Guidelines and requirements for the evaluation of contraceptive steroids

Since their introduction in the early 1960s, the oral contraceptive (OCs) steroids have been subjected to preclinical and clinical investigations unprecedented in medical history. As a result of such extensive studies, it is now possible to make a comprehensive review of preclinical and clinical data on oral contraceptives. The OCs were introduced at a time when the Food and Drug Administration (FDA) was undergoing drastic changes as a result of the thalidomide tragedy, the introduction of the Kefauver-Harris Amendment, and the desire for greater control over the pharmaceutical industry. The initial requirements for the safety evaluation of OCs were identical to those of other drugs. There were no explicit requirements for OCs although it was generally felt that the requirements should be more stringent because the OCs were being used in otherwise healthy women for long periods of time and with minimal medical supervision. In the 1960s when it became apparent from ongoing studies that there was an increased incidence of mammary tumors in dogs treated with some progestins, the FDA made the decision to terminate clinical studies and established the requirement for 7- and 10-yr studies in dogs and monkeys, respectively. The primary purpose of this paper is to present an historical perspective of the evolution of the preclinical requirements for the evaluation of the safety of OCs prior to their use in the various phases (I, II, III) of clinical trials. Some proposed changes in the requirements are discussed. This information will form the basis for other presentations dealing with the safety assessment of OCs in rats, dogs, and monkeys.