Division of Cancer Care and Epidemiology, Queen's University Cancer Research Institute, Kingston, Ontario, Canada.
Department of Oncology, Queen's University, Kingston, Ontario, Canada.
JAMA Oncol. 2021 Mar 1;7(3):379-385. doi: 10.1001/jamaoncol.2020.7478.
The burden of cancer falls disproportionally on low-middle-income countries (LMICs). It is not well known how novel therapies are tested in current clinical trials and the extent to which they match global disease burden.
To describe the design, results, and publication of oncology randomized clinical trials (RCTs) and examine the extent to which trials match global disease burden and how trial methods and results differ across economic settings.
DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, a literature search identified all phase 3 RCTs evaluating anticancer therapies published from 2014 to 2017. Randomized clinical trials were classified based on World Bank economic classification. Descriptive statistics were used to compare RCT design and results from high-income countries (HICs) and low/middle-income countries (LMICs). Statistical analysis was conducted in January 2020.
Differences in the design, results, and output of RCTs between HICs and LMICs.
The study cohort included 694 RCTs: 636 (92%) led by HICs and 58 (8%) led by LMICs. A total of 601 RCTs (87%) tested systemic therapy and 88 RCTs (13%) tested radiotherapy or surgery. The proportion of RCTs relative to global deaths was higher for breast cancer (121 RCTs [17%] and 7% of deaths) but lower for gastroesophageal cancer (38 RCTs [6%] and 14% of deaths), liver cancer (14 RCTs [2%] and 8% of deaths), pancreas cancer (14 RCTs [2%] and 5% of deaths), and cervical cancer (9 RCTs [1%] and 3% of deaths). Randomized clinical trials in HICs were more likely than those in LMICs to be funded by industry (464 [73%] vs 24 [41%]; P < .001). Studies in LMICs were smaller than those in HICs (median, 219 [interquartile range, 137-363] vs 474 [interquartile range, 262-743] participants; P < .001) and more likely to meet their primary end points (39 of 58 [67%] vs 286 of 636 [45%]; P = .001). The observed median effect size among superiority trials was larger in LMICs compared with HICs (hazard ratio, 0.62 [interquartile range, 0.54-0.76] vs 0.84 [interquartile range, 0.67-0.97]; P < .001). Studies from LMICs were published in journals with lower median impact factors than studies from HICs (7 [interquartile range, 4-21] vs 21 [interquartile range, 7-34]; P < .001). Publication bias persisted when adjusted for whether a trial was positive or negative (median impact factor: LMIC negative trial, 5 [interquartile range, 4-6] vs HIC negative trial, 18 [interquartile range, 6-26]; LMIC positive trial, 9 [interquartile range, 5-25] vs HIC positive trial, 25 [interquartile range, 10-48]; P < .001).
This study suggests that oncology RCTs are conducted predominantly by HICs and do not match the global burden of cancer. Randomized clinical trials from LMICs are more likely to identify effective therapies and have a larger effect size than RCTs from HICs. This study suggests that there is a funding and publication bias against RCTs led by LMICs. Policy makers, research funders, and journals need to address this issue with a range of measures including building capacity and capability in RCTs.
重要性：癌症的负担不成比例地落在中低收入国家（LMICs）身上。目前尚不清楚新疗法在当前临床试验中是如何进行测试的，以及它们在多大程度上与全球疾病负担相匹配。
目的：描述肿瘤学随机临床试验（RCTs）的设计、结果和发表情况，并研究试验在多大程度上与全球疾病负担相匹配，以及试验方法和结果在不同经济环境下的差异。
设计、地点和参与者：在这项回顾性队列研究中，通过文献检索确定了所有 2014 年至 2017 年发表的评估抗癌疗法的 3 期 RCTs。根据世界银行的经济分类对随机临床试验进行分类。使用描述性统计比较了高收入国家（HICs）和中低收入国家（LMICs）的 RCT 设计和结果。统计分析于 2020 年 1 月进行。
主要结果和措施：HICs 和 LMICs 的 RCT 设计、结果和输出之间的差异。
结果：研究队列包括 694 项 RCT：636 项（92%）由 HICs 领导，58 项（8%）由 LMICs 领导。601 项 RCT（87%）测试了系统治疗，88 项 RCT（13%）测试了放疗或手术。RCTs 相对于全球死亡人数的比例在乳腺癌（121 项 RCT [17%]和 7%的死亡人数）较高，但在胃癌（38 项 RCT [6%]和 14%的死亡人数）、肝癌（14 项 RCT [2%]和 8%的死亡人数）、胰腺癌（14 项 RCT [2%]和 5%的死亡人数）和宫颈癌（9 项 RCT [1%]和 3%的死亡人数）较低。HICs 中的 RCT 比 LMICs 中的 RCT 更有可能得到工业界的资助（464 [73%] vs 24 [41%]；P <.001）。LMICs 的研究规模小于 HICs（中位数，219 [四分位距，137-363] vs 474 [四分位距，262-743]参与者；P <.001），更有可能达到主要终点（58 项中的 39 项 [67%] vs 636 项中的 286 项 [45%]；P =.001）。在优势试验中观察到的中位效应大小在 LMICs 中比在 HICs 中更大（风险比，0.62 [四分位距，0.54-0.76] vs 0.84 [四分位距，0.67-0.97]；P <.001）。来自 LMICs 的研究发表在期刊上的影响因子中位数低于来自 HICs 的研究（7 [四分位距，4-21] vs 21 [四分位距，7-34]；P <.001）。调整试验阳性或阴性后，仍然存在发表偏倚（中位数影响因子：LMIC 阴性试验，5 [四分位距，4-6] vs HIC 阴性试验，18 [四分位距，6-26]；LMIC 阳性试验，9 [四分位距，5-25] vs HIC 阳性试验，25 [四分位距，10-48]；P <.001）。
结论和相关性：本研究表明，肿瘤学 RCTs 主要由 HICs 进行，与全球癌症负担不匹配。来自 LMICs 的 RCT 更有可能发现有效疗法，并且与来自 HICs 的 RCT 相比，其效应大小更大。本研究表明，针对由 LMICs 领导的 RCT 存在资金和发表偏见。政策制定者、研究资助者和期刊需要通过一系列措施来解决这个问题，包括在 RCT 方面建立能力和能力。
