['To demonstrate average bioequivalence, the ninety-percent confidence intervals (CI) on the ratio of geometric means for area under the concentration-time curve (AUC) and maximum observed plasma concentration (Cmax) must lie within 0.80-1.25. Demonstration of average bioequivalence (ABE) for highly variable drug products requires large numbers of subjects in a standard, adequately powered, two-period crossover.', 'Application of non-traditional study designs can help to meet this hurdle. Study design and analysis for replicate and group sequential-replicate study designs are presented and illustrated using examples. It is demonstrated how to use such approaches to meet the difficult regulatory hurdle of average bioequivalence for a highly variable drug product.', 'To illustrate, data are provided from three separate ABE studies for a highly variable drug product at three dosage strengths. In all three studies, a replicate study design was used to compensate for high intrasubject variation. Additionally, for the last study, a group sequential study design was imposed to provide early evidence of conclusive results.'] Does non-traditional study design to demonstrate average bioequivalence for highly variable drug products?