efficacy 
evaluation) who had ringworm (16), jock itch (15), ringworm and jock 
itch (7), and athlete's foot (23). The fungus infections were 
mycologically confirmed by KOH (potassium hydroxide) preparation and/or 
culture. Subjects applied the assigned products (double-blind, 
randomized, parallel study) twice a day for 28 days and were evaluated 
clinically weekly for 5 weeks, with samples taken each week for KOH 
preparation and culture. Of the 61 cases (27 on active and 34 on 
vehicle) evaluated, mycological conversion rates (a change from 
positive to negative of both KOH preparation and culture) for tinea 
corporis/cruris were 76 percent (13/17) for active and 5 percent (1/21) 
for vehicle (P0.001) and for tinea pedis 60 percent (6/10) for active 
and 0 (0/13) for vehicle (P=0.002). The fungus most frequently detected 
was T. rubrum. Eight of 12 subjects (67 percent) in the clotrimazole 
group who had severe clinical signs and symptoms were clinically cured 
compared to 0 of 14 in the vehicle group (P=0.0003).
    Clayton and Connor (Refs. 2, 3, 4, and 8, Delbay 007) compared 1-
percent clotrimazole cream (50 subjects) to Whitfield's Ointment (3-
percent salicylic acid and 6-percent benzoic acid) (52 subjects) and to 
nystatin ointment (14 subjects) in treating several fungal infections 
in a randomized, double-blind trial based on the subject's condition. 
Subjects with mycologically positive skin infection (by culture and/or 
microscopy of skin scrapings) were assigned to a test medication 
depending on their diagnosis. The nystatin ointment arm of the study 
did not include any subjects with tinea infections and, thus, is not 
discussed further. Subjects with a fungal infection applied 
clotrimazole cream or Whitfield's Ointment twice daily for 28 days. 
Followup examinations were conducted at 2, 4, and 8 weeks for most 
subjects. There were 100 evaluations of subjects who had ringworm/jock 
itch and athlete's foot (some subjects had both) and who applied 
clotrimazole or Whitfield's Ointment. Mycological conversion rates for 
subjects with ringworm/jock itch were 65 percent (13/20) for 
clotrimazole and 63 percent (12/19) for Whitfield's Ointment (P=1.00), 
and for subjects with athlete's foot 63 percent (19/30) for 
clotrimazole and 58 percent (18/31) for Whitfield's Ointment (P=0.795). 
There were no statistically significant differences between the 
treatments, and the 1-percent clotrimazole cream was considered as 
effective as Whitfield's Ointment, the accepted treatment available at 
that time, for treating tinea infections. The investigators noted that 
there were a greater number of side effects, usually mild irritation or 
burning, with the Whitfield's Ointment (14 of 52 subjects) than with 
the clotrimazole cream. Some

[[Page 29061]]

