[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]]
_______________________________________________________________________
Part III
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
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