Detailed statistical assessment of the characteristics of the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) threshold rules

Background The European Society for Medical Oncology (ESMO) has developed the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS), a tool to assess the magnitude of clinical benefit from new cancer therapies. Grading is guided by a dual rule comparing the relative benefit (RB) and the absolute benefit (AB) achieved by the therapy to prespecified threshold values. The ESMO-MCBS v1.0 dual rule evaluates the RB of an experimental treatment based on the lower limit of the 95% CI (LL95% CI) for the hazard ratio (HR) along with an AB threshold. This dual rule addresses two goals: inclusiveness: not unfairly penalising experimental treatments from trials designed with adequate power targeting clinically meaningful relative benefit; and discernment: penalising trials designed to detect a small inconsequential benefit. Methods Based on 50 000 simulations of plausible trial scenarios, the sensitivity and specificity of the LL95% CI rule and the ESMO-MCBS dual rule, the robustness of their characteristics for reasonable power and range of targeted and true HRs, are examined. The per cent acceptance of maximal preliminary grade is compared with other dual rules based on point estimate (PE) thresholds for RB. Results For particularly small or particularly large studies, the observed benefit needs to be relatively big for the ESMO-MCBS dual rule to be satisfied and the maximal grade awarded. Compared with approaches that evaluate RB using the PE thresholds, simulations demonstrate that the MCBS approach better exhibits the desired behaviour achieving the goals of both inclusiveness and discernment. Conclusions RB assessment using the LL95% CI for HR rather than a PE threshold has two advantages: it diminishes the probability of excluding big benefit positive studies from achieving due credit and, when combined with the AB assessment, it increases the probability of downgrading a trial with a statistically significant but clinically insignificant observed benefit