subjects had no side effects, while others had more than one. The total 
of 116 represents side effects recorded for subjects at any visit.
    Smith et al. (Refs. 2, 3, and 4, Delbay 003) compared the 
antifungal and clinical effectiveness of 1-percent clotrimazole topical 
solution against its vehicle (polyethylene glycol 400) in a randomized, 
double-blind study in 169 subjects, of which 131 were eventually 
evaluated. Thirty eight subjects were excluded from the study for 
various reasons, with almost half of these lost to followup. Fungal 
infections were confirmed by KOH preparation and/or culture; 120 
subjects had fungal infections (11 had candidiasis). Subjects applied 
the test solutions twice daily for 28 days (65 used the active and 66 
used the vehicle). Effectiveness was determined on the basis of 
mycological findings, clinical findings (severity of signs and 
symptoms), and overall assessment of the treatment. Mycological 
conversion rates for subjects with tinea corporis/cruris were 96 
percent (27/28) for the active and 34 percent (10/29) for the vehicle 
(P0.001). The conversion rates for subjects with tinea pedis were 39 
percent (12/31) for the active and 25 percent (8/32) for the vehicle. 
Weekly sign and symptom severity was evaluated on a scale of 1 (= none) 
to 4 (= severe). The weekly average for clotrimazole subjects declined 
from 3.25 at week 0 to 1.82 at week 4, while placebo declined from 3.14 
to 2.52 for the same times (P=0.009). The authors stated that the 
treatment results clearly demonstrated the mycological and clinical 
effectiveness of the 1-percent clotrimazole solution and that the 
product was tolerated very well. The agency has some concerns about the 
usefulness of the clinical data as a scale of weekly averages of signs 
and symptoms. This information does not enable a determination to be 
made whether the subjects were actually clinically cured or just 
clinically improved. While the data lack sufficient clinical meaning 
for the agency to consider this a primary supportive study, the agency 
considers this study partially supportive of tinea corporis/cruris 
claims, but not tinea pedis claims. Tinea pedis claims are supported by 
other studies discussed in this document.
    Smith and Knox (Refs. 2 and 3, Delbay 005) used the clotrimazole 
solution to continue to treat 22 subjects from the previous study who 
failed to respond mycologically to the vehicle solution in an open, 
mycologically controlled study with no control group. The drug was 
applied twice a day for 2 to 6 weeks depending on the clinical 
response. Eight subjects' fungal infections cleared completely both 
mycologically and clinically; 4 became negative mycologically and 
improved clinically, but did not heal completely; and 10 improved 
clinically but had residual positive mycology. None of the subjects 
reported any adverse events due to the drug. The agency finds that this 
study lacked sufficient details to be useful to support effectiveness.
    Eaglestein et al. (Refs. 2, 3, and 4, Delbay 008) compared the 
antifungal and clinical effectiveness of 1-percent clotrimazole topical 
solution to its vehicle in a study of 124 subjects with tinea corporis/
cruris using essentially the same design as the Smith et al. study 
(Delbay 003). Of these, 36 were not included in the final evaluation 
(14 were lost to followup and 22 were treated for a longer or shorter 
period than the 4 weeks stipulated in the protocol). Of the 88 subjects 
who met all of the criteria for evaluation of effectiveness, 29 had 
ringworm, 51 had jock itch, and 8 had both conditions; 42 of these 
subjects used the active and 46 used the vehicle. After 28 days of 
treatment, the mycological conversion rates were 88 percent (37 of 42) 
for the active and 28 percent (13 of 46) for the vehicle (P0.001). The 
primary fungus detected was T. rubrum. The clinical investigators 
evaluated overall severity of clinical signs and symptoms (e.g., 
scaling, itching, inflammation) and indicated that 40 of 41 
clotrimazole subjects improved clinically, compared to 24 of 45 vehicle 
subjects (P0.001). One subject in each group could not be evaluated in 
this regard because a pretreatment severity was not specified. The 
clinical investigators' assessment of the treatment was that 34 of 42 
clotrimazole subjects were healed clinically compared to 7 of 46 
vehicle subjects (P0.001). The authors stated that the results 
indicated that 1-percent clotrimazole solution is very effective for 
topical treatment of ringworm, especially on smooth and bare skin. The 
agency finds this study supportive of a ringworm claim.
     Eaglestein et al. (Refs. 2, 3, and 4, Delbay 008) compared the 
anitfungal and clinical effectiveness of 1-percent clotrimazole topical 
solution to its vehicle in a study of 124 subjects with tinea corporis/
crutis using essentially the same design as the Smith et al. study 
(Delbay 003). Eaglestein et al. (Ref. 2, Delbay 011 and 012) compared 
the antifungal and clinical effectiveness of 1-percent clotrimazole 
topical solution to its vehicle in subjects with two nonvesicular types 
of tinea pedis: (1) Plantar hyperkeratosis (moccasin), and (2) 
interdigital and/or instep, using the same design as the Smith et al. 
study (Delbay 003). The mycological conversion rates for subjects with 
plantar hyperkeratosis were 76 percent (28 of 37) for the clotrimazole 
group and 39 percent (16 of 41) for the vehicle group (P=0.001) and for 
subjects with interdigital and/or instep were 66 percent (23 of 35) for 
the drug group and 39 percent (13 of 33) for the vehicle group 
(P=0.026). Thirty of 37 (80 percent) drug treated subjects with plantar 
hyperkeratosis improved clinically compared to 24 of 41 (59 percent) 
vehicle subjects (P=0.027), while 22 of 34 (65 percent) drug treated 
subjects with interdigital and/or instep improved clinically compared 
to 20 of 33 (61 percent) vehicle subjects (not statistically 
significant). While the fungi most frequently detected in the subjects 
were T. rubrum and T. mentagrophytes, organisms for which the drug is 
indicated for OTC use, the OTC product labeling does not include claims 
for plantar hyperkeratosis or interdigital and/or instep tinea pedis. 
Thus, these studies provide support but do not establish effectiveness 
for OTC use.
    Fredriksson (Ref. 9) compared the antifungal and clinical 
effectiveness of 1-percent clotrimazole topical solution to its vehicle 
in a randomized, double-blind, parallel study in 54 subjects. Half of 
the subjects had tinea infections: Tinea pedis (17), tinea cruris (8), 
tinea corporis (1), and tinea capitis (1). T. rubrum was the fungus 
most frequently detected. The 27 subjects applied test products (17 
used clotrimazole and 10 used placebo) twice daily for 21 days, at 
which time the study was decoded. The 10 vehicle-treated failures were 
then crossed-over to an open study with clotrimazole treatment for 
another 21 days. After 3 weeks of applying the 1-percent clotrimazole 
solution, all 27 subjects (both the initial active group and crossover 
vehicle failures) with tinea infections were mycologically cured, and 
19 of the 27 subjects (70 percent) had no clinical evidence of disease. 
The agency considers this study supportive of effectiveness.
    The Advisory Review Panel on OTC Antimicrobial (II) Drug Products 
(the Panel) discussed two studies involving clotrimazole (Refs. 10 and 
11) in its evaluation of haloprogin (47 FR 12480 at 12493 and 12494, 
March 23, 1982). One double-blind, clinical study (Ref. 10) compared 
the effectiveness of 1-percent clotrimazole solution with 1-percent 
haloprogin solution (the topical antifungal drug product monograph 
concentration in Sec.  333.210(b)). Based on the results of the study, 
the authors concluded that clotrimazole was

