OBJECTIVES : Since the introduction of orphan drug legislations (namely in the EU, US and Japan) there has been a large increase in the number of drugs available for Rare Diseases. Each legislation differs in their criteria to obtain orphan designation, particularly in terms of prevalence. However, the EU’s legislation has an additional requirement for products to display ‘significant benefit’ when there is an existing treatment; defined as a clinically relevant advantage to patient care. Orphan designation is also permanent once a drug has obtained marketing authorisation in the US and Japan, however can be withdrawn in the EU. This research reviews products that have withdrawn orphan designation in the EU following marketing authorisation and compares this to the US and Japan.

METHODS : All orphan drugs withdrawn from the European Community Register of orphan medicinal products between January 2000 to December 2019 were extracted. Secondary research on publicly available material was undertaken to deduce reasoning for withdrawal and the product’s orphan status was compared across the US and Japan.

RESULTS : Over the 20-year period, 16 products in Europe had their orphan designation removed following marketing authorisation. Within this period, 7/16 products had been withdrawn since 2018. In 50% of cases, lack of display of significant benefit was identified to be the sole reason or contributor to withdrawal. For 5/16 products, withdrawal was due to indication expansion into non-orphan conditions. In the US and Japan, any products launched without orphan designation was due to the prevalence of the disease being above the threshold for designation in that jurisdiction.

CONCLUSIONS : There has been an increase in orphan designation withdrawals in Europe in recent years, which has coincided with stricter definitions of significant benefit. Learning lessons from international comparisons of different orphan drug legislations is vital to ensuring they contribute to continued innovation for Rare Diseases.