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Original Investigation | Health Care Reform

The Strength of Association Between Surrogate End Points and Survival in Oncology A Systematic Review of Trial-Level Meta-analyses

Vinay Prasad, MD, MPH1; Chul Kim, MD, MPH1; Mauricio Burotto, MD1; Andrae Vandross, MD2
[+] Author Affiliations
1Medical Oncology Service, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
2Division of Medical Oncology, University of California, Los Angeles
JAMA Intern Med. 2015;175(8):1389-1398. doi:10.1001/jamainternmed.2015.2829.
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Importance  The strength of association between surrogate end points and survival in oncology is important to understand because surrogate end points are frequently used in oncology clinical trials, supporting US Food and Drug Administration approvals and National Comprehensive Cancer Network guideline recommendations.

Objective  To identify and evaluate trial-level meta-analyses of randomized clinical trials quantifying the association between a surrogate end point and overall survival in medical oncology. Trial-level correlations test whether treatments that improve the surrogate end point also improve the final end point and are widely considered the strongest evidence to validate a surrogate end point.

Evidence Review  Our literature search was built on earlier reported data sets and updated with Google Scholar and MEDLINE searches conducted on December 26, 2014. For MEDLINE, search terms included (“regression” or “correlation”) and “surrogate” and “end point [or endpoint]” and (“oncology” or “cancer”). For Google scholar, search terms included (“regression” or “correlation”) and “surrogate end point [or endpoint]” and “overall survival” and “trial level.” A total of 108 abstracts were retrieved, and 62 articles were read in full in addition to articles identified through prior reviews.

Findings  We found 36 articles in which 65 specific correlations between a surrogate end point and survival were identified. Surrogate end points were studied in the neoadjuvant, adjuvant, locally advanced, and metastatic settings. The most common sources for trials included in the 36 articles were systematic reviews of the published literature (10 of 36; 28%), and published literature and meeting abstracts (14 of 36; 39%). Four meta-analyses (11%) used a convenience sample, and only 5 studies (14%) attempted to include unpublished trials by surveying clinical trial registries. Among these 5 studies, only 352 of 684 eligible trials (51.1%) were included in the analyses. More than half of reported correlations (34 of 65; 52%) were of low strength (r ≤ 0.7). Approximately a quarter (16 of 65; 25%) were of medium strength (r > 0.7 to r < 0.85), and 15 of 65 (23%) were highly correlated (r ≥ 0.85) with survival.

Conclusions and Relevance  Most trial-level validation studies of surrogate end points in oncology find low correlations with survival. All validation studies use only a subset of available trials. The evidence supporting the use of surrogate end points in oncology is limited.

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Figure 1.
Hierarchy of Evidence for Surrogate End Point and Overall Survival Association
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Figure 2.
Distribution of Data Sources Used in the Evaluated Surrogacy End Point Trials
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Figure 3.
Correlations by Treatment Setting

We scored strength of trial-level correlation according to a modification to surrogate criteria proposed by the Institute of Quality and Efficiency in Health Care34: low correlation (r ≤ 0.7), medium strength correlation (r > 0.7 to r < 0.85), and high correlation (r ≥ 0.85).

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