title: Testing effect of a drug using multiple nested models for the dose-response.
abstract: During development of a drug, typically the choice of dose is based on a Phase II dose-finding trial, where selected doses are included with placebo. Two common statistical dose-finding methods to analyze such trials are separate comparisons of each dose to placebo (using a multiple comparison procedure) or a model-based strategy (where a dose-response model is fitted to all data). The first approach works best when patients are concentrated on few doses, but cannot conclude on doses not tested. Model-based methods allow for interpolation between doses, but the validity depends on the correctness of the assumed dose-response model. Bretz et al. (2005, Biometrics 61, 738-748) suggested a combined approach, which selects one or more suitable models from a set of candidate models using a multiple comparison procedure. The method initially requires a priori estimates of any non-linear parameters of the candidate models, such that there is still a degree of model misspecification possible and one can only evaluate one or a few special cases of a general model. We propose an alternative multiple testing procedure, which evaluates a candidate set of plausible dose-response models against each other to select one final model. The method does not require any a priori parameter estimates and controls the Type I error rate of selecting a too complex model.
authors: H. Lundbeck A/S, Biometrics Division, Ottiliavej 9, 2500 Valby, Denmark.|Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark.
authors: C
authors: C
authors: Baayen
authors: H. Lundbeck A/S, Biometrics Division, Ottiliavej 9, 2500 Valby, Denmark.
authors: P
authors: P
authors: Hougaard
authors: Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark.
authors: C B
authors: CB
authors: Pipper
mesh_terms: D001699:Biometry; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000706:statistics & numerical data; D006801:Humans; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D011336:Probability
keywords: Dose-finding; MCP-Mod; Model selection; Multiple testing