title: The role of the upper sample size limit in two-stage bioequivalence designs.
abstract: Two-stage designs (TSDs) are currently recommended by the regulatory authorities for bioequivalence (BE) assessment. The TSDs presented until now rely on an assumed geometric mean ratio (GMR) value of the BE metric in stage I in order to avoid inflation of type I error. In contrast, this work proposes a more realistic TSD design where sample re-estimation relies not only on the variability of stage I, but also on the observed GMR. In these cases, an upper sample size limit (UL) is introduced in order to prevent inflation of type I error. The aim of this study is to unveil the impact of UL on two TSD bioequivalence approaches which are based entirely on the interim results. Monte Carlo simulations were used to investigate several different scenarios of UL levels, within-subject variability, different starting number of subjects, and GMR. The use of UL leads to no inflation of type I error. As UL values increase, the % probability of declaring BE becomes higher. The starting sample size and the variability of the study affect type I error. Increased UL levels result in higher total sample sizes of the TSD which are more pronounced for highly variable drugs.
authors: Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece. Electronic address: vkaralis@pharm.uoa.gr.
authors: Vangelis
authors: V
authors: Karalis
mesh_terms: D002986:Clinical Trials as Topic; D006801:Humans; D009010:Monte Carlo Method; D010599:Pharmacokinetics; D012107:Research Design; D018401:Sample Size; D013810:Therapeutic Equivalency
keywords: ANOVA; Adaptive designs; BE; Bioequivalence; CI; CVw; GMR; N; N(1); N(2); Pharmacokinetic simulations; TSD; TSD-1; TSD-2; Two-stage designs; UL; additional number of subjects recruited at the second stage; analysis of variance; bioequivalence; coefficient of variation of the within-subject variability of the bioequivalence metric; confidence interval; first type of two-stage design used in this study; geometric mean ratio (test/reference) of the bioequivalence metric; second type of two-stage design used in this study; starting sample size; total number of subjects participating in the study; two-stage design; type I error of the nominal statistical hypothesis; upper sample size limit; α