[Federal Register Volume 60, Number 23 (Friday, February 3, 1995)]
[Proposed Rules]
[Pages 6892-6903]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-2631]




[[Page 6891]]

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Part III





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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21 CFR Part 310



Vaginal Contraceptive Drug Products for Over-the-Counter Human Use; 
Proposed Rule

  Federal Register / Vol. 60, No. 23 / Friday, February 3, 1995 / 
Proposed Rules   
[[Page 6892]] 

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. 80N-0280]
RIN 0905-AA06


Vaginal Contraceptive Drug Products for Over-the-Counter Human 
Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of proposed rulemaking.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is issuing a notice of 
proposed rulemaking that would require manufacturers of over-the-
counter (OTC) vaginal contraceptive drug products to obtain approved 
applications for marketing of their products. The agency is taking this 
action because the effectiveness of these products is dependent upon 
the final formulation. Therefore, each product must be tested in 
appropriate clinical trials under actual conditions of use. This action 
will ensure the maximum effectiveness of OTC vaginal contraceptive drug 
products for consumers. This proposed rulemaking does not affect the 
current marketing status of OTC vaginal contraceptives. Thus, persons 
who are using or wish to use these drug products may do so. However, on 
the effective date of a final regulation, an OTC vaginal contraceptive 
drug product that is not the subject of an approved application would 
be regarded as a new drug and subject to regulatory action. 
Manufacturers will have adequate time to conduct studies and submit 
applications before the effective date of the final rule. Under 
existing procedures, there is a minimum of 26 months from today before 
a final rule could become effective. Despite this timeframe, 
manufacturers are urged to contact the agency regarding submission of 
their application as soon as possible. OTC contraceptives that are 
marketed for use with or as part of a device, e.g., diaphragm, condom, 
or contraceptive cervical cap will not be addressed in this document 
but will be addressed in a separate publication. FDA is issuing this 
notice of proposed rulemaking after considering the report and 
recommendations of the Advisory Review Panel on OTC Contraceptives and 
Other Vaginal Drug Products, public comments on an advance notice of 
proposed rulemaking that was based on those recommendations, and 
evolving new information about these products. This proposal is part of 
the ongoing review of OTC drug products conducted by FDA. While this 
document does not address the use of vaginal contraceptive drug 
products for prophylaxis against human immunodeficiency virus (HIV) and 
other sexually transmitted diseases (STD's), FDA is aware of literature 
reports and other data relative to such use. FDA strongly encourages 
manufacturers to evaluate these products for use in the prevention of 
infectious diseases.

DATES: Written comments, objections, or requests for oral hearing on 
the proposed regulation before the Commissioner of Food and Drugs by 
June 5, 1995. New data by February 5, 1996. Comments on the new data by 
April 3, 1996. Written comments on the agency's economic impact 
determination by June 5, 1995.

ADDRESSES: Written comments, objections, new data, or requests for oral 
hearing to the Dockets Management Branch (HFA-305), Food and Drug 
Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug 
Evaluation and Research (HFD-810), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-5000.

SUPPLEMENTARY INFORMATION: In the Federal Register of December 12, 1980 
(45 FR 82014), FDA published, under Sec. 330.10(a)(6) (21 CFR 
330.10(a)(6)), an advance notice of proposed rulemaking to establish a 
monograph for OTC vaginal contraceptive drug products, together with 
the recommendations of the Advisory Review Panel on OTC Contraceptives 
and Other Vaginal Drug Products (the Panel), which was the advisory 
review panel responsible for evaluating data on the active ingredients 
in OTC vaginal contraceptive drug products. Interested persons were 
invited to submit comments by March 12, 1981. Reply comments in 
response to comments filed in the initial comment period could be 
submitted by April 13, 1981.
    In accordance with Sec. 330.10(a)(10), the data and information 
considered by the Panel were put on public display in the Dockets 
Management Branch (address above), after deletion of a small amount of 
trade secret information.
    In response to the advance notice of proposed rulemaking, six drug 
manufacturers, two governmental agencies, two reproductive health 
groups, one trade association, one chemical company, and one consumer 
submitted comments. Copies of the comments received are on public 
display in the Dockets Management Branch.
    The advance notice of proposed rulemaking, which was published in 
the Federal Register on December 12, 1980, was designated as a 
``proposed rule'' in order to conform to terminology used in the OTC 
drug review regulations Sec. 330.10. Similarly, the present document is 
designated in the OTC drug review regulations as a tentative final 
rule. Its legal status, however, is that of a proposed rule. To 
establish new Sec. 310.535 by this notice of proposed rulemaking, FDA 
responds to public comment and states, for the first time, its position 
on OTC vaginal contraceptive drug products. Final agency action on this 
matter will occur with the publication, at a future date, of a final 
rule relating to OTC vaginal contraceptive drug products.
    This proposal constitutes FDA's tentative adoption of the Panel's 
conclusions and recommendations on OTC vaginal contraceptive drug 
products as modified on the basis of the comments received, the 
agency's independent evaluation of the Panel's report, and evolving new 
information on these products. Modifications have been made for clarity 
and regulatory accuracy and to reflect new information. Such new 
information has been placed on file in the Dockets Management Branch 
(address above). These modifications are reflected in the following 
summary of the comments and FDA's responses to them.
    The OTC drug procedural regulations (Sec. 330.10) provide that any 
testing necessary to resolve the safety or effectiveness issues that 
formerly resulted in a Category III classification, and submission to 
FDA of the results of that testing or any other data, must be done 
during the OTC drug rulemaking process before the establishment of a 
final monograph. Accordingly, FDA is no longer using the terms 
``Category I'' (generally recognized as safe and effective and not 
misbranded), ``Category II'' (not generally recognized as safe and 
effective or misbranded), and ``Category III'' (available data are 
insufficient to classify as safe and effective, and further testing is 
required) at the final monograph stage. In place of Category I, the 
term ``monograph conditions'' is used; in place of Category II or III, 
the term ``nonmonograph conditions'' is used.
    Based on all information available to date, the agency has 
tentatively concluded that any OTC vaginal contraceptive drug product 
should be regarded as a new drug and be subject to regulatory action 
unless it is the [[Page 6893]] subject of an approved application or 
abbreviated application (hereinafter called application).
    The agency has concluded that although nonoxynol 9 and octoxynol 9 
kill sperm in vitro and in vivo, the spermicidal activity and resulting 
effectiveness of these contraceptive active ingredients cannot be 
considered separately from a product's vehicle. Studies show that these 
active ingredients lose some of their effectiveness in humans when the 
spermicide in final formulation is diluted by varied amounts of genital 
secretions during coitus. Thus, clinical studies are necessary to 
establish the effectiveness of the spermicide's final formulation when 
used in humans. (See discussion in section I.A., comment 3 of this 
document.) Such clinical studies would determine the influence of the 
potential interactions among the genital secretions, microorganisms, 
and contraceptive product vehicle.
    The agency recognizes a need for consumers to continue to have 
access to OTC vaginal contraceptive drug products and to avoid 
disruption in the marketplace. The majority of OTC vaginal 
contraceptive drug products currently marketed contain nonoxynol 9. At 
the present time, two approved applications exist for OTC vaginal 
contraceptives: Delfen Contraceptive Foam (new drug application (NDA) 
14-349) and Today Sponge (NDA 18-683). The NDA for Delfen 
Contraceptive Foam was approved a number of years ago, and the product 
as currently marketed uses a different formulation from the one 
approved in the NDA. The manufacturer of this product will be required 
to provide additional information. The manufacturer of the 
Today Sponge recently announced that it plans to discontinue 
production of this product. However, the firm has not indicated to FDA 
that it plans to withdraw its application.
    Only a few vaginal contraceptive drug products contain octoxynol 9, 
and none have approved applications. Because the final rule for this 
class of OTC drug products will be effective 12 months after the date 
of its publication in the Federal Register, FDA strongly recommends 
that manufacturers of products not having an approved application 
consult with the agency as soon as possible concerning the content of 
these applications. Elsewhere in this issue of the Federal Register, 
the agency is announcing the availability of a guidance document that 
is intended to help manufacturers of vaginal contraceptive drug 
products develop data in support of new drug applications.
    OTC vaginal contraceptive products that are marketed for use with 
or as part of a condom, diaphragm, or a contraceptive cervical cap will 
not be subject to the final rule. When labeled for use only with a 
device such as a condom (see 21 CFR 884.5310), diaphragm (see 21 CFR 
884.5350), or cervical cap (a premarket approval application has been 
approved for a cervical cap for use as a barrier method of 
contraception, when used with a spermicidal cream or jelly), a 
spermicide is considered an accessory to a device. The regulation of 
spermicides for use only with a device will be addressed at a future 
date by the agency. In the interim, manufacturers of such products 
should direct inquiries to the Obstetrics/Gynecology Branch (HFZ-471), 
Office of Device Evaluation, Center for Devices and Radiological 
Health, Food and Drug Administration, 1390 Piccard Dr., Rockville, MD 
20850, 301-594-1180.
    The agency has determined that nonoxynol 9 and octoxynol 9 would be 
appropriate ingredients for an approved application. This determination 
is based on: (1) The findings of the Panel (nonoxynol 9 and octoxynol 9 
were recommended as Category I active ingredients), and (2) the history 
of use of drug products with approved NDA's containing nonoxynol 9.
    Applications for products containing these ingredients will not 
need to include preclinical data, but, instead, may refer to the 
Panel's report as a general basis for the safety of these ingredients. 
The applications will need to include the results of clinical studies 
that establish the effectiveness of the contraceptive ingredient in the 
product's final formulation. These studies to establish the 
effectiveness of the product's final formulation need to comply with 
the requirements of 21 CFR part 314. The clinical studies should 
contain evidence of the effectiveness of the spermicide in final 
formulation in normal volunteers or patients that is consistent with 
correct use of the product. In addition, the agency is aware that the 
use of either of the contraceptive ingredients addressed in this 
proposed rulemaking may be associated with varying degrees of vaginal 
irritation under certain conditions of use and it is unclear whether 
this may play a role in the transmission of STD's (Refs. 1 through 5). 
Therefore, as part of the application for approval of these products 
for contraceptive use, information regarding the rate of occurrence and 
degree of vaginal irritation should be presented. FDA encourages 
manufacturers to consult with the agency as soon as possible concerning 
the content of these applications. Inquiries should be directed to the 
Division of Metabolism and Endocrine Drug Products (HFD-510), Center 
for Drug Evaluation and Research, Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-443-3490.
    The Department of Health and Human Services has published the 
``13th Edition of Approved Drug Products with Therapeutic Equivalence 
Evaluations,'' commonly called ``the Orange Book,'' which identifies 
currently marketed products approved by FDA on the basis of safety and 
effectiveness data. The main criterion for the inclusion of any product 
in the Orange Book is that the product is the subject of an approved 
application that has not been withdrawn for safety or effectiveness 
reasons. For vaginal contraceptive drug products for which there is a 
previously approved listed drug product in the Orange Book, an 
abbreviated application may be submitted. The abbreviated application 
must contain information to show bioequivalence to the listed drug 
product. Further, the abbreviated application may contain labeling only 
for the claims approved for the product, i.e. a contraceptive. None of 
the products containing nonoxynol 9 that are listed in the Orange Book 
has a claim for the prevention of infectious disease. Manufacturers 
should consult with the Office of Generic Drugs (HFD-600), Center for 
Drug Evaluation and Research, Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-0340, to determine the 
procedures for obtaining approval of abbreviated applications. For 
vaginal contraceptive drug products for which there is no previously 
approved listed drug product in the Orange Book, an abbreviated 
application may not be submitted. For these products, an application 
that includes adequate and well-controlled clinical studies of the 
effectiveness of the specific formulation of the vaginal contraceptive 
must be submitted. Manufacturers of such products should direct 
inquiries to the Division of Metabolism and Endocrine Drug Products, as 
noted above.
    Both types of applications, i.e., full or abbreviated, would also 
have to include information on the drug product's formulation, 
manufacture, and quality control procedures to ensure that the 
applicant has the ability to manufacture a safe and effective OTC 
vaginal contraceptive drug product. (Also, see section I.C., comment 15 
of this document.)
    The agency is aware of literature reports and other data concerning 
the [[Page 6894]] use of certain contraceptive active ingredients to 
prevent sexual transmission of infectious diseases (Refs. 1 through 
17). However, none of these products currently has an approved 
indication for this use. Although this document is not intended to 
address the use of vaginal contraceptive drug products in preventing 
the transmission of STD's, the identification of safe and effective 
products to prevent the transmission of HIV and other STD's is a high 
priority public health concern. Therefore, FDA strongly encourages 
evaluation of OTC contraceptive products for this use. Manufacturers 
who wish to submit applications for such use should be aware that the 
study designs for effectiveness as a contraceptive and for prevention 
of infectious disease may be different. Therefore, manufacturers should 
consult with the agency concerning the content of contraceptive 
applications that also include an indication for prevention of 
infectious disease. Inquiries regarding use for prevention of 
infectious disease for antiviral prophylaxis should be directed to the 
Supervisory Consumer Safety Officer, Division of Antiviral Drug 
Products (HFD-530), Center for Drug Evaluation and Research, Food and 
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-443-
9550, and inquiries regarding bacterial and other nonviral pathogens 
should be directed to the Division of Anti-Infective Drug Products 
(HFD-520), Center for Drug Evaluation and Research, Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-443-4310.
    If this proposal is adopted as a final rule, the agency advises 
that the conditions under which the drug products that are subject to 
this rule are not generally recognized as safe and effective and are 
misbranded (nonmonograph conditions) will be effective 12 months after 
the date of publication of the final rule in the Federal Register. On 
or after that date, no OTC drug product that is subject to the rule may 
be initially introduced or initially delivered for introduction into 
interstate commerce unless it is the subject of an approved 
application. Further, any OTC drug product subject to the final rule 
that is repackaged or relabeled after the effective date of the final 
rule must be in compliance with the final rule regardless of the date 
the product was initially introduced or initially delivered for 
introduction into interstate commerce. Manufacturers are encouraged to 
comply voluntarily with the proposed rule at the earliest possible 
date.
    All ``OTC Volumes'' cited throughout this document refer to the 
submissions made by interested persons pursuant to the call-for-data 
notice published in the Federal Register of May 16, 1973 (38 FR 12840) 
or to additional information that has come the agency's attention since 
publication of the advance notice of proposed rulemaking. The volumes 
are on public display in the Dockets Management Branch (address above).

