In order to obtain regulatory approval, drug manufacturers must robustly demonstrate a positive benefit:risk balance. Large, multicentre, randomised Phase III trials that demonstrate statistically significant comparative benefits according to a pre-specified primary endpoint are regarded as the gold standard basis for marketing authorization. Some products have secured marketing authorizations despite not showing statistical significance in the primary endpoint of their phase III trials. This research evaluates how commercially viable products with a ‘failed’ phase III trial have fared in reimbursement assessment by major payers. The EMA website was screened for therapies that had been authorized based on a Phase III trial readout which failed to meet its primary endpoint. HTA decisions from EU5 payers (NICE, HAS, G-BA, AEMPS, AIFA) were then screened for these therapies and key data extracted (to 08/01/2020). Atezolizumab, ataluren and pembrolizumab obtained EMA authorisation in second-line (2L) urothelial carcinoma (2017), DMD (2014) and 2L HNSCC (2018), respectively, despite not showing statistical significance in the primary endpoint of their phase III trials. Ataluren was approved based on a Phase II trial under a conditional marketing authorization, whilst atezolizumab and pembrolizumab were approved in a different population to the pre-specified primary endpoint. In the case of pembrolizumab, it was approved in a subset of the trial population where a significant effect was demonstrated. 10 HTA appraisals were identified for the three products (3, 5 and 2 for atezolizumab, ataluren, and pembrolizumab, respectively). 3/3 (100%), 3/5 (60%), and 0/2 (0%) of appraisals were positive and recommended reimbursement for atezolizumab, ataluren, and pembrolizumab, respectively. Despite failed primary endpoints in phase III trials, some therapies have secured regulatory approvals and translated these into successful payer reimbursement.