本文由小咖机器人翻译整理

期刊来源：JAMA

原文链接：https://doi.org/10.1001/jama.2024.4175

摘要内容如下：

重要性

在支持药物批准的临床试验中，替代标记物越来越多地被用作主要终点。

目的

系统总结来自临床试验的荟萃分析、系统评价和荟萃分析以及汇总分析（以下简称荟萃分析）的证据，以检验使用替代标记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强度。

数据源

美国食品和药物管理局（FDA）成人代孕终末表和MEDLINE从开始到2023年3月19日。

研究选择

三位评价者选择了临床试验的Meta分析；排除观察性研究的荟萃分析。

数据提取与合成

两位评价者从替代标记物和临床结果之间的荟萃回归分析中提取相关系数、决定系数、斜率、效应估计或结果。

主要成果和措施

当报告时，相关系数或决定系数被归类为高强度（R≥0.85或R2≥0.72）；对主要研究结果进行了总结。

结果

FDA的表格中列出了37种替代标记物，并在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个（59%）替代指标（21种慢性疾病），未发现合格的荟萃分析。对于15个（41%）替代标记物（14种慢性疾病），至少确定了1个荟萃分析，总共54个（每个替代标记物的中位数为2.5；IQR，1.3-6.0）；其中，试验和荟萃分析患者的中位数分别为18.5（IQR，12.0-43.0）和90056（IQR，20109-170014）。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R2，其中10个（17%）报告了至少1个分类为高强度，而50个（46%）仅报告了斜率、效应估计或荟萃回归分析结果，其中26个（52%）报告了至少1个具有统计学意义的结果。

结论和相关性

大多数替代标记物在临床试验中被用作主要终点，以支持FDA批准治疗非肿瘤性慢性疾病的药物，但缺乏已发表的荟萃分析中与临床结果相关的高强度证据。

英文原文如下：

Abstracts

Importance  Surrogate markers are increasingly used as primary end points in clinical trials supporting drug approvals.

Objective  To 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 sources  The Food and Drug Administration (FDA) Adult Surrogate Endpoint Table and MEDLINE from inception to March 19, 2023.

Study Selection  Three reviewers selected meta-analyses of clinical trials; meta-analyses of observational studies were excluded.

Data Extraction and Synthesis  Two 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 Measures  Correlation coefficient or coefficient of determination, when reported, was classified as high strength (r ≥ 0.85 or R2 ≥ 0.72); primary findings were otherwise summarized.

Results  Thirty-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 Relevance  Most 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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