[Federal Register Volume 67, Number 90 (Thursday, May 9, 2002)]
[Rules and Regulations]
[Pages 31123-31125]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-11511]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. 80N-0280]
RIN 0910-AA01


Status of Certain Additional Over-the-Counter Drug Category II 
and III Active Ingredients

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 
stating that a certain ingredient in over-the-counter (OTC) drug 
products is not generally recognized as safe and effective or is 
misbranded. FDA is issuing this final rule after considering the 
reports and recommendations of various OTC drug advisory review panels 
and public comments on proposed agency regulations. This final rule 
addresses the ingredient octoxynol 9, considered in the rulemaking for 
OTC vaginal contraceptive drug products. Based on the failure of 
interested parties to submit new data or information to FDA under the 
proposed regulation, the agency has determined that the presence of 
this active ingredient in an OTC drug product would result in that drug 
product not being generally recognized as safe and effective for its 
intended use or would result in misbranding. This final rule is part of 
FDA's ongoing OTC drug product review.

DATES: This regulation is effective November 5, 2002.

FOR FURTHER INFORMATION CONTACT: Helen Cothran, 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 November 7, 1990 (55 FR 46914), FDA 
published under Sec. 330.10(a)(7)(ii) (21 CFR 330.10(a)(7)(ii)) a final 
rule on the status of certain OTC drug Category II and III active 
ingredients. That final rule declared as not generally recognized as 
safe and effective certain active ingredients that had been proposed as 
nonmonograph (Category II or III) under the agency's OTC drug review. 
The periods for submission of comments and new data following the 
publication of a notice of proposed rulemaking had closed and no 
significant comments or new data had been submitted to upgrade the 
status of these ingredients. In each instance, a final rule for the 
class of ingredients involved had not been published to date.
    In the Federal Register of May 10, 1993 (58 FR 27636), FDA 
published a final rule establishing that certain additional active 
ingredients in OTC drug products are not generally recognized as safe 
and effective or are misbranded. That final rule included active 
ingredients from a number of OTC drug rulemakings that were not covered 
by the November 7, 1990, final rule (see table I of the May 10, 1993, 
final rule (58 FR 27636 at 27639 to 27641) for a list of OTC drug 
rulemakings and active ingredients covered by that final rule).
    In the proposed rulemaking for OTC vaginal contraceptive drug 
products (45 FR 82014, December 12, 1980), the Advisory Review Panel on 
OTC Contraceptives and Other Vaginal Drug Products (the Panel) placed 
nonoxynol 9 and octoxynol 9 in Category I (safe and effective), placed 
phenylmercuric acetate, phenylmercuric nitrate, and other compounds 
containing mercury in Category II for safety, and placed dodecaethylene 
glycol monolaurate (polyethylene glycol 600 monolaurate), laureth 10S, 
and methoxypolyoxyethylene glycol 550 laurate in Category III for 
efficacy. In the preamble to the Panel's report (45 FR 82014), the 
agency stated that clinical trials of each product or final formulation 
may be the only certain predictor of its effectiveness in humans. The 
agency further stated that if clinical trials are necessary, 
manufacturers may be required to submit a new drug application (NDA) or 
supplement an existing NDA. The agency stated that it would announce 
its decision in a separate Federal Register document or in the 
tentative final order.
    In the proposed rule for OTC vaginal contraceptive drug products 
(60 FR 6892, February 3, 1995), the agency proposed that manufacturers 
of OTC vaginal contraceptive drug products obtain approved applications 
for marketing of their products. The agency took this action because 
the evidence currently available shows that effectiveness of these 
products is dependent upon the final formulation and clinical studies 
in humans are needed to establish the effectiveness of the active 
ingredients in OTC vaginal contraceptive drug products. Therefore, each 
product must be tested in appropriate clinical trials under actual 
conditions of use. FDA encouraged manufacturers to consult with the 
agency regarding testing and the

[[Page 31124]]

submission of applications as soon as possible. In the proposed rule, 
all of the ingredients evaluated by the Panel were considered 
nonmonograph for reasons of safety and/or effectiveness.
    In response to this proposed rule, the agency received no comments 
or data relating to the safety and effectiveness of any of the Panel's 
Category II or III ingredients. Therefore, in theFederal Register of 
April 22, 1998 (63 FR 19799), the agency issued a final rule regarding 
the nonmonograph status of these Category II and III ingredients. Based 
on the absence of substantive comments in opposition to the agency's 
proposed nonmonograph status for these ingredients, as well as the 
failure of interested parties to submit new data or information to FDA 
under the regulation, the agency determined that the presence of these 
ingredients in an OTC drug product would result in the drug product not 
being generally recognized as safe and effective or would result in 
misbranding.
    In response to the proposed rule, the agency was informed of 
ongoing clinical trials involving nonoxynol 9 (Refs. 1, 2, and 3). 
However, the agency is not aware of any clinical trials, nor have any 
comments or data on octoxynol 9 been submitted to the agency since the 
proposed rule. Accordingly, FDA concludes that octoxynol 9 has not been 
shown to be generally recognized as safe and effective for its intended 
use as a vaginal contraceptive and should be eliminated from OTC drug 
products 6 months after the publication of this final rule in the 
Federal Register, regardless of whether further testing is undertaken 
to justify future use. Publication of this final rule does not preclude 
a manufacturer's testing an ingredient. New, relevant data can be 
submitted to the agency at a later date as the subject of a NDA that 
may provide for prescription or OTC marketing status (see part 314 (21 
CFR part 314)).
    The monograph or new drug status of nonoxynol 9 will be addressed 
after completion and analysis of the ongoing clinical trials. This 
final rule for octoxynol 9 does not affect the current marketing status 
of nonoxynol 9 as an OTC vaginal contraceptive.

