BACKGROUND: According to NICE, the prevalence of ultra-rare disease is defined as less than 2/100,000 population while ICER defines ultra-rare disease as affecting less than 10,000 Americans (~3/100,000). Due to the low number of patients and difficult achievement of investment return, orphan drugs are usually priced higher than drugs for common conditions and consequently are less likely to meet the cost-effectiveness thresholds established by HTA bodies.

DISCUSSION: ICER and NICE developed assessment frameworks for ultra-orphan medicines, but the approaches differ in terms of inclusion and decision-making criteria. NICE’s Highly Specialised Technology (HST) is applicable to treatments intended for small populations with chronic and severely disabling conditions, thus used only in few centres in the NHS. The acquisition cost is expected to be very high and the therapy is expected to be life-long. ICER’s adapted framework is considered for treatments for less than 10,000 individuals, offering a major improvement in quality of life and/or life extension. The key HST adaptation allows to increase the cost-effectiveness threshold to £300,000/QALY if the technology provides additional ≥30 QALYs. In ICER the threshold is increased to $500,000/QALY (~£392,000), without any association with QALY gains. Additional societal perspective can be adopted if the technology significantly impacts productivity, education, disability, or nursing costs.

CONCLUSIONS: NICE and ICER frameworks for ultra-orphan drugs adopt different eligibility and assessment criteria, which may result in different outcomes for the same drug. Extensive criteria for HST, which all need to be met, may cause less drugs to be eligible for this path. In such case demonstration of cost-effectiveness under less flexible Single Technology Appraisal will be required. Fewer, mainly epidemiology-based criteria in ICER could allow more drugs to be assessed under the framework, which automatically adopts higher willingness-to-pay threshold, increasing the probability that those drugs will be considered as cost-effective.