Deviation from the Proportional Hazards Assumption in Randomized Phase 3 Clinical Trials in Oncology: Prevalence, Associated Factors, and Implications
Deviation from the Proportional Hazards Assumption in Randomized Phase 3 Clinical Trials in Oncology: Prevalence, Associated Factors, and Implications
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DOI：
10.1158/1078-0432.ccr-18-3999
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发表时间：
2019-11-01
影响因子：
11.5
通讯作者：
Alexander, Brian M.
中科院分区：
文献类型：
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作者：
Rahman, Rifaquat;Fell, Geoffrey;Alexander, Brian M.
目的：在精准医学和免疫治疗时代，比例风险 (DPH) 的偏差可能更为普遍，可能导致试验效力不足或得出误导性结论。我们使用荟萃分析方法来估计癌症试验中的 DPH，调查相关因素，并评估未来试验的数据分析方法。 实验设计：我们在 PubMed 中搜索了 2014 年至 2016 年间在预先选定的期刊列表中发表的乳腺癌、肺癌、前列腺癌和结直肠癌的 III 期试验，并从 Kaplan-Meier 曲线中提取了个体患者水平数据 (IPLD)。我们重新分析 IPLD 以识别 DPH。当存在 DPH 时，替代统计方法相对于基于标准对数排序的分析的潜在效率增益表示为固定功率水平的样本量要求。结果：从 152 项试验中，我们获得了 129,401 名患者的 IPLD。在 304 个 Kaplan-Meier 模型中，75 个 (24.7%) 显示出 DPH 的证据，其中包括来自免疫治疗试验的 14 个 KM 对中的 8 个 (57%)。试验类型[免疫治疗，优势比（OR），4.29； 95% 置信区间 (CI)，1.11-16.6]、转移患者群体（OR，3.18；95% CI，1.26-8.05）和非 OS 终点（OR，3.23；95% CI，1.79-5.88）与 DPH 相关。在免疫治疗试验中，相对于对数秩测试，替代统计方法允许以更少的患者（最多减少 74%）进行更有效的临床试验。结论：在已发表的肿瘤学临床试验中，DPH 在事件发生时间结果中发现了显着比例，并且在免疫治疗试验和非 OS 终点中更为常见。当 DPH 的可能性较高时，在临床试验的设计和分析中应考虑使用没有比例风险假设的替代统计方法。
Purpose: Deviations from proportional hazards (DPHs), which may be more prevalent in the era of precision medicine and immunotherapy, can lead to underpowered trials or misleading conclusions. We used a meta-analytic approach to estimate DPHs across cancer trials, investigate associated factors, and evaluate data-analysis approaches for future trials.Experimental Design: We searched PubMed for phase III trials in breast, lung, prostate, and colorectal cancer published in a preselected list of journals between 2014 and 2016 and extracted individual patient-level data (IPLD) from Kaplan-Meier curves. We re-analyzed IPLD to identify DPHs. Potential efficiency gains, when DPHs were present, of alternative statistical methods relative to standard log-rank based analysis were expressed as sample-size requirements for a fixed power level.Results: From 152 trials, we obtained IPLD on 129,401 patients. Among 304 Kaplan-Meier figures, 75 (24.7%) exhibited evidence of DPHs, including eight of 14 (57%) KM pairs from immunotherapy trials. Trial type [immunotherapy, odds ratio (OR), 4.29; 95% confidence interval (CI), 1.11-16.6], metastatic patient population (OR, 3.18; 95% CI, 1.26-8.05), and non-OS endpoints (OR, 3.23; 95% CI, 1.79-5.88) were associated with DPHs. In immunotherapy trials, alternative statistical approaches allowed for more efficient clinical trials with fewer patients (up to 74% reduction) relative to log-rank testing.Conclusions: DPHs were found in a notable proportion of time-to-event outcomes in published clinical trials in oncology and was more common for immunotherapy trials and non-OS endpoints. Alternative statistical methods, without proportional hazards assumptions, should be considered in the design and analysis of clinical trials when the likelihood of DPHs is high.