OBJECTIVES: The recent European Medicines Agency (EMA) approval of crizotinib has highlighted the potential for regulatory approval to be gained on the basis of pivotal non-comparative Phase II data. This research aims to determine the circumstances under which the EMA will approve submissions on this basis. METHODS: All publicly available European Public Assessment Reports (EPARs) were screened up to June 2013. Submissions that were based on pivotal Phase II data were identified and the acceptance decision, disease, and level of benefit were extracted. RESULTS: Eight drugs (bevacizumab, bortezomib, crizotinib, dasatinib, everolimus, gefitinib, imatinib, ofatumumab) across ten indications been submitted to the EMA on the basis of pivotal non-comparative Phase II data. All submissions were for entry indications except imatinib, which was also submitted for two further indications on this basis. All, except crizotinib, were for indications with no alternative therapies and all were for onology indications except everolimus which was for subependymal giant cell astrocytoma (SEGA). All, except crizotinib, were EMA designated orphan medical products for these indications. One submission was rejected (bevacizumab), one was restricted (ofatumumab), and eight were approved. Top-line supportive Phase III data was only available in two submissions (crizotinib and everolimus). Overall response rates (ORRs) were the primary endpoints in all submissions except imantinib and dasatinib in leukaemia indications and everolimus in SEGA. Rejected drugs had ORRs of 47% (ofatumumab, rejected subpopulation) and 38% (bevacizumab). Approved drugs had ORRs of 60% (crizotinib), 58% (ofatumumab, approved subpopulation), 40% (imatinib), and 35% (bortezomib). Despite low ORRs, imatinib was used to treat a disease with no licensed therapies (gastrointestinal stromal tumours), and bortezomib offered a 10% complete remission rate. CONCLUSIONS: Pivotal Phase II data can support EMA approval if it demonstrates substantial clinical benefits for small patient populations with severe diseases that lack therapeutic alternatives.