OBJECTIVES: The European Commission (EC) introduced Orphan drug legislation in 2000 to encourage manufacturers to develop treatments for neglected, rare diseases. These incentives include fee reductions for scientific advice and 10 years’ market exclusivity. To qualify, a therapy must be indicated for a life-threatening or chronically debilitating disease, with a prevalence <5/10,000, and offer significant benefit over existing therapies. Eligibility is assessed at two time points: early in the medicine’s development and again at marketing authorization. In January 2018, the EMA began publishing Orphan Maintenance Assessment Reports (OMARs) for every medicine with an orphan designation after marketing authorization. This research systematically evaluates all OMARs published to date. METHODS: Publicly-available OMARs were identified (01/01/2018—31/12/2018) and key data extracted, alongside respective FDA orphan designations. RESULTS: 33 OMARs were identified. In 82% (27/33), orphan status was maintained. No OMARs contained a final negative opinion; however, 18% (6/33) reported withdrawal of the orphan designation by the sponsor prior to final opinion. 100% (6/6) of withdrawals were due to inability to meet both the disease prevalence and the significant benefit criteria, and none due to the unmet need criterion. 89% (24/27) EC designated orphan medicines also were designated orphan drugs by the FDA with 79% (19/24) receiving FDA marketing authorization, of which 89% (17/19) received marketing authorization in the USA prior to Europe. CONCLUSIONS: Most medicines receiving an initial Orphan Designation in Europe maintain this at market authorization. For the ones that do not, this is due to withdrawal of the orphan designation by the sponsor, caused by the disease prevalence and the significant benefit criteria no longer being met. Although orphan drug legislation has incentivized drug development for rare diseases in Europe, most of these drugs received an earlier FDA approval and overcoming the frequently greater reimbursement/payer hurdle in Europe can further add to this access discrepancy.