title: Assessing individual bioequivalence with high-order cross-over designs: a unified procedure.
abstract: The U.S. FDA's newly issued guidance on bioequivalence recommends the use of individual bioequivalence (IBE) for highly variable drugs and possibly for modified release dosage forms. The recommended approach to the analysis is to follow the methodology of Hyslop, Hsuan and Holder (HHH), based on a linear mixed model. A limitation of the HHH method is that it works only for uniform designs, such as RTRT/TRTR. In this paper, we present an alternative approach based on a multivariate model. The multivariate model is shown to be a strict superset of the linear mixed model and can successfully model data where the mixed model fails. Our multivariate approach coincides with the HHH method where the HHH method applies, but generalizes to any high-order cross-over design, such as the Balaam design, RTR/TRT, and TRSS/RSTT/STRR. We present numerical examples to demonstrate the proposed method, and examine its properties with a simulation study.
authors.affiliation: Temple University, Philadelphia, PA 19122, USA. francis.hsuan@temple.edu
authors.forename: Francis C
authors.initials: FC
authors.lastname: Hsuan
authors.forename: Russell
authors.initials: R
authors.lastname: Reeve
mesh_terms: D000704:Analysis of Variance; D018592:Cross-Over Studies; D006801:Humans; D016014:Linear Models; D015999:Multivariate Analysis; D012107:Research Design; D013810:Therapeutic Equivalency; D014481:United States; D014486:United States Food and Drug Administration; D014700:Verapamil / Q000627:therapeutic use
chemical_list: D014700:Verapamil