Accelerated approval (AA) regulations were established by the US FDA to improve access to drugs for life-threatening diseases. Pharmaceutical companies must confirm efficacy in post-approval trials as predicted by the surrogate endpoint. 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 confirmatory RCTs supporting conversions from AA to regular approval (RA) and their association with ESMO defined thresholds for meaningful clinical benefit.
We searched the Drugs@FDA website to identify anticancer drugs that had received AA from January 2000 to December 2016 and to assess the status regarding conversion to full approval. Drug labels and reports of post-approval trials supporting conversion to RA were reviewed and study characteristics, efficacy, toxicity and quality of life outcomes were collected. For RCTs ESMO-MCBS grades were applied. Meaningful clinical benefit was defined as a grade of A or B for trials of curative intent and 4 or 5 for those of palliative intent.
Of the 37 new indications granted AA, 17 (46%) were subsequently converted to RA based on 17 RCTs. The median time between AA and RA of oncology drugs was 3.1 years (range = 1.02–7.6). Two confirmatory trials (5%) failed to show clinical benefit. Confirmatory trials were still not completed for 18 (49%) indications; among these, the three longest intervals since AA up to the December 2016 cut-off date were 6.6, 5.9 and 2.3 years. ESMO-MCBS could be applied to 16 RCTs and 11 (69%) met the ESMO-MCBS clinically meaningful benefit threshold (100% of adjuvant trials and 58% of palliative trials).
Two thirds of RCTs supporting FDA conversion from accelerated to full approval of anticancer therapies meet the threshold for clinically meaningful benefit. AA indications should not be on the market for unacceptably prolonged intervals before confirmatory trials are completed.
Clinical trial identification
Legal entity responsible for the study
Hospital de la Santa Creu i Sant Pau
All authors have declared no conflicts of interest.