Objectives: Medicines granted with an Orphan Drug (OD) designation by the European Commission are offered a range of incentives beyond access to the centralized authorization procedure and inevitably receive reimbursement within the German health technology assessment. This analysis investigated whether German regulatory requirements give incentives for high level evidence generation for ODs. MethOds: Medicines with an OD designation were graduated in two evidence groups evaluated by the German Federal Joint Committee (GBA): a non-quantifiable benefit or a quantifiable benefit. Trials of both groups were compared regarding study design and patient relevant endpoints. Furthermore, the reimbursement price was analyzed (launch price vs reimbursement price after one year). Results: 52 dossiers with OD designation were evaluated by the GBA since implementation of the Act on the Reform of the Market for Medicinal Products (German: Arzneimittelmarktneuordnungsgesetz, AMNOG) in 2011. 60% (n= 31) of the dossiers received the statutory non-quantifiable additional benefit. 40% (n= 21) acquired a quantifiable additional benefit. Almost all assessments resulting in a quantifiable benefit were based on at least one RCT (91%, n= 20). This subgroup succeeded in demonstrating a statistically significant advantage in a mortality endpoint in 23% (n= 7), a morbidity endpoint in 43% (n= 13) or a morbidity endpoint in 23% (n= 7) of the cases. 63% (n= 19) of the dossiers with a non-quantifiable benefit also presented RCTs. Even though some endpoints were significant, they were not acknowledged. Major reasons for not acknowledging these RCTs were the lack of patient relevant data, the usage of surrogate or combined endpoints and a high bias potential. cOnclusiOns: German regulatory requirements give incentives for high level evidence generation. ODs presenting significant and patient relevant data from RCTs have a higher chance to achieve a quantifiable benefit that leads to a better positioning in price negotiations. Patient relevance of endpoints and effect sizes are key success factors.
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