title: Exact calculation of power and sample size in bioequivalence studies using two one-sided tests.
abstract: The number of subjects in a pharmacokinetic two-period two-treatment crossover bioequivalence study is typically small, most often less than 60. The most common approach to testing for bioequivalence is the two one-sided tests procedure. No explicit mathematical formula for the power function in the context of the two one-sided tests procedure exists in the statistical literature, although the exact power based on Owen's special case of bivariate noncentral t-distribution has been tabulated and graphed. Several approximations have previously been published for the probability of rejection in the two one-sided tests procedure for crossover bioequivalence studies. These approximations and associated sample size formulas are reviewed in this article and compared for various parameter combinations with exact power formulas derived here, which are computed analytically as univariate integrals and which have been validated by Monte Carlo simulations. The exact formulas for power and sample size are shown to improve markedly in realistic parameter settings over the previous approximations.
authors.affiliation: Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, USA.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Shen
authors.forename: Estelle
authors.initials: E
authors.lastname: Russek-Cohen
authors.forename: Eric V
authors.initials: EV
authors.lastname: Slud
mesh_terms: D018592:Cross-Over Studies; D006801:Humans; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000378:metabolism; D018401:Sample Size; D013810:Therapeutic Equivalency
chemical_list: D004364:Pharmaceutical Preparations
keywords: bioequivalence; crossover; pharmacokinetic study; power; sample size; single endpoint