Statistical aspects of bioequivalence testing between two medicinal products.

A generic drug product (test product) is bioequivalent to an innovator product (reference product) when their bioavailabilities in the same molar dose are similar. Bioavailability is expressed by pharmacokinetic parameters such as the area under plasma concentration-time curve (AUC), the maximum plasma concentration (Cmax) and the time of maximum plasma concentration (tmax). The assessment of bioequivalence is carried out by in vivo bioequivalence studies. This paper examines and appraises design issues for performing a bioequivalence study: the use of crossover, parallel, replicated, and add-on designs; and the determination of sample size. In addition, it presents the valid statistical approaches for proving bioequivalence: average bioequivalence on transformed and untransformed data; parametric and non-parametric analyses; moment based individual bioequivalence; direct curve comparison metrics.