Monnereau Matthias, Delord Jean-Pierre, Michiels Stefan, Le Tourneau Christophe, Marque Sebastien, Baschet Louise, Filleron Thomas
Université Paris-Saclay, CESP, INSERM U1018 Oncostat, Labeled Ligue Contre le Cancer, Villejuif, France.
Horiana, Bordeaux, France.
Br J Cancer. 2025 Sep 12. doi: 10.1038/s41416-025-03155-6.
External control arms (ECAs) are sometimes considered as an alternative to phase III trials, enabling comparisons without head-to-head trials. Deploying ECAs is complex, partially due to varying regulatory guidelines. We aimed to assess their acceptance in oncology by Health Technology Assessment (HTA) bodies across France, England, Germany, and Norway from 2021 to 2023.
We conducted a review of HTA evaluation reports for oncology treatments using ECAs. Reports were extracted from national HTA body websites and systematically reviewed. Data extraction included drug characteristics, ECA methodology, acceptance status, and reported issues. ECAs were categorized by type of data: Individual Patient Data (IPD), Aggregated Data (AgD), or naive comparisons.
We analysed 175 ECAs from 123 reviews, none were accepted without restrictions, and only 17% were not rejected. Acceptance rates varied significantly between countries, with England showing the highest non-rejection rate (accepted with restrictions) (41%), followed by France (14%) while Germany and Norway rejected all ECAs. The main methodological issues identified were lack of/unclear data (54%), heterogeneity between studies or risk of bias (51%), study design concerns (29%), and statistical methodology limitations (26%). These challenges were consistent across different types of ECAs, though their relative importance varied by country.
Despite the increasing use of ECAs in oncology trials, their acceptance by HTA bodies remains limited. Our findings highlight significant disparities in assessment approaches between countries and persistent challenges in data quality and methodological consistency. Future efforts should focus on improving transparency, robustness, and residual bias assessment of ECA methodologies.
外部对照臂（ECA）有时被视为III期试验的替代方案，可在不进行直接对比试验的情况下进行比较。部署ECA很复杂，部分原因是监管指南各不相同。我们旨在评估2021年至2023年法国、英国、德国和挪威的卫生技术评估（HTA）机构对其在肿瘤学领域的接受情况。
我们对使用ECA的肿瘤治疗的HTA评估报告进行了综述。报告从国家HTA机构网站提取并进行系统综述。数据提取包括药物特征、ECA方法、接受状态和报告的问题。ECA按数据类型分类：个体患者数据（IPD）、汇总数据（AgD）或单纯比较。
我们分析了123篇综述中的175个ECA，无一被无限制接受，只有17%未被拒绝。各国的接受率差异显著，英国的非拒绝率最高（有条件接受）（41%），其次是法国（14%），而德国和挪威拒绝了所有ECA。确定的主要方法学问题是数据缺乏/不明确（54%）、研究之间的异质性或偏倚风险（51%）、研究设计问题（29%）和统计方法局限性（26%）。这些挑战在不同类型的ECA中都是一致的，尽管其相对重要性因国家而异。
尽管ECA在肿瘤学试验中的使用日益增加，但其被HTA机构接受的程度仍然有限。我们的研究结果凸显了各国在评估方法上的显著差异以及数据质量和方法一致性方面持续存在的挑战。未来的努力应集中在提高ECA方法的透明度、稳健性和残余偏倚评估上。
