FDA requirements for nonclinical testing of contraceptive steroids.

Written guidelines for the preclinical testing of contraceptive steroids have not been revised since 1968 despite the fact that many important changes have been implemented by the FDA's Division of Metabolism and Endocrine Drug Products. This paper describes the new preclinical testing requirements and the rationale for their implementation. The Division of Metabolism and Endocrine Drug Products of the US Food and Drug Administration (FDA) has effected many significant changes since it last revised its written guidelines for preclinical testing of contraceptive steroids in 1968. Yet it did not update the guidelines, which pertain to both male and female contraceptives, until 1992. Type and duration of preclinical studies for Clinical Phase I are single-dose studies in rats and mice using an amount that produces overt toxicity and which is administered through the same route as intended for humans and repeat dose studies in rats and monkeys (up to 200 times the human dose for rats and 50 times the human dose for monkeys) for at least 1 month. The FDA is flexible about the duration of preclinical studies for Phase II as long as the duration is at least as long as the duration of the proposed clinical trial (6-month maximum for rats and 1-year maximum for monkeys). Preclinical trials for Phase II are the same studies as for Phase II as well as genotoxicity tests. For genotoxicity tests, the FDA recommends in vitro mammalian cell gene mutation assay with and without metabolic activation, in vitro chromosome aberration test in mammalian cells with and without metabolic activation, and the mouse micronucleus test for chromosome damage. Preclinical studies for FDA are a 6-month toxicology study in rats, a 12-month toxicology study in monkeys, and a 2-year carcinogenicity study in rats or mice. The FDA can consider other species for toxicology testing. Pharmacology tests, generally done in rodents, determine drug effects on neurological, cardiovascular, and immunological parameters. Researchers should use steady state conditions to study pharmacokinetic parameters including, Tmax, Cmax, T1/2, and area under the curve. Toxicologic tests on contraceptives with estrogen/progestogen combinations should use the ratio to be marketed or, if they have more than 1 ratio, the lowest ratio. FDA remains flexible to any deviations for which there is a sound scientific rationale.

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