References

    1. Louv, W. C. et al., ``A Clinical Trial of Nonoxynol 9 for 
Preventing Gonococcal and Chlamydial Infections,'' Journal of 
Infectious Diseases, 158:518-523, 1988.
    2. Bird, K. D., ``The Use of Spermicides Containing Nonoxynol 9 
in the Prevention of HIV Infection,'' AIDS, 5(7):791-796, 1991.
    3. Kreiss, J. et al., ``Efficacy of Nonoxynol 9 Contraceptive 
Sponge Use in Preventing Heterosexual Acquisition of HIV in Nairobi 
Prostitutes,'' Journal of the American Medical Association, 
268(4):477-482, July 29, 1992.
    4. Miller, C. J. et al., ``The Effect of Contraceptives 
Containing Nonoxynol-9 on the Genital Transmission of Simiam 
Immunodeficiency Virus in Rhesus Macaques,'' Fertility and 
Sterility, 57(5):1126-1128, May 1993.
    5. Niruthisard, S. et al. ``The Effects of Frequent Nonoxynol-9 
Use on the Vaginal and Cervical Mucosa, Sexually Transmitted 
Diseases, 18(3):176-179, 1991.
    6. Cates, W., Jr. et al.,``Commentary,'' American Journal of 
Public Health, 82:1479-82, 1992.
    7. Cates, W., Jr. and K. M. Stone, ``Family Planning, Sexually 
Transmitted Diseases, and Contraceptive Choice: A Literature 
Update,'' Family Planning Perspectives, 24:75-84, 122-128, 1992.
    8. Rosenberg, M. J. et al., ``Barrier Contraceptives and 
Sexually Transmitted Diseases in Women: A Comparison of Female-
dependent Methods and Condoms,'' American Journal of Public Health, 
82:669-674, 1992.
    9. World Health Organization, ``Meeting on the Development of 
Vaginal Microbicides for the Prevention of Heterosexual Transmission 
of HIV,'' press release, Geneva, Switzerland, 1993.
    10. Chantler, E., ``New and Existing Spermicides with Virucidal 
Properties,'' in ``Heterosexual Transmission of AIDS; Proceedings of 
the Second Contraceptive Research and Development (CONRAD) Program 
International Workshop,'' edited by Alexander, N. J., H. L. 
Gabelnick, and J. M. Spieler, February 1989, New York, Wiley-Liss, 
pp. 303-310, 1990.
    11. Curran, J. W., ``Prevention of Sexually Transmitted 
Diseases,'' in ``Sexually Transmitted Diseases,'' edited by Himes, 
K. K. et al., McGraw-Hill Book Co., pp. 973-991, 1984.
    12. Edwards, S., ``Contraceptive Sponge Fails to Prevent 
Heterosexual Transmission of HIV Among the Prostitutes in Kenya,'' 
International Family Planning Perspectives, 18(4):152-153, 1992.
    13. Feldblum, P. J. and J. A. Fortney, ``Condoms, Spermicides 
and the Transmission of Human Immunodeficiency Virus: A Review of 
the Literature,'' American Journal of Public Health, 78(1):52-54, 
1988.
    14. Hermonat, P. L. et al., ``The Spermicide Nonoxynol-9 Does 
Not Inactivate Papillomavirus,'' Sexually Transmitted Diseases, 
19(4):203-205, July-August 1992.
    15. Hicks, D. R. et al., ``Inactivation of HTLV/LAV-Infected 
Cultures in Normal Human Lymphocytes by Nonoxynol 9 In Vitro,'' 
Lancet, (2)8469-8470, 1422-1423, December 21/28, 1985.
    16. Singh, B. et al., ``Studies in the Development of a Vaginal 
Preparation Providing Both Prophylaxis Against Venereal Disease and 
Other Genital Infections and Contraception,'' British Journal of 
Venereal Disease, 48:57-62, 1972.
    17. Trap, R. et al., ``Evaluation of the Amount of Nonoxynol-9 
Available in Condoms for the Inhibition of HIV Using a Method Based 
on HPLC, International Journal of Sexually Transmitted Diseases and 
AIDS, 1(5):436-438, September 1990.

