What Key Areas of Clinical and Economic Uncertainty Have Scottish Medicines Consortium (SMC) Identified in Ultra-Orphan Initial Assessments to Date?

OBJECTIVES: Since 2018, SMC has assessed medicines for very rare conditions via the ultra-orphan pathway. After a manufacturer receives validation of ultra‑orphan status, SMC conduct an initial assessment of the clinical‑ and cost‑effectiveness of the medicine and report key uncertainties, to inform the data collection stage. We aimed to identify key areas of clinical and economic uncertainty identified by SMC to date in initial assessments of the ultra-orphan pathway.

METHODS: All published initial assessments of medicines in SMC’s ultra-orphan pathway up to May 2024 were retrieved; areas of uncertainty were extracted and grouped, and a thematic analysis was performed.

RESULTS: Twelve medicines have undergone SMC ultra-orphan initial assessment. Areas of clinical uncertainty related to: clinical study design (e.g. trial length, sample size and population variability; in n=12/12 initial assessments), robustness of treatment effect (e.g. across patient subgroups, long-term maintenance of effect; n=12/12), choice of comparators/method of comparison (e.g. naïve or indirect evidence; n=8/12), clinical relevance (e.g. surrogate endpoints, thresholds for clinically relevant improvement; n=6/12), generalisability (n=5/12), patient impact (e.g. on quality of life; n=5/12), choice of outcomes (e.g. ceiling effects, missing outcomes; n=2/12) and tolerability (n=1/12).

In economic evaluations, uncertainties related to: clinical data inputs (n=11/12), model assumptions (n=10/12), health-related quality of life inputs (e.g. methods to estimate utilities; n=9/12), modelling methods (e.g. inappropriate time horizons, pooling health states; n=9/12), cost versus benefit (n=8/12), choice of comparators/method of comparison (n=3/12) and cost/resource use inputs (n=2/12).

CONCLUSIONS: All ultra-orphan initial assessments highlighted multiple areas of uncertainty in both the clinical and economic evidence, reflecting common challenges with generating robust evidence for ultra-rare diseases. Understanding areas of uncertainty identified by SMC may help manufacturers of rare disease medicines better prepare for the ultra-orphan pathway and inform data collection strategies. Future evaluation of how uncertainties are addressed and re-assessed following data collection will be valuable.