Evidence Mapping of Concepts, Methods, and Outcomes in the Evaluation of Diagnostic and Therapeutic Technologies for Ultrarare Diseases: A Systematic Scoping Review

OBJECTIVES: This systematic scoping review provides an overview of the concepts, methodological approaches, and outcome measures used to evaluate diagnostic and therapeutic technologies for ultrarare diseases (URDs). METHODS: Searches covered countries where English, Portuguese, or Spanish are official languages and were expanded to International Network of Agencies for Health Technology Assessment and International Coalition of Medicines Regulatory Authorities countries using additional Roman-character languages. A search was conducted for official documents, reports, recommendations, and legal frameworks from health technology assessment (HTA) agencies and regulatory authorities in these countries. Data were extracted on URD definitions, primary sources, methodological approaches, and outcome measures used in HTA. RESULTS: A total of 55 publications were included. The definitions of URDs varied, with most countries adopting a prevalence threshold of ≤1 in 50 000 people, whereas others applied stricter criteria (≤1 in 100 000). Conventional methods, such as randomized controlled trials, were seldom feasible, with evidence often derived from observational studies, historical cohorts, or real-world data. Innovative approaches, including matching-adjusted indirect comparisons, simulated treatment comparisons, and multicriteria decision analysis, were increasingly used. Outcome measures prioritized overall survival, quality of life, functional independence, and caregiver burden, with jurisdiction allowing more flexible cost-effectiveness thresholds or exceptional coverage criteria. CONCLUSIONS: Despite heterogeneity, there is growing convergence on prevalence-based criteria and adaptive strategies for URDs, highlighting the need for robust patient registries, international data sharing, and HTA frameworks that incorporate severity, equity, and social value.