OTC vaginal contraceptives TFM vacated; FDA asks for NDAs/ANDAs.

OTC VAGINAL CONTRACEPTIVE CLINICAL TRIALS UNDER "ACTUAL USE" CONDITIONS are required under FDA's tentative final monograph covering over-the-counter vaginal contraceptives. Published in the Feb. 3 Federal Register, the TFM would require manufacturers of OTC vaginal contraceptives to obtain approved NDAs or ANDAs for their products and test each product "in appropriate clinical trials under actual conditions of use."

The agency explained that trials under NDAs or ANDAs are necessary because the "effectiveness of these products is dependent upon the final formulation." FDA noted 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 these actives lose some of their efficacy in humans when the spermicide in "final formulation is diluted by varied amounts of genital secretions during coitus, FDA said. Consequently, clinical studies are necessary to establish the effectiveness of the spermicide's final formulation when used in humans," FDA declared. Clinicals should evaluate the "influence of the potential interactions among the genital secretions, microorganisms and contraceptive product vehicle," the agency added.

"At present," FDA continued, "there is no in vitro test available that can be considered a reliable reflection of in vivo conditions" and there is no "reliable in vivo animal model that can simulate the human condition."

Although "postcoital tests in humans have been considered as an alternative to clinical trials," FDA said the currently available postcoital tests cannot "be relied upon."

FDA noted that use of vaginal contraceptives "may be associated with varying degrees of vaginal irritation under certain conditions of use and [that] it is unclear whether this may play a role" in the transmission of sexually transmitted diseases. Therefore, the TFM states, "information regarding the rate of occurrence and degree of vaginal irritation should be presented" in applications.

Other information that will be requested by FDA, according to the TFM, are data specifying the levels of 1,4 dioxane and ethylene oxide that are contained in the finished product. The agency explained that the two "suspected carcinogens" have been found in low levels as residuals from the manufacturing process for a vaginal contraceptive sponge and "it is possible that other products could contain different levels of these contaminants."

With regard to products requiring ANDAs, FDA clarified that such an application should be filed only if there is a listing for that ingredient in the "Orange Book" of generic drugs. More generally, FDA stated that for both NDAed and ANDAed drugs, manufacturers should submit information on the drug's formulation, manufacture and quality control procedures.

By requiring approved NDAs or ANDAs for all OTC vaginal contraceptives, FDA is essentially dissolving a monograph for the category.

The document notes that there are currently two vaginal contraceptive product applications that have been approved by FDA -- for Whitehall's Today Sponge and Ortho's Delfen Contraceptive Foam. However, the agency said, the NDA for the Delfen foam was approved "a number of years ago" and the product's current formulation is different from the formulation covered by the NDA. Therefore, the agency said that Delfen's manufacturer "will be required to provide additional information."

FDA also pointed out in the TFM that Whitehall recently announced its plans to discontinue production of the Today Sponge ("The Tan Sheet" Jan. 16, p. 17), but has "not indicated to FDA that it plans to withdraw its application."

Other vaginal contraceptive ingredients that have been present in OTC vaginal contraceptives include: dodecaethyleneglycol monolaurate, laureth 10S, methoxypolyoxyethyleneglycol 550 laurate, nonoxynol-9, octoxynol-9, phenylmercuric acetate and phenylmercuric nitrate. However, the TFM states, "there are inadequate data to establish the safety and effectiveness" of any of these ingredients. Nonoxynol-9 and octoxynol-9 are one step ahead because they only require clinicals to establish their efficacy in final formulation in humans, FDA indicated.

Specifically, the agency stated that nonoxynol-9 and octoxynol-9 "would be appropriate ingredients for an approved application" based on a determination in the December 1980 advance notice of proposed rulemaking on vaginal contraceptives that those ingredients are safe and effective (Category I) as well as the "history of use" of drugs containing nonoxynol-9 with approved NDAs. Therefore, FDA said that products containing nonoxynol-9 and octoxynol-9 will not need to include preclinical data, but may refer to the OTC Review Panel's report "as a general basis of safety" for those ingredients.

Among products containing nonoxynol-9 are Lake Pharmaceuticals/Columbia Labs' recently launched Advantage 24 spermicide gel ("The Tan Sheet" Oct. 24, 1994, p. 7), Whitehall's Semicid inserts, Thompson Medical's Encare suppositories, Ortho's Conceptrol gel and inserts, and Gynol I and Gynol II contraceptive jellies. Products containing octoxynol-9 include Ortho's Ortho-Gynol jelly.

FDA clarified that OTC vaginal contraceptives that "are marketed for use with or as part of" a condom, diaphragm, or a contraceptive cervical cap will not be subject to the TFM or final rule because they are considered accessories to a device. A separate regulation will address such products in the future, FDA said.

The agency emphasized that, because the final rule for OTC vaginal contraceptives will become effective 12 months after its publication in the Federal Register, FDA "strongly recommends that manufacturers of products not having an approved NDA or ANDA consult with the agency as soon as possible" on potential applications. In a Feb. 3 "Talk Paper" issued by FDA, the agency promised action on the applications as "quickly as feasible" to "assure continued availability" of the products. To assist manufacturers in devising protocols, the agency announced the availability of a guidance document on development of vaginal contraceptives in the same issue of the Federal Register.

Comments on the proposal are due by June 5. New data should be submitted by Feb. 5, 1996, with comments on the new data due by April 3, 1996. Comments on the economic impact of the rule, including assessments of the "costs associated with product testing, relabeling, repackaging or reformulating," are due by June 5, 1995. The vaginal contraceptive document represents the final TFM issued under the OTC Review.