The use of a large number of subjects for an average bioequivalence (ABE) trial for Narrow Therapeutic Index drugs should be questioned.

Regarding the size of the within-subject variability, use of a large number of subjects for an ABE trial nullifies a precautionary intention implicit in the European Union bioequivalence guideline when it recommends shortening the a priori acceptance interval.

For Narrow Therapeutic Index drugs, if an ABE data analysis trial is planned, it is proposed that, as a minimal requirement, a fully replicated design be required to compare test and reference products using the within-subject variability.