Global insight into rare disease and orphan drug definitions: a systematic literature review.

Objectives: This study sheds light on the available global definitions, classifications, and criteria used for rare diseases (RDs), ultrarare diseases (URDs), orphan drugs (ODs) and ultraorphan drugs (UODs) and provides insights into the rationale behind these definitions.
Design: A systematic literature review was conducted to identify existing definitions and the criteria used to define RDs, ODs and their subtypes.
Data Sources: Searches were performed in the PubMed/Medline, Embase, Scopus and Web of Science (Science and Social Sciences Citation Index) databases covering articles published from 1985 to 2021.
Eligibility Criteria for Selecting Studies: English-language studies on the general human population were included if they provided definitions or criteria for RDs, ODs and/or their subtypes without restrictions on publication year, country or jurisdiction.
Data Extraction and Synthesis: Two independent reviewers conducted the search, screening and data extraction. Narrative synthesis, content analysis and descriptive analyses were conducted to extract and categorise definitions and criteria from these sources. Study quality was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools.
Results: Online searches identified 2712 published articles. Only 93 articles met the inclusion criteria, with 209 distinct definitions extracted. Specifically, 93 of these articles pertained to 119 RDs, 11 URDs, 67 ODs and 12 UODs. These definitions varied in their reliance on prevalence based and other contextual criteria.
Conclusion: Prevalence-based criteria alone pose challenges, as disease frequencies differ by country. Establishing country-specific definitions can enhance understanding, support intercountry evaluations, improve healthcare efficiency and access to ODs, and strengthen equity and equality in healthcare. Such efforts would also promote research and development and support better outcomes for patients with complex and rare conditions.
Prospero Registration Number: CRD42021252701.
Competing Interests: Competing interests: None declared.
(© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.)