Why do health technology assessment coverage recommendations for the same drugs differ across settings? Applying a mixed methods framework to systematically compare orphan drug decisions in four European countries

PURPOSE: Health technology assessment (HTA) coverage recommendations differ across countries for the same drugs. Unlike previous studies, this study adopts a mixed methods research design to investigate, in a systematic manner, these differences. METHODS: HTA recommendations for ten orphan drugs appraised in England (NICE), Scotland (SMC), Sweden (TLV) and France (HAS) (N = 35) were compared using a validated methodological framework that breaks down these complex decision processes into stages facilitating their understanding, analysis and comparison, namely: (1) the clinical/cost-effectiveness evidence, (2) its interpretation (e.g. part of the deliberative process) and (3) influence on the final decision. This allowed qualitative and quantitative identification of the criteria driving recommendations and highlighted cross-country differences. RESULTS: Six out of ten drugs received diverging HTA recommendations. Reasons for cross-country differences included heterogeneity in the evidence appraised, in the interpretation of the same evidence, and in the different ways of dealing with the same uncertainty. These may have been influenced by agency-specific evidentiary, risk and value preferences, or stakeholder input. “Other considerations” (e.g. severity, orphan status) and other decision modulators (e.g. patient access schemes, lower discount rates, restrictions, re-assessments) also rendered uncertainty and cost-effectiveness estimates more acceptable. The different HTA approaches (clinical versus cost-effectiveness) and ways identified of dealing with orphan drug particularities also had implications on the final decisions. CONCLUSIONS: This research contributes to better understanding the drivers of these complex decisions and why countries make different decisions. It also contributed to identifying those factors beyond the standard clinical and cost-effectiveness tools used in HTA, and their role in shaping these decisions.