title: Statistical design of noninferiority multiple region clinical trials to assess global and consistent treatment effects.
abstract: Noninferiority multiregional clinical trials (MRCTs) have recently received increasing attention in drug development. While a major goal in an MRCT is to estimate the global treatment effect, it is also important to assess the consistency of treatment effects across multiple regions. In this paper, we propose an intuitive definition of consistency of noninferior treatment effects across regions under the random-effects modeling framework. Specifically, we quantify the consistency of treatment effects by the percentage of regions that meet a predefined treatment margin. This new approach enables us to achieve both goals in one modeling framework. We propose to use a signed likelihood ratio test for testing the global treatment effect and the consistency of noninferior treatment effects. In addition, we provide guidelines for the allocation rule to achieve optimal power for testing consistency among multiple regions. Extensive simulation studies are conducted to examine the performance of the proposed methodology. An application to a real data example is provided.
authors.affiliation: a Department of Statistics , George Mason University , Fairfax , Virginia , USA.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Diao
authors.affiliation: b Department of Biostatistics , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina , USA.
authors.forename: Donglin
authors.initials: D
authors.lastname: Zeng
authors.affiliation: b Department of Biostatistics , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina , USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Ibrahim
authors.affiliation: c Amgen Inc ., Thousand Oaks , California , USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Rong
authors.affiliation: c Amgen Inc ., Thousand Oaks , California , USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Lee
authors.affiliation: c Amgen Inc ., Thousand Oaks , California , USA.
authors.forename: Kathy
authors.initials: K
authors.lastname: Zhang
authors.affiliation: d Department of Biostatistics , Vanderbilt University , Nashville , Tennessee , USA.
authors.forename: Qingxia
authors.initials: Q
authors.lastname: Chen
mesh_terms: D017277:Drug Approval / Q000379:methods / Q000706:statistics & numerical data*; D014943:Global Health / Q000706:statistics & numerical data*; D006801:Humans; D015233:Models, Statistical; D015337:Multicenter Studies as Topic / Q000379:methods / Q000706:statistics & numerical data*; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000706:statistics & numerical data*; D018401:Sample Size; D016896:Treatment Outcome
keywords: Consistency of treatment effects; global treatment effect; multiregional clinical trial; noninferiority clinical trial; random effects model; signed likelihood ratio test