[[Page 29062]]

significantly more effective than haloprogin for jock itch. The other 
double-blind, randomized study (Ref. 11) compared 1-percent 
clotrimazole cream and solution and 1-percent haloprogin ointment and 
solution in the treatment of subjects with athlete's foot and ringworm 
of the body. The author concluded that there were no marked differences 
in the antifungal effectiveness of clotrimazole and haloprogin.

D. Response to Comment

    One comment (Ref. 12), submitted in response to the citizen 
petition (Ref. 1), opposed monograph status for clotrimazole. The 
comment contended that safety, effectiveness, and therapeutic effect 
will not be assured through the OTC drug monograph process because 
neither bioequivalence nor formulation changes will be monitored by the 
agency. The comment argued that topical antifungal drug products 
present interesting formulation and manufacturing issues and that the 
agency could assure safety, effectiveness, and interchangeability of 
clotrimazole products only through its application preapproval process. 
The comment noted the Panel's discussion about vehicles for OTC topical 
antifungal drug products (47 FR 12480 at 12489 and 12490). The Panel 
discussed types and effects of different vehicles, vehicle solubility 
and viscosity, and the rate of diffusion of an antifungal drug from a 
vehicle.
    The agency disagrees with the comment. The agency does not consider 
the inclusion of clotrimazole in the topical antifungal drug products 
monograph at this time as any different than the previous inclusion of 
the former new drugs haloprogin and miconazole nitrate in the 
monograph. Bioequivalence testing is not required for either of those 
drugs currently marketed under the monograph. Based on the previous 
monograph determinations for haloprogin and micinazole nitrate and the 
marketing of clotrimazole OTC under NDA's since 1989, the agency 
considers all three of these ingredients to have an extensive history 
of safe and effective OTC use. While formulation and manufacturing 
issues for topical products may prevent FDA from allowing monograph 
status, the agency has no evidence at this time to indicate that 
formulation and manufacturing issues have affected the safety and 
effectiveness of clotrimazole.
    The Panel's discussion about vehicles for these products was based 
on the Panel's general knowledge. Data on specific vehicles were not 
submitted to or reviewed by the Panel. No comments were received on the 
Panel's discussion about vehicles for these products, and this issue 
did not arise further in the rulemaking in determining which antifungal 
ingredients could be included in the final monograph. The agency 
monitors the quality of all products marketed under OTC drug monographs 
through its current good manufacturing practice regulations in 21 CFR 
part 211 and its inspection authority. If clotrimazole is marketed 
under the final monograph, the agency will monitor the quality of 
clotrimazole products in the same manner as other products currently 
marketed under the monograph.

