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Recently, the European Medicines Agency (EMA) issued a new guideline on the investigation of bioequivalence (BE). In case of highly variable drugs, this guideline proposes that the acceptance limits for C_max can gradually be expanded as a function of within-subject variability (CV_wR). Actually, these BE limits exhibit leveling-off properties since they are not allowed to scale continuously, but only up to CV_wR=50%. To avoid the risk of accepting two drug products which may differ significantly, this EMA guideline also proposes the use of a secondary constraint criterion on the geometric mean ratio (GMR) of the two products under comparison. Aim of this study was to explore the leveling-off properties of the new EMA limits in comparison to other approaches, as well as to assess the impact of the complementary GMR criterion on the ability to declare bioequivalence. Simulated bioequivalence studies and extreme …