Interim futility analysis with intermediate endpoints
Interim futility analysis with intermediate endpoints
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DOI：
10.1177/1740774507086648
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发表时间：
2008-01-01
期刊：
影响因子：
2.7
通讯作者：
Crowley, John
中科院分区：
文献类型：
--
作者：
Goldman, Bryan;LeBlanc, Michael;Crowley, John
III期试验的中期分析通常包括有效性和无效性的测试。在最终分析之前，通常在非常低的水平（例如，单侧α =0.0025）对主要结果进行一次或两次无效试验。当总生存期是主要结局，事件发生缓慢时，如果有合适的中间终点，那么在没有任何治疗效果的情况下，使用该终点进行中期无效试验可能会产生更高的因无效而提前停止的可能性。本研究的目的是探讨将中间终点纳入III期试验中期有效性检验的可能性。方法基于最近西南肿瘤组在几种疾病环境下的III期研究，采用简单的两阶段指数生存模型，我们进行了一系列模拟研究。在零假设和备选假设下模拟生存数据，并使用总生存期、无进展生存期和无效检验的复合终点进行分析。在所有的疾病环境中，当生存数据在零假设下模拟时，通过将PFS纳入中期无效分析，早期因无效而停止试验的概率大大增加。当用复合终点检测无效时，在各种疾病情况下，患者的平均应计收益减少了6- 11%。在生存时间最长的研究方案中，研究时间的节省比患者资源的节省更为显著。当数据在替代假设下进行模拟时，该过程导致的功率损失可以忽略不计。该方法在癌症临床试验和/或使用不同中间终点之外的特性未被检查。这些结果也没有解决它的性能在不太保守的停止规则的背景下。结论：在没有治疗效果的情况下，使用合适的中间终点对III期试验进行中期无效监测可能会大大增加因无效而早期停止的可能性。这些模拟研究表明，在许多疾病环境中，这将导致研究持续时间和患者资源的有意义的减少，而对疗效的主要测试没有实质性的损失。未来的工作需要详细探讨在此过程中使用的停止规则的修改是否可以在不影响功率的情况下产生更大的节省。
Background Interim analysis of Phase III trials typically includes testing for both efficacy and futility. Futility testing is commonly performed on the primary outcome at very low levels (e.g., one-sided alpha=0.0025) at one or two times before final analysis. When overall survival is the primary outcome and events accrue slowly, and if a suitable intermediate endpoint is available, then using this endpoint for interim futility testing may yield a higher probability of stopping early for futility in the absence of any treatment effect.Purpose The purpose of this study is to explore the possibility of incorporating an intermediate endpoint into interim futility testing of Phase III trials.Methods Using a simple two-stage exponential survival model based on recent Southwest Oncology Group Phase III studies in several disease settings, we perform a series of simulation studies. Survival data are simulated under both the null and alternative hypotheses, and analyzed using overall survival, progression-free survival, and a composite endpoint for futility testing.Results In all disease settings examined here, when survival data were simulated under the null hypothesis, the probability of stopping a trial early for futility was substantially increased by incorporating PFS into interim futility analyses. When testing for futility with the composite endpoint, average patient accrual was reduced by 6-11 % in a wide variety of disease settings. In the study scenario with the longest survival, the savings in study duration was more dramatic than in patient resources. When data were simulated under the alternative hypothesis, this procedure resulted in a negligible loss of power.Limitations The properties of this procedure outside of the context of cancer clinical trials and/or using a different intermediate endpoint are not examined. These results also do not address its performance in the context of less conservative stopping rules.Conclusions Interim futility monitoring of Phase III trials using a suitable intermediate endpoint may substantially increase the probability of stopping early for futility when there is no treatment effect. These simulation studies suggest that this would lead to meaningful reductions in study duration and patient resources in many disease settings, with no substantial loss of power for the primary test of efficacy. Future work is needed to explore in detail whether modifications to the stopping rules used in this procedure may yield greater savings without compromising power.