OBJECTIVES: Rare diseases impact a small patient population, defined as 1 in 2,000 individuals in the EU, and frequently lack appropriate therapeutic options. Orphan drugs (ODs) are granted special support to incentivize their development. Under Germany’s AMNOG, ODs undergo a limited benefit assessment by the G-BA without competing with an appropriate comparative therapy. An added benefit is granted by law; however, a mandatory re-evaluation is triggered upon reaching a sales threshold of €30 million. These privileges afforded to ODs are subject to ongoing debate, particularly concerning therapeutic costs and evidence standards. This analysis aims to compare evidence levels in OD and non-OD benefit assessments.

METHODS: Benefit assessments for all ODs and non-ODs from 2011 to May 2024 were analyzed using the Pharmanalytics database, which includes G-BA data. Where applicable, benefit assessments were categorized with their respective re-assessments.

RESULTS: ODs constituted 27 % of benefit assessments in Germany. Further, 15 % of all assessments underwent both initial and re-assessments (7 % ODs, 8 % non-ODs). On average, ODs were approximately 10.2 – 13.5 times more expensive than non-ODs, consistently before and after benefit assessments across initial and re-assessments. In initial assessments, three times more studies (1.2 vs. 0.4) were accepted for OD evaluations compared to non-ODs; however, re-assessments considered a similar number of studies (0.9) for both groups. Randomized controlled trials (RCTs) were the predominant study type for both categories. In OD re-assessments, there was a 27 % decrease in accepted RCTs compared to initial benefit assessments, whereas non-ODs saw a 29 % increase.

CONCLUSIONS: Despite the persistently high costs of ODs post-assessment compared to non-ODs, evidential standards remain comparable between the two groups during re-evaluation. However, fewer RCTs are accepted for ODs, often due to challenges in appropriately addressing the comparator therapy as defined by the G‑BA.