OBJECTIVES : This research explored health technology assessment (HTA) outcomes for orphan therapies launching in therapeutic areas with no approved standard of care to identify optimal evidence development strategies.

METHODS : The EMA website was searched to identify 97 orphan therapies approved in 2011-2020, which were screened for mention of no alternative treatment options in the HTA decision summaries from G-BA in Germany, HAS in France and NICE in the UK. This identified 15 therapies to explore the trial design, efficacy outcomes and supplementary evidence.

RESULTS : 5 of 15 prioritized therapies launched with open-label, single-arm trial data, while in 10 of 15 cases randomized evidence vs. placebo was presented. In 4 of the 5 cases with non-randomized trial design, historical control data was used for estimates of relative treatment effects. While a non-quantifiable added benefit rating was assigned to most studied therapies in Germany given the orphan status, French and UK HTA bodies requested more data to confirm the extent of the benefit (e.g., data from indirect treatment comparisons (ITCs) or post-treatment follow-up). Despite the lack of randomized evidence, in France, an ASMR II or III was granted for therapies with ITC data (3 of 4), while an ASMR IV was assigned to 5 of 10 therapies with randomized data when extent of the benefit was uncertain. In the UK, NICE recommended funding for 6 of 7 therapies assessed; however, a managed access agreement and further data collection has been required for 4 of these therapies to address uncertainties in the clinical evidence.

CONCLUSIONS : The research demonstrated that, despite the high unmet need, the complexity of trial design for orphan drugs raises several challenges in the HTA process. Evidence strategies, such as follow up data collection or indirect comparison with historic control can be employed to support understanding of the benefit during the HTA process.