As part of the National Institute for Health and Clinical Excellence (NICE) single technology appraisal (STA) process, the manufacturer of febuxostat (Adenuric®; Ipsen, UK) was invited to submit evidence for the clinical and cost effectiveness of febuxostat for the management of hyperuricaemia in patients with gout. The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield were commissioned to act as the independent Evidence Review Group (ERG). This article provides details of the company's initial submission, the ERG's clarification questions and the ERG report submitted to NICE. The decision made by NICE is provided alongside a brief comment on additional results produced by a substantially different model, which were presented by the manufacturer after the production of the appraisal consultation document. The ERG produced a critical review of the evidence for the clinical evidence and cost effectiveness of the technology based upon the manufacturer's submission to NICE. The clinical evidence was derived from two head-to-head, phase III, multi-arm, randomized, double blind, controlled trials comparing the efficacy and safety of febuxostat with fixed-dose allopurinol (300/100 mg/day) in patients with hyperuricaemia and gout. The ERG considered that the trials were of reasonable methodological quality and measured a clinically relevant range of outcomes. Although a simple pooled analysis of the individual patient-level data from the two trials was undertaken, the statistical approach for combining the data was considered inappropriate by the ERG as it failed to preserve randomization and introduced bias and confounding. There was substantial uncertainty in the relationships reported by the manufacturer regarding serum uric acid levels and the incidence of gout flares and underlying patient utility. The mathematical model developed was flawed and was not corrected despite ERG comments. It focused only on patients receiving febuxostat (80 mg/day titrated to 120 mg/day if necessary) with fixed-dose allopurinol (300/100 mg/day). Sequential treatment was not modeled, nor was titrating allopurinol to 900 mg/day, which is regarded as best practice. Numerous other errors were identified, which included the uncertain price of febuxostat being sampled within the probabilistic sensitivity analyses. Supplementary exploratory modelling addressing the position of febuxostat where patients were intolerant or contraindicated to allopurinol was provided to the NICE Appraisal Committee following the release of the appraisal consultation document. The NICE Appraisal Committee concluded that febuxostat be recommended as an option for the management of chronic hyperuricaemia in gout only for people who are intolerant to allopurinol or for whom allopurinol is contraindicated.
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