title: Characterization of dose-response for count data using a generalized MCP-Mod approach in an adaptive dose-ranging trial.
abstract: Understanding the dose-response relationship is a key objective in Phase II clinical development. Yet, designing a dose-ranging trial is a challenging task, as it requires identifying the therapeutic window and the shape of the dose-response curve for a new drug on the basis of a limited number of doses. Adaptive designs have been proposed as a solution to improve both quality and efficiency of Phase II trials as they give the possibility to select the dose to be tested as the trial goes. In this article, we present a 'shapebased' two-stage adaptive trial design where the doses to be tested in the second stage are determined based on the correlation observed between efficacy of the doses tested in the first stage and a set of pre-specified candidate dose-response profiles. At the end of the trial, the data are analyzed using the generalized MCP-Mod approach in order to account for model uncertainty. A simulation study shows that this approach gives more precise estimates of a desired target dose (e.g. ED70) than a single-stage (fixed-dose) design and performs as well as a two-stage D-optimal design. We present the results of an adaptive model-based dose-ranging trial in multiple sclerosis that motivated this research and was conducted using the presented methodology.
authors.affiliation: F. Hoffmann-La Roche Ltd., Clinical Pharmacology, Basel, Switzerland.
authors.forename: Francois
authors.initials: F
authors.lastname: Mercier
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Bornkamp
authors.affiliation: Novartis Pharmaceutical, East Hanover, NJ, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ohlssen
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Erik
authors.initials: E
authors.lastname: Wallstroem
mesh_terms: D017322:Clinical Trials, Phase II as Topic / Q000379:methods / Q000706:statistics & numerical data*; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage; D016014:Linear Models; D008279:Magnetic Resonance Imaging; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis / Q000188:drug therapy; D017711:Nonlinear Dynamics; D012107:Research Design / Q000706:statistics & numerical data*; D013997:Time Factors; D016896:Treatment Outcome; D035501:Uncertainty
chemical_list: D007155:Immunologic Factors
keywords: Emax model; dose-finding; multiple sclerosis; non-linear regression; optimal design; two-stage design