Regulatory Perspective Gender

In 1977, FDA issued a guidance which recommended that all women of child bearing potential be excluded from clinical trials, unless adequate safety, efficacy, animal fertility, and teratology information was available for the drug being investigated [89]. This was done to protect the fetus, and the assumption that men and women metabolize and respond to drugs in a similar way [2]. In 1988, guidelines for the "format and content of the clinical and statistical sections of the drug application" were issued which required of the sponsors to discern dose-response relationships in the AEs and examination of rates of AEs in various demographics (age, race, gender) and other subgroups (metabolic status, renal function) [27]. In 1993, FDA revoked the 1977 guidelines and issued a guidance calling for the inclusion of analyses of efficacy and safety data by gender, and inclusion of characterization of pharmacokinetics of drugs in men and women. The "Refuse to file" (RTF) guidance published by the FDA also in 1993, stated that NDA could be RTF if there was "clearly inadequate evaluation for safety and/or effectiveness in the population intended to use the drug, including pertinent subsets, such as gender, age, and racial subsets" [90].

The U.S. FDA and other regulatory agencies have emphasized the need to include subgroups such as gender, age, and race in the clinical trials. In order to encourage recruitment of subgroups in clinical trails in all phases of drug development, the Demographic Rule [91] was published in 1988, which includes the following publications (2): for NDAs (21 CFR 314.50 (d)(5)(v) and (d)(5)(vi)(a)); and for INDs (21 CFR 312.33 (a)(2)) and the clinical hold rule. Guidance on Bioavailability and Bioequivalence issued by the FDA in 2000 also recommends that attempts should be made to include both sexes, and representative ages and race. The International Harmonization Conference (ICH) issued guidelines on clinical study reports (ICH E3) [92] asking to include demographics and subgroup information to evaluate safety and effectiveness in the subpopulations. It is evident that regulatory agencies including ICH require inclusion of subgroups such as gender, age, and race. The regulatory guidelines call for including enough number of subjects to perform subgroup analysis.

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