An Adaptive Three‐Arm Comparative Clinical Endpoint Bioequivalence Study Design With Unblinded Sample Size Re‐Estimation and Optimized Allocation Ratio

ABSTRACT

A three‐arm comparative clinical endpoint bioequivalence (BE) study is often used to establish bioequivalence (BE) between a locally acting generic drug (T) and reference drug (R), where superiority needs to be established for T and R over Placebo (P) and equivalence needs to be established for T vs. R. Sometimes, when study design parameters are uncertain, a fixed design study may be under‐ or over‐powered and result in study failure or unnecessary cost. In this paper, we propose a two‐stage adaptive clinical endpoint BE study with unblinded sample size re‐estimation, standard or maximum combination method, optimized allocation ratio, optional re‐estimation of the effect size based on likelihood estimation, and optional re‐estimation of the R and P treatment means at interim analysis, which have not been done previously. Our proposed method guarantees control of Type 1 error rate analytically. It helps to reduce the average sample size when the original fixed design is overpowered and increases the sample size and power when the original study and group sequential design are under‐powered. Our proposed adaptive design can help generic drug sponsors cut cost and improve success rate, making clinical study endpoint BE studies more affordable and more generic drugs accessible to the public.