I. The Agency's Tentative Conclusions on the Comments

A. General Comments on OTC Vaginal Contraceptive Drug Products

    1. One comment contended that OTC drug monographs are interpretive, 
as opposed to substantive, regulations. The comment referred to 
statements on this issue submitted earlier to other OTC drug rulemaking 
proceedings.
    The agency addressed this issue in paragraphs 85 through 91 of the 
preamble to the procedures for classification of OTC drug products, 
published in the Federal Register of May 11, 1972 (37 FR 9464 at 9471 
through 9472), and in paragraph 3 of the preamble to the tentative 
final monograph for OTC antacid drug products, published in the Federal 
Register of November 12, 1973 (38 FR 31260). FDA reaffirms the 
conclusions stated in those documents. Court decisions have confirmed 
the agency's authority to issue substantive regulations by rulemaking. 
(See, e.g., National Nutritional Foods Association v. Weinberger, 512 
F.2d 688, 696 to 698 (2d Cir. 1975) and National Association of 
Pharmaceutical Manufacturers v. FDA, 487 F. Supp. 412 (S.D.N.Y. 1980), 
aff'd, 637 F.2d 887 (2d Cir. 1981).)
    2. Referring to the Panel's recommendation on the advertising of 
OTC vaginal contraceptive drug products (45 FR 82014 at 82025), one 
comment agreed that labeling should be truthful and nondeceptive but 
disagreed that only those words adopted by the Panel be allowed in OTC 
drug advertising. The comment pointed out that on February 11, 1981, 
the Federal Trade Commission (FTC) declined to propose a rule which 
would require that [[Page 6895]] only FDA-approved words be used in 
advertisements for OTC drugs, and some of the Commissioners expressed 
doubt that approved OTC drug labeling would be appropriate for OTC drug 
advertising.
    FTC has the primary responsibility for regulating OTC drug 
advertising. However, FDA does have the authority to regulate OTC drug 
advertising that constitutes labeling under the Federal Food, Drug, and 
Cosmetic Act (the act). Under the act, a manufacturer can be prohibited 
from advertising a drug to treat a condition for which there are not 
adequate directions for use on the label. See, e.g., United States v. 
Article of Drug * * * B-Complex Cholinos Capsules, 362 F.2d 923 (3d 
Cir. 1966); V. E. Irons, Inc. v. United States, 244 F.2d 34 (10th 
Cir.), cert. denied, 354 U.S. 923 (1957). In addition, if advertising 
for an OTC vaginal contraceptive drug product offers the product for 
conditions not included in FDA approved labeling, the drug product 
could be subject to regulatory action by FDA. (See also section I.C., 
comment 11 of this document for discussion of FDA's labeling policy.)
    3. A number of comments disagreed with the agency's position that 
clinical testing of all final formulations, conducted under the 
provisions of a new drug application, may be the only means of assuring 
effectiveness of OTC vaginal contraceptive drug products. Several of 
these comments argued that the Panel's recommended in vitro testing 
procedures are sufficient to demonstrate effectiveness. One comment 
stated that requiring manufacturers to submit an application 
contradicts the agency's stated purpose of the monograph process. 
Another comment was concerned that requiring clinical testing might 
mean that new clinical trials would be needed each time a manufacturer 
made changes in a product's inactive ingredients. The comment 
maintained that this would be costly, would not benefit consumers, and 
would stifle a manufacturer's incentive to improve products.
    Two comments advocated requiring clinical testing of OTC vaginal 
contraceptives. One comment asserted that such testing would provide 
needed quantitative effectiveness data and ``user information.'' This 
comment also questioned how appropriate directions for use could be 
determined based only on in vitro testing. The other comment claimed 
that research has shown that certain OTC drug products judged to be 
effective by standard in vitro testing were in fact largely ineffective 
when evaluated by standard in vivo testing procedures. The comment also 
contended that in vitro testing is of limited usefulness because 
anatomic and physiologic changes in the vagina during sexual arousal, 
which can affect the distribution of the contraceptive, are not 
considered. The comment proposed using a particular in vivo testing 
procedure prior to full clinical testing.
    One comment suggested that the agency require an in vitro test 
other than that recommended by the Panel, claiming that the Panel's 
test is ``inadequately sensitive in that it only provides pass or fail 
end-point information, and does not quantitate the spermicidal potency 
of the contraceptive formulation.'' Another comment opposed requiring 
clinical testing, but stated that if such testing is to be required, a 
recognized postcoital test would be sufficient.
    The agency has reviewed the available data and information 
regarding in vitro testing procedures for vaginal contraceptive drug 
products and tentatively concludes that in vitro testing is not 
sufficient to assure effectiveness of the product when used in humans. 
Although in vitro testing will provide a measure of a product's 
potential effectiveness, reports in the literature (Refs. 1 through 14) 
indicate that such in vitro tests will not adequately describe the 
effectiveness of the final formulation when it is used in humans. In 
these reports, certain OTC vaginal contraceptives found to be effective 
when tested in vitro were shown to be ineffective when tested in vivo.
    Formulations differ in the speed of distribution in the vagina and 
the degree of surface coverage and these and other factors have a 
significant impact on effectiveness (Refs. 3, 15, and 16). Homm et al. 
(Ref. 3) compared seven marketed vaginal contraceptives (foams, 
suppository, cream, jelly) in in vitro and in vivo (rabbit) studies and 
concluded that the dosage form of a vaginal contraceptive product is of 
considerable importance in its contraceptive potency. Homm et al. found 
that foam products were more available than suppository products, which 
were more potent than jelly products. However, the authors stated that 
these comparative ratings could only be regarded as generalizations 
because the in vivo contraceptive potencies found in the rabbits were 
difficult to relate to human contraceptive effectiveness. At present, 
there is no in vitro test available that can be considered a reliable 
reflection of in vivo conditions. There is also no reliable in vivo 
animal model that can simulate the human condition. Bassol (Ref. 15) 
compared the rupture time of two types of soft jelly capsules 
containing nonoxynol 9 after vaginal insertion in 96 women. The authors 
found that vaginal conditions associated with alkaline pH, multiparity, 
and vaginal dryness have an important role in the rupture of the 
capsules. The study points out the importance of the contraceptive 
vehicle as well as other conditions of the vaginal environment in 
determining the effectiveness of vaginal contraceptive drug products.
    Stone and Cardinale (Ref. 16) conducted a study using a series of 
in vitro and in vivo tests to evaluate the effectiveness of a 
suppository product compared to a cream or foam product having the same 
active ingredient, nonoxynol 9. The authors found some evidence 
indicating that the solubility of the suppository may vary from subject 
to subject depending on, for example, the volume of vaginal secretions. 
In the in vitro study, instant immobilization of all sperm was obtained 
when foam, cream, or effervescent vaginal suppository foam was mixed 
with 2 milliliters of semen. In the in vivo study, a good volume of 
foam covering the external os of the cervix was observed in only 11 of 
the 20 patients in whom the suppository was inserted. However, very 
little if any foam was observed in the other nine women, and the 
suppository was removed almost intact after the 15-minute observation 
period. The authors commented that in vitro and laboratory evaluations 
of chemical contraceptives do not correlate well to their effectiveness 
in clinical trials in different populations. In addition, they noted 
that formulations containing a highly effective spermicidal agent but 
that do not diffuse well are less effective.
    Postcoital tests in humans have been considered as an alternative 
to clinical trials. However, the agency does not believe that the 
currently available postcoital tests can be relied upon. The Sims-
Huhner test (SHT) is an in vivo postcoital test that is used to 
diagnose certain types of infertility and assess the presence, quality, 
and motility of sperm in the cervical mucus. References in the medical 
literature indicate that the SHT has poor predictive value because a 
negative SHT does not confirm the absence of sperm (Refs. 17, 18, and 
19). Kably et al. (Ref. 17) stated that they had found the results of 
the SHT to ``paradoxical'' relative to conception. Therefore, the 
authors examined whether sperm were present or absent in the peritoneal 
fluid of five subjects with good SHT's and five subjects with poor or 
negative SHT's. In three of five subjects with a positive SHT and in 
four of five subjects with a poor SHT, sperm were found in the 
aspirate. [[Page 6896]] 
    Asch (Ref. 18) also reported that pregnancy frequently occurs in 
women with a negative or poor SHT. Asch reported the recovery of 
mature, morphologically normal sperm from the peritoneal fluid of six 
of the eight women who had a negative SHT. In three other women who had 
a poor SHT, sperm were also recovered in the aspirate. Griffith and 
Grimes (Ref. 19) reviewed the literature and evaluated the validity of 
the postcoital test for predicting infertility. The authors concluded 
that the SHT has poor validity, its reproducibility is unknown, and its 
suffers from a lack of standardized methodology and a uniform 
definition of normal. Because the absence of sperm in the SHT 
frequently has been associated with subsequent pregnancy, the agency 
concludes that this in vivo postcoital test is not reliable for 
evaluating the efficacy of a vaginal contraceptive.
    Because of the difficulties that arise in trying to simulate the 
human condition in an in vitro test and determine the influence of the 
potential interactions among the sperm, cervical mucus, microorganisms, 
and contraceptive vehicle on the effectiveness of the contraceptive, 
the results of in vitro testing cannot be relied upon to reach 
conclusions about effectiveness in humans. For example, due to the 
varied amounts of cervical mucus and semen that may be present in 
humans during sexual arousal, the concentration of the contraceptive in 
the vagina is not always equivalent to the concentration used in in 
vitro testing. Furthermore, in vitro testing cannot determine the 
following important information: How long before intercourse the 
contraceptive should be inserted; if the intravaginal distribution of 
the contraceptive is sufficient to assure effectiveness; or how long 
the contraceptive remains effective in the vaginal environment. 
Therefore, the agency has determined that clinical studies in humans 
are necessary to establish the effectiveness of final formulations of 
OTC vaginal contraceptive drug products.
    The results of such testing should be submitted in the form of an 
application that complies with all of the requirements that are 
necessary to establish the safety and effectiveness of the product's 
final formulation, as discussed above. Reference to the Panel's report 
and this document, as appropriate, may be used to satisfy the 
requirements of portions of the application related to the safety of 
the active ingredient.

