Participation of Women in Clinical Trials of Drug Therapies: A Context for the Controversies

Marianne N. Prout, MD, MPH, Susan S. Fish, PharmD, MPH

Disclosures
In This Article

Issues and Perceptions of Women as Research Subjects

The barriers to participation of women in clinical research are well documented. Physiologic variations and "potential pregnancies" are emphasized in FDA reports and pharmacology journals. Lower age-specific mortality rates for women compared with men and problems in recruitment and retention are discussed in NIH summaries and medical journals.[27,28,29,30,31] Because women have lower age-specific mortality rates, a larger sample size is needed for research, leading to longer and more costly studies. Recruitment and retention challenges are varied, but many can be summarized into 1 of 2 areas: (1) women are frequently caretakers of others and these responsibilities make participation in research more difficult, and (2) women are more likely than men to work less than full-time and thus may not have health insurance coverage and may not have paid sick time.

Physiologic variability among research subjects increases with inclusion of both males and females and may necessitate larger sample sizes.[32] The desire for homogeneity extends to animal studies, encompassing not only species and breed but also sex.[27] Isn't it simpler and more cost-effective to study only male rats rather than to include males and females, both fertile and oophorectomized female animals? The lack of data from animal assays compounds the problem of exclusion of women from phase 1 and 2 drug studies. Sex-specific variations in dose-response and adverse reactions to drugs are discovered late in drug development or not at all. The absence of women in early studies of drugs fosters dismissal of women's symptoms and side effects of medications, ranging from headaches to hot flushes.

By including women in earlier (phase 1 and 2) studies, research on personalized dosing could examine mechanisms by which women's responses to drugs may differ from men's, including pharmacokinetics, pharmacodynamics, drug metabolism, hormonal interactions, binding with hormonal receptors, and vascular dynamics.[12,18,33]

The concept and definition of vulnerable groups in need of increased protections or prohibitions from research studies arose partly from prior research mistakes and partly from an attitude of paternalism among the medical profession at that time. The participation of pregnant women in clinical trials, however, remains problematic, even though the protection is directed toward the fetus, not the woman. Clinical trials of drug therapies for AIDS and HIV infections precipitated more forthright discussions and guidelines for clinical trials of pregnant women.[34] The revised regulations intended to "enhance the opportunity for participation of pregnant women in research" were issued January 17, 2001, but implementation has been delayed by directive from President George W. Bush.

The view that all premenopausal women are "potential pregnancies" continues in spite of regulatory changes to 45 CRF 46, as demonstrated by the extensive documentation of contraceptive practices required before participation in clinical trials.[35,36] Many studies require that women of childbearing age use 2 forms of contraception during participation. The implication that women are not responsible and cannot be trusted with their fertility is obvious on many research consent forms, and the lack of data on fetal effects limits the "informed" part of the informed consent process.

Women in the United States live longer than men; some suggest that women therefore need less medical research than men.[37] The decreased number of outcomes expected in women compared with men of the same age for cardiovascular disease, in particular, has provided a rationale to focus trials on men. Eligibility restrictions by age (eg, studies that exclude subjects of both sexes over age 65 or 70 or 75) also disproportionately exclude women's participation from studies of diseases that are more prevalent in women at older ages.[38] Until 2000, Medicare coverage for participation in clinical trials was unavailable, thus limiting the participation of older women. Direct and indirect costs of participation may continue to discriminate against women because of the diminished value of life at greater age and the diminished economic value of women.[30]

Recruitment and retention of women in clinical trials are considered more complex and more expensive than recruitment and retention of men. Cohorts of men are readily available, with healthcare ensured through veterans' services, workplaces, and unions, and it is presumed that cohorts of women are less available in these organized groups. Yet such sex-specific studies as breast cancer screening and therapy trials have successfully enrolled women for decades.

Some obstacles to participation, such as the need for child or other dependent care, lack of transportation, lack of health insurance or inadequate health insurance, and lack of time for healthcare visits because of joint demands of work and family, can be problems for both women and men but disproportionately affect women.[39,40,41,42] The successful recruitment and retention to large studies, such as the Women's Health Initiative and the Breast Cancer Prevention Trial,[43,44] and others, have resulted in many reports on methods for recruitment of women.

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