Even though orphan drugs currently account for almost 50% of all new medicine approved in USA and EU, many conditions still lack therapeutic options, and it has been estimated that 90-95% of the more than 7,000 known rare diseases do not have an approved treatment. This is particularly true for conditions which only affect very few individuals or where the underlying biology is poorly understood. Despite most major regulatory authorities having implemented legislation to stimulate and support development of medicines for rare diseases, several challenges persist. Generating robust evidence and managing uncertainty when dealing with small populations calls for global collaboration and regulatory alignment to agree on surrogate endpoints; external/historical controls; patient engagement in defining meaningful outcomes; and leveraging digital health technologies and decentralized clinical trials. This session will focus on how to leverage the evidentiary requirements to support global development for ultra rare diseases.