title: Conditionally unbiased estimation in phase II/III clinical trials with early stopping for futility.
abstract: Seamless phase II/III clinical trials combine traditional phases II and III into a single trial that is conducted in two stages, with stage 1 used to answer phase II objectives such as treatment selection and stage 2 used for the confirmatory analysis, which is a phase III objective. Although seamless phase II/III clinical trials are efficient because the confirmatory analysis includes phase II data from stage 1, inference can pose statistical challenges. In this paper, we consider point estimation following seamless phase II/III clinical trials in which stage 1 is used to select the most effective experimental treatment and to decide if, compared with a control, the trial should stop at stage 1 for futility. If the trial is not stopped, then the phase III confirmatory part of the trial involves evaluation of the selected most effective experimental treatment and the control. We have developed two new estimators for the treatment difference between these two treatments with the aim of reducing bias conditional on the treatment selection made and on the fact that the trial continues to stage 2. We have demonstrated the properties of these estimators using simulations.
authors: Warwick Medical School, The University of Warwick, Coventry, CV4 7AL, UK. peter.k-u.kimani@warwick.ac.uk
authors: Peter K
authors: PK
authors: Kimani
authors: Susan
authors: S
authors: Todd
authors: Nigel
authors: N
authors: Stallard
mesh_terms: D015982:Bias; D056808:Biostatistics; 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; D018849:Controlled Clinical Trials as Topic / Q000379:methods / Q000706:statistics & numerical data; D006801:Humans; D015233:Models, Statistical
keywords: adaptive seamless designs; estimation; phase II/III clinical trials