Women in Clinical Trials
With its recent publication of "Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs," 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 enrollment 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 with "childbearing potential" from the earliest phases of clinical trials.
These changes have occurred in response to growing concerns that the drug development process does not produce adequate information about the effects of drugs in women. These concerns have arisen at a time when FDA, drug developers, and the scientific community have voiced a need to have available data on drug responses in the subsets of the population to receive the drug. Responses to drugs may be influenced by many factors, including age, gender, ethnic background, metabolic phenotype, body-fat content and distribution, and body size. Concurrent illnesses and concomitant medications can also influence the effects of a drug. All these factors, either singly or in combination, can influence a drug's pharmacokinetics (the concentration of the drug in the blood or body tissues over time) and/or its pharmacodynamics (the body's response to a given concentration of a drug). When such differences are recognized, appropriate therapeutic recommendations can be made so that overall benefit of the drug can be enhanced.
Gender-related differences in pharmacokinetics have been identified for some drugs. For example, propranolol is metabolized more slowly in women than in men; this is thought to be due to the interaction of the sex hormones and the enzymes that metabolize this drug. Most differences in pharmacokinetics between men and women are probably related to body size, body composition, and hormonal influences. The hormonal environment may influence both pharmacokinetics and pharmacodynamic parameters of drugs. Four factors can be identified that might 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) differences in the hormonal milieu between premenopausal and postmenopausal women, including the use of exogenous hormonal replacement therapy; (3) 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. The influence of the variable levels of the sex hormones during the menstrual cycle on insulin binding is an example of a pharmacodynamic effect. In one study, it was shown that the binding of insulin to blood cells was higher in the follicular phase than in the luteal phase of the menstrual cycle. There appears to be an inverse relationship between the binding of insulin to certain blood cells and the levels of estradiol and progesterone. This relationship may result in episodes of hyperglycemia during the luteal phase of women with insulin-dependent diabetes mellitus.
Since 1988, FDA has taken steps to encourage development of data that support informed individualization of treatment, including issuance in 1988 of the "Guideline for the Format and Content of the Clinical and Statistical Sections of New Drug Applications (NDAs)." Recognizing the importance of gender analysis, FDA conducted a retrospective study analysis of NDA data to identify variations in drug safety and effectiveness among population subsets, including subsets based on gender, age, race, concurrent therapies, and concomitant illnesses. In this analysis, it was determined that safety data had been examined according to gender only 54% of the time and that efficacy data had been examined in this manner only 43% of the time.
In light of these findings, FDA will now review all new drug applications shortly after submission to determine if they include the appropriate analyses by gender. If they do not, the applicant will be instructed to submit these analyses promptly to allow the completion of the review of the application.
In addition to the request for appropriate gender analyses for current and future new drug applications, 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. Such pharmacokinetic differences could be particularly important in the case of a drug with a low therapeutic index, where the smaller average size of women might necessitate modified dosing. The guidelines emphasize three pharmacokinetic issues that should be considered during drug development: (1) the effects of the menstrual cycle and menopausal status on a drug's pharmacokinetics; (2) the effects of concomitant estrogen supplementation or use of systemic contraceptive agents, including both estrogen-progestin combinations and long-acting progesterones on a drug's pharmacokinetics; 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, FDA urges that women of all ages be studied, including early in drug development. 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 study subjects. In addition, it places the responsibility for initial determinations about the adequacy of these precautions in the hands of patients, physicians, Institutional Review Boards, and drug sponsors, with review and guidance by FDA.
FDA and the scientific community are also concerned about the lack of data on the effects of drugs and biological agents in pregnant women. The potential for teratogenicity and the fear of liability have often been cited for the paucity of studies in this population, but the result is that many drugs are ultimately administered during pregnancy without reliable data on their maternal and fetal effects. FDA intends to explore the difficult issues associated with the evaluation of the effects of new drugs and biological agents in pregnant women in a series of public workshops and conferences similar to those that led to the policy changes described in this article.
To obtain a copy of "Guideline for the Study 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 Pl., Rockville, MD 20855. Please send two self-addressed adhesive labels with your request.
--Ruth B. Merkatz, Ph.D., R.N.
--Robert Temple, M.D.