Pilot and Repeat Trials as Development Tools Associated with Demonstration of Bioequivalence.

The purpose of this work is to use simulated trials to study how pilot trials can be implemented in relation to bioequivalence testing, and how the use of the information obtained at the pilot stage can influence the overall chance of showing bioequivalence (power) or the chance of approving a truly bioinequivalent product (type I error). The work also covers the use of repeat pivotal trials since the difference between a pilot trial followed by a pivotal trial and a pivotal trial followed by a repeat trial is mainly a question of whether a conclusion of bioequivalence can be allowed after the first trial. Repeating a pivotal trial after a failed trial involves dual or serial testing of the bioequivalence null hypothesis, and the paper illustrates how this may inflate the type I error up to almost 10%. Hence, it is questioned if such practice is in the interest of patients. Tables for power, type I error, and sample sizes are provided for a total of six different decision trees which allow the developer to use either the observed geometric mean ratio (GMR) from the first or trial or to assume that the GMR is 0.95. In cases when the true GMR can be controlled so as not to deviate more from unity than 0.95, sequential design methods ad modum Potvin may be superior to pilot trials. The tables provide a quantitative basis for choosing between sequential designs and pivotal trials preceded by pilot trials.