[Federal Register Volume 67, Number 193 (Friday, October 4, 2002)]
[Proposed Rules]
[Pages 62218-62221]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-25251]


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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: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a proposed 
rule to establish 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 proposes to amend the regulation that lists 
nonmonograph active ingredients in OTC drug products for ingrown 
toenail relief by removing sodium sulfide from that list. This proposal 
is part of FDA's ongoing review of OTC drug products.

DATES: Submit written or electronic comments by December 3, 2002. 
Please 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 Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Nahid Mokhtari, Center for Drug 
Evaluation and Research (HFD-560), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2222.

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.
    A manufacturer subsequently conducted an additional safety study 
and requested the agency to find sodium sulfide 1 percent in a gel 
vehicle safe and effective for this OTC use (Ref. 1). The study 
involved four treatment groups who applied sodium sulfide nonahydrate 
gel: (1) One percent twice daily using a retainer ring system, (2) 2 
percent twice daily using a retainer ring system, (3) 2 percent once 
daily using a retainer ring system, and (4) 2 percent twice daily using 
an absorptive bandage system. The gel was applied for 7 days or until 
the nail became sufficiently softened to allow for trimming, whichever 
occurred first. Of 64 ingrown toenail sufferers enrolled, 61 completed 
all aspects of the study. No adverse reactions were reported during the 
study, and no subjects reported any irritation. Four subjects noted 
some stinging and burning on day 1 and moderate discomfort on days 3 
and 4, but the subjects did not discontinue treatment. The manufacturer 
stated that of the two systems tested the retainer ring is the 
preferred one because it provides ease of use and cushioning while 
further enhancing safety through the use of a medical grade adhesive. 
The design of the system allows for easy administration of sodium 
sulfide to the affected area by the consumer while retaining the drug 
in contact with the toe. The manufacturer requested approval of its 
revised instructions using the retainer ring system.
    The agency found this study inadequate for a number of reasons. 
First, it was not designed as a safety study. There was no vehicle 
control, and safety cannot be determined without a vehicle control. The 
trial size was too small. The daily supervision by a podiatrist was not 
reflective of OTC use. Safety has to be assessed in context with the 
indications; the ``days to trimming'' in the study were outside of the 
prior proposed monograph description of product uses. The agency 
concluded that the study was not adequate to resolve the outstanding

[[Page 62219]]

safety concerns for using sodium sulfide for ingrown toenail relief 
(Ref. 2). The manufacturer subsequently conducted additional safety 
studies and submitted new data to the agency (Ref. 3).

II. The Agency's Evaluation of the New Data

    The new data were in a study entitled ``An Investigator-Blind, 
Vehicle-Controlled and Retainer Ring/Taping-controlled, Parallel Study 
of the Safety of a 1 percent Sodium Sulfide Nonahydrate Gel Used 
Topically for the Temporary Relief of Discomfort (Pain) from Ingrown 
Toenails.'' The data resulted from a randomized, two-center, three-arm, 
evaluator-blind safety study involving 157 subjects over 18 years of 
age with painful ingrown toenail. Eligible subjects were randomized 
into treatment arms that used sodium sulfide 1 percent gel with a taped 
retainer ring, gel vehicle with a taped retainer ring, and the taped 
retainer ring alone in a 3:1:1 ratio.
    The gel vehicle was an aqueous, semisolid system with large organic 
molecules interpenetrated with a liquid (Ref. 4). The retainer ring was 
die cut from polyethylene foam coated on one side with a medical grade 
acrylic pressure-sensitive adhesive and had slots, center-cut 
completely through the foam with the cut of sufficient size to allow 
for application of the product to the ingrown toenail (Ref. 4). All 
subjects were to apply the test product twice daily for 7 days after 
cleansing and adequately drying the foot. Each subject had a daily 
diary in which to record product applications and any discomfort 
resulting from the test product. At each study visit (days 1, 4, and 
8), the investigator also asked the subject, ``How are you feeling?'', 
recorded any subject-reported adverse events, and reviewed the daily 
diary for compliance and concomitant medications. The investigator also 
evaluated and recorded the condition of the skin surrounding the target 
ingrown toenail for erythema, edema, and maceration using the following 
scale: 0 = none, 1 = mild, 2 = moderate, and 3 = severe.
    The majority of the subjects in both the sodium sulfide 1 percent 
gel and vehicle groups (65 percent and 55 percent, respectively) 
experienced no discomfort. Most discomfort occurred in the first 3 days 
of treatment. During this period, the frequency of discomfort appeared 
somewhat higher in the control gel treatment group than in the sodium 
sulfide 1 percent gel group. Pain and burning were the most commonly 
reported diary entries in all groups. The data suggested that the 
incidence of pain and burning using sodium sulfide 1 percent gel was 
comparable to or less than that observed in the two control groups, 
except that burning from use of the sodium sulfide gel was greater than 
for the retainer ring alone, but less than for the control gel vehicle. 
No serious adverse events were recorded.
    At baseline, the proportion of subjects with mild or moderate 
erythema (skin redness) was generally comparable among treatment 
groups. Over the course of the study, erythema decreased in all three 
groups, suggesting that sodium sulfide 1 percent gel is not an 
irritant. A similar pattern was observed for mild or moderate edema 
(swelling), although the decreases at day 4 were less dramatic. At day 
8, the change from baseline was most pronounced in the gel vehicle 
group. Percentage changes in the sodium sulfide and retainer ring 
groups appeared comparable. No subject in any of the treatment groups 
had maceration (skin degeneration). The agency's detailed comments on 
the data are on file in the Dockets Management Branch (see ADDRESSES) 
(Ref. 5).

