OBJECTIVES: There is a lack of harmonization in terms of regulation for Pharmaco-epidemiological studies in Europe. This conveys challenges in local interpretation of applicable requirements. Among other consequences, patient Information and Consent Form (ICF) are regularly requested for adaptations after submissions, leading to delays in study approval and site initiation. This analysis aims to describe the various requests for modifications received for ICFs, for different studies conducted in a broad range of countries. METHODS: The analysis was based on 6 post-marketing studies submitted from 2012 to 2016. Feedbacks of regulatory authorities after initial submissions in 26 European countries were analysed. Requests for modifications were categorized by scope of modifications (data access, insurance, format…) and by impact level (major: mandatory as per local laws before approval; minor: local regulatory-authority recommendations). RESULTS: Among the 853 submissions performed, 163 requests for modifications were received, among which 86 (53%), which required at least one modification of patient ICF. Requests for modifications related to ICF were more frequent in Italy (22% of submissions) and in France (17%). In total, 170 modifications of patient ICF were required. The most frequent modifications concerned the ICF format (27%), data access (16%), patient participation in the study (9%), costs and compensations (8%), direct to patient contacts (DtPC) (8%) or data storage (6%). Almost half of the requests (45%) required major modifications, mainly focused on data protection (43%, including data access and storage, DtPC and access to patient file), patient participation in the study (13%) and ICF format (11%). CONCLUSIONS: This analysis highlights that for Pharmaco-epidemiological studies, regulatory authorities put a particular attention on data protection. The information compiled for this analysis should be capitalized for future studies in order to accelerate the submission process and improve the time to site activation and patient inclusion.