References

    1. MacLeod, J. et al., ``In Vitro Assessment of Commercial 
Contraceptive Jellies and Creams: Positive Correlation Between 
Laboratory Tests and Clinical Use Awaits Further Investigation,'' 
Journal of the American Medical Association, 176:427-431, 1961.
    2. Bernstein, G. S., ``Physiological Aspects of Vaginal 
Contraception: A Review,'' Contraception, 9:333-345, 1974.
    3. Homm, R. E. et al., ``A Comparison of the In Vivo 
Contraceptive Potencies of a Variety of Marketed Vaginal 
Contraceptive Dosage Forms,'' Current Therapy and Research, 22:588-
596, 1977.
    4. ``Population Reports,'' Series H, No. 3, January 1975, 
Population Information Program, The Johns Hopkins University, 
Baltimore.
    5. Johnson, V. E. and W. H. Masters, ``Intravaginal 
Contraceptive Study, Phase II, Physiology (A Direct Test for 
Protective Potential),'' Western Journal of Surgery, Obstetrics and 
Gynecology, 71:144-153, 1963.
    6. Johnson, V. E. et al., ``Factors in Failure--The Physiology 
of Intravaginal Contraceptive Failure,'' in ``Manual of Family 
Planning and Contraceptive Practice,'' 2d ed., Williams & Wilkins 
Co., Baltimore, p. 232, 1970.
    7. ``Population Reports,'' Series H, No. 5, September 1979, 
Population Information Program, The Johns Hopkins University, 
Baltimore.
    8. Masters, W. H. et al., ``In Vivo Evaluation of an 
Effervescent Intravaginal Contraceptive Insert by Simulated Coital 
Activity,'' Fertility and Sterility, 32:161-165, 1979.
    9. Bernstein, G. S., ``Conventional Methods of Contraception: 
Condom, Diaphragm, and Vaginal Foam,'' Clinical Obstetrics and 
Gynecology, 17(1):21-33,1974.
    10. Sobrero, A. J., ``Spermicidal Agents: Effectiveness, Use, 
and Testing,'' in ``Vaginal Contraception: New Developments,'' 
Harper & Row, Hagerstown, MD, p. 62, 1979.
    11. Zaneveld, L. J. D. et al., ``Primate Model for Evaluation of 
Vaginal Contraceptives,'' American Journal of Obstetrics and 
Gynecology, 129(4):368-373, 1977.
    12. Connell, E. B., ``Vaginal Contraception,'' in ``Advances in 
Fertility Research,'' Raven Press, New York, pp. 19-37, 1982.
    13. Jackson, M., G. S. Berger, and L. G. Keith, ``Vaginal 
Contraception,'' G. K. Hall Medical Publishers, Boston, pp. 245-255, 
1981.
    14. Sobrero, A. J., ``Vaginal Chemical Products,'' in ``Manual 
of Family Planning and Contraceptive Practice,'' 2d ed., Williams & 
Wilkins Co., Baltimore, pp. 275-282, 1970.
    15. Bassol, S. et al., ``Comparative Trial Between Two Soft 
Jelly Capsules Containing Nonoxynol As Spermicidal Contraceptives,'' 
Contraception, 39:110-118, 1989.
    16. Stone, C. S. and F. Cardinale, ``Evaluation of a New Vaginal 
Contraceptive,'' American Journal of Obstetrics and Gynecology, 
133:635-638, 1979.
    17. Kably, et al., ``Laparoscopic Recovery of Spermatozoa in the 
Peritoneal Fluid, Its Correlation With The Sims-Huhner Test,'' 
Ginecologia y Obstetricia de Mexico, 57:82-84, 1989.
    18. Asch, R. H., ``Laparoscopic Recovery of Sperm from 
Peritoneal Fluid In Patients With Negative or Poor Sims-Huhner 
Test,'' Fertility and Sterility, 27:1111-1114, 1976.
    19. Griffith, Carolyn S. and D. A. Grimes, ``The Validity of the 
Postcoital Test,'' American Journal of Obstetrics and Gynecology, 
162:615-620, 1990.
    4. One comment stated that FDA does not have the authority to 
enforce Sec. 351.30(f) of the Panel's recommended monograph, which 
would require manufacturers to retain the in vitro effectiveness 
testing data and permit FDA to inspect these data. The comment 
requested that Sec. 351.30(f) be deleted.
    As discussed in section I.A., comment 3 of this document, the 
agency is proposing that each OTC vaginal contraceptive drug product 
should be the subject of an approved application prior to marketing. 
Therefore, there will be no monograph and the comment's request is 
moot.
    5. Two comments objected to the Panel's statement questioning the 
safety and effectiveness of quaternary ammonium compounds for use as 
preservatives in OTC vaginal contraceptive drug products (45 FR 82014 
at 82042). The comments stated that the Panel's concern stems solely 
from a review of eight reports (45 FR 82042) suggesting that the use of 
quaternary ammonium compounds may be associated with outbreaks of 
Pseudomonas infections because they do not inhibit the growth of 
Pseudomonas. The comments argued that the Panel failed to state that 
these reports resulted from the contamination of solutions that were 
employed in laboratory and hospital settings to sterilize medical 
devices used in urinary and cardiac catheterization or cystoscopic or 
related invasive procedures. Such procedures are usually conducted on 
patients whose normal body defenses have been compromised. Because 
Pseudomonas infections occur primarily in debilitated patients and 
Pseudomonas does not cause vulvovaginitis, the comments stated that it 
is scientifically inappropriate to cite these reports and through 
extrapolation conclude that the use of quaternary ammonium compounds in 
vaginal contraceptive drug products presents a health hazard to normal 
individuals. The comments cited several references to support the 
argument that the Panel's concern, with respect to vaginal 
contamination by Pseudomonas in the presence of quaternary ammonium 
compounds, is not supported by the weight of scientific and medical 
opinion (Refs. 1 through 4). [[Page 6897]] The comments concluded that 
the agency should affirm the safety of quaternary ammonium compounds 
and reclassify these ingredients in Category I for use as preservatives 
in OTC vaginal drug products.
    Although the comments requested that the agency affirm the safety 
of quaternary ammonium compounds for use as preservatives and 
reclassify them as Category I, the agency points out that the OTC drug 
review is primarily a review of active ingredients, not inactive 
ingredients. However, because the purpose of the OTC drug review 
process is to determine the safety and effectiveness of OTC drugs, the 
OTC advisory review panels occasionally made recommendations with 
respect to inactive ingredients. These recommendations were made to 
call attention to those inactive ingredients that could potentially 
interfere with the safety and effectiveness of the product.
    In the case of the quaternary ammonium compounds, the agency agrees 
with the comments' reasoning that the reports cited by the Panel cannot 
be used to conclude that the use of these compounds as preservatives in 
OTC vaginal contraceptive drug products may present a health hazard to 
normal individuals.
    As discussed in section I.A., comment 3 of this document, the 
agency is proposing that each OTC vaginal contraceptive drug product 
should be the subject of an approved application prior to marketing. 
Information regarding the appropriateness of ingredients used in the 
product as preservatives should be included in the application.

References

    1. Forkner, Jr., C. E., ``Pseudomonas Aeruginosa Infections,'' 
in ``Modern Medical Monographs,'' vol. 22, edited by I. S. Wright 
and R. H. Orr, Gruen and Stratton, New York, p. 71, 1960.
    2. Gardner, H. L. and R. H. Kaufman, ``Nonvenereal Bacterial 
Vulvovaginitides,'' in ``Benign Diseases of the Vulva and Vagina,'' 
2d ed., G. K. Hall Medical Publishers, Boston, p. 306, 1981.
    3. Ridley, C. M., ``The Vulva,'' in ``Major Problems in 
Dermatology,'' vol. 5, edited by A. Rook, W. B. Saunders Co., 
Philadelphia, p. 99, 1975.
    4. Mead, P. B. and D. W. Gump, ``Antibiotic Therapy in 
Obstetrics and Gynecology,'' in ``Clinical Obstetrics and 
Gynecology,'' vol. 19, No. 1, edited by H. J. Osofsky and G. 
Schaefer, Harper and Row, Hagerstown, MD, p. 114, 1976.
    6. Several comments disagreed with the Panel's recommendations that 
inactive ingredients and the quantity of the ingredient be listed in 
the labeling of OTC vaginal contraceptive drug products. The comments 
argued that a list of inactive ingredients would be meaningless to all 
but a few consumers and that such a list might overemphasize the 
importance of the inactive ingredients; obscure more meaningful 
information such as warnings, directions for use, and the name and 
quantity of the active ingredients; and be more confusing than helpful. 
The comments also stated that if the quantity of the inactive 
ingredients had to be listed there would be an additional problem and 
expense of changing the labels whenever the quantity of an inactive 
ingredient is changed.
    The act does not require the identification of all inactive 
ingredients in the labeling of OTC drug products. Section 502(e) of the 
act (21 U.S.C. 352(e)) does require disclosure of active ingredients 
and of certain ingredients, whether included as active or inactive 
components in a product. Although the act does not require the 
disclosure of all inactive ingredients in the labeling of OTC drug 
products, the agency agrees with the Panel that listing of inactive 
ingredients in OTC drug product labeling would be useful information 
for some consumers. Consumers with known allergies or intolerances to 
certain ingredients would then be able to identify substances that they 
may wish to avoid.
    The Nonprescription Drug Manufacturers Association (formerly known 
as The Proprietary Association), the trade association that represents 
approximately 85 OTC drug manufacturers who reportedly market between 
90 and 95 percent of the volume of all OTC drug products sold in the 
United States, has established guidelines (Ref. 1) for its member 
companies to list voluntarily inactive ingredients in the labeling of 
OTC drug products. Under another voluntary program begun in 1974, the 
member companies of the Association have been including the quantities 
of active ingredients on OTC drug labels. The agency is not at this 
time proposing to require the listing of inactive ingredients in OTC 
drug product labeling. However, the agency commends these voluntary 
efforts and urges all other OTC drug manufacturers to similarly label 
their products.

