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A systematic review of 36 trial-level meta-analyses found that in over half the surrogate endpoint (response rate, progression-free survival) had a low correlation with overall survival, and only about a quarter showed a strong correlation.
Prasad and colleagues searched for trial-level meta-analyses that quantified the correlation between a surrogate endpoint and overall survival across randomised oncology trials. They identified 36 articles covering 65 surrogate-survival associations in many tumour types and settings.
Using a conventional threshold, 52% of reported correlations were low (r below 0.7), 25% medium (0.7 to 0.85) and 23% high (0.85 or more). Correlations were weakest in the metastatic setting and for response rate. A companion analysis by the same group (Kim and Prasad, JAMA Internal Medicine 2015) showed that of 54 FDA cancer drug approvals in 2008-2012, 36 were based on surrogates, and after a median 4.4 years only 5 had demonstrated an overall survival benefit.
The work catalysed the debate over accelerated approval, the FDA's 2023-2025 reforms requiring confirmatory trials to be under way at approval, and the growing use of quality-of-life and patient-reported endpoints.
A drug that shrinks tumours or delays progression on scans has not necessarily been shown to help patients live longer or better. Patients and clinicians should ask what the endpoint was; regulators should insist on timely confirmatory trials; and trialists should validate surrogates before relying on them.
Shares Accelerated approval, Progression-free survival (PFS), Regulatory divergence between regions, Overall survival (OS).
Shares RECIST, Objective response rate (ORR), Accelerated approval, Progression-free survival (PFS).
Shares RECIST, Hazard ratio (HR), Progression-free survival (PFS), Trial design, endpoints and cost.
Shares Patients lack understanding, navigation and agency, Progression-free survival (PFS), Overall survival (OS), Trial design, endpoints and cost.
Shares Power trials to detect a benefit patients would value, not the smallest detectable one, Win-ratio endpoints that weigh survival, toxicity and quality of life together.
Shares JAMA Internal Medicine, Objective response rate (ORR), Accelerated approval, Progression-free survival (PFS).
Shares Patients lack understanding, navigation and agency, Progression-free survival (PFS), Overall survival (OS).
Shares RECIST, Objective response rate (ORR), Progression-free survival (PFS).