OBJECTIVES: To identify clinical evidence supporting FIX replacement therapy in HB and assess its applicability to health economic modelling of comparative cost-effectiveness. METHODS: A SLR was initiated in April 2014 and updated in November 2015. Searches were carried out in MEDLINE, EMBASE, The Cochrane Library and CINAHL and supplemented with hand-searching of conference proceedings. Existing SLRs, randomised controlled trials (RCTs), prospective non-RCTs and observational studies of patients with moderate/severe HB treated with plasma-derived or recombinant FIX products were included. RESULTS: A total of 73 studies were identified, reported in 98 papers. The majority of studies were non-RCTs with only 1 RCT investigating the comparative efficacy of different recombinant FIX products identified. Across all clinical trials, 44 investigated recombinant FIX products with significant variation observed in regard to study design, sample size (5 to 99 patients) and study duration (2 days to 34 months). The most common and consistently reported outcome was pharmacokinetic (PK) data with a clear distinction in the half-life of newer recombinant FIX products, extending steady state half-life to over 100 hours in adults. Efficacy outcomes such as annualised bleeding rates (ABR) and target joints were less common, reported in only 16 and 3 of the recombinant FIX trials, respectively, and no trials reported longer-term outcomes. Bleeding episodes were self-reported by patients across trials but definitions of efficacy outcomes based on bleeding episodes were inconsistent. Health-related quality of life (HRQoL) data were reported in 5 studies in total but variance was observed in HRQoL tools adopted. CONCLUSIONS: A paucity of comparable, objective evidence for efficacy and HRQoL outcomes poses a significant hurdle in assessing the economic impact associated with the extended half-life of recombinant FIX products. The economic impact of this new paradigm is a key consideration; efforts are therefore needed to overcome these challenges in health-economic modelling of comparative cost-effectiveness.