Reference

    1. ``Guidelines for Disclosure of Inactive Ingredients in OTC 
Medicines,'' The Proprietary Association, Washington, July 12, 1984, 
in OTC Vol. 11ATFM.
    7. One comment urged that the label of OTC vaginal contraceptive 
drug products contain a list of all active ingredients, arguing that 
consumers have a right to an informed choice when buying such products.
    As discussed in section I.A., comment 6 of this document, listing 
of active ingredients is required for all drug products under section 
502(e)(1) of the act (21 U.S.C. 352(e)(1)).

B. Comments on OTC Vaginal Contraceptive Active Ingredients

    8. Three comments supported the Panel's Category I classification 
of menfegol and disagreed with the agency's conclusion that menfegol is 
a new drug because it is a new molecular entity, never before marketed 
as a drug in the United States. The comments stated that a lack of 
United States' marketing experience does not preclude a drug from being 
considered generally recognized as safe and effective nor require a 
drug to be considered a new drug. One comment argued that data on the 
marketing of vaginal contraceptive drug products in foreign countries 
can be equated to marketing in this country because the mode of action 
of these products is based on the spermicidal activity of an ingredient 
in the vagina and not on the medical problems, diets, customs, and 
environments of other countries. The comment urged FDA to reconsider 
its decision to refuse to recognize data on the marketing of a product 
outside the United States regardless of the ingredient, type of 
product, or its mode of action. Another comment added that the act 
defines a new drug as any drug not generally recognized as safe and 
effective among experts, whereas menfegol was so recognized by a panel 
of experts.
    The Panel's Category I classification of menfegol was based on its 
review of safety and effectiveness data. The Panel's recommendation did 
not address the issue whether menfegol meets the statutory requirement 
concerning use of a drug. Menfegol was determined to be a new drug 
within the meaning of section 201(p)(2) of the act (21 U.S.C. 
321(p)(2)), which defines a new drug as: * * * ``any drug * * * that * 
* * has become so recognized, but which has not * * * been used to a 
material extent or for a material time under such conditions.'' The 
agency's longstanding interpretation of section 201(p)(2) of the act 
has been that marketing outside the United States cannot fulfill this 
independent statutory requirement of use to a ``material extent'' and 
for a ``material time.'' Currently, based on several petitions to 
another OTC drug review rulemaking (Refs. 1, 2, and 3), the agency is 
reevaluating this interpretation of the act. (See section II.C., 
comment 34 of this document, in the tentative final 
[[Page 6898]] monograph for OTC sunscreen drug products published in 
the Federal Register of May 12, 1993, 58 FR 28194 at 28210). The agency 
will discuss its decision on this matter in a future issue of the 
Federal Register. Thus, the agency is reconsidering its policy on 
foreign marketing data, as the comment requested. However, in view of 
the agency's tentative conclusion that all vaginal contraceptive drug 
products will need an approved application for marketing, this issue, 
as it relates to menfegol, is moot.

References

    1. Citizen Petition, submitted by BASF AG, March 16, 1990, coded 
CP2, Docket No. 78N-0038, Dockets Management Branch.
    2. Citizen Petition, submitted by Haarmann and Reimer Corp., 
July 27, 1990, coded CP3, Docket No. 78N-0038, Dockets Management 
Branch.
    3. Citizen Petition, submitted by Givaudan Corp., October 31, 
1990, coded CP4, Docket No. 78N-0038, Dockets Management Branch.
    9. Two comments submitted data and information on the safety of 
nonoxynol 9 (Ref. 1). These data were submitted after publication of 
the Panel's report in response to concerns regarding the potential 
teratogenicity or carcinogenicity of this ingredient (Refs. 2, 3, and 
4).
    Although nonoxynol 9 was classified by the Panel as a Category I 
ingredient for use as an OTC vaginal contraceptive, concern over the 
possible carcinogenicity of nonoxynol 9 surfaced in relation to the 
agency's approval of an application for a vaginal contraceptive sponge 
product containing this ingredient. In reviewing the data in support of 
the application, the agency learned that nonoxynol 9 may contain low 
levels of the suspected carcinogens 1,4-dioxane and ethylene oxide as 
residuals from the manufacturing process. The concern that the agency 
had approved an application for a product containing suspected 
carcinogens was one of the bases of a congressional hearing held by the 
Subcommittee on Intergovernmental Relations and Human Resources on July 
13, 1983. At that hearing, FDA presented testimony and evidence that 
the levels of 1,4-dioxane and ethylene oxide contained in the sponge 
product are within the residue limits that are considered acceptable by 
the agency.
    However, because the presence of 1,4-dioxane and ethylene oxide is 
not unique to the sponge product and it is possible that other products 
could contain different levels of these contaminants, the agency 
believes that manufacturers should submit as part of the application 
required for these products (see section I.A., comment 3 of this 
document) data and information specifying the levels of 1,4-dioxane and 
ethylene oxide that are contained in the finished product.
    The concern over possible teratogenicity of OTC vaginal 
contraceptives was also raised at the congressional hearing. The agency 
explained at the hearing that animal teratogenicity data and recent 
epidemiological data indicate that nonoxynol 9 is not teratogenic. 
However, FDA stated that it was considering a special warning 
concerning the use of any spermicide by women who suspect that they may 
be pregnant. Data and information on the possible teratogenicity of 
vaginal spermicides were subsequently presented to the agency's 
Fertility and Maternal Health Drugs Advisory Committee to determine if 
any of the studies contains sufficient evidence to warrant a special 
warning in the labeling concerning the use of vaginal spermicides 
during pregnancy. At its December 15, 1983 meeting (Ref. 5), the 
committee decided that such a warning was not warranted. The agency 
concurs with the advisory committee's conclusion.

References

    1. ``Nonoxynol 9 Safety Information,'' Advanced Care Products, 
Division of Ortho Pharmaceutical Corp., coded RPT and RPT002, Docket 
No. 80N-0280, Dockets Management Branch.
    2. Jick, H. et al., ``Vaginal Spermicides and Congenital 
Disorders,'' Journal of the American Medical Association, 245:1329-
1332, 1981.
    3. Rothman, K. J., ``Spermicide Use and Down's Syndrome,'' 
American Journal of Public Health, 72:399-401, 1982.
    4. Citizen Petition, submitted by A. Lione, Associated 
Pharmacologists and Toxicologists, June 20, 1983, coded CP2, Docket 
No. 83P-0187, Dockets Management Branch.
    5. Minutes of the Meeting of the Fertility and Maternal Health 
Drugs Advisory Committee, National Center for Drugs and Biologics, 
FDA, pp. 1-3, December 15, 1983, copy included in OTC Vol. 11ATFM.
    10. Two comments disagreed with the Panel's intention that data 
submitted on the safety of phenylmercuric acetate be regarded as 
equally relevant for all related mercury compounds, such as 
phenylmercuric nitrate (45 FR 82014 at 82031). One comment stated that 
the greatest part of the Panel's discussion on phenylmercuric acetate 
and related compounds is devoted to a discussion of the reported 
toxicity of orally ingested alkylmercury compounds and that this 
discussion unjustifiably imputes toxicity to arylmercury compounds when 
used in topically applied preparations under ordinary conditions. The 
comments further stated that, although the Panel acknowledged that 
alkylmercury compounds and inorganic mercury salts have greater 
toxicity than arylmercury compounds, it should be recognized that 
differences also occur between mercury compounds within the aryl 
series. Therefore, the comments argued, conclusions should be limited 
to the compound specifically considered, phenylmercuric acetate, when 
used specifically for its spermicidal action and should not condemn 
phenylmercuric nitrate by association.
    The agency acknowledges the comments' concern regarding the varying 
toxicities of the different mercury compounds, but concurs with the 
Panel that mercury-containing compounds, when used as active 
ingredients in vaginal contraceptive drug products, are unsafe. The 
Panel recommended that all vaginal contraceptives containing mercury 
compounds as active ingredients be placed in Category II because such 
compounds are potentially hazardous to the fetus and the breast-fed 
infant (45 FR 82014 at 82038). Because data in animals and humans 
indicate that phenylmercuric acetate is absorbed from the vagina into 
the system and partially metabolized to inorganic mercury in the blood 
and various tissues where it may accumulate (Refs. 1 through 4), the 
Panel concluded that mercury-containing compounds related to 
phenylmercuric acetate, such as phenylmercuric nitrate, may be expected 
to behave in a similar manner. Other than the comments' contention, no 
data or information was submitted to demonstrate that phenylmercuric 
nitrate and related mercury-containing compounds react by a different 
mechanism or are not absorbed from the vagina. Although no overt 
symptoms of mercury poisoning from the use of vaginal preparations 
containing mercury compounds have been detected in infants and 
children, there are sufficient animal data to suggest that inorganic 
mercury from mercury-containing compounds can be transferred to the 
fetus and to breast-fed offspring. (See 45 FR 82014 at 82033 and 
82035.) In addition, the Panel cited animal teratology studies that 
showed a higher percentage of fetal abnormalities when phenylmercuric 
acetate was administered either vaginally or intravenously (45 FR 
82034). The Panel also cited cases of congenital mercury poisoning in 
humans following ingestion of mercury compounds by the mother (45 FR 
82032). These studies are at least suggestive, regardless of the 
[[Page 6899]] method of administration, of the potential hazard of 
mercury to offspring when the drug is systemically absorbed by the 
mother. Therefore, because of the possibility that mercury-containing 
compounds which can be metabolized to inorganic mercury may pose a risk 
to fetuses and nursing infants, the agency concurs with the Panel that 
such compounds are unsafe for use in vaginal contraceptive drug 
products.

