OBJECTIVES: This study, part of the Belgian Healthcare Knowledge Centre (KCE) NEED-project, aims to gain insights into (1) definitions used for rare diseases by healthcare stakeholders (regulatory authorities, patient organisations and pharmaceutical industry associations) across Europe, and (2) methodological challenges for identifying and assessing unmet health-related patient and societal needs in rare diseases. Results aim to inform the KCE-NEED Framework for identifying unmet needs in rare diseases and contribute to the Belgian Presidency of the Council of the European Union in 2024.

METHODS: A grey literature review was conducted, including a systematic screening of 127 relevant stakeholders' websites and a dedicated search in grey literature databases (Google, Google Scholar, ProQuest). Forward and backward snowballing techniques were employed. Data extraction followed a standardized Excel sheet.

RESULTS: Most websites (54%) did not provide a concrete definition of rare diseases, focusing instead on specific aspects or issues without explicitly defining the term. While heterogeneity was found in the particular wording used, most of the definitions were based on the Regulation (EU) on Orphan Medicinal Products. Variations in the availability of rare disease definitions were observed across websites: patient organizations consistently mentioned a definition (80%), whereas industry websites (33%) and regulatory authorities (42%) included a specific definition less frequently. Additionally, this study identified several methodological challenges regarding unmet health-related needs in rare diseases.

CONCLUSIONS: This study reveals that many industry and regulatory websites lack clear definitions of rare diseases. When a definition is provided, it generally relies on the Regulation on Orphan Medicinal Products. This study provides insights into rare disease definitions and lays the foundation to address remaining needs in those areas, pointing out methodological research challenges.