Sex-by-formulation interaction in bioequivalence studies: the importance of formulations and experimental conditions

In a recently published investigation, the authors argued against the likelihood of sex-based subject-by-formulation interactions in bioequivalence studies, i.e. male and female subjects exhibiting different discriminatory potential to detect bioavailability differences between formulations. The researchers performed a strong methodological study showing the increased probability of false-positive findings in exploratory subgroup analysis, a well-known and documented statistical issue. Indeed, the main limitation of assessing a sex-by-formulation interaction in average bioequivalence studies lies in the fact that these clinical trials are not designed for this purpose. In this commentary, we further discuss on why the impact of sex differences in gastrointestinal physiology over in vivo drug dissolution and absorption rate cannot remain hidden behind statistical limitations, particularly when average bioequivalence conclusions could be affected. Regulatory agencies should encourage and support these important issues related to biopharmaceutical quality of drug products in both sexes. In addition, a sex-based analysis of bioequivalence results will enhance the representativeness of conclusions and provide important information regarding formulation performance, thereby promoting the efficacy and safety of generic drugs and reducing consumer risk. The extrapolation of study conclusions from one sex to another is far away from being scientifically proven.