Schandelmaier Stefan, Schmitt Andreas M, Herbrand Amanda K, Glinz Dominik, Ewald Hannah, Briel Matthias, Guyatt Gordon H, Hemkens Lars G, Kasenda Benjamin
Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital and University of Basel, Basel, Switzerland
Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.
BMJ Open. 2020 May 30;10(5):e034565. doi: 10.1136/bmjopen-2019-034565.
Target-specific anticancer drugs are under rapid development. Little is known, however, about the risk of administering target-specific drugs to patients who have tumours with molecular alterations or other characteristics that can make the drug ineffective or even harmful. An increasing number of randomised clinical trials (RCTs) investigating target-specific anticancer drugs include subgroup analyses based on tumour characteristics. Such subgroup analyses have the potential to be more credible and influential than subgroup analyses based on traditional factors such as sex or tumour stage. In addition, they may more frequently lead to qualitative subgroup effects, that is, show benefit in one but harm in another subgroup of patients (eg, if the tumour characteristic makes the drug ineffective or even enhance tumour growth). If so, subgroup analyses based on tumour characteristics would be highly relevant for patient safety. The aim of this study is to systematically assess the frequency and characteristics of subgroup analyses based on tumour characteristics, the frequency of qualitative subgroup effects, their credibility, and the interpretations that investigators and guidelines developers report.
We will perform a systematic survey of 433 RCTs testing the effect of target-specific anticancer drugs. Teams of methodologically trained investigators and oncologists will identify eligible studies, extract relevant data and assess the credibility of putative subgroup effects using a recently developed formal instrument. We will systematically assess how trial investigators interpret apparent subgroup effects based on tumour characteristics and the extent to which they influence subsequent practice guidelines. Our results will provide empirical data characterising an increasingly used type of subgroup analysis in cancer trials and its potential impact on precision medicine to predict benefit or harm.
Formal ethical approval is not required for this study. We will disseminate the findings in a peer-reviewed and open-access journal publication.
针对特定靶点的抗癌药物正在迅速发展。然而，对于将针对特定靶点的药物应用于肿瘤具有分子改变或其他可能使药物无效甚至有害特征的患者的风险，我们知之甚少。越来越多研究针对特定靶点抗癌药物的随机临床试验（RCT）包括基于肿瘤特征的亚组分析。这种亚组分析可能比基于性别或肿瘤分期等传统因素的亚组分析更具可信度和影响力。此外，它们可能更频繁地导致定性亚组效应，即对一组患者显示有益，而对另一组患者显示有害（例如，如果肿瘤特征使药物无效甚至促进肿瘤生长）。如果是这样，基于肿瘤特征的亚组分析对于患者安全将具有高度相关性。本研究的目的是系统评估基于肿瘤特征的亚组分析的频率和特征、定性亚组效应的频率、其可信度以及研究者和指南制定者报告的解读。
我们将对433项测试针对特定靶点抗癌药物效果的RCT进行系统调查。经过方法学培训的研究者和肿瘤学家团队将识别符合条件的研究，提取相关数据，并使用最近开发的正式工具评估假定亚组效应的可信度。我们将系统评估试验研究者如何解读基于肿瘤特征的明显亚组效应以及它们对后续实践指南的影响程度。我们的结果将提供实证数据，以描述癌症试验中越来越常用的一种亚组分析类型及其对精准医学预测获益或危害的潜在影响。
本研究无需正式伦理批准。我们将在同行评审的开放获取期刊上发表研究结果。
