Magnitude of clinical benefit of randomized controlled trials supporting US Food and Drug Administration approval of drugs for solid tumours

Abstract

Background: The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a validated and reproducible tool to assess the magnitude of clinical benefit from drugs for solid tumors. Here, we evaluate characteristics and outcomes of clinical trials supporting approval by the FDA and their association with ESMO-MCBS. Method(s): We searched the Drugs@FDA website for applications of anticancer drugs from January 2006 to December 2016. Drug labels and reports of registration trials were reviewed and study characteristics, efficacy, toxicity and quality of life outcomes as well as regulatory pathways were collected. For randomized controlled trials (RCTs) ESMO-MCBS grades were applied. Meaningful clinical benefit was defined as a grade of A or B for trials of neo/adjuvant intent and 4 or 5 for those of palliative intent. Comparisons between groups were assessed using Logistic regression and the Mann Whitney U test. Result(s): We identified 137 studies; 109 (80%) of which were RCTs. These led to the approval of 63 individual drugs for 118 licensed indications. Among the 105 RCTs for which the ESMO-MCBS could be applied, 7 (6%) were in the neo/adjuvant setting and 98 (94%) in the palliative setting. Only 46 (44%) met the ESMO-MCBS clinically meaningful benefit threshold (100% of neo/adjuvant trials and 41% of palliative trials). In multivariable analysis of palliative therapy trials, meaningful ESMO-MCBS grades were associated with phase III trials (compared to phase II; OR 38.45, P=0.004), those with overall survival as their primary endpoint (compared to intermediate endpoints; OR 8.28, P=0.001) and trials of targeted drugs with companion diagnostics (OR 11.62, P<0.001). Over time, there has been an increase in the number of trials meeting the ESMO-MCBS threshold (33% in 2006 vs. 67% in 2016, P for trend = 0.04). There was an insufficient number of neo/adjuvant studies to perform statistical analysis. Conclusion(s): In patients with advanced solid tumours, fewer than half of RCTs supporting FDA approval meet the threshold for clinically meaningful benefit using validated scales.