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00925njm 22002777a 4500 dc Molins Lleonart, Eduard author Cobo Valeri, Erik author Ocaña Rebull, Jordi author 2017-12 This is the peer reviewed version of the following article: Molins, E., Cobo, E., Ocaña, J. Two-stage designs versus European scaled average designs in bioequivalence studies for highly variable drugs: which to choose?. "Statistics in medicine", Desembre 2017, vol. 36, núm. 30, p. 4777-4788, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/sim.7452/pdf. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. The usual approach to determine bioequivalence for highly variable drugs is scaled average bioequivalence, which is based on expanding the limits as a function of the within-subject variability in the reference formulation. This requires separately estimating this variability and thus using replicated or semireplicated crossover designs. On the other hand, regulations also allow using common 2 × 2 crossover designs based on two-stage adaptive approaches with sample size reestimation at an interim analysis. The choice between scaled or two-stage designs is crucial and must be fully described in the protocol. Using Monte Carlo simulations, we show that both methodologies achieve comparable statistical power, though the scaled method usually requires less sample size, but at the expense of each subject being exposed more times to the treatments. With an adequate initial sample size (not too low, eg, 24 subjects), two-stage methods are a flexible and efficient option to consider: They have enough power (eg, 80%) at the first stage for non-highly variable drugs, and, if otherwise, they provide the opportunity to step up to a second stage that includes additional subjects. Peer Reviewed Postprint (author's final draft) Àrees temàtiques de la UPC::Matemàtiques i estadística::Anàlisi numèrica::Modelització matemàtica Àrees temàtiques de la UPC::Matemàtiques i estadística::Anàlisi numèrica Àrees temàtiques de la UPC::Matemàtiques i estadística::Matemàtica aplicada a les ciències Numerical analysis--Simulation methods Numerical analysis Biomathematics Average Bioequivalence (ABE) Reference Scaled Average Bioequivalence (RSABE) Two-Stage Designs (TSD) Highly Variable Drugs (HVD) Significance Level Adjustment Anàlisi numèrica -- Processament de dades Anàlisi numèrica Biomatemàtica Classificació AMS::65 Numerical analysis::65C Probabilistic methods, simulation and stochastic differential equations Classificació AMS::65 Numerical analysis::65K Mathematical programming, optimization and variational techniques Classificació AMS::92 Biology and other natural sciences::92B Mathematical biology in general Two-stage designs versus European scaled average designs in bioequivalence studies for highly variable drugs: which to choose?