Importance: The American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) have independently published value frameworks. To date, whether the clinical benefit scoring algorithms from these framework were intended to measure absolute or relative survival benefit remains unclear.
Objective: To empirically examine the measurement characteristics of these frameworks by comparing their survival efficacy components (ASCO clinical benefit score [CBS] and ESMO preliminary magnitude of clinical benefit grade [PMCBG]) with established measures of absolute (median survival difference and restricted mean survival time [RMST] difference) and relative (hazard ratios [HRs]) survival benefit.
Data sources: The US Food and Drug Administration (FDA)'s Hematology and Oncology Approvals and Safety Notifications database was retrospectively reviewed to identify phase 3 randomized controlled trials (RCTs) cited for clinical efficacy evidence in oncology drug approvals from January 1, 2006, through December 31, 2017.
Study selection: Two reviewers searched the database for initial trials cited for approval. Phase 3 trials with overall survival, progression-free survival, and/or time to progression as their primary or coprimary end points were included. Notifications for noncancer indications or presenting label changes and trials that did not report HRs for the required end points and/or did not publish survival curves with number-at-risk data were excluded. Of 269 notifications initially identified, 107 met the selection criteria.
Data extraction and synthesis: Sensitivity analyses were conducted by calculating the scores using (1) the framework-defined end point, including tail-of-curve bonus points (ASCO) or long-term plateau adjustments (ESMO) (framework-defined end point plus tail-of-curve bonus), (2) overall survival data only, and (3) progression-free survival data only. For primary and sensitivity analyses, Spearman correlation coefficients were calculated to examine the relationships between (1) ASCO-CBS or ESMO-PMCBG and RMST difference, (2) ASCO-CBS or ESMO-PMCBG and median survival difference, and (3) ASCO-CBS or ESMO-PMCBG and HR. Data were analyzed from January 7 through April 30, 2018.
Main outcomes and measures: In the primary analysis, ASCO-CBSs and ESMO-PMCBGs were calculated for the included trials using the framework-defined end point.
Results: Compared with measures of absolute survival benefit, ESMO-PMCBGs showed low to moderate correlations with RMST difference (ρ = 0.44) and moderate to high correlations with median survival difference (ρ = 0.64). ASCO-CBSs showed low to moderate correlations with both measures of absolute benefit (ρ = 0.43 for RMST difference; ρ = 0.44 for median survival). Compared with a relative measure of survival (HRs), ESMO-PMCBGs showed a low correlation (ρ = 0.47) and ASCO-CBSs showed a higher correlation (ρ = 0.76).
Conclusions and relevance: Neither framework consistently performed as an absolute measure of survival benefit. The incorporation of a direct measure of absolute clinical benefit, such as RMST difference, into the survival efficacy components of their algorithms should be considered.