The effect of variability and carryover on average bioequivalence assessment: A simulation study

• Published in: Pharmaceutical statistics : the journal of the pharmaceutical industry Vol. 10; no. 2; pp. 135 - 142
• Main Authors: Sánchez O, María Pilar, Ocaña, Jordi, Carrasco, Josep L.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.03.2011
• Subjects: average bioequivalence; carryover; Computer Simulation; confidence interval inclusion; Cross-Over Studies; crossover trial simulation; Humans; Sample Size; Therapeutic Equivalency
• ISSN: 1539-1604; 1539-1612
• DOI: 10.1002/pst.431

The purpose of this study was to evaluate the effect of residual variability and carryover on average bioequivalence (ABE) studies performed under a 2×2 crossover design. ABE is usually assessed by means of the confidence interval inclusion principle. Here, the interval under consideration was the standard ‘shortest’ interval, which is the mainstream approach in practice. The evaluation was performed by means of a simulation study under different combinations of carryover and residual variability besides of formulation effect and sample size. The evaluation was made in terms of percentage of ABE declaration, coverage and interval precision. As is well known, high levels of variability distort the ABE procedures, particularly its type II error control (i.e. high variabilities make difficult to declare bioequivalence when it holds). The effect of carryover is modulated by variability and is especially disturbing for the type I error control. In the presence of carryover, the risk of erroneously declaring bioequivalence may become high, especially for low variabilities and large sample sizes. We end up with some hints concerning the controversy about pretesting for carryover before performing ABE analysis. Copyright © 2010 John Wiley & Sons, Ltd.