OBJECTIVES: In Europe, orphan designation status provides treatments indicated for rare diseases with incentives like market exclusivity. However, orphan designation status for second- and third-to-market treatments can be negatively impacted by first-to-market orphan products. This can be due to factors including significant benefit outcomes within the same indication and time of approval. This review explores how first-to-market orphan products affect orphan designation outcomes of subsequent products within the same indication.

METHODS: Targeted secondary research was conducted to identify a sample of second- and third-to-market products that were initially granted orphan designation by the EMA. The final sample included Uplizna, Zilbrysq, Lytgobi, Amvuttra. Secondary research and consulting expertise was used to assess the impact on orphan designation across the EU4 (Germany, Italy, France and Spain).

RESULTS: The initial findings showed that Uplizna failed to maintain its orphan designation, while Zilbrysq and Lytgobi’s sponsors withdrew their applications at the market authorization stage. All three products were approved within one to two years after the first-to-market product. They also failed to demonstrate significant benefit due to methodological uncertainties and inconclusive data. This meant a clinically relevant advantage or major contribution to patient care over the first-to-market product was not proven, which is a key criterion for orphan designation. Amvuttra, a third-to-market orphan product, successfully demonstrated significant benefit using protocol assistance against its first- and second-to-market products within the same indication.

CONCLUSIONS: Orphan drug designation status can facilitate market access in countries like Germany and France. However, manufacturers of second- and third-to-market products must consider factors such as the significant benefit and time of approval to successfully maintain its orphan designation status. Direct comparative data, indirect comparisons, and protocol assistance can aid in demonstrating benefit.