II. The Agency's Final Conclusions on Certain OTC Drug Category II 
and III Ingredients

    For the reasons discussed in section I of this document, the agency 
has determined that octoxynol 9 should be deemed not generally 
recognized as safe and effective for OTC use before a final rule is 
established for OTC vaginal contraceptive drug products. Accordingly, 
any drug product containing octoxynol 9 and labeled for OTC use as a 
vaginal contraceptive or spermicide will be considered nonmonograph and 
misbranded under section 502 of the Federal Food, Drug, and Cosmetic 
Act (the act) (21 U.S.C. 352) and a new drug under section 201(p) of 
the act (21 U.S.C. 321(p)) for which an approved application under 
section 505 of the act (21 U.S.C. 355) and part 314 of the regulations 
is required for marketing. This applies to any OTC drug product 
containing octoxynol 9 and labeled for use as a vaginal contraceptive 
or vaginal spermicide that is initially introduced or initially 
delivered for introduction into interstate commerce after the effective 
date of this final rule. Further, any OTC drug product that was 
previously initially introduced or initially delivered for introduction 
into interstate commerce cannot be repackaged or relabeled after the 
effective date of the rule. Manufacturers are encouraged to comply 
voluntarily with the rule at the earliest possible date.

III. Analysis of Impacts

    FDA has examined the impacts of the 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 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 concludes that this final rule is consistent with the 
principles set out in the Executive order and in these two statutes. 
Further, since this final rule is not expected to result in any 1-year 
expenditure that would exceed $100 million adjusted for inflation, FDA 
need not prepare additional analyses under the Unfunded Mandates Reform 
Act.
    The purpose of this final rule is to finalize the proposed 
nonmonograph status of octoxynol 9 in order to expedite completion of 
the OTC drug review. There are a limited number of products currently 
marketed that will be affected by this rule. The agency's Drug Listing 
System identifies two manufacturers of OTC vaginal contraceptive drug 
products containing octoxynol 9, although there may be some additional 
products that are not currently included in the agency's system. One 
manufacturer markets four products and the other manufacturer markets 
one product, for a total of five products. At least one of the 
manufacturers is considered a small entity, using the U.S. Small 
Business Administration designation for this industry (750 employees).
    Manufacturers of these products will no longer be able to market 
products containing octoxynol 9 after the effective date of this final 
rule. One of the manufacturers of octoxynol 9 also produces products 
that contain nonoxynol 9, which is currently being tested in clinical 
trials. Other manufacturers will be able to reformulate vaginal 
contraceptive drug products that contain octoxynol 9 and continue to 
market them with nonoxynol 9, pending completion of the final rule for 
these products. The agency estimates the cost of reformulation and 
relabeling to range from $100,000 to $500,000 per product. Using the 
midpoint of the cost estimate implies total costs up to $1.5 million. 
However, the agency believes the total costs will be smaller because 
all currently marketed products may not be reformulated. The 
manufacturers have known since the publication of the proposed rule in 
the Federal Register of February 3, 1995, that if adequate data from 
clinical trials were not submitted to support safety and effectiveness, 
cessation of marketing of the current products would be required when 
the final rule is published. Generally, when safety is not a concern, 
manufacturers will continue to market products that they know will 
become nonmonograph for as long as legally possible to maximize their 
profits for that product line.
    The agency considered but rejected not acting on this ingredient in 
advance of the completion of the final rule on OTC vaginal 
contraceptive drug products. The ongoing clinical trials involving 
nonoxynol 9 are not expected to be completed for a period of time. 
However, safety and effectiveness have not been established for 
octoxynol 9 and

[[Page 31125]]

no testing is currently being done. Therefore, the agency concludes 
that consumers will benefit from the early removal from the marketplace 
of products containing octoxynol 9.
    Because so few small firms will be affected, the agency certifies 
that there will not be a significant economic impact on a substantial 
number of small firms.

IV. Paperwork Reduction Act of 1995

    This final rule contains no collections of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

V. 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.

VI. 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.

VII. References

    The following references are on display in the Dockets Management 
Branch (address above) under Docket No. 80N-0280 and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.

    1. FDA, Transcript of Joint Meeting of the Nonprescription 
Drugs, Reproductive Health Drugs, Anti-Infective Drugs and Antiviral 
Drugs Advisory Committees, November 22, 1996, pp. 86-99, in OTC Vol. 
11ATFM2.
    2. Letter from D. L. Bowen, FDA, to R. W. Soller, 
Nonprescription Drug Manufacturers Association, coded LET 6.
    3. Letter from D. L. Bowen, FDA, to R. W. Soller, 
Nonprescription Drug Manufacturers Association, coded LET 7.

List of Subjects in 21 CFR Part 310

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

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
310 is 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 310.545 is amended by adding a paragraph heading 
(a)(28)(i) after the existing paragraph heading, by adding paragraphs 
(a)(28)(ii) and (d)(36), by revising paragraph (d)(28), and by adding 
and reserving paragraphs (d)(34) and (d)(35) to read as follows:


Sec. 310.545  Drug products containing certain active ingredients 
offered over-the-counter (OTC) for certain uses.

    (a) * * * 
    (28) Vaginal contraceptive drug products--(i)  Approved as of 
October 22, 1998. * * * 
    (ii) Approved as of November 5, 2002.

Octoxynol 9
* * * * *
    (d) * * * 
    (28) October 22, 1998, for products subject to paragraphs (a)(27) 
and (a)(28)(i) of this section.
* * * * *
    (34) [Reserved]
    (35) [Reserved]
    (36) November 5, 2002, for products subject to paragraph 
(a)(28)(ii) of this section.

    Dated: April 29, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-11511 Filed 5-8-02; 8:45 am]
BILLING CODE 4160-01-S