Real-world evidence at the European Medicines Agency
The European Medicines Agency was building real-world evidence into its regulatory decisions by 2025. It organised the work under one framework, built data networks, catalogues and guidance for it, had used the evidence in decisions and worked on it with other regulators, while obstacles remained and a direction was set for the work ahead.
Why the agency took up real-world evidence
Regulatory decisions have traditionally rested primarily on randomised controlled trials, but real-world data, collected in everyday clinical settings such as registries, health records and insurance claims, has emerged as a complementary resource. The agency views real-world evidence as a key tool for enhancing drug development, supporting adaptive licensing and assessing more accurately the safety and effectiveness of medicines once they are on the market. Its commitment to integrating the evidence signifies a paradigm shift in regulatory science, towards a fuller understanding of how medicines perform and how safe they are in the real world. The approach acknowledges some limitations of randomised trials, such as small and highly selected samples, and seeks to use the growing availability of digital health data for more effective regulatory decisions. It reflects a growing recognition that real-world evidence can complement trial data across the lifecycle of a medicine, particularly in addressing evidence gaps, monitoring safety and informing post-approval assessments.
The agency has taken a proactive approach, through strategic initiatives, infrastructure, pilot programmes and collaboration with stakeholders meant to foster trust in the utility of real-world data and evidence. The approach rests on several foundations, including fit-for-purpose data, collaboration with stakeholders and robust methods that ensure the quality and reliability of the evidence. Through initiatives including DARWIN EU and the Big Data Steering Group, the agency works to ensure the scientific validity and regulatory acceptability of real-world evidence across the lifecycle of a medicine. In its strategic reflection Regulatory Science to 2025, the agency proposed driving collaborative real-world evidence generation to improve the scientific quality of evaluations as one of five strategic goals in human medicine. Its strategy stresses continuous dialogue with stakeholders to optimise the use of real-world evidence in regulatory evaluations, aiming to improve benefit–risk assessment.
By late 2021 the European regulators' vision, anchored in the network strategy to 2025, was to enable the use of real-world evidence and establish its value for decisions on the development, authorisation and supervision of medicines in Europe by 2025. They planned to establish methods and standards for collecting and using the evidence to a high quality, in cooperation with patients, healthcare professionals, industry, regulatory and public health agencies, health technology assessment bodies, payers and academia. In the vision, real-world evidence and randomised trials, the gold standard for demonstrating efficacy, should be seen as complementary: each has strengths and weaknesses, and their relative importance depends on the regulatory question. A rigorous, systematic approach to learning from doing will help to identify the uses in regulatory decisions for which real-world evidence adds most value.
The OPTIMAL framework and the pathways for generating evidence
The agency structures its approach around three pillars, operational, technical and methodological, which together form the OPTIMAL framework and could collectively aim to maximise the potential of real-world evidence in regulatory decisions. The operational pillar concerns the quality and governance of data and their sources: provenance, access and governance structures; completeness, consistency, accuracy, traceability and sustainability of collection; data-sharing agreements aligned with the General Data Protection Regulation and national law, and use of the ENCePP code of conduct; and transparent documentation of data-source policies and collaboration models. The technical pillar concerns structure, interoperability and management: standardised terminologies and coding, interoperability and linkage across registries, records and claims, mapping to common data models with validation, quality assurance and audits, benchmarking against external sources, capture of critical time elements with consistent recording, and the agency's qualification procedure for data sources. The methodological pillar concerns scientific rigour: appropriate, validated designs for regulatory purposes, identification and control of confounding and bias, documented feasibility analysis, protocol registration and transparent reporting, epidemiological and statistical best practice, and scientific advice on the protocol.
The agency has named three major pathways for generating the evidence itself: the DARWIN EU network, its in-house electronic health databases, and studies commissioned through its framework contracts. On these pathways and the pillars it has built several initiatives.
