OBJECTIVES: Enzyme replacement therapies (ERTs) are used to treat rare genetic metabolic diseases, presenting extremely heterogeneous disease manifestations. ERTs replace the missing enzyme exogenously and represent a new treatment option compared to the hitherto available symptomatic, non-curative therapies. These factors impede the evaluation of ERTs within the German HTA (AMNOG) process. METHODS: ERTs assessed by the Federal Joint Committee (G-BA) and the Institute for Quality and Efficiency in Health Care (IQWiG) were examined in a systematic database search. Subsequently, the relevant entries were analyzed in terms of indication, trials, treatment costs, added benefit and reimbursement rebate. The research considered all completed AMNOG assessment procedures. RESULTS: Since the introduction of AMNOG in 2011, four ERTs have been evaluated: elosulfase alfa (Vimizim®), cerliponase alfa (Brineura®), sebelipase alfa (Kanuma®) and asfotase alfa (Strensiq®). In Germany, the estimated target population of these drugs ranges between 4 and 1000 patients. The G-BA granted a benefit for all analyzed ERTs. However, the benefit was not quantifiable for three of the four active substances. Solely, elosulfase alfa was granted a minor added benefit. At the time of launch, annual treatment costs were in the range of 270,505 € - 2,423,305 € per patient. After price negotiation, the respective reimbursement price has been down-negotiated by 15-35%. Because of the scarce evidence the G-BA set a time limit of the resolution in three of the four ERTs. CONCLUSIONS: ERTs for the treatment of orphan diseases face different challenges during the market access process. Due to the small number of study patients and the heterogeneity of the diseases the evidence regarding the benefit is limited. The current regulations grant an at least non-quantifiable benefit by the G-BA. The price negotiations may, however be driven by other factors, e.g. the launch price, precedents and the severity of the disease.