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Designing a seamless phase II/III clinical trial using early outcomes for treatment selection: An application in multiple sclerosis
Author(s) -
Friede T.,
Parsons N.,
Stallard N.,
Todd S.,
Valdes Marquez E.,
Chataway J.,
Nicholas R.
Publication year - 2011
Publication title -
statistics in medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.996
H-Index - 183
eISSN - 1097-0258
pISSN - 0277-6715
DOI - 10.1002/sim.4202
Subject(s) - type i and type ii errors , computer science , interim , interim analysis , selection (genetic algorithm) , outcome (game theory) , multiple comparisons problem , clinical trial , statistics , medicine , machine learning , mathematics , archaeology , mathematical economics , history
Abstract In recent years adaptive seamless phase II/III designs (ASDs) allowing treatment or dose selection at an interim analysis have gained much attention because of their potential to save development costs and to shorten time‐to‐market of a new compound compared to conventional drug development programmes with separate trials for individual phases. In this paper, we describe an ASD with treatment selection based on early outcome data, specifically considering the situation where no final outcomes are observed at the time of the interim analysis. Bringing together combination tests for adaptive designs and the closure principle for multiple testing, control of the familywise type I error rate in the strong sense is achieved. Furthermore, a simulation model is proposed based on standardized test statistics that allows the generation of virtual trials for a variety of outcomes. We use this simulation model to investigate the actual type I error rate of the proposed testing procedure and find that the familywise type I error rate is controlled as expected. The method is often conservative, with the degree of conservatism depending on the correlation between early and late outcome, the true mean values of the early outcome in the different treatment groups and the selection rule. The investigations are motivated and illustrated by an application of the proposed design and simulation model to progressive multiple sclerosis. Copyright © 2011 John Wiley & Sons, Ltd.