The Big Data Task Force and the Big Data Steering Group
The joint Big Data Task Force of the Heads of Medicines Agencies and the agency was established in 2017 to tackle the challenges and opportunities of big data, and its members are regulators and data experts appointed by the national authorities, the agency and the European Commission. The first phase of its work, published early in 2019, reviewed the landscape of big data, and on 20 January 2020 the second phase set out ten priority actions for the European regulatory network. The most ambitious was an EU platform to access and analyse healthcare data from across the EU, the Data Analysis and Real World Interrogation Network (DARWIN): a network of databases of verified quality and content, with the highest levels of data security, that would inform regulatory decisions with evidence from healthcare practice. By mid-2020 no such platform was yet available in the EU. The other priorities were guidance and resources on data quality and discoverability, including the choice of key metadata; computing and analytical capacity; training so that regulators could assess applications that use big data as part of the evidence on benefits and risks; a learning initiative to track the outcomes of such submissions; and management and analysis within a secure and ethical governance framework, in dialogue with patients, healthcare professionals, industry, health technology assessment bodies, payers, device regulators and technology companies, and in collaboration with international initiatives on big data. The second phase was meant to inform the strategic decisions and planning of the Heads of Medicines Agencies and the agency and to contribute to the upcoming EU network strategy to 2025. The rapidly changing data landscape forces regulators to evolve and change how they access, manage and analyse data and to keep pace with rapid advances in science and technology.
The agency and the Heads of Medicines Agencies set up the Big Data Steering Group in February 2020 to advise the agency's Management Board and the Heads of Medicines Agencies on implementing the ten priority recommendations. It published its first workplan, with actions for 2020–2021, on 14 September 2020. With the network focused on the response to the COVID-19 pandemic, the workplan set out to progress towards data-driven regulation through smart working, collaboration with stakeholders and remote expert workshops. It aimed to increase the utility of big data in regulation, from the quality of data through study methods to assessment and decision-making. It foresaw closely involving patients and was guided by advances in science and technology, and it intended to involve other stakeholders and leverage international collaboration, with a virtual multistakeholder forum on the workplan and its implementation scheduled for late 2020. In 2020 the network had to prioritise the unprecedented public health challenge of the pandemic, and the workplan was to be implemented flexibly, and some actions might be rescheduled as the pandemic developed. The group's work builds on the Regulatory Science Strategy to 2025, published in March 2020, and was to support the network strategy to 2025, then under development.
On 28 July 2022 the group published its third workplan, for 2022 to 2025, which follows the task force's 2020 priority recommendations. It foresaw more than a hundred DARWIN EU studies a year by 2025; a data quality framework for the EU network by the end of 2022; a good practice guide on real-world metadata and a public catalogue of European real-world data, with analytics tools and standardised clinical trial protocols to make regulatory documents easier to search; and training in biostatistics, pharmacoepidemiology and data science for regulators, with targeted access for patients, healthcare professionals and academics. The workplan covers mainly human medicines, with a separate section for veterinary ones. It was to make data analysis a further and more efficient part of regulators' evaluation of medicines, and novel technologies and evidence from big data were to benefit public health by accelerating medicine development, improving treatment outcomes and allowing earlier patient access to new treatments.
The group is also meant to build the European network's capacity to use big data, real-world data included. It sets priorities on data quality, analytics and the acceptability of real-world evidence, and aims to advance the integration of big data into the regulatory framework to improve public health outcomes. In 2025 it was exploring mobile health data from smartphones and wearables, such as heart rate and sleep quality, for regulatory decisions; such data show promise, but challenges such as data quality and privacy must be addressed.
DARWIN EU
DARWIN EU, a network to access and analyse healthcare data from across the EU, was to be key to delivering the regulators' vision for 2025. It was to launch in early 2022 with a coordination centre to on-board data partners and to drive the conduct of studies requested by regulators and, at a later stage, by other stakeholders.
