Discounting phase 2 results when planning phase 3 clinical trials
Discounting phase 2 results when planning phase 3 clinical trials
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DOI：
10.1002/pst.1521
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发表时间：
2012-09-01
影响因子：
1.5
通讯作者：
Sin, C.
中科院分区：
文献类型：
--
作者：
Kirby, S.;Burke, J.;Sin, C.
样本量规划是设计阶段的重要考虑因素。3试验。在本文中，我们考虑了如何在使用阶段数据时改进该计划。2试验。我们使用一种基于保证概念的方法。我们考虑调整相位吗？由于两种可能的偏倚来源，2个结果。第一个来源来自于选择具有预先指定的有利相的化合物。2个结果，并使用这些有利的结果作为阶段治疗效果的基础？3 .样本量规划。下一个来源来自投影阶段？2 .治疗效果到哪期？当这个预测是乐观的，因为在确认阶段的患者群体通常更异质。为了减少这两种偏差来源的影响，我们调整（贴现）相位？2 .治疗效果评估。我们考虑乘法和加性平差。根据先前提出的概念，我们考虑几个标准的属性，称为启动标准，以决定是否将开发进展到阶段3。我们使用模拟来研究在不同情况下有或没有偏差调整的发射标准来计算样本量。对模拟结果进行了实证的补充，以支持贴现阶段的必要性。当后者在阶段中使用时，结果如何？3规划。最后，基于模拟和实证研究，提出了一些建议。版权所有：John Wiley & Sons， Ltd
Sample size planning is an important design consideration for a phase?3 trial. In this paper, we consider how to improve this planning when using data from phase?2 trials. We use an approach based on the concept of assurance. We consider adjusting phase?2 results because of two possible sources of bias. The first source arises from selecting compounds with pre-specified favourable phase?2 results and using these favourable results as the basis of treatment effect for phase?3 sample size planning. The next source arises from projecting phase?2 treatment effect to the phase?3 population when this projection is optimistic because of a generally more heterogeneous patient population at the confirmatory stage. In an attempt to reduce the impact of these two sources of bias, we adjust (discount) the phase?2 estimate of treatment effect. We consider multiplicative and additive adjustment. Following a previously proposed concept, we consider the properties of several criteria, termed launch criteria, for deciding whether or not to progress development to phase?3. We use simulations to investigate launch criteria with or without bias adjustment for the sample size calculation under various scenarios. The simulation results are supplemented with empirical evidence to support the need to discount phase?2 results when the latter are used in phase?3 planning. Finally, we offer some recommendations based on both the simulations and the empirical investigations. Copyright (C) 2012 John Wiley & Sons, Ltd.