基于生存资料探讨Ⅱ/Ⅲ期无缝设计靶向人群选择策略研究

The Strategy for Selecting Target Population Using Adaptive Phase Ⅱ /Ⅲ Seamless Design Based on Time-to-event Data

目的尽管对临床试验的数据进行事后分析可以鉴别出有意义的亚组人群,但是,这往往需要额外的验证性试验,导致研发周期延长,成本增加。据此,本文提出在无缝试验的设计阶段既考虑全人群效应也考虑亚组效应,并对该试验设计方案的统计学性质(I类错误,检验效能)进行评价。方法采用两阶段无缝设计的思想,在一阶段结束后同时对替代指标无进展生存期及主要研究总生存期指标进行期中分析,判断是只有亚组、只有全人群或两者均进入下一阶段的研究。二阶段结束后,采用Fisher法合并两个阶段的信息对主要研究指标OS进行最终的分析。结果观察OS与PFS不同相关程度下对总I类错误的影响,结果显示I类错误均能控制在0.025以内;不同情境下做出正确选择的概率均较高,试验结果与现实接近。结论在肿瘤临床试验中,若事先已存在某个亚组人群疗效更好的假设,且能通过一定的方法筛选出这些亚组人群,则可采用本文提出的试验设计方案,达到缩短临床试验周期、降低研究成本的目的。

Objective Although subgroups can be identified on the basis of post-analysis, it needs an additional con-firmatory trial and this may lead to an inflation in development time and cost. We present an approach that view treatment comparisons in both a predefined subgroup and the full population in the design period of a seamless trial, then evaluate the statistical characteristics. Methods It is based on the adaptive phase Ⅱ/Ⅲ design. The decision of continuing seamlessly either in a sub- group or the full population is on the basis of analysis of PFS and OS obtained from the first stage. Final analysis is conducted only for OS using Fisher combination method after the second stage trial. Results It is shown that the type-I-error rate is less than 2. 5% and is independent of the correlation of OS and PFS. The simulations demonstrate that correct conclusions are reached sufficiently often in the various scenarios. Conclusion In oncology trials if there is an priori hypothesis about increased efficacy in a defined subgroup and this subgroup can be well characterized , our design can shorten the time and cost.