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Background: vaccines are complex products used in healthy populations. They should be carefully regulated, and benefits should clearly outweigh risks., Objectives: To describe the evidence used to support benefit-risk evaluations of vaccines centrally assessed by the European Medicines Agency (EMA), and to identify if real-world data (RWD) was used throughout the vaccine life cycle., Methods: Cohort study of vaccines approved in the European Union. Inclusion criteria comprised having ATC code J07 and being centrally approved between 2012 and 2022. We collected data from regulatory documents, study protocols, and, when necessary, from scientific publications. Vaccines were followed from initial approval up to March 2023., Results: We included 31 vaccines addressing 17 therapeutic areas. More than 390 studies were used in the process of initial marketing authorisation (MA) and monitoring, and 174 studies were listed in initial risk management plans. We also identified 93 studies in the EU PAS register. At MA, all vaccines had at least one pivotal trial and 27 vaccines had at least one supportive study. Most pivotal trials were randomized, double-blinded and active-controlled, with immunogenicity endpoints as primary outcome. RWD was used for extension of indications and monitoring of at least 4 vaccines, and the undertaking of RWE studies was foreseen in the RMP of at least 17 vaccines., Discussion: Our study revealed an important reliance on randomized controlled trials with individual-level randomization, and a significant focus on immunogenicity endpoints. The use of RWD in vaccine assessments so far has been restricted to COVID-19, and despite its challenges and limitations, we believe that efforts to expand adoption of RWE in continuous benefit-risk assessments should be made. We further highlight the need to enhance data transparency and reporting standards since heterogeneity among regulatory documents made it difficult to identify all the studies considered in vaccine evaluations., Competing Interests: Declaration of competing interest CEH is employed by the Copenhagen Centre for Regulatory Sciences (CORS), Department of Pharmacy, University of Copenhagen. CORS is a cross-faculty university-anchored institution involving various public (the Danish Medicines Agency, Copenhagen University) and private stakeholders (Novo Nordisk, Lundbeck, Ferring Pharmaceuticals, LEO Pharma) as well as patient organizations (Rare Diseases Denmark). The centre is purely devoted to the scientific aspects of the regulatory field and has a patient-oriented focus, and the research is not a company-specific product or directly company related. In the last three years, CORS and CEH have received funding from Novo Nordisk for projects not related to this study. LFW is a PhD student at CORS and his PhD fellowship is funded by a grant to CORS from Novo Nordisk A/S. However, the company was not involved in any aspect of the described work. DDG is also a PhD student at CORS, and she declares no competing interests. The authors declare no other known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)