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

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