[Federal Register Volume 68, Number 88 (Wednesday, May 7, 2003)]
[Rules and Regulations]
[Pages 24347-24349]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-11285]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310 and 358

[Docket No. 02N-0359]
RIN 0910-AA01


Ingrown Toenail Relief Drug Products for Over-the-Counter Human 
Use

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 
establishing conditions under which over-the-counter (OTC) ingrown 
toenail relief drug products containing sodium sulfide 1 percent in a 
gel vehicle are generally recognized as safe and effective and not 
misbranded. This rule also amends the regulation that lists 
nonmonograph active ingredients in OTC drug products for ingrown 
toenail relief by removing sodium sulfide from that list. This final 
rule is part of FDA's ongoing review of OTC drug products.

DATES: This rule is effective June 6, 2003.

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 9, 1993 (58 FR 47602), FDA 
published a final rule establishing that any ingrown toenail relief 
drug product for OTC human use is not generally recognized as safe and 
effective and is misbranded. (See 21 CFR 310.538.) In that final rule, 
sodium sulfide 1 percent was considered effective but not safe for the 
temporary relief of pain associated with ingrown toenails because of 
its potential for causing adverse reactions, particularly burning 
sensations and skin irritation.
    In the Federal Register of October 4, 2002 (67 FR 62218), after 
reviewing new data that had been submitted, FDA proposed to establish 
conditions under which OTC ingrown toenail relief drug products 
containing sodium sulfide 1 percent in a gel vehicle are generally 
recognized as safe and effective and not misbranded. The product is 
used with a retainer ring to keep the product at the area of 
application. The agency also proposed to amend the regulation (21 CFR 
310.538) that lists nonmonograph active ingredients in OTC drug 
products for ingrown toenail relief by removing sodium sulfide from 
that list.

II. Comments Received in Response to the Proposal

    In response to the proposal, the agency received two comments, 
which are on public display in the Dockets Management Branch (HFA-305), 
Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, 
MD 20852. One comment, from a drug manufacturer, supported the agency's 
proposals and requested that the agency's review of the comments and 
publication of the final rule be completed as expeditiously as 
possible. The second comment, from a consumer, stated that the use of 
the product with a ``restraining'' ring as indicated should have a 
``green light.'' The comment added that there are many people who 
experience the pain of an ingrown toenail, and that these products will 
help.

III. The Agency's Final Conclusions

    The agency concludes that the data support OTC drug monograph 
status for 1 percent sodium sulfide in a gel vehicle applied topically 
for the relief of discomfort (pain) of ingrown toenail. The product is 
used with a retainer ring to keep the product at the area of 
application. Accordingly, the agency is proposing a new monograph in 
part 358, subpart D (21 CFR part 358, subpart D) for ingrown toenail 
relief drug products that includes 1 percent sodium sulfide gel. The 
agency is also amending Sec.  310.538 to state that it no longer 
applies to sodium sulfide.
    Mandating warnings in an OTC drug monograph does not require a 
finding that any or all of the OTC drug products covered by the 
monograph actually caused an adverse event, and FDA does not so find. 
Nor does FDA's requirement of warnings repudiate the prior OTC drug 
monographs and monograph rulemakings under which the affected drug 
products have been lawfully marketed. Rather, as a consumer protection 
agency, FDA has determined that warnings are necessary to ensure that 
these OTC drug products continue to be safe and effective for their 
labeled indications under ordinary conditions of use as those terms are 
defined in the Federal Food, Drug, and Cosmetic Act. This judgment 
balances the benefits of these drug products against their potential 
risks (see 21 CFR 330.10(a)).
    FDA's decision to act in this instance need not meet the standard 
of proof required to prevail in a private tort action (Glastetter v. 
Novartis Pharmaceuticals, Corp., 252 F.3d 986, 991 (8th Cir. 2001)). To 
mandate warnings, or take similar regulatory action, FDA need not show, 
nor do we allege, actual causation. For an expanded discussion of case 
law supporting FDA's authority to require such warnings, see Labeling 
of Diphenhydramine-Containing Drug Products for Over-the-Counter Human 
Use, Final Rule (67 FR 72555, December 6, 2002).

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. 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 of 1995 
requires that agencies prepare a written statement of anticipated costs 
and benefits 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 
principles set out in Executive Order 12866 and in these two statutes. 
FDA has determined that 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. As explained later in this section, 
FDA concludes that the final rule will not have a significant economic 
impact on a substantial number of small entities. The Unfunded Mandates 
Reform Act

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does not require FDA to prepare a statement of costs and benefits for 
this final rule, because the rule is not expected to result in any 1-
year expenditure that would exceed $100 million adjusted for inflation. 
The current inflation adjusted statutory threshold is about $110 
million.
    The purpose of this final rule is to establish a monograph for 
ingrown toenail relief drug products for OTC human use and include 
sodium sulfide 1 percent in a gel vehicle in the monograph. This final 
rule provides for OTC availability of this type of product.
    Manufacturers who wish to market this type of product have the 
standard costs associated with the introduction of any new product. 
These include preparation of labeling, stability testing, and 
implementing manufacturing procedures. Any cost incurred will be 
voluntary if manufacturers elect to market this type of product. This 
cost may vary from manufacturer to manufacturer; however, the burden on 
small manufacturers is not greater than that for large manufacturers. 
Manufacturers will not incur any costs related to proving safety and 
effectiveness of the active ingredient for this intended use.
    Under the Regulatory Flexibility Act, if a rule has a significant 
impact on a substantial number of small entities, an agency must 
analyze regulatory options that would minimize any significant impact 
of a rule on small entities. This final rule allows manufacturers to 
market OTC ingrown toenail relief drug products containing sodium 
sulfide 1 percent in a gel vehicle without having to obtain an approved 
new drug application, as is currently required, and is beneficial to 
small entities. Thus, this final rule will not impose a significant 
economic burden on affected entities. Therefore, under the Regulatory 
Flexibility Act, the agency certifies that the final rule will not have 
a significant economic impact on a substantial number of small 
entities. No further analysis is required.

