title: Utility-based optimization of phase II/III programs.
abstract: Phase II and phase III trials play a crucial role in drug development programs. They are costly and time consuming and, because of high failure rates in late development stages, at the same time risky investments. Commonly, sample size calculation of phase III is based on the treatment effect observed in phase II. Therefore, planning of phases II and III can be linked. The performance of the phase II/III program crucially depends on the allocation of the resources to phases II and III by appropriate choice of the sample size and the rule applied to decide whether to stop the program after phase II or to proceed. We present methods for a program-wise phase II/III planning that aim at determining optimal phase II sample sizes and go/no-go decisions in a time-to-event setting. Optimization is based on a utility function that takes into account (fixed and variable) costs of the drug development program and potential gains after successful launch. The proposed methods are illustrated by application to a variety of scenarios typically met in oncology drug development.
authors.affiliation: Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Marietta
authors.initials: M
authors.lastname: Kirchner
authors.affiliation: Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Meinhard
authors.initials: M
authors.lastname: Kieser
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Götte
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Schüler
mesh_terms: D056808:Biostatistics / Q000379:methods; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data*; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data*; D055808:Drug Discovery / Q000706:statistics & numerical data; D006801:Humans; D015233:Models, Statistical; D018401:Sample Size; D012984:Software
keywords: drug development; expected utility; optimization; probability of success; program-wise planning