A systematic review of trial-level meta-analyses measuring the strength of association between surrogate end-points and overall survival in oncology

Haslam, Alyson; Hey, Spencer Phillips; Gill, Jennifer; Prasad, Vinay

doi:10.1016/j.ejca.2018.11.012

Cited by 145 publications

(139 citation statements)

References 86 publications

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“…They generally have the primary endpoint of objective response rate, which captures the number of patients who have had a minimum pre-defined reduction in tumour size. Response rate allows the pooling of responses across different tumour histologies but is a surrogate outcome for progression-free survival and overall survival, which are typically preferred for HTA 2. When only response data are available, assumptions need to be made about the drug’s clinical benefit, which increases the uncertainty in the HTA.…”

Section: Clinical Evidence For Histology Independent Cancer Drugsmentioning

confidence: 99%

How should we assess the clinical and cost effectiveness of histology independent cancer drugs?

Cooper

Bouvy

Baker

et al. 2020

BMJ

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Section: Clinical Evidence For Histology Independent Cancer Drugsmentioning

confidence: 99%

How should we assess the clinical and cost effectiveness of histology independent cancer drugs?

Cooper

Bouvy

Baker

et al. 2020

BMJ

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“…5 Another review of trial-level meta-analyses in 2019 showed a low to moderate correlation between surrogate measures and OS. 8 Licensing agencies such as the European Medicines Agency (EMA) focus on a drug's benefit-risk profile for granting marketing authorizations. 1,4 Nevertheless, health technology assessment (HTA) bodies, such as the National Institute of Health and Care Excellence (NICE) in England and the Canadian Agency for Drugs and Technologies in Health (CADTH) in Canada, are concerned with long-term comparative clinical effectiveness and costeffectiveness in addition to efficacy and safety.…”

Section: Introductionmentioning

confidence: 99%

Association Between the Use of Surrogate Measures in Pivotal Trials and Health Technology Assessment Decisions: A Retrospective Analysis of NICE and CADTH Reviews of Cancer Drugs

et al. 2020

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Methods: Cancer drug approvals from 2012 to 2016 were categorized by demonstrating benefit on overall survival (OS), progression-free survival, disease response, or having no comparator. Approvals were analyzed by benefit category and health technology assessment recommendation. The association between benefit (surrogate vs OS) and recommending a drug was examined using descriptive statistics and linear probability models controlling for unmet need, orphan designation, and costeffectiveness.Results: Of 42 cancer indications that NICE recommended, 15 (36%) demonstrated OS benefit. Cancer indications with OS benefit were less likely to receive a recommendation from NICE than those without (P = .04). In linear probability models, availability of OS benefit was no longer associated with a recommendation from NICE (P = .32). Cost-effective cancer drugs had a 55.6% (95% CI: 38.9%-72.3%) higher probability of receiving a recommendation from NICE than those that were not. In Canada, 15 of 37 (41%) cancer indications that were recommended showed OS benefit. There was no detectable association between surrogate measures and CADTH recommendations based on descriptive statistics (P = .62) or in linear probability models (P = .73).Conclusion: When cost-effectiveness was considered, pivotal trial endpoints were not associated with NICE recommendations. Pivotal trial endpoints, unmet need, orphan status, and cost-effectiveness did not explain CADTH recommendations.

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“…16 It is worth noting that responses observed even in RCTs are usually poor surrogates for the true clinical benefits-improved survival or quality of life resulting from use of cancer drugs. 17 For this reason, RCTs usually use RR or DoR only as a secondary endpoint, and it is unusual to see a phase III RCT in oncology with a primary endpoint of RR or DoR. Our analysis also showed that the RRs and DoRs derived from non-RCTs have weak and nonsignificant associations with OS derived from RCTs, the ultimate marker of clinical benefit.…”

Section: Discussionmentioning

confidence: 62%

Response Rates and Durations of Response for Biomarker-Based Cancer Drugs in Nonrandomized Versus Randomized Trials

Gyawali

D’Andrea

Franklin

et al. 2020

Journal of the National Comprehensive Cancer Network

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Background: Many new targeted cancer drugs have received FDA approval based on durable responses in nonrandomized controlled trials (non-RCTs). The goal of this study was to evaluate whether the response rates (RRs) and durations of response (DoRs) of targeted cancer drugs observed in non-RCTs are consistent when these drugs are tested in RCTs. Methods: We used the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling to identify cancer drugs that were approved based on changes in biomarker endpoints through December 2017. We then identified the non-RCTs and RCTs for these drugs for the given indications and extracted the RRs and DoRs. We compared the RRs and median DoR in non-RCTs versus RCTs using the ratio of RRs and the ratio of DoRs, defined as the RRs (or DoRs) in non-RCTs divided by the RRs (or DoRs) in RCTs. The ratio of RRs or DoRs was pooled across the trial pairs using random-effects meta-analysis. Results: Of the 21 drug–indication pairs selected, both non-RCTs and RCTs were available for 19. The RRs and DoRs in non-RCTs were greater than those in RCTs in 63% and 87% of cases, respectively. The pooled ratio of RRs was 1.06 (95% CI, 0.95–1.20), and the pooled ratio of DoRs was 1.17 (95% CI, 1.03–1.33). RRs and DoRs derived from non-RCTs were also poor surrogates for overall survival derived from RCTs. Conclusions: The RRs were not different between non-RCTs and RCTs of cancer drugs approved based on changes to a biomarker, but the DoRs in non-RCTs were significantly higher than in RCTs. Caution must be exercised when approving or prescribing targeted drugs based on data on durable responses derived from non-RCTs, because the responses could be overestimates and poor predictors of survival benefit.

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A systematic review of trial-level meta-analyses measuring the strength of association between surrogate end-points and overall survival in oncology

Cited by 145 publications

References 86 publications

How should we assess the clinical and cost effectiveness of histology independent cancer drugs?

How should we assess the clinical and cost effectiveness of histology independent cancer drugs?

Association Between the Use of Surrogate Measures in Pivotal Trials and Health Technology Assessment Decisions: A Retrospective Analysis of NICE and CADTH Reviews of Cancer Drugs

Response Rates and Durations of Response for Biomarker-Based Cancer Drugs in Nonrandomized Versus Randomized Trials

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