E. Labeling

    Since 1989, antifungal drug products containing clotrimazole 1 
percent have been marketed OTC in the United States with indications 
for the treatment of athlete's foot (tinea pedis), jock itch (tinea 
cruris), and ringworm (tinea corporis). The warnings and directions in 
the approved applications for these products are very similar to those 
contained in Sec. 333.250(c) and (d) of the final monograph for OTC 
antifungal drug products. If a manufacturer chooses to market its 
clotrimazole product that is currently marketed OTC under an approved 
application under the monograph in the future, it will have to modify 
the product's labeling to conform to the OTC drug monograph labeling in 
Sec. 333.250. In either case, the manufacturer will need to follow the 
new OTC drug content and format labeling requirements in Sec. 201.66 
(21 CFR 201.66).

III. The Agency's Tentative Conclusions and Proposals

    The agency has determined that clotrimazole has been marketed to a 
material extent and for a material time as a topical antifungal drug 
and, based on the available data, can be generally recognized as safe 
and effective for this use and included in the OTC drug monograph for 
this class of products. Therefore, the agency is proposing to add 
clotrimazole 1 percent as new paragraph (g) in Sec. 333.210.
    The agency is allowing interim marketing of OTC topical antifungal 
drug products containing 1-percent clotrimazole with claims for the 
treatment of athlete's foot (tinea pedis), jock itch (tinea cruris), 
and ringworm (tinea corporis) to begin with the publication of this 
proposal to amend the monograph based on the OTC marketing experience 
in the United States since 1989 and because there are no labeling 
issues to be addressed at this time. Such interim marketing is subject 
to the risk that the agency may adopt a different position in the final 
rule that could require relabeling, recall, or other regulatory action. 
Any product containing clotrimazole that is marketed under the 
monograph before a final rule is issued must use all of the labeling 
that is required by the final monograph (part 333, subpart C) and must 
follow the content and format requirements in Sec. 201.66.
    This proposal does not apply to clotrimazole marketed OTC as an 
antifungal agent in intravaginal drug products labeled for the 
treatment of vaginal yeast infections. The existing monograph for 
topical antifungal drug products does not contain any claims for 
intravaginal use.

IV. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.

    1. Comment No. CP1, Docket No. 96P-0460, Dockets Management 
Branch.
    2. Comment No. SUP1, Docket No. 96P-0460, Dockets Management 
Branch.
    3. Comment No. LET3, Docket No. 96P-0460, Dockets Management 
Branch.
    4. Comment No. LET4, Docket No. 96P-0460, Dockets Management 
Branch.
    5. Comment No. LET5, Docket No. 96P-0460, Dockets Management 
Branch.
    6. The United States Pharmacopeia 24-The National Formulary 19, 
The United States Pharmacopeial Convention, Inc., Rockville, MD, p. 
451, 1999.
    7. Duhm, B. et al., ``Pharmacokinetics of Topically Applied 
Bisphenyl-(2-chlorophenyl) -1-imidazolyl-methane-[14C],'' 
Arzneittelforschung, 22:1289-191, 1972, English version, Drugs Made 
in Germany, 15:126-132, 1972.
    8. Clayton, Y. M. and B. L. Connor, ``Comparison of Clotrimazole 
Cream, Whitfield's Ointment and Nystatin Ointment for the Topical 
Treatment of Ringworm Infections, Pityriasis Versicolor, Erythrasma, 
and Candidiasis,'' British Journal of Dermatology, 89:297-303, 1973.
    9. Fredriksson, T., ``Topical Treatment with Bay b 5097, A New 
Broad Spectrum Antimycotic Agent,'' British Journal of Dermatology, 
86:628-630, 1972.
    10. Van Dersarl, J. V. and R. H. Sheppard, ``Clotrimazole vs. 
Haloprogin Treatment of Tinea Cruris,'' Archives of Dermatology, 
113:1233-1235, 1977.
    11. Weitgasser, H., ``Clinical and Mycologic Trials with the 
Antifungal Medication Haloprogin,'' Mykosen, 20:15-24, 1977.
    12. Comment No. C1, Docket No. 96P-0460, Dockets Management 
Branch.