In November 2022 the agency announced the first set of DARWIN EU data partners. They are public and private institutions with access to real-world healthcare data from hospitals, primary care, health insurance, biobanks or disease-specific registries, and they supply the coordination centre with the results of analyses of those data, for studies that generate real-world evidence to support scientific evaluations and regulatory decisions. The first three studies were on the epidemiology of rare blood cancers, the use of valproate, and antibiotic use to inform work on antimicrobial resistance, with protocols and reports to be published in the EU post-authorisation studies register. They marked the start of a rapid ramp-up, with a target of about 150 studies a year by 2025. Partners were selected by prioritisation criteria, after consultation with the DARWIN EU Advisory Board: continuous collection with at least annual updates, a lag of under six months, capture of health outcomes and of prescribing or dispensing, data already converted to the OMOP common data model so the same analytical code runs everywhere, and, across the network, coverage of primary, secondary and specialist settings and of the EU population, with non-EU sources considered where they add value to real-world evidence analyses. At least ten partners a year were to be added, with a call for expressions of interest from potential new partners in 2023. The network is federated, giving the national authorities, the agency and the Commission access to results whenever needed across a medicine's lifecycle. The agency manages it and oversees the coordination centre at Erasmus University Medical Center Rotterdam, appointed in February 2022, and the network was to act as a pathfinder for the proposed European Health Data Space and eventually connect to it. Knowledge of diseases, of medicines use and of how medicines perform in clinical practice can inform regulatory decisions and support the development, authorisation and safe and effective use of medicines.
Launched in 2022, DARWIN EU lets the agency access and analyse real-world data through a network of data partners across the Union, and its timely and robust analyses let regulators assess the safety and effectiveness of medicines more efficiently. In 2025 it gave access to anonymised data from around 180 million patients across Europe and aimed for about 40 partners by February 2026. It supports regulatory assessments, such as benefit–risk evaluations, safety signals and post-marketing surveillance, as well as the understanding of disease epidemiology and treatment patterns, and research and innovation through high-quality studies at scale.
The catalogues of real-world data sources and studies
On 15 February 2024 the agency and the Heads of Medicines Agencies launched two public electronic catalogues, one of real-world data (RWD) sources and one of RWD studies. The catalogues help medicines regulators, researchers and pharmaceutical companies to identify the most suitable data sources for specific research questions, and support the assessment of study protocols and results. They aim to promote transparency, encourage good practice and build trust in research based on RWD. They build on more than 15 years of operation of the former databases of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP).
- The catalogue of RWD sources enhances and replaces the ENCePP Resources Database, an index, coordinated by the agency, of the research organisations, networks and data sources available in pharmacoepidemiology and pharmacovigilance within Europe.
- The catalogue of RWD studies expands and replaces the EU electronic register of post-authorisation studies (EU PAS Register).
The ENCePP website was renewed. Some data sources and all centres and networks moved to the new catalogues, while other content, such as the ENCePP Guide on Methodological Standards in Pharmacoepidemiology and the ENCePP Code of Conduct, remains on the renewed website.
Following the FAIR (findable, accessible, interoperable and reusable) data principles, the catalogues describe data sources and connect them to studies with an agreed set of metadata. The set is based on the list of metadata published by the HMA-EMA Big Data Steering Group in May 2022, and a revised list was to be published. The catalogues also offer search on a wider set of metadata, an enhanced view, and functions for export and data submission.
In the two bodies' account, the publication of the catalogues brings the network closer to more data-driven regulation. Improving the discoverability of data is one of the priorities set in the final report (phase two) of the HMA-EMA joint Big Data Task Force; the network strategy to 2025 reflects it, and the Big Data Steering Group workplan implements it. The agency and the Heads of Medicines Agencies expect these developments ultimately to help European patients receive better medicines faster and promote the safe and effective use of the medicines on the market. All European data holders, marketing authorisation holders, networks, researchers and institutions who want their data used for medicines regulation, or who are obliged by policy on non-interventional post-authorisation safety studies (PASS), are encouraged to use the catalogues.