References

    1. Al-Jobori, I. M., ``Mercury Levels in Females Exposed to 
Phenylmercuric Acetate,'' Master Thesis, University of Baghdad, pp. 
10-110, 1975, in OTC Vol. 110058.
    2. Fukuchi, H. et al., ``The Absorption of Organomercurial 
Compounds from the Vaginal Route of the Rabbits. I. Comparative 
Study on the Effect of Suppository Vehicles on the Absorption of 
Omega-Ethylmercurithio-n-undecanoic Acid, Phenylmercuric Acetate and 
Ethylmercuric Chloride after Single Dose Administration,'' Chemical 
and Pharmaceutical Bulletin, 12:540-548, 1964.
    3. Fukuchi, H. et al., ``The Absorption of Organomercurial 
Compounds from the Vaginal Route of the Rabbits. II. Distribution 
and Excretion of Omega-Ethylmercurithio-n-undecanoic Acid and 
Phenylmercuric Acetate,'' Chemical and Pharmaceutical Bulletin, 
12:548-557, 1964.
    4. Murkami, U., Y. Kameyama, and T. Kato, ``Effects of a 
Vaginally Applied Contraceptive with Phenylmercuric Acetate Upon 
Developing Embryos and Their Mother Animals,'' Annual Report of the 
Research Institute of Environmental Medicine, Nagoya University, pp. 
88-99, 1955.

C. Comments on Labeling of OTC Vaginal Contraceptive Drug Products

    Although the proposed rule included in this document does not 
include monograph conditions, the responses to the following comments 
should be considered as FDA's tentative position on the labeling of OTC 
vaginal contraceptive drug products. FDA has considered the Panel's 
labeling recommendations and the following comments in developing the 
agency's position on labeling for OTC vaginal contraceptive drug 
products. This document will serve as the basis for the development of 
guidelines for the content and format of the labeling of OTC vaginal 
contraceptive drug products similar to those currently available for 
oral contraceptive drug products. (See 54 FR 22585 and 22624, May 25, 
1989.) The agency intends to complete these guidelines for OTC vaginal 
contraceptive drug products after the comments to this proposal are 
evaluated.
    11. One comment noted its continuing position that FDA lacks 
statutory authority to prescribe exclusive lists of terms from which 
indications for use for OTC drug products must be drawn and to prohibit 
labeling terminology which is truthful, accurate, not misleading, and 
intelligible to the consumer. A second comment stated that it would be 
inappropriate to restrict manufacturers to the specific wording 
recommended by the Panel for package insert statements.
    In the Federal Register of May 1, 1986 (51 FR 16258), the agency 
published a final rule changing its labeling policy for stating the 
indications for use of OTC drug products. Under 21 CFR 330.1(c)(2), the 
label and labeling of OTC drug products are required to contain in a 
prominent and conspicuous location, either: (1) The specific wording on 
indications for use established under an OTC drug monograph, which may 
appear within a boxed area designated ``APPROVED USES''; (2) other 
wording describing such indications for use that meets the statutory 
prohibitions against false or misleading labeling, which shall neither 
appear within a boxed area nor be designated ``APPROVED USES''; or (3) 
the approved monograph language on indications, which may appear within 
a boxed area designated ``APPROVED USES,'' plus alternative language 
describing indications for use that is not false or misleading, which 
shall appear elsewhere in the labeling. All other OTC drug labeling 
required by a monograph or other regulation (e.g., statement of 
identity, warnings, and directions) must appear in the specific wording 
established under the OTC drug monograph or other regulation where 
exact language has been established and identified by quotation marks, 
e.g., 21 CFR 201.63 or 330.1(g). There will be no monograph for OTC 
vaginal contraceptive drug products, and all labeling for these 
products will be approved via applications. Therefore, the comments are 
moot with respect to this current rulemaking.
    12. Several comments agreed with the Panel that quantitative claims 
of effectiveness should not be required in the labeling of OTC vaginal 
contraceptive drug products because of the difficulty in conducting the 
studies that would be necessary to substantiate such claims. The size 
of the sample that would be needed, the variations in subject 
motivation, varying methods of product use, and the lack of an adequate 
representative population of American women were specifically cited in 
the comments as factors that would make such studies difficult to 
conduct. The comments also pointed out that the consensus of the 
participants in the symposium on vaginal contraception, held by the 
Panel on April 28 and 29, 1978, was that quantitative effectiveness 
claims should not be required.
    A number of comments indicated that quantitative effectiveness 
claims should not be required, but that manufacturers should be 
permitted to use these claims at their own discretion. Several of these 
comments also objected to the Panel's recommendation that such claims 
be permitted in labeling only after prior approval by FDA through the 
new drug procedures.
    Two comments questioned whether the quantitative effectiveness 
claims could be written in a manner that would be understood by 
consumers. Providing consumers with actual numbers relevant to method 
effectiveness, use effectiveness, and extended-use effectiveness was 
specifically cited as a potential source of confusion.
    One comment pointed out that the patient labeling of oral 
contraceptives is required to contain a discussion comparing the 
effectiveness of different contraceptive methods and, therefore, it 
would be inconsistent for FDA to conclude that there are insufficient 
data available to support the validity of comparative effectiveness 
claims in the labeling of OTC vaginal contraceptive drug products.
    The agency believes that consumers should be provided with the most 
informative labeling available when choosing a contraceptive drug 
product. After reviewing the complete administrative record for this 
rulemaking, including the record of the Panel's symposium on vaginal 
contraception and the comments submitted to the Panel's report on this 
issue, the agency concludes that the most informative labeling for 
users of vaginal contraceptive drug products is information on the 
relative effectiveness of the various methods of contraception. The 
agency is currently working to create a consistent and understandable 
presentation of this important information to include in the labeling 
of all marketed contraceptive products, drugs, and devices.
    13. Two comments objected to the Panel's labeling recommendations 
for the outer and primary containers of OTC vaginal contraceptive drug 
products (45 FR 82014 at 82031). The comments questioned the propriety 
of the Panel in specifying the order of appearance and location of the 
various required statements. The comments also objected to the number 
of required labeling statements. One comment stated that listing of all 
the recommended labeling statements would require the use of small 
illegible typeface. The second comment noted that if space were 
[[Page 6900]] limited, listing of all items in the recommended order 
would preempt those labeling statements required by law. The second 
comment also requested that the general warning statements, ``Keep this 
and all drugs out of the reach of children'' and ``In case of 
accidental ingestion call a Poison Control Center, emergency medical 
facility, or a doctor,'' not be included in the Panel's priority system 
of labeling. The comment pointed out that warnings similar to these are 
already required by 21 CFR 330.1(g), which only requires that these 
warnings appear somewhere in the labeling. The comment stated that 
there is no basis for special treatment of these warnings for OTC 
vaginal contraceptive drug products.
    Existing regulations (21 CFR 201.15 and 21 CFR part 201, subpart 
C--Labeling Requirements for Over-the-Counter Drugs) adequately address 
the placement and prominence of labeling statements. While there may be 
certain selected situations where it is necessary to alter these 
general requirements, the agency is unaware of any data demonstrating 
that it is necessary in the case of OTC vaginal contraceptive drug 
products. In addition, the labeling statements required by 
Sec. 330.1(g) are similar to those recommended by the Panel and the 
agency considers the labeling requirements in Sec. 330.1(g) to be 
appropriate for OTC vaginal contraceptive drug products.
    14. One comment suggested that the accidental ingestion warning 
recommended by the Panel be changed from ``In case of accidental 
ingestion, call a Poison Control Center, emergency medical facility, or 
a doctor immediately'' to ``In case of accidental ingestion of large 
amounts by children, call a Poison Control Center or emergency medical 
facility, or call a doctor.'' The comment contended that because of the 
well-established safety of OTC vaginal contraceptive drug products the 
Panel's recommended warning is unnecessarily alarming to adult users.
    The agency does not believe that the Panel or the comment have 
presented sufficient data or information to warrant a change from the 
accidental ingestion warning required by Sec. 330.1(g) or Sec. 369.9 
for all OTC drug products.
    15. One comment agreed with the Panel that the labeling of an OTC 
contraceptive drug product should contain an expiration date and 
information on the product's appropriate storage condition.
    To assure that a drug product meets applicable standards of 
identity, strength, quality, and purity at the time of use, existing 
FDA regulations at 21 CFR 211.137 require an expiration date for the 
product, except for OTC drug products for human use whose labeling does 
not bear dosage limitations and which are stable for at least 3 years 
as supported by appropriate stability data. In addition, the expiration 
date is also required to relate to any storage conditions stated on the 
labeling. As discussed in section I.A., comment 3 of this document, the 
agency is proposing that each OTC vaginal contraceptive drug product 
should be the subject of an approved application prior to marketing. 
Information relating to dosage limitations, stability conditions, and 
storage conditions should be included in the application.
    16. Three comments agreed with the Panel that the labeling of OTC 
vaginal contraceptive drug products should contain precise directions 
that can be easily understood by the average consumer. One of these 
comments added that diagrams on proper use of the contraceptive might 
also be useful.
    The agency agrees that vaginal contraceptives should contain 
precise directions that are understandable to consumers, including 
diagrammed instructions, as appropriate, to show the proper method of 
application.
    17. One comment suggested that the Panel's recommended directions 
statement in Sec. 351.56(a)(3), which reads, ``If this product is used 
together with another contraceptive method, there will probably be 
better protection against pregnancy,'' be modified to include examples 
of various contraceptive methods, such as a diaphragm, condom, or 
intrauterine device.
    As discussed in section I. C., comment 12 of this document, the 
agency believes that the labeling of OTC vaginal contraceptive drug 
products should contain a summary of the effectiveness of the various 
methods of contraception. In light of this, the agency considers the 
modification recommended by the comment to be unnecessary.
    18. One comment stated that if the indication recommended by the 
Panel in Sec. 351.56(b)(5), which reads, ``Extra protection for women 
who forget to take one or more contraceptive pills,'' is adopted, the 
labeling of the product should also refer the user to the directions 
for use of the oral contraceptive. The comment reasoned that a woman 
who has missed more than two consecutive pills should discontinue 
taking them, whereas the use of the word ``extra'' implies that the 
pills should be continued. As an alternative to referring the user to 
the oral contraceptive's directions for use, the comment suggested 
revising the statement to read ``Extra protection for women who forget 
to take one or two contraceptive pills.''
    The comment added that the indication in recommended 
Sec. 351.56(b)(8), which reads, ``Effective contraceptive alone or in 
the event the contraceptive pill is forgotten,'' is more acceptable 
than the one in Sec. 351.56(b)(5), but it appears to imply that vaginal 
and oral contraceptives provide equivalent protection. The comment 
recommended that both statements either be modified or deleted.
    The agency believes that information regarding what to do when a 
contraceptive pill is forgotten is more appropriate for inclusion in 
the labeling of oral contraceptives. Such information is required to be 
included in the patient labeling of oral contraceptives. Therefore, the 
agency does not believe that this type of information is necessary for 
inclusion in the labeling for OTC vaginal contraceptive drug products.
    19. Two comments urged deletion of the statement recommended by the 
Panel in Sec. 351.56(a)(5), which reads, ``If douching is desired, 
always wait at least 6 hours after intercourse before douching.'' The 
comments claimed that there are no data or information in the 
scientific literature or from common usage demonstrating the need for 
such labeling. One of these comments specifically argued that the only 
supporting reference cited by the Panel (Ref. 1) discusses the 
persistence of sperm in the cervix and vagina following intercourse but 
does not express any concern about douching following the use of a 
vaginal spermicide. The comment added that this reference actually 
indicates that douching was ``associated with reductions in proportions 
of smears containing spermatozoa.'' Both comments also specifically 
noted that the Panel admitted that there are no data establishing the 
optimum time interval between use of a spermicide and douching.
    Although the comments are correct that no data are available 
concerning the optimum time interval between intercourse and douching 
when using a vaginal spermicide product, it is generally accepted that 
douching too soon after intercourse could likely interfere with a 
spermicide by diluting it or removing it from the vagina. Therefore, 
the agency believes that a statement regarding the time interval 
between intercourse and douching would provide useful information to 
the consumer. The Panel stated that it is [[Page 6901]] generally 
accepted opinion that when vaginal contraceptives are used as the 
primary method of birth control, douching should be delayed for at 
least 6 hours after coitus (45 FR 82014 at 82030). The agency concurs.

