Lawrence Nicola Jane, Roncolato Felicia, Martin Andrew, Simes Robert John, Stockler Martin R
NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia.
Macarthur Cancer Therapy Centre, Campbelltown, New South Wales, Australia.
JNCI Cancer Spectr. 2018 Nov 27;2(4):pky037. doi: 10.1093/jncics/pky037. eCollection 2018 Oct.
We sought to compare the effect sizes hypothesized in the trial design, observed in the trial results, and considered clinically meaningful by the American Society of Clinical Oncology (ASCO) 2014 recommendations, in phase III trials of targeted and immunological therapies.
We studied phase III, superiority trials of targeted and immunological therapies in advanced cancers published from 2005 to 2015. We recorded the characteristics, design parameters, and observed results for the primary endpoint of each trial. The effect sizes hypothesized in the trial design were compared with the ASCO 2014 recommendation that phase III trials be designed to detect overall survival (OS) benefits that are clinically meaningful (hazard ratio ≤0.8).
All critical elements of the trial design (effect sizes hypothesized, estimated survival in the control group, power, and significance level) were identified in 165 of 213 included trials (77%). Of trials with a statistically significant result for the primary endpoint, 16 of 30 (53%) with a primary endpoint of OS and 20 of 53 (38%) with a primary endpoint of progression free survival (PFS) had an observed effect size less extreme than hypothesized; and 7 of 30 trials (23%) reported an observed effect size for OS that was statistically significant but not clinically meaningful (HR > 0.80) according to the ASCO 2014 recommendations.
Many trials were designed such that an observed benefit in OS or PFS that was not clinically meaningful would be statistically significant. Phase III trials should be designed to provide results that are statistically significant for observed effects that are clinically meaningful but not for observed results that are of dubious clinical importance.
我们试图比较在靶向和免疫治疗的III期试验中，试验设计中假设的效应大小、试验结果中观察到的效应大小以及美国临床肿瘤学会（ASCO）2014年推荐中认为具有临床意义的效应大小。
我们研究了2005年至2015年发表的晚期癌症靶向和免疫治疗的III期优效性试验。我们记录了每个试验主要终点的特征、设计参数和观察结果。将试验设计中假设的效应大小与ASCO 2014年的建议进行比较，该建议认为III期试验应设计为检测具有临床意义的总生存期（OS）获益（风险比≤0.8）。
在纳入的213项试验中的165项（77%）中确定了试验设计的所有关键要素（假设的效应大小、对照组的估计生存期、检验效能和显著性水平）。对于主要终点有统计学显著结果的试验，30项以OS为主要终点的试验中有16项（53%），53项以无进展生存期（PFS）为主要终点的试验中有20项（38%），观察到的效应大小比假设的要小；根据ASCO 2014年的建议，30项试验中有7项（23%）报告的OS观察效应大小具有统计学显著性但无临床意义（HR>0.80）。
许多试验的设计使得在OS或PFS方面观察到的无临床意义的获益具有统计学显著性。III期试验的设计应能为具有临床意义的观察效应提供具有统计学显著性的结果，而不是为具有可疑临床重要性的观察结果提供统计学显著性结果。
