Evolution of the Randomized Clinical Trial in the Era of Precision Oncology
Evolution of the Randomized Clinical Trial in the Era of Precision Oncology
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DOI：
10.1001/jamaoncol.2021.0379
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发表时间：
2021-03-25
期刊：
影响因子：
28.4
通讯作者：
Booth, Christopher M.
中科院分区：
文献类型：
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作者：
Del Paggio, Joseph C.;Berry, John S.;Booth, Christopher M.
肿瘤学随机临床试验（RCT）自20世纪70年代广泛采用以来一直在发展。近年来，出现了关于使用假定的替代终点，如无进展生存期（PFS）和边际效应大小的关注。目的描述肿瘤学RCT的当代趋势，并将这些结果与早期RCT设计和输出进行比较。2010年至2020年期间，非小细胞肺癌在7种主要期刊上发表。该策略复制了先前的工作，并允许与1995 - 2004年和2005 - 2009年之间发表的RCT进行趋势比较。主要结果和指标关于RCT设计、资金、结果和报告的数据摘自已发表的RCT报告。将当前时期（2010-2020年）的结果与1995 - 2004年和2005 - 2009年发表的RCT数据进行比较。描述性和双变量统计被用来分析时间trends. Results队列包括298项随机对照试验（132 [44%]乳腺癌，111 [37%]非小细胞肺癌，55 [19%]结直肠癌）。实验性治疗包括分子抑制剂（171/298 [57%]）、细胞毒性（83/298 [28%]）、激素（15/298 [5%]）和免疫（24/298 [8%]）治疗。69%（206/298）的随机对照试验是姑息性的。目前最常见的主要终点是PFS;随着时间的推移，PFS显著增加（从0% [0/167]到18%[25/137]再到42%[125/298]; P < .001）。在298项随机对照试验中，265项（89%）现在由行业资助（以前为167项中的95项[57%]和137项中的107项[78%]; P < .001）。58%（173/298）的试验达到了主要终点。在阳性试验中，总生存期和PFS的中位改善分别为3.4和2.9个月。超过三分之一（298份报告中的117份[39%]）使用了专业医学作家;这在研究期间大幅增加（从2010年的27个中的3个[11%]到2020年的18个中的12个[67%]; P <0.001），但不影响正常工作。结论和相关性这项队列研究表明，当代肿瘤学RCT现在主要测量假定的替代终点，由制药业资助。医学作家的作用越来越大，值得关注。为了证明新的癌症治疗方法具有高价值，肿瘤学界需要考虑研究终点和目标效应量为患者提供有意义获益的程度。
IMPORTANCE The randomized clinical trial (RCT) in oncology has evolved since its widespread adoption in the 1970s. In recent years, concerns have emerged regarding the use of putative surrogate end points, such as progression-free survival (PFS), and marginal effect sizes.OBJECTIVE To describe contemporary trends in oncology RCTs and compare these findings with earlier eras of RCT design and output.DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of systemic therapy RCTs in breast, colorectal, and non-small cell lung cancer published in 7 major journals between 2010 and 2020. This strategy replicates prior work and allows for comparison of trends with RCTs published between 1995 to 2004 and 2005 to 2009.MAIN OUTCOMES AND MEASURES Data on RCT design, funding, results, and reporting were extracted from the published RCT report. Findings from the current period (2010-2020) were compared with data from RCTs published from 1995 to 2004 and 2005 to 2009. Descriptive and bivariate statistics were used to analyze temporal trends.RESULTS The cohort included 298 RCTs (132 [44%] breast, 111 [37%] non-small cell lung cancer, 55 [19%] colorectal cancer). Experimental treatment included molecular inhibitor (171 of 298 [57%]), cytotoxic (83 of 298 [28%]), hormone (15 of 298 [5%]), and immune (24 of 298 [8%]) therapies. Sixty-nine percent (206 of 298) of RCTs were of palliative intent. The most common primary end point is now PFS; this has increased substantially over time (from 0% [0 of 167] to 18%[25 of 137] to 42%[125 of 298]; P < .001). Of 298 RCTs, 265 (89%) are now funded by industry (previously 95 of 167 [57%] and 107 of 137 [78%]; P < .001). Fifty-eight percent (173 of 298) of trials met their primary end point. Among positive trials, median improvement in overall survival and PFS was 3.4 and 2.9 months, respectively. More than one-third (117 of 298 [39%]) of reports used a professional medical writer; this increased substantially during the study period (from 3 of 27 [11%] in 2010 to 12 of 18 [67%] in 2020; P < .001).CONCLUSIONS AND RELEVANCE This cohort study suggests that contemporary oncology RCTs now largely measure putative surrogate end points and are almost exclusively funded by the pharmaceutical industry. The increasing role of medical writers warrants attention. To demonstrate that new cancer treatments are high value, the oncology community needs to consider the extent to which study end points and target effect size provide meaningful benefit to patients.