Vangelis Karalis, Panos Macheras
Laboratory of Biopharmaceutics-Pharmacokinetics, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece.
Objectives: To introduce and unveil the properties of a two-stage design (TSD) for bioequivalence (BE) studies.
Methods: A TSD with an upper sample size limit (UL) is described and analyzed under different conditions using Monte Carlo simulations. This TSD was split into three branches: A, B1, and B2. The first stage included branches A and B1, while stage two referred to branch B2. Sample size re-estimation at B2 relies on the observed geometric mean ratio (GMR) and variability of the pharmacokinetic parameters at stage 1. The properties studied were % BE acceptance, % uses and % efficiency of each branch, as well as the reason of BE failure.
Results: No inflation of type I error was observed. Each TSD branch exhibits different performance. Branch A exerts the highest ability to declare BE either when variability is low to moderate, or an adequately high number of subjects is recruited.Second stage becomes mainly useful when highly variable drugs are assessed with a low number of subjects (N1) enrolled at stage 1 and/or the two drug products differ significantly. Branch A is more frequently used when variability is low, drug products are similar, and a large N1 is included. BE assessment at branch A exhibits high efficiency to declare BE. On the contrary, branches B1 and B2 are usually less efficient in declaring BE.
Conclusions: BE assessment at branch A exhibits high efficiency to declare BE, while branches B1 and B2 are usually less efficient. Inclusion of a UL is necessary to avoid inflation of type I error.
Reference: PAGE 22 (2013) Abstr 2729 [www.page-meeting.org/?abstract=2729]
Poster: Study Design