Clinical trials supporting approval for new drugs often evaluate surrogate endpoints, and data on meaningful outcomes like OS or QoL may not be available. Here, we evaluated changes in the magnitude of clinical benefit, OS and QoL after approval.
We examined data on pivotal trials supporting FDA accelerated (AA) and regular (RA) cancer drug approvals between January 2006, and December 2015. For AA drugs, if conversion to RA was granted, only the confirmatory trial was analysed. To determine any new evidence on OS and QoL in the postmarketing period (PMP) we performed a systematic search of Pubmed and ClinicalTrials.gov. European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) grades were applied for trials at approval and in the PMP. Substantial 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.
We identified 96 pivotal trials supporting the approval of 47 drugs for 94 solid tumour indications. Of these indications, 22 (23%) were granted AA and 21 (22%) were converted to RA. At time of approval, 45 (48%) trials showed improved OS, 15 (16%) improved QoL and 33 (34%) had substantial clinical benefit. With a median PMP of 3.7 years, 50 (52%) trials reported OS data and 27 (28%) on QoL. Of these, 48 could be graded by the ESMO-MCBS. Of the updated 51 trials approved based on surrogate endpoints, only 7 (14%) showed an improvement in OS. In advanced disease, out of 74 trials for which there was no evidence on QoL at the time of approval, 12 (16%) showed improved QoL subsequently. Updated results led to changes in clinical benefit in 11 trials (10 upgrades, 1 downgrade) with 30 (62%) showing substantial clinical benefit. Among all trials, 52 (54%) showed improved OS, 27 (28%) improved QoL and 42 (44%) met the threshold for substantial clinical benefit.
After 3.7 years of post-marketing time, 54% of FDA approved cancer drugs showed statistically significant improvement in OS and 28% in QoL. Less than a half of trials supporting FDA approval met the threshold for substantial clinical benefit using ESMO-MCBS.
The authors.
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E. Amir: Speaker Bureau / Expert testimony: Genentech/Roche; Advisory / Consultancy: Apobiologix; Advisory / Consultancy: Agendia; Advisory / Consultancy: Myriad Genetics. All other authors have declared no conflicts of interest.