Properties of a confirmatory two-stage adaptive procedure for assessing average bioequivalence

Abstract

We investigate a confirmatory two stage adaptive procedure for assessing average bioequivalence and provide some insights to its theoretical properties. Effectively, we perform Two One-Sided Tests (TOST) to reach overall decision about each of the two traditional null-hypotheses involved in declaring average bioequivalence. The tests are performed as combination tests separately for each hypothesis based on the corresponding pair of stagewise p-values. Features of the procedure include a built in futility, sample size reassessment, and the ability to simultaneously assess average bioequivalence with respect to multiple endpoints while controlling the familywise error rate. To facilitate inference at the end of a trial we also derive overall confidence limits that match the decision reached on each one sided hypothesis and provide theory ensuring their appropriateness. The performance is assessed by simulation in the context of planning a study to compare two different administrations of a biologic treatment of atopic dermatitis.