Women in clinical trials: new FDA guidelines.

The FDA has taken two important steps to ensure that new drugs are properly evaluated in women. First, it has provided formal guidance to drug sponsors to emphasize the importance of appropriate gender representation in clinical studies and of analyses capable of identifying potential gender differences in drug efficacy and/or safety. Second, the agency has altered a 16-year-old policy that had excluded the participation of women of "childbearing potential" from the earliest phases of clinical trials.

Gender-related differences in pharmacokinetics (the concentration of the drug in the blood or body tissues over time) have been identified for some drugs. Most differences in pharmacokinetics between men and women are probably related to body size, body composition., and hormonal influences.

Hormones may influence both pharmacokinetics and pharmacodynamic (the body's response to a given concentration of a drug) parameters of drugs. Four factors can lead to hormonally mediated gender differences in drug effects: 1) variations in levels of gonadotropins and circulating steroidal hormones, notably estradiol and progesterone, during the menstrual cycle; 2) hormonal differences between premenopausal and postmenopausal women, including the use of exogenous hormonal replacement therapy; 31) the effects of different hormonal levels during pregnancy and the metabolic consequences of pregnancy itself, and 4) the effects of steroidal contraceptives on the metabolism of drugs taken concomitantly and. conversely, the effects of other drugs on the efficacy of contraceptives.

Recognizing the importance of gender analysis. the FDA conducted a retrospective study of new drug applications to identify gender variations in drug safety and effectiveness. They found that the applications examined safety data according to gender only 54% of the time and efficacy data only 43% of the time, In light of these findings, the FDA will no," review all new drug applications for appropriate analyses by gender. if gender analyses are not included, the applicant will be instructed to submit them in order to complete review of the application.

In addition, the FDA has issued new guidelines on the participation of women in drug evaluations. The guidelines urge that women be enrolled in studies of new drugs in numbers adequate to allow detection of clinically significant differences in drug response. and stress the importance of assessing possible pharmacokinetic differences between women and men. The guidelines emphasize three pharmacokinetic issues that should be considered during drug development: 1) the effects of the menstrual cycle and menopausal status, 2) the effects of concomitant estrogen supplementation or use of systemic contraceptive agents, including both estrogen-progestin combinations and long-acting progesterones, and 3) the influence of a drug on the effectiveness of oral contraceptives.

In order to fully evaluate the potential for gender differences in drug effects, the MA urges that women of all ages be studied. There is no longer any restriction on the enrollment of women of childbearing potential in even the earliest phase of clinical trials. Instead, the new guideline calls for appropriate measures for minimizing the risk of fetal exposure. such as pregnancy testing, contraception. and provision of full information about potential fetal risks to prospective stud;. subjects.

To obtain Al copy of "Guideline for the Stud and Evaluation of Gender Differences in the Clinical Evaluation of Drugs," Published July 22, 1993, write to the Center for Drug Evaluation and Research (HFD-8), Food and Drug Administration. 7500 Standish Place, Rockville, MD 20855. Please send two self-addressed adhesive labels with your request.