Ethical and Economic Issues in the Appraisal of Medicines for Ultra-rare (or Ultra-orphan) Conditions

Article by: Nadine Henderson, Maria Errea, Chris Skedgel and Mireia Jofre-Bonet

A new OHE Consulting Report by Nadine Henderson, Maria Errea, Chris Skedgel, and Mireia Jofre-Bonet discusses the ethical and economic issues in the appraisal of medicines for ultra-rare conditions (also known as ultra-orphan medicines). The authors examine the current literature and identify three key areas of discussion, namely: ethical arguments for and against special priority for ultra-rare conditions, the different appraisal processes for ultra-rare disease medicines, and why standard appraisal process, designed for medicines for more common conditions, may not be appropriate for medicines for ultra-rare conditions.

Previous OHE research on availability and access to medicines for rare conditions (also known as orphan medicines) across Europe found that less than half of all centrally authorised medicines for these conditions were routinely funded by the NHS. For our latest report, the authors sought to describe the distinct ethical and economic challenges associated with the commercialisation and assessment of medicines for ultra-rare conditions, with a focus on health technology appraisal routes in the UK.  

In 2015, the National Institute for Health and Care Excellence (NICE) introduced an alternative appraisal pathway which exclusively evaluates medicines for ultra-rare conditions, i.e. the Highly Specialised Technology (HST) programme. It is intended to improve patient access to technologies for chronic and severely disabling ultra-rare conditions that would otherwise be unlikely to be approved under NICE’s standard appraisal process. This is driven largely by egalitarian concerns over inequality of access to medicines and treatments between people with rare and more common conditions.

Prior to the implementation of this specialised pathway, all medicines were evaluated against the same cost-effectiveness threshold. Medicines for rare and ultra-rare conditions are typically more costly compared to those for more common conditions and, moreover, these costs must be recouped from – by definition – a substantially smaller patient group. Paired with challenges in generating robust clinical evidence, it is generally acknowledged that it is exceptionally difficult for medicines for ultra-rare conditions to meet NICE’s standard cost-effectiveness threshold.  In the absence of the special considerations offered by the HST route, individuals who suffer from ultra-rare diseases may be more likely to be denied access to treatment on the basis of cost considerations, placing them at a disadvantage relative to patients with more common conditions in terms of access to innovative medicines and health outcomes.

Despite the positive motivations of an auxiliary route for medicines for ultra-rare conditions, there are concerns that the current HST process fails to fully address the challenges it aims to overcome. Both patient groups and manufacturers of medicines for ultra-rare diseases have expressed fears over the lack of clarity in the phrasing of the selection criteria for HST appraisal, which has led to some medicines for ultra-rare conditions being evaluated under the same threshold as medicines for more common conditions. There are additional concerns that the HST eligibility criteria discriminate against medicines that are not used exclusively to treat ultra-rare conditions, as well as medicines that are potentially curative rather than for chronic use. The authors also highlight the potential for inequity in access to ultra-rare medicines across the devolved nations of the UK, owing to the fact that Scotland has its own HTA body (Scottish Medicines Consortium) and an ultra-orphan evaluation pathway with broader and more explicit eligibility criteria.

The report concludes that whilst in principle NICE’s HST programme offers an important route to patient access for ultra-orphan medicines, there is significant potential for improved clarity and consistency regarding the criteria and methods applied.  A failure to consistently consider all ultra-rare medicines under the HST process could lead to inequalities in access and health outcomes for patients with ultra-rare conditions.


This research was funded by Novartis Pharmaceuticals UK.


Posted in Health Technology Assessment, OHE Consulting, NICE | Tagged Consulting Reports