Testing effect of a drug using multiple nested models for the dose-response

• Published in: Biometrics 2015-06, Vol.71 (2), p.417-427
• Main Authors: Baayen, C., Hougaard, P., Pipper, C. B.
• Format: Article
• Language: English
• Subjects: Biometrics; Biometry; Clinical trials; Computer Simulation; DISCUSSION PAPER; Dose-finding; Dose-Response Relationship, Drug; Drug Discovery - statistics & numerical data; Humans; MCP-Mod; Model selection; Models, Statistical; Multiple testing; Nonlinear Dynamics; Pharmacology; Probability; Simulation
• ISSN: 0006-341X; 1541-0420
• DOI: 10.1111/biom.12276

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.