The Public Health Service Task Force on Women's Health Issues (1985) and the National Institutes of
Health (NIH) Guide (1989) both recommended that biomedical and behavioral research should be expanded to ensure emphasis on conditions unique to, or most prevalent in, women of all age groups: 'in addition, studies are needed to study the metabolism and disposition of drugs and alcohol by age and gender'. The National Institute for Drug and Alcohol Abuse (NIDAA) (1990) policy provides detailed, almost affirmative-action instructions for the inclusion of women and minorities into study designs, according to their prevalence in the diseases being studied.
Since 1988, the FDA has requested tabulations of gender, age, and racial distributions in NDA submissions. Many of their senior officials, e.g. Drs. Peck and Temple, had forcefully stated that women should be included in drug development studies. Indeed, the 1977 guideline, General Consideration for the Clinical Evaluation of Drugs, included a policy for the inclusion of women of child-bearing potential in clinical trials but excluded them, in general, from Phase I and early Phase II studies, with exceptions for life-saving or life-prolonging treatments. Child-bearing potential was strictly defined as 'any woman capable of becoming pregnant', including women using reversible contraceptive precautions and those with vasectomized partners.
The FDA issued new guidelines in 1993 (Fed Reg 1993), perhaps spurred by its own findings in 1989, and confirmed by the General Accounting Office (GAO), that in only 50% of submissions were gender analysis discussed in NDA submissions. Temple (1992) reported that two FDA surveys demonstrated that women were included routinely and in proportion to the presence in the treatment population, and young women in large numbers (Bush et al, 1993). Not recorded were his concluding remarks, in which he said many NDAs did not adequately discuss gender difference, which would be addressed in the new amended guideline. The FDA, in its discourse in the 1993 guidelines, Revised Policy on Inclusion of Women of Childbearing Potential in Clinical Trials, mentions that it was swayed by a legal precedent. In 1991 the US Supreme Court found on behalf of the plaintiff workers union that their pregnant members had been unfairly excluded from jobs by the Johnson Control Company, because the working conditions exposed their fetuses to potential risk. The court wrote: 'Welfare of future children should be left to the parents . . . rather than to employers who hire them'. While not quite the same circumstances, the FDA were of the mind that this opinion would also apply to pregnant (informed) women, giving them the right to enter drug trials irrespective of phase of development.
The FDA revised guidelines on this and ethnic differences which appeared in July 1993 in the Federal Register, in essence abolished the prior ban on women of childbearing age from Phase I and Phase II studies, and stipulated additional topics, including the embryotoxic and teratogenic risk potential, to be covered in the patients' informed consent.
Earlier, the NIH had issued its own guidelines to its staff, grant applicants, and academic centers it supported. It called for all research on human subjects concerning drugs, devices, epidemiology, non-drug device studies and treatment outcomes, to include both genders and minority representatives whenever possible. In Phase III studies, 'women and minorities and their subpopulations in sufficient numbers should be included, such that valid analyses of differences can be accomplished'. It stipulated that 'cost was not an acceptable reason for exclusion, and that programs and support for outreach efforts to recruit these groups be undertaken'. (NIH, 1986). Failure to ensure adequate effort to implement could be reason for grant rejection or loss of financial support.
To amplify the female view both the FDA and NIH during the last decade have appointed women to significant roles. Dr Bernadette Healy headed the NIH and created the Office of Research in Women's Health; Dr Henny led the FDA until 2001 and within the FDA, Dr Janet Woodcock and Dr Kathy Zoon were appointed to head CDER (drugs), and CBER (biologics), respectively, two of the largest centers perhaps partly in response to an article by LaRosa and Pinn (1993), both women bemoaning exclusion of women in decisions of research.
The industry is now encouraged by the FDA to include women earlier in the clinical development program, but there are also still good reasons why the FDA might deny inclusion of women of child-bearing potential—insufficient toxicology data; a disagreement over the interpretation of such data; agency knowledge of another company's confiden tial data indicating a potential risk with a drug class-related compound; and, finally, an FDA reviewer's individual comfort level with 'high-risk population exposure'. Such an event has now become rarer.
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