Average bioequivalence evaluation: general methods for pilot trials

Abstract

In clinical development of a bioequivalent (BE) drug product, a two-step strategy is commonly adopted. In the first step, a pilot BE trial is conducted to evaluate the acceptability of the test drug product as a candidate for further evaluation in a subsequent pivotal BE trial. In the second step, a full-scale pivotal BE trial is conducted to formally establish bioequivalence. The objective and criterion of a pilot BE trial are different from those of a pivotal BE trial. In practice, however, a pilot BE trial is often inappropriately designed and analyzed based on the criterion for a pivotal BE trial. One main reason is the lack of well-established design and analysis methods for a pilot BE trial. To close this gap in practice, this study proposes a Pilot Acceptance Range method specfically constructed for analyzing a pilot BE trial within the framework of a two-step strategy. For designing a crossover pilot BE trial, this paper derives the power function and provides an easy-to-use method for determining the sample size.