ImportanceSurrogate markers are increasingly used as primary end points in clinical trials supporting drug approvals.ObjectiveTo systematically summarize the evidence from meta-analyses, systematic reviews and meta-analyses, and pooled analyses (hereafter, meta-analyses) of clinical trials examining the strength of association between treatment effects measured using surrogate markers and clinical outcomes in nononcologic chronic diseases.Data sourcesThe Food and Drug Administration (FDA) Adult Surrogate Endpoint Table and MEDLINE from inception to March 19, 2023.Study SelectionThree reviewers selected meta-analyses of clinical trials; meta-analyses of observational studies were excluded.Data Extraction and SynthesisTwo reviewers extracted correlation coefficients, coefficients of determination, slopes, effect estimates, or results from meta-regression analyses between surrogate markers and clinical outcomes.Main Outcomes and MeasuresCorrelation coefficient or coefficient of determination, when reported, was classified as high strength (r ≥ 0.85 or R2 ≥ 0.72); primary findings were otherwise summarized.ResultsThirty-seven surrogate markers listed in FDA’s table and used as primary end points in clinical trials across 32 unique nononcologic chronic diseases were included. For 22 (59%) surrogate markers (21 chronic diseases), no eligible meta-analysis was identified. For 15 (41%) surrogate markers (14 chronic diseases), at least 1 meta-analysis was identified, 54 in total (median per surrogate marker, 2.5; IQR, 1.3-6.0); among these, median number of trials and patients meta-analyzed was 18.5 (IQR, 12.0-43.0) and 90 056 (IQR, 20 109-170 014), respectively. The 54 meta-analyses reported 109 unique surrogate marker–clinical outcome pairs: 59 (54%) reported at least 1 r or R2, 10 (17%) of which reported at least 1 classified as high strength, whereas 50 (46%) reported slopes, effect estimates, or results of meta-regression analyses only, 26 (52%) of which reported at least 1 statistically significant result.Conclusions and RelevanceMost surrogate markers used as primary end points in clinical trials to support FDA approval of drugs treating nononcologic chronic diseases lacked high-strength evidence of associations with clinical outcomes from published meta-analyses.

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替代标志物与非肿瘤性慢性病治疗临床结果之间的关联

重要性替代标志物越来越多地用作支持药物批准的临床试验中的主要终点。目的系统地总结来自荟萃分析、系统评价和荟萃分析以及临床试验的汇总分析（以下简称荟萃分析）的证据，以检验替代标志物的强度使用替代标志物测量的治疗效果与非肿瘤性慢性疾病的临床结果之间的关联。数据来源美国食品和药物管理局 (FDA) 成人替代终点表和 MEDLINE，从开始到 2023 年 3 月 19 日。研究选择三位评审员选择了临床试验的荟萃分析；观察性研究的荟萃分析被排除在外。数据提取和合成两位评价者提取了相关系数、决定系数、斜率、效应估计或替代标志物与临床结果之间荟萃回归分析的结果。主要结果和措施相关系数或决定系数，在报告时被归类为高强度（r≥ 0.85 或右2≥0.72）；主要研究结果另有总结。结果 FDA 表中列出了 37 个替代标志物，这些标志物在 32 种独特的非肿瘤性慢性疾病的临床试验中用作主要终点。对于 22 种 (59%) 替代标记（21 种慢性疾病），未发现合格的荟萃分析。对于 15 个 (41%) 替代标志物（14 种慢性病），至少确定了 1 项荟萃分析，总共 54 项（每个替代标志物的中位数为 2.5；IQR，1.3-6.0）；其中，荟萃分析的试验和患者数量中位数分别为 18.5（IQR，12.0-43.0）和 90 056（IQR，20 109-170 014）。 54 项荟萃分析报告了 109 个独特的替代标志物 - 临床结果对：59 个 (54%) 报告了至少 1 个r或者右2，其中 10 个 (17%) 报告至少 1 个分类为高强度，而 50 个 (46%) 仅报告斜率、效应估计或元回归分析结果，其中 26 个 (52%) 报告至少 1 个统计数据结论和相关性大多数在临床试验中用作主要终点以支持 FDA 批准治疗非肿瘤性慢性疾病的药物的替代标志物缺乏已发表的荟萃分析中与临床结果相关的高强度证据。