{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T04:09:03Z","timestamp":1793938143620,"version":"4.8.0"},"reference-count":40,"publisher":"American Medical Association (AMA)","issue":"19","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"published-print":{"date-parts":[[2024,5,21]]},"abstract":"\n Importance<\/jats:title>\n Surrogate markers are increasingly used as primary end points in clinical trials supporting drug approvals.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Data sources<\/jats:title>\n The Food and Drug Administration (FDA) Adult Surrogate Endpoint Table and MEDLINE from inception to March 19, 2023.<\/jats:p>\n <\/jats:sec>\n \n Study Selection<\/jats:title>\n Three reviewers selected meta-analyses of clinical trials; meta-analyses of observational studies were excluded.<\/jats:p>\n <\/jats:sec>\n \n Data Extraction and Synthesis<\/jats:title>\n Two reviewers extracted correlation coefficients, coefficients of determination, slopes, effect estimates, or results from meta-regression analyses between surrogate markers and clinical outcomes.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n Correlation coefficient or coefficient of determination, when reported, was classified as high strength (\n r<\/jats:italic>\n \u2009\u2265\u20090.85 or\n R<\/jats:italic>\n 2<\/jats:sup>\n \u2009\u2265\u20090.72); primary findings were otherwise summarized.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Thirty-seven surrogate markers listed in FDA\u2019s 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\u202f056 (IQR, 20\u202f109-170\u202f014), respectively. The 54 meta-analyses reported 109 unique surrogate marker\u2013clinical outcome pairs: 59 (54%) reported at least 1\n r<\/jats:italic>\n or\n R<\/jats:italic>\n 2<\/jats:sup>\n , 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.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jama.2024.4175","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T11:32:18Z","timestamp":1713785538000},"page":"1646","source":"Crossref","is-referenced-by-count":54,"title":["Associations 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