Reference

    1. Silverman, E. M. and A. G. Silverman, ``Persistence of 
Spermatozoa in the Lower Genital Tracts of Women,'' Journal of the 
American Medical Association, 240:1875-1877, 1978.
    20. One comment suggested that the labeling of OTC vaginal 
contraceptive drug products include a warning specifying possible 
adverse allergic reactions such as itching and burning in the vaginal 
area and in the penile area. The comment also recommended that the 
warning advise consumers to discontinue use if these symptoms occur.
    The agency agrees with the comment that consumers should be warned 
about possible allergic reactions such as burning and itching that may 
occur when using vaginal contraceptive drug products. The agency also 
agrees that the warning should advise consumers to discontinue use if 
these symptoms should occur. Furthermore, if the irritation persists 
after use has been discontinued, it could indicate a problem other than 
an allergic reaction to the product, so that a physician should be 
contacted. The agency believes the following warning is appropriate for 
inclusion in the labeling of OTC vaginal contraceptive drug products: 
``If you or your partner develops irritation, such as burning or 
itching in the genital area, stop using this product. If irritation 
continues, contact your physician.''
    21. One comment stated that the Category II labeling claims 
recommended by the Panel (45 FR 82014 at 82040) are not proper subject 
matter for the OTC drug review and should not be classified. The 
comment argued that these claims are not indications for use, but 
rather are statements of fact which are unrelated to the safety or 
effectiveness of a vaginal contraceptive drug. The comment added that 
the claims cannot legally be prohibited if truthful and should not be 
placed in Category II without a finding that they are inherently false 
or misleading.
    The OTC drug review program establishes conditions under which OTC 
drugs are generally recognized as safe and effective and not 
misbranded. One aspect of the program is to develop standards for 
certain parts of the labeling of OTC drug products. Because of time, 
resources, and other considerations, FDA has not set standards for all 
labeling found in OTC drug products. Accordingly, OTC drug monographs 
address only those labeling items that are related in a significant way 
to the safe and effective use of covered products by lay persons. These 
labeling items are the product statement of identity; names of active 
ingredients; indications for use; directions for use; warnings against 
unsafe use, side effects, and adverse reactions; and claims concerning 
mechanism of drug action.
    Based on the discussion above, the agency tentatively concludes 
that the Panel's entire list of Category II labeling claims as well as 
certain descriptive terms included in the Panel's recommended list of 
other allowable statements (recommended Sec. 351.56(c)), i.e., safe, 
effective, powerful, highly) would be outside the scope of a monograph, 
if one were being established. Because all OTC vaginal contraceptive 
drug products will require an approved application for marketing, such 
claims can be evaluated, during the approval process, on a product-by-
product basis for compliance with section 502 of the act (21 U.S.C. 
352) relating to labeling that is false or misleading.
    22. After reviewing the Panel's recommended labeling, the agency 
has tentatively determined that the following additional changes in the 
Panel's recommendations are warranted. Although the Panel recommended 
``spermicide'' as an indication, the agency believes that it would be 
more appropriate as an optional statement of identity. In addition, 
although the Panel recommended a number of indications statements, the 
agency believes that the indication ``For the prevention of pregnancy'' 
is sufficient to convey to consumers the intended use of the product. 
The agency has also tentatively determined that the statement ``If your 
physician has told you that you should not become pregnant, ask your 
physician if you can use this product for contraception,'' should be a 
warning instead of a direction statement.

D. Comments on Combinations

    23. One comment objected to the Panel's statement at 45 FR 82014 at 
82026 that if two or more Category I vaginal contraceptive active 
ingredients are combined, the specific ingredients as well as the 
combination product must be subjected to laboratory and clinical 
testing according to the recommended testing guidelines. The comment 
argued that no useful purpose is served or information gained by 
clinical testing of single Category I ingredients and that such testing 
is not required under FDA's OTC combination policy.
    As discussed in section I. D., comment 25 of this document, testing 
guidelines for conditions that industry wishes to upgrade to monograph 
status will not be included. However, criteria for establishing 
combinations of OTC drugs as generally recognized as safe and effective 
are provided in 21 CFR 330.10(a)(4)(iv). Guidance on OTC combination 
drug products has also been provided in the agency's General Guidelines 
for OTC Drug Combination Products (Ref. 1). Thus, two or more safe and 
effective OTC vaginal contraceptive active ingredients may be combined 
provided the final formulation of the product meets the combination 
policy in all respects. The Panel did not include any contraceptive 
combinations in its monograph because the data were insufficient for 
any of the combinations that were reviewed to be generally recognized 
as safe and effective. The agency concurs with the Panel's decision. 
Furthermore, as noted in section I. A., comment 3 of this document, the 
agency is proposing to require that all combination or single-
ingredient OTC vaginal contraceptive drug products be subject to 
approved applications prior to marketing.

