OBJECTIVES: Early benefit assessment pursuant to AMNOG was introduced to cut costs and illustrate the additional benefit of new pharmaceuticals including orphan drugs at launch in Germany. In this process orphan drugs have a special status. The EMA orphan drug designation implies the assumption that at least a not-quantifiable additional benefit is set by law. However the extent of the additional benefit still has to be demonstrated by the manufacturer. METHODS: By June 2013 seven orphan drug dossiers have been submitted and assessed. Only one product has been admitted an important additional benefit. Four substances had a minor additional benefit and two substances had a not-quantifiable additional benefit. RESULTS: An additional benefit needs to be proven against a comparator. But the G-BA will not define an appropriate comparator as for non-orphan drugs. Instead, the assessment of orphan drugs is based on the pivotal trial; the comparator will be derived from this trial. Due to the early phase of pivotal trials in rare diseases, using a comparator is not common. Furthermore, phase II trials often do not meet requirements in terms of evidence level requested: randomized controlled trials with large patient populations are unusual in orphan diseases as well as investigation of valid patient relevant endpoints or validated surrogate endpoints. CONCLUSIONS: The G-BA requirements for HTA assessments are drawn from phase III trials and demonstration of an additional benefit over an appropriate comparator, which also serves as price benchmark. The requirements derived for all newly launched products do not reflect orphan drug reality, which is indication and not agent based. In summary the EMA declaration of early admission of orphan drugs in phase II conflicts with the G-BA’s methodological requirements for the quantification of an additional benefit. In fact, manufacturers of orphan drugs face an additional barrier before launch in Germany.