title: Consumer's risk in the EMA and FDA regulatory approaches for bioequivalence in highly variable drugs.
abstract: The 2010 US Food and Drug Administration and European Medicines Agency regulatory approaches to establish bioequivalence in highly variable drugs are both based on linearly scaling the bioequivalence limits, both take a 'scaled average bioequivalence' approach. The present paper corroborates previous work suggesting that none of them adequately controls type I error or consumer's risk, so they result in invalid test procedures in the neighbourhood of a within-subject coefficient of variation osf 30% for the reference (R) formulation. The problem is particularly serious in the US Food and Drug Administration regulation, but it is also appreciable in the European Medicines Agency one. For the partially replicated TRR/RTR/RRT and the replicated TRTR/RTRT crossover designs, we quantify these type I error problems by means of a simulation study, discuss their possible causes and propose straightforward improvements on both regulatory procedures that improve their type I error control while maintaining an adequate power. Copyright © 2015 John Wiley & Sons, Ltd.
authors.affiliation: Department of Statistics, Universitat de Barcelona, Av. Diagonal 643, Barcelona, 08028, Spain.
authors.forename: Joel
authors.initials: J
authors.lastname: Muñoz
authors.affiliation: BioClever S.L. Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Alcaide
authors.affiliation: Department of Statistics, Universitat de Barcelona, Av. Diagonal 643, Barcelona, 08028, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Ocaña
mesh_terms: D004335:Drug and Narcotic Control; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology; D005060:Europe; D006801:Humans; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000592:standards*; D010599:Pharmacokinetics; D012306:Risk; D013810:Therapeutic Equivalency; D014481:United States; D014486:United States Food and Drug Administration / Q000592:standards*
chemical_list: D004364:Pharmaceutical Preparations
keywords: interval inclusion principle; point estimate constraint; scaled average bioequivalence