Ethics of umbrella and basket trials in precision oncology

Karolina Strzebonska
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Abstract

To the Editor, the project Ethics of research with human subjects in precision medicine funded by the National Science Centre in Poland concerns a new approach in treating clinical trial participants by tailoring appropriate therapy to the molecular targets within the patient’s disease. The aim of the project is to perform theoretical and ethical analyses of novel research designs in precision oncology, umbrella trials, and basket trials, in the context of 7 fundamental ethical requirements of conducting research with human participants: 1) social or scientific value, 2) scientific validity, 3) fair subject selection, 4) favourable risk-benefit ratio, 5) independent review, 6) informed consent, and 7) respect for potential and enrolled subjects. The project applies evidence-based medicine and evidence-based ethics methodology to provide necessary information for making decisions in medicine and health care. The results of the project may contribute to the current debate on the ethical aspects of the research in precision medicine. The first findings can be found in the article Risk and benefit for umbrella trials in oncology: a systematic review and meta-analysis published in BMC Medicine (2022) [1]. The article considers a favourable risk-benefit ratio criterion, which is met when the risk for participants is minimized, the expected benefits are maximized, and the benefits to trial participants and society outweigh or are proportional to the risks associated with participation in the research study [2]. This ethical requirement is particularly important in umbrella trials, which are considered to maximize direct health benefits to trial participants by dividing cancer patients into groups that will most likely respond to a given therapy [3, 4]. Within an umbrella trial multiple drugs matched to different molecular changes in one cancer type can be evaluated simultaneously in parallel sub-studies or cohorts [5]. Thus, we may expect better risk-benefit balance in umbrella trials than in classical trial designs. To assess the overall benefit and risk in umbrella cancer trials my colleagues and I systematically searched for umbrella trials published between 1 January 2006 and 7 October 2019. Of the 6207 records screened, 31 sub-trials or arms of 9 umbrella trials enrolling 1637 patients were included in the analyses. We measured the benefit by the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The overall ORR was 17.7%, the median PFS was 2.4 months, and the median OS was 7.1 months. We observed a significant difference in ORR between therapy types (13.3% for targeted therapies vs. 39.0% for a combination of targeted therapy and chemotherapy). We calculated the risk by the proportion of participants experiencing grade 3, 4, or 5 drug-related adverse events (AEs). The average drug-related grade 3/4 AE rate per person was 0.45, and the drug-related grade 5 AEs rate was 0.8%. We compared these results to other studies analysing risk and benefit in classical trial designs and found that the ORR and AE rates were similar. Our findings do not support the expectation of increased patient benefit in umbrella trials in precision oncology. Further analyses of the ethical aspects of umbrella and basket trials are ongoing.
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精确肿瘤学中伞篮试验的伦理学
致编辑,由波兰国家科学中心资助的精准医学人类受试者研究伦理项目涉及一种治疗临床试验参与者的新方法,即根据患者疾病的分子靶点定制适当的治疗方法。该项目的目的是在开展人类受试者研究的7项基本伦理要求的背景下,对精确肿瘤学、保护伞试验和篮子试验的新研究设计进行理论和伦理分析:1)社会或科学价值,2)科学有效性,3)公平的受试者选择,4)有利的风险-收益比,5)独立审查,6)知情同意,7)尊重潜在和入组受试者。该项目运用循证医学和循证伦理学方法论,为医学和卫生保健决策提供必要的信息。该项目的结果可能有助于当前关于精确医学研究的伦理方面的辩论。第一个发现可以在《BMC Medicine(2022)[1]》上发表的文章《肿瘤学保护伞试验的风险和益处:一项系统评价和荟萃分析》中找到。本文考虑了一个有利的风险-收益比标准,当参与者的风险最小,预期收益最大化,试验参与者和社会的收益超过或与参与研究相关的风险成正比时,该标准得到满足。这一伦理要求在伞形试验中尤为重要,伞形试验被认为通过将癌症患者分成最有可能对特定治疗产生反应的组,从而最大限度地提高试验参与者的直接健康效益[3,4]。在一项总括性试验中,可以在平行子研究或队列中同时评估与一种癌症类型的不同分子变化相匹配的多种药物。因此,我们可以期望在伞式试验中比在经典试验设计中更好地平衡风险-收益。为了评估总体癌症试验的总体收益和风险,我和我的同事系统地检索了2006年1月1日至2019年10月7日期间发表的总体试验。在筛选的6207份记录中,纳入1637名患者的9个总括试验的31个亚试验或组被纳入分析。我们通过客观缓解率(ORR)、无进展生存期(PFS)和总生存期(OS)来衡量获益。总ORR为17.7%,中位PFS为2.4个月,中位OS为7.1个月。我们观察到治疗类型之间的ORR有显著差异(靶向治疗为13.3%,而靶向治疗和化疗联合为39.0%)。我们通过经历3,4或5级药物相关不良事件(ae)的参与者比例来计算风险。人均药物相关3/4级AE发生率为0.45,人均药物相关5级AE发生率为0.8%。我们将这些结果与其他分析经典试验设计的风险和获益的研究进行了比较,发现ORR和AE率相似。我们的研究结果不支持在精确肿瘤学的伞形试验中增加患者获益的期望。目前正在对伞式试验和篮子式试验的伦理问题进行进一步分析。
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