Exploring the benefits of adaptive sequential designs in time-to-event endpoint settings.
Exploring the benefits of adaptive sequential designs in time-to-event endpoint settings.
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DOI：
10.1002/sim.4156
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发表时间：
2011-05-20
影响因子：
2
通讯作者：
Emerson, Scott S.
中科院分区：
文献类型：
--
作者：
Emerson, Sarah C.;Rudser, Kyle D.;Emerson, Scott S.
关键词：
序贯分析经常用于解决临床试验中的伦理和财务问题。序贯分析可以使用标准组序贯设计进行，或者最近使用自适应设计进行，自适应设计使用治疗效果的估计来修改要收集的最大统计信息。在一般情况下，统计信息和临床试验成本是所用受试者数量的函数，尚未确定自适应设计与传统的成组序贯设计相比是否有任何重大的效率优势。然而，在生存分析中，统计信息（以及效率）与观察到的事件数量关系最为密切，而试验成本仍然取决于累积的患者数量。由于受试者数量可能主导试验成本，当观察到极端治疗效应时，规定减少最大可能样本量的适应性设计可能允许提前终止累积，因此试验更具成本效益。我们调查和比较效率之间的权衡（所需的观察事件的平均数），功率和成本（累积的受试者的数量和观察长度的函数）标准组序贯方法和自适应设计，允许提前终止应计。我们发现，当某些试验设计参数受到约束时，终止受试者累积的自适应方法可能会提高调查至事件发生时间终点的组序贯临床试验的成本效率。然而，当考虑的组序贯设计的范围扩大时，自适应设计的优势就不那么明显了。
Sequential analysis is frequently employed to address ethical and financial issues in clinical trials. Sequential analysis may be performed using standard group sequential designs, or, more recently, with adaptive designs that use estimates of treatment effect to modify the maximal statistical information to be collected. In the general setting in which statistical information and clinical trial costs are functions of the number of subjects used, it has yet to be established whether there is any major efficiency advantage to adaptive designs over traditional group sequential designs. In survival analysis, however, statistical information (and hence efficiency) is most closely related to the observed number of events, while trial costs still depend on the number of patients accrued. As the number of subjects may dominate the cost of a trial, an adaptive design that specifies a reduced maximal possible sample size when an extreme treatment effect has been observed may allow early termination of accrual and therefore a more cost-efficient trial. We investigate and compare the tradeoffs between efficiency (as measured by average number of observed events required), power, and cost (a function of the number of subjects accrued and length of observation) for standard group sequential methods and an adaptive design that allows for early termination of accrual. We find that when certain trial design parameters are constrained, an adaptive approach to terminating subject accrual may improve upon the cost efficiency of a group sequential clinical trial investigating time-to-event endpoints. However, when the spectrum of group sequential designs considered is broadened, the advantage of the adaptive designs is less clear.
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