III. The Agency's Tentative Conclusions

    The agency tentatively concludes that the new safety data and the 
agency's previous determination of effectiveness (58 FR 47602 at 47604) 
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. The agency, since 1989, has 
believed that monograph ingredients need to be recognized in an 
official United States Pharmacopeia-National Formulary (USP-NF) drug 
monograph. (See 54 FR 13480 at 13486, April 3, 1989, and 54 FR 40808 at 
40810, October 3, 1989.) The agency recently included such a 
requirement in Sec.  330.14(i) (21 CFR 330.14(i)). (See 67 FR 3060 at 
3076, January 23, 2002.) A USP-NF monograph currently exists for sodium 
sulfide gel (Ref. 6). 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.
    The manufacturer stated its intent to market only the retainer 
ring/bandage strip system at this time, but noted that its safety and 
effectiveness data also support use of a bandage system (without a 
retainer ring) (Ref. 4). The only safety data for use with a bandage 
system were included in the manufacturer's first submission (Ref. 1), 
which the agency found inadequate to support safety (Ref. 2). The key 
data that adequately support safety involved use with the retainer ring 
system (Ref. 3). Therefore, the agency is including a warning that 
states: ``When using this product [bullet] use with a retainer ring''.
    The manufacturer requested that it be allowed to begin marketing 1 
percent sodium sulfide gel upon publication of this proposed rule. 
Current Sec.  310.538 prohibits marketing of ingrown toenail relief 
drug products containing sodium sulfide. The agency today is proposing 
to allow the marketing of such products, but until the agency's final 
conclusions on the status of these products are presented in a final 
rule and Sec.  310.538 is amended in a future issue of the Federal 
Register, any such product initially introduced or initially delivered 
for introduction into interstate commerce is subject to regulatory 
action.

IV. Analysis of Impacts

    FDA has examined the impacts of this proposed 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 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 proposed rule is consistent with the 
principles set out in the Executive order and in these two statutes. 
FDA has determined that the proposed 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 believes that the proposed rule will not have a 
significant economic impact

[[Page 62220]]

on a substantial number of small entities. The Unfunded Mandates Reform 
Act does not require FDA to prepare a statement of costs and benefits 
for this proposed rule, because the proposed 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 proposed 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 
proposal, when finalized, will provide for OTC availability of this 
type of product.
    Manufacturers who wish to market this type of product will 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 proposed rule would allow 
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 
would be beneficial to small entities. Thus, this proposed rule will 
not impose a significant economic burden on affected entities. 
Therefore, under the Regulatory Flexibility Act, the agency certifies 
that the proposed rule will not have a significant economic impact on a 
substantial number of small entities. No further analysis is required.
    The agency invites public comment regarding any substantial or 
significant economic impact that this rulemaking would have on 
manufacturers who wish to market OTC ingrown toenail relief drug 
products. Comments regarding the impact of this rulemaking on such 
manufacturers should be accompanied by appropriate documentation. The 
agency is providing a period of 60 days from the date of publication of 
this proposed rulemaking in the Federal Register for comments to be 
developed and submitted. The agency will evaluate any comments and 
supporting data that are received and will reassess the economic impact 
of this rulemaking in the preamble to the final rule.

V. Paperwork Reduction Act of 1995

    FDA tentatively 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 proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed 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 tentatively concludes that the proposed rule does not 
contain policies that have federalism implications as defined in the 
Executive order and, consequently, a federalism summary impact 
statement has not been prepared.

VIII. Request for Comments

    Three copies of all written comments are to be submitted. 
Individuals submitting written comments or anyone submitting electronic 
comments 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 Dockets Management Branch 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.

X. References

    The following references are on display in the Dockets Management 
Branch (see ADDRESSES) under Docket No. 80N-0348 and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Comment No. CP1.
    2. Comment No. PDN1.
    3. Comment No. CP2.
    4. Letter from A. Mart, Schering-Plough HealthCare Products, to 
W. Ellenberg, FDA, dated December 21, 2000.
    5. Comment No. LET3.
    6. The United States Pharmacopeia 24--The National Formulary 19, 
The United States Pharmacopeial Convention, Inc., Rockville, MD, 
Supplement 2, p. 2858, July 1, 2000.

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.

    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 parts 310 and 358 are amended as follows:

PART 310--NEW DRUGS

    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.
    2. Section 310.538 is amended by removing the ingredient sodium 
sulfide in paragraph (a) and adding new 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 [effective 
date of final rule].

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.

[[Page 62221]]

    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 I 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 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: September 25, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-25251 Filed 10-3-02; 8:45 am]
BILLING CODE 4160-01-S