Optimizing Trial Designs for Targeted Therapies

PLoS One. 2016 Sep 29;11(9):e0163726. doi: 10.1371/journal.pone.0163726. eCollection 2016.

Abstract

An important objective in the development of targeted therapies is to identify the populations where the treatment under consideration has positive benefit risk balance. We consider pivotal clinical trials, where the efficacy of a treatment is tested in an overall population and/or in a pre-specified subpopulation. Based on a decision theoretic framework we derive optimized trial designs by maximizing utility functions. Features to be optimized include the sample size and the population in which the trial is performed (the full population or the targeted subgroup only) as well as the underlying multiple test procedure. The approach accounts for prior knowledge of the efficacy of the drug in the considered populations using a two dimensional prior distribution. The considered utility functions account for the costs of the clinical trial as well as the expected benefit when demonstrating efficacy in the different subpopulations. We model utility functions from a sponsor's as well as from a public health perspective, reflecting actual civil interests. Examples of optimized trial designs obtained by numerical optimization are presented for both perspectives.

Grants and funding

MP, NS, TO, were funded by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement number FP7 HEALTH 2013-602144 and CFB, FK, SJ under grant number FP7 HEALTH 2013-602552. The funder provided support in the form of salaries for authors SJ, FK, TO, MP, NS, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. CFB is an employee of AstraZeneca and was funded by grant number FP7 HEALTH 2013-602552 under a consultancy contract from AstraZeneca to Chalmers University for the purpose of conducting the work described herein. AstraZeneca did not play a role in the study data collection and analysis, decision to publish, preparation of the manuscript or financial support to CFB. The specific roles of these authors are articulated in the ‘author contributions’ section.