title: Carryover negligibility and relevance in bioequivalence studies.
abstract: The carryover effect is a recurring issue in the pharmaceutical field. It may strongly influence the final outcome of an average bioequivalence study. Testing a null hypothesis of zero carryover is useless: not rejecting it does not guarantee the non-existence of carryover, and rejecting it is not informative of the true degree of carryover and its influence on the validity of the final outcome of the bioequivalence study. We propose a more consistent approach: even if some carryover is present, is it enough to seriously distort the study conclusions or is it negligible? This is the central aim of this paper, which focuses on average bioequivalence studies based on 2 × 2 crossover designs and on the main problem associated with carryover: type I error inflation. We propose an equivalence testing approach to these questions and suggest reasonable negligibility or relevance limits for carryover. Finally, we illustrate this approach on some real datasets.
authors.affiliation: Department of Statistics, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Ocaña
authors.affiliation: Statistical Institute, Faculty of Science, University of Valparaiso, Valparaiso, Chile.|Department of Biology, Faculty of Chemistry and Biology, University of Santiago, Santiago, Chile.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Sanchez O
authors.affiliation: Department of Public Health, Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Josep L
authors.initials: JL
authors.lastname: Carrasco
mesh_terms: D002986:Clinical Trials as Topic / Q000379:methods*; D018592:Cross-Over Studies; D003627:Data Interpretation, Statistical; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism; D012107:Research Design; D013810:Therapeutic Equivalency
chemical_list: D004364:Pharmaceutical Preparations
keywords: average bioequivalence; bioequivalence study; carryover; crossover design