A comparison of group sequential and fixed sample size designs for bioequivalence trials with highly variable drugs.

PURPOSE

A drug is defined as highly variable if its intra-individual coefficient of variation (CV) is greater than or equal to 30%. In such a case, bioequivalence may be assessed by means of methods that take the (high) variability into account. The Scaled Average Bioequivalence (SABE) approach is such a procedure and represents the recommendations of FDA. The aim of this investigation is to compare the performance characteristics of classical group sequential designs (GSD) and fixed design settings for three-period crossover bioequivalence studies with highly variable drugs, where the SABE procedure is utilized.

METHODS

Monte Carlo simulations were performed to assess type I error rate, power, and average sample size for GSDs with Pocock's and O'Brien-Fleming's stopping rules and various timings of the interim analysis and for fixed design settings.

RESULTS

Based on our investigated scenarios, the GSDs show comparable properties with regard to power and type I error rate as compared to the corresponding fixed designs. However, due to an advantage in average sample size, the most appealing design is Pocock's approach with interim analysis after 50% information fraction.

CONCLUSIONS

Due to their favorable performance characteristics, two-stage GSDs are an appealing alternative to fixed sample designs when assessing bioequivalence in highly variable drugs.