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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.

Importance: Although nonfatal myocardial infarction (MI) is associated with an increased risk of mortality, evidence validating nonfatal MI as a surrogate end point for all-cause or cardiovascular (CV) mortality is lacking., Objective: To examine whether nonfatal MI may be a surrogate for all-cause or CV mortality in patients with or at risk for coronary artery disease., Data Sources: In this meta-analysis, PubMed was searched from inception until December 31, 2020, for randomized clinical trials of interventions to treat or prevent coronary artery disease reporting mortality and nonfatal MI published in 3 leading journals., Study Selection: Randomized clinical trials including at least 1000 patients with 24 months of follow-up., Data Extraction and Synthesis: Trial-level correlations between nonfatal MI and all-cause or CV mortality were assessed for surrogacy using the coefficient of determination (R2). The criterion for surrogacy was set at 0.8. Subgroup analyses based on study subject (primary prevention, secondary prevention, mixed primary and secondary prevention, and revascularization), era of trial (before 2000, 2000-2009, and 2010 and after), and follow-up duration (2.0-3.9, 4.0-5.9, and ≥6.0 years) were performed., Main Outcomes and Measures: All-cause or CV mortality and nonfatal MI., Results: A total of 144 articles randomizing 1 211 897 patients met the criteria for inclusion. Nonfatal MI did not meet the threshold for surrogacy for all-cause (R2 = 0.02; 95% CI, 0.00-0.08) or CV (R2 = 0.11; 95% CI, 0.02-0.27) mortality. Nonfatal MI was not a surrogate for all-cause mortality in primary (R2 = 0.01; 95% CI, 0.001-0.26), secondary (R2 = 0.03; 95% CI, 0.00-0.20), mixed primary and secondary prevention (R2 = 0.001; 95% CI, 0.00-0.08), or revascularization trials (R2 = 0.21; 95% CI, 0.002-0.50). For trials enrolling patients before 2000 (R2 = 0.22; 95% CI, 0.08-0.36), between 2000 and 2009 (R2 = 0.02; 95% CI, 0.00-0.17), and from 2010 and after (R2 = 0.01; 95% CI, 0.00-0.09), nonfatal MI was not a surrogate for all-cause mortality. Nonfatal MI was not a surrogate for all-cause mortality in randomized clinical trials with 2.0 to 3.9 (R2 = 0.004; 95% CI, 0.00-0.08), 4.0 to 5.9 (R2 = 0.06; 95% CI, 0.001-0.16), or 6.0 or more years of follow-up (R2 = 0.30; 95% CI, 0.01-0.55)., Conclusions and Relevance: The findings of this meta-analysis do not appear to establish nonfatal MI as a surrogate for all-cause or CV mortality in randomized clinical trials of interventions to treat or prevent coronary artery disease.