Establishing rarity in the context of orphan medicinal product designation in the European Union

•Establishing rarity for orphan designation is linked to a precise case definition.•Diagnosed cases and updated criteria are in the epicentre of orphan discussions.•The duration of an orphan condition affects the prevalence considerations.•A numerical conclusion below the statutory threshold is required for orphan designation. In the European Union (EU) legislative framework for orphan medicinal product designation, establishing that a condition affects not more than five in 10,000 people is a prerequisite for applications based on rarity. Demonstrating this requirement to the Committee of Orphan Medicinal Products (COMP) can be a particularly challenging task for sponsors. Here, we identify and examine three common issues with the estimation of prevalence in orphan drug applications in the EU (the discernment between diagnosed and undiagnosed cases; the duration of the disease; and the need for an explicit contemporary conclusion) as critical factors for acceptable prevalence estimation. These concerns are discussed in detail based on recent examples of applications, which are reflected in published European Medicines Agency (EMA) documents.