Guidance, scientific advice and analysis
The agency has developed and refined technical methods to incorporate real-world evidence into its regulatory processes, designed to deal with the complexities of real-world data and ensure their quality, reliability and relevance for decisions. Its guidance on the design, conduct and reporting of real-world evidence studies includes the guideline on registry-based studies and the guideline on good pharmacovigilance practices, which set out expectations for the quality and transparency of the evidence. Developers can seek the agency's scientific advice on planned real-world studies, which helps align the design with regulatory expectations early and makes it more likely that the evidence is accepted at review. The agency also stresses fit-for-purpose sources, such as health records, claims databases and registries, and early interaction with stakeholders such as marketing authorisation holders to understand research questions better and optimise the generation of the evidence.
On analysis, the agency advocates transparent study design and analysis, with a focus on reproducibility and robustness, and recommends that sensitivity analyses be considered to assess the reliability of findings under uncertainty and potential bias. Ensuring the quality of real-world data is a critical challenge, and the agency has emphasised the need for standardised data collection and reporting. The European Health Data and Evidence Network and the GetReal Institute aim to improve data interoperability and facilitate the use of real-world evidence in regulatory and health technology assessment processes.
Where the evidence has been used
The agency's pilot programme identified 61 research topics for real-world evidence, focused on medicine safety, trial design, drug utilisation and disease epidemiology, each needing fit-for-purpose data relevant to its regulatory question. External controls derived from real-world data have been explored to put the outcomes of uncontrolled trials in context, though they need careful consideration of eligibility, temporality and population representation. Other pilots tested the regulatory acceptability of the evidence: one, with post-authorisation safety studies, showed how real-world evidence could supplement traditional sources in assessing long-term safety, and another used patient registries to evaluate effectiveness in rare diseases in support of label extensions. Through these pilots the agency showed that well-conducted real-world studies can give reliable, actionable evidence for regulatory purposes.
The uses run across the lifecycle of a medicine, from pre-approval to post-marketing surveillance. Real-world evidence is widely used in post-marketing surveillance to identify safety signals and adverse events, and DARWIN EU has been instrumental in monitoring the safety of approved medicines. It increasingly supports regulatory decisions where trial data are limited, as with orphan medicines, and the agency has used it to inform decisions on drug utilisation and clinical management, particularly during the COVID-19 pandemic. A review of applications submitted in 2018 and 2019 found real-world evidence in 40% of initial marketing authorisation applications, mainly from registries and hospital data to support assessments of safety and efficacy, and in 18% of applications to extend the indication of a marketed product. Real-world evidence has also informed post-marketing safety evaluations, particularly of rare adverse events and subgroups, and the agency has recognised its value for evaluating risk minimisation measures and understanding how products are used and misused.
Real-world evidence has been particularly valuable in approving orphan medicines, where trial data are often limited, and the approval of abaloparatide for osteoporosis relied on it to fill gaps in trial data. In oncology it has been used to evaluate the real-world effectiveness of cancer treatments: a review of targeted therapies approved between 2018 and 2022 found that it contributed to regulatory decisions in 21% of cases. A case study of a novel oncology medicine showed it bridging trial results and real-world outcomes for regulatory and HTA decisions. For rare diseases, the SATURN initiative used the existing Registry of Osteogenesis Imperfecta to generate evidence on treatment practices and outcomes for regulatory and HTA decisions.
Joint work by the agency and EUnetHTA highlighted the importance of extrapolating from adults to children in paediatric drug development, which addresses ethical concerns, supports robust evidence generation and aids benefit–risk judgements by regulators and HTA bodies alike.
