title: Flexible selection of a single treatment incorporating short-term endpoint information in a phase II/III clinical trial.
abstract: Seamless phase II/III clinical trials in which an experimental treatment is selected at an interim analysis have been the focus of much recent research interest. Many of the methods proposed are based on the group sequential approach. This paper considers designs of this type in which the treatment selection can be based on short-term endpoint information for more patients than have primary endpoint data available. We show that in such a case, the familywise type I error rate may be inflated if previously proposed group sequential methods are used and the treatment selection rule is not specified in advance. A method is proposed to avoid this inflation by considering the treatment selection that maximises the conditional error given the data available at the interim analysis. A simulation study is reported that illustrates the type I error rate inflation and compares the power of the new approach with two other methods: a combination testing approach and a group sequential method that does not use the short-term endpoint data, both of which also strongly control the type I error rate. The new method is also illustrated through application to a study in Alzheimer's disease.
authors.affiliation: Statistics and Epidemiology, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, U.K.
authors.forename: Nigel
authors.initials: N
authors.lastname: Stallard
authors.affiliation: Statistics and Epidemiology, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, U.K.
authors.forename: Cornelia Ursula
authors.initials: CU
authors.lastname: Kunz
authors.affiliation: Department of Mathematics and Statistics, University of Reading, Reading, U.K.
authors.forename: Susan
authors.initials: S
authors.lastname: Todd
authors.affiliation: Statistics and Epidemiology, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, U.K.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Parsons
authors.affiliation: Department of Medical Statistics, University Medical Center, Göttingen, Germany.
authors.forename: Tim
authors.identifier: http://orcid.org/0000-0001-5347-7441
authors.initials: T
authors.lastname: Friede
mesh_terms: D000544:Alzheimer Disease; D017322:Clinical Trials, Phase II as Topic / Q000379:methods / Q000706:statistics & numerical data*; D017326:Clinical Trials, Phase III as Topic / Q000379:methods / Q000706:statistics & numerical data*; D003198:Computer Simulation; D023381:Endpoint Determination / Q000379:methods / Q000706:statistics & numerical data*; D006801:Humans; D012107:Research Design
keywords: adaptive design; conditional error; error rate control; multiple testing; sequential clinical trial