Abstract
Introduction (with objective): Ultra-rare diseases (URDs) pose challenges in Health Technology Assessment (HTA) due to the limited available evidence, the high costs of the technologies evaluated, and the restrictions on the applicability of traditional methods of evidence synthesis and cost-effectiveness analysis (1-3). These limitations represent barriers to the incorporation of new technologies in the context of URDs. The objective of this study was to analyze the concepts, methodological approaches, and outcomes used in HTA applied to URDs. Material and Method: A scoping systematic review was conducted according to the recommendations of the Joanna Briggs Institute, and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for scoping reviews (PRISMA-ScR) guidelines, with a protocol registered in the International Prospective Register of Systematic Reviews (PROSPERO) under code CRD420251007802. The research question guiding this review was: “What is the evidence regarding the concepts, methods, and outcomes used in the evaluation of diagnostic or therapeutic technologies for ultra-rare diseases?” The search was conducted in April 2025 on Google, focusing on official documents not indexed in traditional databases, such as legislation, reports, and guidelines. Documents from countries whose official languages are English, Portuguese, or Spanish were included. The identification of countries and institutional websites was based on international organizations and collaborative networks of HTA and health regulation. The search strategies combined terms related to ultra-rare diseases with domains of regulatory agency websites, HTA agencies, and official journals. The extracted data included definitions of URDs, sources of evidence, methods for comparing interventions, and outcomes considered in the evaluations. Results: Forty-eight documents published between 2009 and 2025 were identified, predominantly recommendations (n=29) and technical reports (n=15), mainly from Portugal (n=10), the United Kingdom (n=6), and Australia (n=6). Heterogeneity was observed in the definitions of DURs, with a predominance of prevalence thresholds of ≤ 1 per 50,000 (n=12) and ≤ 1 per 100,000 (n=8). Regarding the sources of evidence, observational studies, such as historical cohorts and real-world data, were used in the context of limitations in randomized clinical trials. Indirect comparison methods such as matching-adjusted indirect comparisons, simulated treatment comparisons, and multicriteria decision analysis were applied to address uncertainty and the absence of robust direct comparisons. Outcomes included overall survival, quality of life, functionality, and impact on caregivers. In cost-effectiveness assessments, more flexible quality-adjusted life years (QALY) thresholds were observed, associated with budget impact analyses, risk-sharing agreements, and conditional reimbursement mechanisms, demonstrating the adaptation of economic models to uncertainties and financial sustainability. Conclusions: The results show a process of adaptation of HTA models for DURs, characterized by the incorporation of more flexible approaches in the face of limitations in evidence and uncertainty regarding these conditions. These findings provide support for strengthening policies for the incorporation of technologies in the Brazilian Unified Health System (SUS).
