Evaluate Group Sequential Design Sample Sizes for Reference-Scaled Average Bioequivalence Based on Monte Carlo Simulations in Highly Variable Drugs

The U.S. Food and Drug Administration (FDA) suggests the “Reference-Scaled Average Bioequivalence†(RSABE) method in the average bioequivalence (ABE) study of highly variable drugs. The classic sample size estimation method for grouping sequential design (GSD) of the RSABE method is a single-stage sample size multiplied by the inflation factor. This study proposed a new method for calculating the sample size for the GSD of the RSABE: using simulation experiments directly. In this work, our focal point is on a two-stage GSD that adheres to the Pocock guideline, comprising a single interim analysis and a final analysis. We consider that the sample size of the two stages is equal; that is, the interim analysis is carried out at 50% of the information fraction. Extensive Monte Carlo simulations have shown that the new method is more accurate in estimating sample size than the inflation factor method, and the type I error rate is controlled below 5% in all conditions. In 90% power semireplicate studies, the average sample size required for the Pocock design is only 40% to 90% of the single-stage design sample size.