International collaboration
In early 2021 ICH regulators emphasised the importance of international collaboration on observational studies of real-world data for regulatory decisions on COVID-19 vaccines and treatments. A workshop on 25 January 2021, convened under the International Coalition of Medicines Regulatory Authorities and co-chaired by Health Canada and the agency, shared information on ongoing observational studies of real-world data, identified key learnings and opportunities for collaboration, and discussed international cohort building, pregnancy studies, and vaccine surveillance and vigilance. Its report of 8 February 2021 stressed that, as COVID-19 vaccines were rolled out, regulators had to ensure the continuous monitoring of their safety and effectiveness, especially in special populations, and that real-world evidence from observational research was critical to understanding the benefits and risks of medicines for preventing and treating COVID-19 in everyday use. Regulators outside ICH had been contributing to the agency's COVID-19 pandemic task force since December 2020.
By 2022 the use of real-world data and evidence in the development, authorisation and monitoring of medicines was rapidly increasing. Real-world evidence can help bridge knowledge gaps, but data sources across the globe were heterogeneous, their quality varied, and processes for data sharing and access differed. During the COVID-19 pandemic, regulators and researchers had worked together to share data and experience on real-world evidence, and they agreed to continue that collaboration beyond the pandemic. On 22 July 2022 the agency endorsed a joint statement of the International Coalition of Medicines Regulatory Authorities calling for international collaboration on real-world evidence. Its members pledged to foster global efforts to integrate real-world evidence into regulatory decisions and named four areas for cooperation: harmonised terminology for real-world data and evidence, regulatory convergence on guidance and best practice, readiness for public health challenges and emerging threats, and transparency. These could be taken forward through existing fora, including ICH, international standardisation bodies and clusters of interested regulators. The statement followed a June 2022 workshop in Amsterdam, co-organised by the agency, the FDA and Health Canada, with participants from more than 40 countries and the WHO, and the regulators were next to discuss concrete actions in the four areas.
Obstacles: harmonisation, privacy and heterogeneity
Integrating real-world evidence into the agency's framework still faced several challenges. The lack of harmonised guidelines across member states and HTA bodies remained a barrier, and although the agency had made progress on its own guidance, terminology and methodological preferences still differed. Real-world data raise ethical and privacy concerns, particularly about patient confidentiality and data protection, and the General Data Protection Regulation has added complexity to using them. Sources differed between member states in health systems, collection practices and privacy rules, which complicates pooling and analysing them.
Future directions
To realise the potential of real-world evidence, the agency and other stakeholders must address those challenges and invest in initiatives that enhance the quality, accessibility and harmonisation of real-world data. Harmonised guidelines across member states and HTA bodies are essential. The IDERHA public–private partnership, launched in April 2023, aims to align real-world evidence requirements and reduce fragmentation between regulatory and HTA processes, and to apply artificial intelligence and machine learning to link diverse health data for early detection of lung cancer and better quality of life for those affected. Investing in robust data infrastructure is critical to overcoming the limitations of real-world data. The European Health Data Space is meant to improve interoperability and cross-border sharing and to let individuals access and manage their health data across the EU, with a primary-use strand, MyHealth@EU, for care, and a secondary-use strand, HealthData@EU, for research, innovation, policy and regulation. Artificial intelligence and machine learning hold promise for generating and analysing real-world evidence, and collaboration among regulators, industry and academia will be key to driving innovation and addressing methodological challenges. The network's strategy to 2025 set out to use real-world evidence further to address critical research questions and enhance the evaluation of medicines, and its strategy to 2028 plans to build on that with a stronger contribution from digital transformation and artificial intelligence.
One 2025 review judges the agency to be at the forefront of integrating real-world evidence into the regulatory framework, and through DARWIN EU, guidance documents and engagement with stakeholders to be enabling the generation and use of high-quality, regulatory-grade evidence. It finds the outlook promising despite challenges in data quality, methodology and interoperability. Continued investment in data infrastructure, methods and regulatory alignment will be key to unlocking the evidence's potential. As the evidence becomes embedded in decisions, it promises to enhance the evaluation of medicines, improve patient outcomes and support more dynamic and responsive regulatory practice.