The Subject-by-Formulation Interaction as a Criterion of Interchangeability of Drugs

Abstract

The primary purpose of a bioequivalence study is often to meet the regulatory requirement of similar average bioavailabilities. This is usually done by estimating the mean difference between formulations in a crossover design. However, a small difference, as well as a rather narrow confidence interval, might be obtained also if the subjects respond differently to the formulations, i.e., if there is a nonnegligible subject-by-formulation interaction. Hence, it can be argued that this interaction should be part of the criterion of interchangeability. To be able to study this interaction the ordinary simple crossover design is not appropriate. Instead, a design where each formulation is administered at least twice to each subject is desirable. Such a design is obtained by repeating a simple crossover layout. To evaluate the impact of the subject-by-formulation interaction, the ratio of the variance components of the interaction and the error is estimated. This approach is illustrated by an example.