Women in Bioavailability/Bioequivalence Trials — A Regulatory Perspective

Abstract

There has been a debate on the issue of inclusion of women in bioequivalence trials since the publication of a Federal Register notice by the Food and Drug Administration (FDA) in 1993 entitled “Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs.” Women are now generally not included in bioequivalence trials. A primary reason for the exclusion lies in the concern that hormonal fluctuation during different phases of the menstrual cycle in women might increase the intrasubject variability and thereby decrease the statistical power of the bioequivalence study.

A comprehensive review of literature conducted by the FDA has revealed little or no evidence for a significant impact of the menstrual cycle on the intrasubject variance of pharmacokinetic parameters of drugs. In a small number of reports, an alteration in pharmacokinetics of the drug was noted in different phases of the menstrual cycle, which might suggest an increase in intrasubject variability in women compared to men. The results of these studies are inconclusive, however, because of the small sample size and failure to assess male intrasubject variability over a similar timeframe. A retrospective analysis of four in-house bioequivalence studies conducted in both genders seemed to show similar magnitudes of intrasubject variability in men and women. To resolve the gender issues in bioequivalence, further data collection and clinical research are currently underway in the agency.