V. Analysis of Impacts

    FDA has examined the impacts of this proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5

[[Page 29063]]

U.S.C. 601-612) (as amended by subtitle D of the Small Business and 
Regulatory Fairness Act of 1996 (Public Law 104-121)), and the Unfunded 
Mandates Reform Act of 1995 (Public Law 104-4) (2 U.S.C. 1501 et 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 proposed rule is consistent with the 
regulatory philosophy and principles identified in the Executive Order. 
In addition, the proposed rule is not a significant regulatory action 
as defined by the Executive Order, as explained below, and so is not 
subject to review under the Executive Order.
    The purpose of this proposed rule is to include clotrimazole 1 
percent in the monograph for OTC topical antifungal drug products. This 
proposal allows current manufacturers of these products to market their 
products under the OTC drug monograph instead of an NDA and enables 
other manufacturers who wish to market clotrimazole products OTC to 
enter the marketplace without having to obtain an NDA. In both cases, 
there will be cost savings from marketing without an NDA.
    If current manufacturers of these products choose to market them 
under the OTC drug monograph, they should incur only minor costs to 
relabel their products to meet the monograph. Some manufacturers may 
have to add a warning that was included in the final monograph, but not 
required when some products containing clotrimazole were approved for 
OTC marketing under an NDA. These manufacturers can make this change 
whenever they are ready to order new product labeling. Manufacturers 
have informed the agency that this type of relabeling cost generally 
averages about $2,000 to $3,000 per stock keeping unit (SKU) 
(individual products, packages, and sizes). Based on information in the 
agency's Drug Listing System, there are less than 10 manufacturers and 
distributors that together produce about 25 SKU's of OTC topical 
antifungal drug products that contain clotrimazole. Assuming that there 
are about 25 affected OTC SKU's in the marketplace, total one-time 
costs of relabeling would be $50,000 to $75,000 if the manufacturers of 
these products changed their marketing from under an approved 
application to under the OTC drug monograph. In making this change, 
these manufacturers would save money by eliminating all costs 
associated with maintaining an application. Likewise, other 
manufacturers who now wish to market topical clotrimazole drug products 
will be able to enter the marketplace without the costs associated with 
an application. Their costs would involve the standard start-up costs 
of any OTC drug marketed under the monograph.
    The agency considered but rejected several alternatives: (1) Not 
including clotrimazole in the monograph, (2) a longer implementation 
period, and (3) no interim marketing. The agency rejected the first 
alternative because it considers the data presented supportive of 
monograph status. The agency does not see a need for the second or 
third alternatives because these clotrimazole drug products are already 
marketed OTC under approved applications and compendial standards 
currently exist for clotrimazole. The agency does not consider an 
exemption for small entities necessary because those manufacturers can 
enter the marketplace under the monograph at any time.
    Under the Unfunded Mandates Reform Act, FDA is not required to 
prepare a statement of costs and benefits for this proposed rule 
because this proposed 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 initial 
regulatory flexibility analysis, as required under the Regulatory 
Flexibility Act.

VI. Paperwork Reduction Act of 1995

    FDA tentatively concludes that the labeling requirements for 
clotrimazole 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 existing monograph labeling is 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)).

VII. 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.

VIII. Request for Comments

    Interested persons may submit to the Dockets Management Branch 
(address above) written comments regarding the proposal by August 27, 
2001. Written comments on the agency's economic impact determination 
may be submitted on or before August 27, 2001. Three copies of all 
comments are to be submitted, except that individuals may submit one 
copy. Comments are to be identified with the docket number found in 
brackets in the heading of this document and may be accompanied by a 
supporting memorandum or brief. Received comments may be seen in the 
office above between 9 a.m. and 4 p.m., Monday through Friday.

IX. Proposed Effective Date

    The agency is proposing that any final rule that may issue based on 
this proposal become effective 30 days after its date of publication in 
the Federal Register.

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, it is 
proposed that 21 CFR part 333 be 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 333.210 is amended by adding paragraph (g) to read as 
follows:


Sec. 333.210  Antifungal active ingredients.

* * * * *
    (g) Clotrimazole 1 percent.


[[Page 29064]]


    Dated: May 17, 2001.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 01-13299 Filed 5-25-01; 8:45 am]
BILLING CODE 4160-01-S