Premature Clinical Trial Discontinuation in the Era of Immune Checkpoint Inhibitors
Premature Clinical Trial Discontinuation in the Era of Immune Checkpoint Inhibitors
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DOI：
10.1634/theoncologist.2018-0003
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发表时间：
2018-12-01
期刊：
影响因子：
5.8
通讯作者：
Grivas, Petros
中科院分区：
文献类型：
--
作者：
Khunger, Monica;Rakshit, Sagar;Grivas, Petros
背景资料。临床试验的完成对新的癌症疗法至关重要。过早终止或撤回审判是很常见的，并阻碍了进展。我们评估了早期终止/撤销的肿瘤学试验的因素，重点放在使用免疫检查点抑制剂(ICI)的试验上，假设后者可能与较低的过早中止率有关。我们回顾了在2011年11月16日至2015年4月16日登记的所有成人、干预和肿瘤学试验，以确定所有终止/撤回的试验和终止的原因。使用Logistic回归模型确定与提前终止/停药相关的因素。在有无ICI的试验中比较了停药率。我们确定了12,875项试验(35%由行业资助，12%由联邦资助)，其中8.5%被提前终止(5%)或撤回(3.5%)；主要原因是应计利润较低(33%)和后勤(24%)。与所有其他肿瘤学试验相比，ICI试验(n=350)的终止或撤销率(5.4%比8.5%；p=.9)没有显著降低，而且由于收益不佳而不太可能终止(非显著差异：21%比33%；p=.4)。与所有其他肿瘤药物试验(如化疗、靶向抑制剂、抗血管生成、生物制剂；分别为5.4%和7.9%，无显著差异)相比，ICI试验中止的可能性也较小。由于与毒性或疗效无关的原因而未能完成的4年累积发生率为18%(95%可信区间为16%-20%)。不同肿瘤类型或应计目标的年发病率与试验终止率之间没有相关性。低收益是早期癌症试验终止的主要原因。与其他试验相比，ICI组的提前终止/停药率并不显著降低。临床试验的完成仍然是一个高度优先的问题，可能会受到提供者和患者因素的影响。
Background. Clinical trial completion is critical for new cancer therapies. Premature trial termination or withdrawal is common and impairs progress. We assessed factors of early terminated/withdrawn oncology trials focusing on trials with immune checkpoint inhibitors (ICI), hypothesizing that the latter may be associated with lower rates of premature discontinuation.Materials and Methods. We reviewed all adult, intervention, oncology trials registered in (November 16, 2011, to April 16, 2015) to identify all terminated/withdrawn trials and reasons for termination. Logistics regression model was used to identify factors associated with early termination/withdrawal. Discontinuation rate was compared in trials with and without ICI.Results. We identified 12,875 trials (35% industry funded, 12% federal funded), of which 8.5% were prematurely terminated (5%) or withdrawn (3.5%); the main reasons were poor accrual (33%) and logistical (24%). ICI trials (n=350) had a nonsignificant lower rate of termination or withdrawal compared with all other oncology trials (5.4% vs. 8.5%; p=.9) and were less likely to discontinue due to poor accrual (nonsignificant difference: 21% vs. 33%; p=.4). ICI trials were also less likely to discontinue compared with all other oncology drug trials (e.g., chemotherapy, targeted inhibitors, antiangiogenesis, biologics; 5.4% vs. 7.9%, respectively, nonsignificant difference). The 4-year cumulative incidence of failing to complete for reasons unrelated to toxicity or efficacy was 18% (95% confidence interval 16%-20%). There was no association between annual incidence across different tumor types or accrual goal and rate of trial termination.Conclusion. Poor accrual represents the main cause of early cancer trial termination. Premature termination/withdrawal rate was not significantly lower in ICI compared with other trials. Clinical trial completion remains a high priority and can be influenced by provider and patient factors.