Bioequivalence Studies of Generic Medicines

Abstract

Bioequivalence (BE) studies form the regulatory cornerstone of generic medicine approval, requiring demonstration that the test generic formulation delivers equivalent systemic drug exposure to the reference innovator product within pre-specified statistical acceptance criteria. This study conducted a comprehensive evaluation of BE study design and statistical methodology across ten generic drug candidates representing diverse BCS classifications, drug properties, and regulatory complexity. Using a prospective two-period crossover design in 240 healthy adult volunteers (24 per drug; 10 drugs), BE was assessed for AUC0-inf, AUC0-t, and Cmax using the standard average bioequivalence (ABE) criterion (90% confidence interval within 80-125%) and, where applicable, the scaled average bioequivalence (SABE) criterion for high within-subject variability (HVDP) drugs. The BE acceptance rate was 82.0% overall (41/50 AUC and Cmax pairs meeting the 80-125% criterion); three formulations failed BE solely due to Cmax variability, not AUC, highlighting Cmax as the more challenging BE endpoint. For the three HVDP drugs (within-subject CV > 30%), SABE expanded acceptance limits correctly classified all three as bioequivalent when conventional ABE had failed. Population pharmacokinetic (PopPK) modelling identified food effect as the strongest predictor of BE outcome variability (OFV reduction 18.4 for fed vs fasted state), with a 2.1-fold higher BE pass rate for fasted versus fed administration. These results provide quantitative evidence for formulation and study design optimisation to maximise generic medicine regulatory approval success rates while maintaining patient safety standards.