Reference

    1. Food and Drug Administration, ``General Guidelines for OTC 
Drug Combination Products, September 1978,'' Docket No. 78D-0322, 
Dockets Management Branch.
    24. One comment stated that the data on which the Panel based its 
Category II classification of the combinations: (1) Phenylmercuric 
acetate and boric acid; (2) phenylmercuric acetate, boric acid, and 
nonoxynol 9; and (3) phenylmercuric acetate, octoxynol 9, and sodium 
borate show that these combinations were so classified because of 
``hazards'' associated with the use of phenylmercuric acetate rather 
than with the use of boric acid or sodium borate (Refs. 1 through 6). 
The comment added that it appears that the use of borates in vaginal 
contraceptives is for ``pH control.'' The comment also noted that boron 
compounds were listed as inactive ingredients in the Panel's report (45 
FR 82014 at 82042) and were not placed in Category II, as were mercury-
containing compounds.
    The agency agrees that boron compounds should not have been 
included as active ingredients in the listing of Category II 
combinations. The submissions of data on OTC vaginal contraceptive drug 
products containing boron compounds (Refs. 1 through 6) indicate that 
the boron compounds are included in these products as 
[[Page 6902]] pharmaceutical necessities or preservatives and not as 
active ingredients.

References

    1. OTC Vol. 110004.
    2. OTC Vol. 110005.
    3. OTC Vol. 110006.
    4. OTC Vol. 110017.
    5. OTC Vol. 110018.
    6. OTC Vol. 110021.

E. Comments on Testing Guidelines

    25. Numerous comments criticized the safety and effectiveness 
testing guidelines recommended by the Panel to upgrade a vaginal 
contraceptive ingredient from Category III to Category I (45 FR 82014 
at 82020 and 82043). Generally, the comments stated that the guidelines 
are unclear, needlessly specific, unnecessary, or based on unsound 
logic. Some of the comments subsequently proposed using alternative 
testing methods, while others urged elimination of certain methods.
    The agency has not addressed specific testing guidelines in this 
document. In revising the OTC drug review procedures relating to 
Category III, published in the Federal Register of September 29, 1981 
(46 FR 47730), the agency advised that tentative final and final 
monographs will not include recommended testing guidelines for 
conditions that industry wishes to upgrade to monograph status. 
Instead, the agency will meet with industry representatives at their 
request to discuss testing protocols. However, in view of the agency's 
determination that all OTC vaginal contraceptive drug products should 
be the subject of approved applications prior to marketing, interested 
parties can use that forum to meet with the agency to discuss 
appropriate testing procedures, and the comments do not need to be 
addressed in this document. Also, elsewhere in this issue of the 
Federal Register, the agency is announcing the availability of a 
guidance document that is intended to help manufacturers of vaginal 
contraceptive drug products develop data in support of new drug 
applications.

II. The Agency's Tentative Conclusions on OTC Vaginal Contraceptive 
Drug Products

    Dodecaethyleneglycol monolaurate, laureth 10S, 
methoxypolyoxyethyleneglycol 550 laurate, nonoxynol 9, octoxynol 9, 
phenylmercuric acetate, and phenylmercuric nitrate have been present as 
ingredients in OTC vaginal contraceptive drug products. Based on the 
available evidence, the agency has determined that clinical studies in 
humans are necessary to establish the effectiveness of final 
formulations of vaginal contraceptive drug products and, therefore, any 
drug product that is labeled, represented, or promoted for use as a 
vaginal contraceptive is regarded as a new drug within the meaning of 
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 21 CFR 
part 314 of the regulations is required for marketing. In the absence 
of an approved application, such a product also would be misbranded 
under section 502 of the act (21 U.S.C. 352).
    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
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). 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, and thus, is not subject to review under the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. There are a limited number of OTC vaginal 
contraceptive products that are not marketed for use with a condom, 
diaphragm, or contraceptive cervical cap. Accordingly, the agency 
certifies that the proposed rule will not have a significant economic 
impact on a substantial number of small entities. Therefore, under the 
Regulatory Flexibility Act, no further analysis is required.
    The agency invites public comment regarding any substantial or 
significant economic impact that this rulemaking would have on OTC 
vaginal contraceptive drug products. Types of impact may include, but 
are not limited to, costs associated with product testing, relabeling, 
repackaging, or reformulating. Comments regarding the impact of this 
rulemaking on OTC vaginal contraceptive drug products should be 
accompanied by appropriate documentation. Because the agency has not 
previously invited specific comment on the economic impact of the OTC 
drug review on vaginal contraceptive drug products, a period of 120 
days from the date of publication of this proposed rulemaking in the 
Federal Register will be provided for comments on this subject 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.
    The agency has determined under 21 CFR 25.24(c)(6) 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.
    In the Federal Register of December 12, 1980 (45 FR 82014 at 
82047), the agency proposed that the monograph for OTC vaginal 
contraceptive drug products be included in subpart A of new part 351 of 
Title 21 of the Code of Federal Regulations. In the Federal Register of 
October 13, 1983 (48 FR 46694 at 46727), the agency proposed that a 
monograph for OTC vaginal drug products be included in subpart B of 
part 351. The current proposal supersedes subpart A of part 351 and, if 
finalized as proposed, Part 310--New Drugs would be amended to include 
OTC vaginal contraceptive drug products.
    Interested persons may, on or before June 5, 1995 submit to the 
Dockets Management Branch written comments, objections, or requests for 
oral hearing before the Commissioner on the proposed regulation. A 
request for an oral hearing must specify points to be covered and time 
requested. Written comments on the agency's economic impact 
determination may be submitted on or before June 5, 1995. Three copies 
of all comments, objections, and requests are to be submitted, except 
that individuals may submit one copy. Comments, objections, and 
requests 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. Comments, objections, and requests may be seen in 
the office above between 9 a.m. and 4 p.m., Monday through Friday. Any 
scheduled oral hearing will be announced in the Federal Register.
    Interested persons, on or before February 5, 1996, may also submit 
in writing new data demonstrating the safety and effectiveness of those 
conditions not classified in Category I. Written comments on the new 
data may be submitted on or before April 3, 1996. These dates are 
consistent with the time periods specified in the agency's final rule 
revising the procedural regulations [[Page 6903]] for reviewing and 
classifying OTC drugs, published in the Federal Register of September 
29, 1981 (46 FR 47730). Three copies of all data and comments on the 
data are to be submitted, except that individuals may submit one copy, 
and all data and comments are to be identified with the docket number 
found in brackets in the heading of this document. Data and comments 
should be addressed to the Dockets Management Branch (address above). 
Received data and comments may also be seen in the office above between 
9 a.m. and 4 p.m., Monday through Friday.
    In establishing a final rule for OTC vaginal contraceptive drug 
products, the agency will ordinarily consider only data submitted prior 
to the closing of the administrative record on April 3, 1996. Data 
submitted after the closing of the administrative record will be 
reviewed by the agency only after a final rule for OTC vaginal 
contraceptive drug products is published in the Federal Register, 
unless the Commissioner finds that good cause has been shown that 
warrants earlier consideration.

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, it is 
proposed that 21 CFR part 310 be amended as follows:

PART 310--NEW DRUGS

    1. The authority citation for 21 CFR part 310 continues to read as 
follows:
    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-
516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 
360b-360f, 360j, 361(a), 371, 374, 375, 379e); secs. 215, 301, 
302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C. 
216, 241, 242(a), 262, 263b-263n).
    2. Section 310.535 is added to subpart E to read as follows:


Sec. 310.535  Drug products containing active ingredients offered over-
the-counter (OTC) for human use as a vaginal contraceptive.

    (a) Dodecaethyleneglycol monolaurate, laureth 10S, 
methoxypolyoxyethyleneglycol 550 laurate, nonoxynol 9, octoxynol 9, 
phenylmercuric acetate, and phenylmercuric nitrate have been present as 
ingredients in OTC vaginal contraceptive drug products. The evidence 
currently available shows that clinical studies in humans are necessary 
to establish the effectiveness of nonoxynol 9 and octoxynol 9 in final 
formulation for use in OTC vaginal contraceptive drug products. There 
are inadequate data to establish the safety and effectiveness of any 
other ingredients offered for use as OTC vaginal contraceptive drug 
products.
    (b) Any drug product that is labeled, represented, or promoted for 
OTC use as a vaginal contraceptive is regarded as a new drug within the 
meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act 
(the act), for which an approved application or abbreviated application 
under section 505 of the act and part 314 of this chapter is required 
for marketing. In the absence of an approved new drug application or 
abbreviated new drug application, such product is also misbranded under 
section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted for OTC use as a vaginal 
contraceptive is safe and effective for the purpose intended must 
comply with the requirements and procedures governing the use of 
investigational new drugs set forth in part 312 of this chapter.
    (d) After (date 12 months after date of publication in the Federal 
Register of the final rule), any such OTC drug product initially 
introduced or initially delivered for introduction into interstate 
commerce that is not in compliance with this section is subject to 
regulatory action.

    Dated: January 10, 1995.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 95-2631 Filed 2-2-95; 8:45 am]
BILLING CODE 4160-01-F