Successfully applying for and maintaining orphan designation (OD) in the European Union (EU) is a critical pathway for sponsors developing treatments for rare diseases. The process involves navigating regulatory frameworks set by the European Medicines Agency (EMA) under Regulation (EC) No 141/2000.

To obtain an OD, the applicant must demonstrate that:

• the condition affects no more than 5 in 10,000 individuals in the EU,
• the product offers significant therapeutic benefit over existing treatments, or
• no satisfactory method of diagnosis, prevention, or treatment exists.

Once granted, maintaining this status requires ongoing compliance with regulatory obligations, including regular reporting on the development status, marketing exclusivity updates, and adherence to timelines.

In this whitepaper we provide key reflections for navigating potential challenges in the preparation of an OD application, such as classification of the orphan condition, prevalence estimation, evidence of significant benefit, and medical plausibility. We emphasise the importance of a pre‑submission meeting for obtaining an OD, and about generating evidence during the marketing authorisation (MA) process to maintain the designation. We also review the benefits and incentives of ODs such as protocol assistance, market exclusivity, access to EU grants, and fee reductions, which are vital for the commercial viability of orphan drugs in the EU. Finally, we highlight how the new EU pharmaceutical reforms are going to impact ODs.