BACKGROUND: The term ultra-rare diseases was first introduced in 2004 by the National Institute for Health and Care Excellence during the evaluation of drugs indicated for conditions with a prevalence of fewer than 1 case per 50,000 people. This review aims to systematically examine the clinical evidence synthesis practices used worldwide to support decision-making on the incorporation of new drugs for treating ultra-rare diseases and to identify the definitions of ultra-rare diseases adopted internationally. METHODS: This review follows the JBI methodology for reviews of textual evidence, including narrative reports, expert opinions, and policy documents. Eligible sources will include texts and studies addressing patients with ultra-rare diseases. The phenomenon of interest is the set of methods and practices used for synthesizing clinical evidence to inform the incorporation of health technologies for ultra-rare genetic diseases. This review focuses on the context of global health technology assessment (HTA) agencies. Searches will be conducted in the PubMed, Embase, CENTRAL, and Virtual Health Library databases, as well as on the websites of major international HTA agencies. Study selection, data extraction, and risk-of-bias assessment will be performed independently and in duplicate. Proportional meta-analyses will be conducted to summarize the frequency of study designs, outcomes, and recommendations according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach applied by HTA agencies when assessing drugs for ultra-rare diseases. EXPECTED RESULTS: The findings of this review are expected to inform the development of methodological guidelines for evidence synthesis in ultra-rare diseases-from defining ultra-rare conditions to establishing best practices for evidence generation and evaluation. In the long term, the results may guide strategies to address methodological challenges in primary studies on the efficacy and safety of health technologies for ultra-rare diseases, such as strengthening national patient registries and promoting multicenter collaborative research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD420250652106.
Novo et al. (Tue,) studied this question.