Group sequential extensions of a standard bioequivalence testing procedure.

Abstract

Bioequivalence trials compare the relative bioavailability of different formulations of a drug. Regulatory requirements for demonstrating average bioequivalence of two formulations generally include showing that a (say) 90% confidence interval for the ratio of expected pharmacologic end point values of the formulations lies between specified end points, e.g., 0.8-1.25. The likelihood of demonstrating bioequivalence when the formulations truly are equivalent depends on the sample size and on the variability of the pharmacologic end point. Group sequential bioequivalence testing provides a statistically valid way to accommodate misspecification of the variability in designing the trial by allowing for additional observations if a clear decision to accept or reject bioequivalence cannot be reached with the initial set of observations. This paper describes group sequential bioequivalence designs applicable in most practical situations that allow a decision to be reached with fewer observations than fixed-sample designs about 60% of the time at approximately the same average cost. The designs can be used in trials where the formulations are expected to have equal bioavailability and in trials where the formulations are expected to differ slightly. Data analyses are carried out exactly as for fixed-sample designs. Providing the capability of sequential decisions modestly affects the nominal significance levels, e.g., the required confidence level may be 93-94% instead of 90%.