Ultra-orphan drugs challenge conventional reimbursement assessments because related evidence generation is constrained by very small patient populations, exceptionally high per-patient treatment costs, and uncertain long-term outcomes.To address these challenges, through a review of relevant policy documents, health technology assessment guidelines, and peer-reviewed literature, this review comparatively examined the evaluation and reimbursement frameworks for ultraorphan drugs in England, Canada, Australia, and South Korea.Focus was placed on eligibility criteria, approaches to value assessment, and mechanisms for uncertainty management after listing.All four countries recognized that conventional costeffectiveness standards alone are insufficient for ultra-orphan drugs, but their institutional responses differed.England applies an explicit pathway through Highly Specialised Technologies with higher thresholds, quality-adjusted life year weighting, and formal consideration of patient and caregiver perspectives.Canada uses a deliberative framework across five value domains, linking conditional or time-limited recommendations to future evidence generation.Australia combines Pharmaceutical Benefits Advisory Committee assessment with supplementary pathways, such as the Life Saving Drugs Program and Highly Specialised Therapies Program funding.South Korea has mainly relied on the cost-effectiveness analysis waiver track and risk-sharing agreements, while also being less explicit in defining ultra-orphan drugs as a distinct category, formally incorporating broader value elements and systematically linking entry decisions with post-listing reassessments.Future reforms in South Korea should move beyond a procedural exemption model and toward a more explicit framework that clarifies eligibility criteria, incorporates broader value elements (e.g., severity, unmet needs, and patient and caregiver burden), and connects initial access with the generation and reassessment of lifecycle evidence.
An et al. (Thu,) studied this question.