V. Paperwork Reduction Act of 1995

    FDA concludes that the labeling requirements in this document 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 
labeling 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.

VII. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

List of Subjects

21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

21 CFR Part 358

    Labeling, Over-the-counter drugs.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
310 and 358 are amended as follows:

PART 310--NEW DRUGS

0
1. The authority citation for 21 CFR part 310 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262, 
263b-263n.

0
2. Section 310.538 is amended by removing the ingredient sodium sulfide 
in paragraph (a) and by adding paragraph (e) to read as follows:


Sec.  310.538  Drug products containing active ingredients offered 
over-the-counter (OTC) for use for ingrown toenail relief.

* * * * *
    (e) This section does not apply to sodium sulfide labeled, 
represented, or promoted for OTC topical use for ingrown toenail relief 
in accordance with part 358, subpart D of this chapter, after June 6, 
2003.

PART 358--MISCELLANEOUS EXTERNAL DRUG PRODUCTS FOR OVER-THE-COUNTER 
HUMAN USE

    3. The authority citation for 21 CFR part 358 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.


0
4. Part 358 is amended by adding new subpart D, consisting of 
Sec. Sec.  358.301 to 358.350, to read as follows:
Subpart D--Ingrown Toenail Relief Drug Products

Sec.

358.301 Scope.
358.303 Definitions.
358.310 Ingrown toenail relief active ingredient.
358.350 Labeling of ingrown toenail relief drug products.

Subpart D--Ingrown Toenail Relief Drug Products


Sec.  358.301  Scope.

    (a) An over-the-counter ingrown toenail relief drug product in a 
form suitable for topical administration is generally recognized as 
safe and effective and is not misbranded if it meets each condition in 
this subpart and each general condition established in Sec.  330.1 of 
this chapter.
    (b) References in this subpart to regulatory sections of the Code 
of Federal Regulations are to chapter 1 of title 21 unless otherwise 
noted.


Sec.  358.303  Definitions.

    As used in this subpart:
    (a) Ingrown toenail relief drug product. A drug product applied to 
an ingrown toenail that relieves pain or discomfort either by softening 
the nail or by hardening the nail bed.
    (b) Retainer ring. A die cut polyethylene foam pad coated on one 
side with medical grade acrylic pressure-sensitive adhesive. The 
retainer ring has slots, center-cut completely through the foam with 
the cut of sufficient size to allow for localization of an active 
ingredient in a gel vehicle to a specific target area. The retainer 
ring is used with adhesive bandage strips to place over the retainer 
ring to hold it in place.


Sec.  358.310  Ingrown toenail relief active ingredient.

    The active ingredient of the product is sodium sulfide 1 percent in 
a gel vehicle. The gel vehicle is an aqueous, semisolid system with 
large organic molecules interpenetrated with a liquid.


Sec.  358.350  Labeling of ingrown toenail relief drug products.

    (a) Statement of identity. The labeling of the product contains the 
established

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name of the product, if any, and identifies the product as an ``ingrown 
toenail relief product'' or as an ``ingrown toenail discomfort 
reliever.''
    (b) Indications. The labeling of the product states, under the 
heading ``Use,'' the following: ``for temporary relief of'' [select one 
or both of the following: 'pain' or 'discomfort'] ``from ingrown 
toenails''. Other truthful and nonmisleading statements, describing 
only the use that has been established and listed in this paragraph 
(b), may also be used, as provided in Sec.  330.1(c)(2) of this 
chapter, subject to the provisions of section 502 of the Federal Food, 
Drug, and Cosmetic Act (the act) relating to misbranding and the 
prohibition in section 301(d) of the act against the introduction or 
delivery for introduction into interstate commerce of unapproved new 
drugs in violation of section 505(a) of the act.
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) ``For external use only'' in accord with Sec.  201.66(c)(5)(i) 
of this chapter.
    (2) ``Do not use [bullet]\1\ on open sores''.
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    \1\See Sec.  201.66(b)(4) of this chapter for definition of 
bullet.
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    (3) ``Ask a doctor before use if you have [bullet] diabetes 
[bullet] poor circulation [bullet] gout''.
    (4) ``When using this product [bullet] use with a retainer ring''.
    (5) ``Stop use and ask a doctor if [bullet] redness or swelling of 
your toe increases [bullet] discharge is present around the nail 
[bullet] symptoms last more than 7 days or clear up and occur again 
within a few days''.
    (d) Directions. The labeling of the product contains the following 
statements under the heading ``Directions'':
    (1) ``[Bullet] adults and children 12 years and over:''
    (i) ``[Bullet] wash the affected area and dry thoroughly [bullet] 
place retainer ring on toe with slot over the area where the ingrown 
nail and the skin meet. Smooth ring down firmly. [bullet] apply enough 
gel product to fill the slot in the ring [bullet] place round center 
section of bandage strip directly over the gel-filled ring to seal the 
gel in place. Smooth ends of bandage strip around toes.''
    (ii) ``[Bullet] repeat twice daily (morning and night) for up to 7 
days until discomfort is relieved or until the nail can be lifted out 
of the nail groove and easily trimmed''.
    (2) ``[Bullet] children under 12 years: ask a doctor''.

    Dated: April 23, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-11285 Filed 5-6-03; 8:45 am]
BILLING CODE 4160-01-S