OTS VAGINAL CONTRACEPTIVES WILL REQUIRE CLINICAL TRIALS

OTS VAGINAL CONTRACEPTIVES WILL REQUIRE CLINICAL TRIALS and NDA approval in order to be marketed, FDA declared in a notice of proposed rulemaking that is expected to appear in the Nov. 15 Federal Register. "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 subject of an approved" NDA or ANDA supported by clinical studies, FDA said. Although "certain contraceptive active ingredients (nonoxynol- 9 and octoxynol-9 are safe for OTC use" because they "kill sperm in vitro and in vivo," FDA noted that "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 cervical mucus and semen during coitus." Thus, FDA concluded, "clinical studies are necessary to establish the effectiveness of the spermicide's final formulation when used in humans." Clinical studies, the agency continued, "would determine the influence of the potential interactions among the sperm, cervical mucus, microorganisms and contraceptive product vehicle." FDA added that nonoxynol-9 and octoxynol-9 "would be appropriate ingredients for an approved application" because they are safe for OTC use and kill sperm in vivo when "properly formulated." Because of the accepted safety of nonoxynol-9 and octoxynol-9, "applications for these products will not need to include preclinical data, but instead may refer" to the OTC panel report on vaginal contraceptives "as a basis for the safety of these ingredients," FDA explained. Clinical trials to support an NDA or ANDA, FDA said, 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." Applications also would be required 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," the agency said. Information regarding the "appropriateness of ingredients used in the product as preservatives" also should be included in an application, FDA added. FDA encouraged manufacturers to "consult with the agency as soon as possible concerning the content of these applications" in order for consumers to "continue to have access to OTC vaginal contraceptive drug products and to avoid disruption in the marketplace." OTC vaginal contraceptives for use with a diaphragm or a contraceptive cervical cap are not subject to the proposal. FDA noted that "the regulation of spermicides for use only with a device will be addressed at a future date by the agency." A combination of two or more vaginal contraceptive drug ingredients is subject to the reg, however. In addition to nonoxynol-9 and octoxynol-9, FDA listed a number of other potential OTC vaginal contraceptive ingredients, including dodecaethyleneglycol monolaurate, laureth 10S, methoxypolyoxy-ethyleneglycol 550 laurate and phenylmercuric nitrate. The proposal carries a 120-day comment period. The proposal also reviews comments received in response to a December 1980 advance notice of proposed rulemaking to establish a monograph for OTC vaginal contraceptives. Several comments, FDA said, disagreed with the agency's position that clinical testing of all final formulations under an NDA is the appropriate way to assure the efficacy of OTC vaginal contraceptives. Besides pointing out that it is difficult to simulate the human condition in an in vitro test, FDA asserted that in vitro testing cannot determine: "how long before intercourse the contraceptive should be inserted; if the intravaginal distribution of the contraceptive is sufficient to ensure effectiveness; or how long the contraceptive remains effective in the vaginal environment." FDA also suggested that listing inactive ingredients in labeling would provide "useful information for some consumers" with "known allergies or intolerances to certain ingredients." Although FDA is not requiring that inactives be listed in OTC labeling "at this time," FDA applauded voluntary guidelines on the listing of inactives developed by the Nonprescription Drug Manufacturers Association and urged "all other OTC drug manufacturers to similarly label their products." Regarding nonoxynol-9 safety in the wake of reports that the ingredient may contain low levels of suspected carcinogens 1,4- dioxane and ethylene oxide as residuals from the manufacturing process, FDA asked manufacturers to submit "data and information specifying the levels of 1,4-dioxane and ethylene oxide that are contained in the finished product" in NDAs for products containing the ingredient. In response to comments on mercury-containing compounds, FDA determined that studies on phenylmercuric acetate are "at least suggestive" that mercury-containing compounds may be metabolized to "inorganic mercury" that may "pose a risk to fetuses and nursing infants." FDA concluded that such products are "unsafe for use in vaginal contraceptive drug products." In a section of the Nov. 15 proposal on labeling, FDA noted that the document "will serve as the basis for development of guidelines for the content and format of labeling of OTC vaginal contraceptive drug products similar to those currently available for oral contraceptive drug products." FDA said it intends to complete the OTC vaginal contraceptive labeling guidelines "after the comments to this proposal are evaluated." The agency underscored that because "there will be no monograph for OTC vaginal contraceptive drug products," all labeling for "these products will be approved via applications." Regarding quantitative efficacy claims, FDA said it "does not believe that adequate data are available at this time to require the use of product-specific quantitative effectiveness claims in the labeling of OTC vaginal contraceptive products." However, the agency continued, "in the interest of providing fully informative labeling to consumers, the agency believes that information summarizing the comparative effectiveness of the various contraceptive methods should be included in the package insert" of OTC vaginal contraceptives. The comparative summary of contraceptive methods, FDA explained, "would be helpful to consumers" and should be provided in "narrative or chart form." The chart "may include effectiveness figures reflecting the range of effectiveness reported" and should be followed by the statement: "The effectiveness of any of these methods of contraception (except the IUD) depends on how closely the directions for each method are followed." Among other essential components of OTC vaginal contraceptive labeling, FDA said, are "precise directions that are understandable to consumers, including diagrammed instructions, as appropriate, to show the proper method of application" as well as a statement that douching should be delayed for at least six hours after coitus when vaginal contraceptives are used as the primary method of birth control. FDA also suggested a specific warning to warn consumers about the "possible allergic reactions such as burning and itching that may occur when using" vaginal contraceptives: "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." The proposed rule would also change the OTC panel's report on OTC vaginal contraceptives by removing "spermicide" as an indication. Instead, it would be considered an "optional statement of identity." Furthermore, 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." FDA also 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.