title: Optimal adaptive sequential designs for crossover bioequivalence studies.
abstract: In prior works, this group demonstrated the feasibility of valid adaptive sequential designs for crossover bioequivalence studies. In this paper, we extend the prior work to optimize adaptive sequential designs over a range of geometric mean test/reference ratios (GMRs) of 70-143% within each of two ranges of intra-subject coefficient of variation (10-30% and 30-55%). These designs also introduce a futility decision for stopping the study after the first stage if there is sufficiently low likelihood of meeting bioequivalence criteria if the second stage were completed, as well as an upper limit on total study size. The optimized designs exhibited substantially improved performance characteristics over our previous adaptive sequential designs. Even though the optimized designs avoided undue inflation of type I error and maintained power at ≥ 80%, their average sample sizes were similar to or less than those of conventional single stage designs.
authors.affiliation: Merck & Co., Inc.,, Upper Gwynedd, PA,, USA.
authors.forename: Jialin
authors.initials: J
authors.lastname: Xu
authors.affiliation: GERAD and Ecole Polytechnique de Montreal,, Montreal, H3C 3A7,, QC,, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Audet
authors.affiliation: Montclair Bioequivalence Services, LLC, Montclair, NJ, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: DiLiberti
authors.affiliation: Sycamore Consulting LLC, New Hope, PA,, USA.
authors.forename: Walter W
authors.initials: WW
authors.lastname: Hauck
authors.affiliation: GlaxoSmithKline, Inc., King of Prussia, PA,, USA.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Montague
authors.affiliation: GlaxoSmithKline, Inc., Research Triangle Park, Durham, NC, USA.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Parr
authors.affiliation: Excelsus Statistics Inc., Montreal, QC, Canada.
authors.forename: Diane
authors.initials: D
authors.lastname: Potvin
authors.affiliation: Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Schuirmann
mesh_terms: D018592:Cross-Over Studies; D006801:Humans; D012107:Research Design / Q000592:standards* / Q000706:statistics & numerical data; D013810:Therapeutic Equivalency
keywords: adaptive design; bioequivalence; sample size re-estimation; sequential design