{"entity":{"id":"paper-prasad-surrogate-endpoints-jama-im-2015","kind":"paper","name":"Prasad: most surrogate endpoints in cancer trials correlate poorly with survival","aka":[],"tldr":"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.","summary":"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.\n\nUsing 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.\n\nThe 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.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1001/jamainternmed.2015.2829"},{"label":"Kim and Prasad: FDA approvals on surrogates (2015)","url":"https://doi.org/10.1001/jamainternmed.2015.5868"}],"tags":[],"related":["idea-tr1-surrogate-validation-programme","idea-tr1-power-for-meaningful-benefit","idea-prev-mced-stage-endpoint-surrogate","idea-tr1-win-ratio-net-benefit-endpoint"],"cancers":[],"sections":["drug-discovery"],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["pfs","os","orr","accelerated-approval","hazard-ratio","recist"],"trials":[],"people":[],"bottlenecks":["b-trial-design","b-regulatory-fragmentation","b-drug-pricing","b-patient-voice"],"keyPapers":[],"journals":["jama-internal-medicine"],"dependsOn":[],"notes":[],"journal":"JAMA Internal Medicine","year":2015,"doi":"10.1001/jamainternmed.2015.2829","pmid":"26098871","authors":"Prasad V, Kim C, Burotto M, Vandross A","paperType":"meta-analysis","findings":["36 trial-level meta-analyses covering 65 surrogate-OS associations reviewed","52% of surrogate-survival correlations were low (r below 0.7), 25% medium, 23% high","Response rate and PFS in the metastatic setting were the weakest surrogates","Companion analysis: of 36 approvals on surrogates (2008-2012), 5 later showed an OS benefit, 18 failed to or were not tested, and 13 remained unknown"],"whatItMeans":"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.","caveats":["Trial-level correlation is only one way to validate a surrogate; some settings (adjuvant DFS in colon cancer) have well-validated surrogates","Low correlation may reflect crossover and post-progression therapy diluting the OS signal rather than a useless surrogate","The review depended on published meta-analyses and their heterogeneous methods","PFS can be a meaningful endpoint in itself when progression is symptomatic and treatment is tolerable"],"changedPractice":false},"route":"/key-papers/paper-prasad-surrogate-endpoints-jama-im-2015/","neighbours":{"idea":[{"id":"idea-tr1-surrogate-validation-programme","kind":"idea","name":"An independent programme that validates surrogate endpoints, setting by setting","route":"/ideas/idea-tr1-surrogate-validation-programme/"},{"id":"idea-prev-mced-stage-endpoint-surrogate","kind":"idea","name":"Let MCED trials read out on late-stage incidence, with mortality follow-up mandated","route":"/ideas/idea-prev-mced-stage-endpoint-surrogate/"},{"id":"idea-tr1-power-for-meaningful-benefit","kind":"idea","name":"Power trials to detect a benefit patients would value, not the smallest detectable one","route":"/ideas/idea-tr1-power-for-meaningful-benefit/"},{"id":"idea-tr1-win-ratio-net-benefit-endpoint","kind":"idea","name":"Win-ratio endpoints that weigh survival, toxicity and quality of life together","route":"/ideas/idea-tr1-win-ratio-net-benefit-endpoint/"}],"section":[{"id":"drug-discovery","kind":"section","name":"Drug Discovery Platforms","route":"/fronts/drug-discovery/"}],"term":[{"id":"accelerated-approval","kind":"term","name":"Accelerated approval","route":"/terms/accelerated-approval/"},{"id":"hazard-ratio","kind":"term","name":"Hazard ratio (HR)","route":"/terms/hazard-ratio/"},{"id":"orr","kind":"term","name":"Objective response rate (ORR)","route":"/terms/orr/"},{"id":"os","kind":"term","name":"Overall survival (OS)","route":"/terms/os/"},{"id":"pfs","kind":"term","name":"Progression-free survival (PFS)","route":"/terms/pfs/"},{"id":"recist","kind":"term","name":"RECIST","route":"/terms/recist/"}],"bottleneck":[{"id":"b-patient-voice","kind":"bottleneck","name":"Patients lack understanding, navigation and agency","route":"/bottlenecks/b-patient-voice/"},{"id":"b-drug-pricing","kind":"bottleneck","name":"Prices and value","route":"/bottlenecks/b-drug-pricing/"},{"id":"b-regulatory-fragmentation","kind":"bottleneck","name":"Regulatory divergence between regions","route":"/bottlenecks/b-regulatory-fragmentation/"},{"id":"b-trial-design","kind":"bottleneck","name":"Trial design, endpoints and cost","route":"/bottlenecks/b-trial-design/"}],"journal":[{"id":"jama-internal-medicine","kind":"journal","name":"JAMA Internal Medicine","route":"/journals/jama-internal-medicine/"}],"person":[{"id":"christopher-booth","kind":"person","name":"Christopher M. Booth","route":"/people/christopher-booth/"},{"id":"ian-tannock","kind":"person","name":"Ian F. Tannock","route":"/people/ian-tannock/"}]}}