Designing a seamless phase II/III clinical trial using early outcomes for treatment selection: An application in multiple sclerosis
Designing a seamless phase II/III clinical trial using early outcomes for treatment selection: An application in multiple sclerosis
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DOI：
10.1002/sim.4202
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发表时间：
2011-06-15
影响因子：
2
通讯作者：
Nicholas, R.
中科院分区：
文献类型：
--
作者：
Friede, T.;Parsons, N.;Nicholas, R.
近年来，允许在中期分析中进行治疗或剂量选择的自适应无缝II/III期设计（ASD）受到了广泛关注，因为与单个阶段单独试验的传统药物开发计划相比，它们可能节省开发成本并缩短新化合物的上市时间。在本文中，我们描述了一个ASD的治疗选择的基础上，早期的结果数据，特别是考虑到没有最终结果的情况下，在中期分析时观察。将自适应设计的组合检验和多重检验的闭合原理结合在一起，实现了强意义上的族I型错误率的控制。此外，提出了一个模拟模型的基础上，标准化的测试统计，允许生成虚拟试验的各种结果。我们使用这个模拟模型来调查实际的I型错误率的建议的测试程序，并发现，家庭的I型错误率控制预期。该方法通常是保守的，保守程度取决于早期和晚期结局之间的相关性、不同治疗组早期结局的真实平均值以及选择规则。调查的动机和说明所提出的设计和模拟模型进行性多发性硬化症的应用。版权所有（C）2011约翰威利父子有限公司
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 (C) 2011 John Wiley & Sons, Ltd.