HMA-EMA roadmap advances EU regulatory guidance on real-world evidence

The European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) are advancing a multi-year roadmap to strengthen regulatory guidance on the use of real-world evidence (RWE) in the European Union. The initiative focuses on data quality, non-interventional studies, clinical trials, and regulatory submissions to support the generation of high-quality evidence for medicines regulation.

Work on the roadmap began in 2022, as part of a broader effort to promote the consistent and appropriate use of real-world data (RWD) in regulatory decision making across the EU. The initiative was first introduced in the joint HMA EMA Big Data Steering Group (BDSG) 2022–2025 workplan and has since been reinforced through annual workplans of the Committee for Medicinal Products for Human Use (CHMP). The CHMP 2025 workplan includes the key objective to:

“Develop a roadmap of RWE guidance to support high-quality RWE generation and continue strengthening the use of RWE for regulatory decision-making.”

Mapping the current landscape

To implement this objective, the CHMP’s Methodological Working Party (MWP), formed a drafting group with experts from both the MWP and the European Specialized Expert Community (ESEC) for Methodology. The group launched its activities in November 2022, beginning with a comprehensive review of existing guidance from regulatory authorities in the EU, US, UK, Canada, Switzerland, and Japan, along with health technology assessment (HTA) bodies in France, the UK, and Canada.

This review identified four priority areas where additional EU regulatory guidance could be valuable:

• Data quality and access
• Use of RWD in non-interventional studies (NIS)
• Use of RWD in clinical trials
• RWD use in regulatory submissions

Establishing standards for data quality

Data quality emerged as a central concern across all jurisdictions reviewed, though the level of detail and focus varied. Some agencies addressed it as part of broader guidance documents, while others published standalone materials dedicated to the topic.

In the EU, the HMA-EMA Data Quality Framework for EU medicines regulation adopted by the CHMP in October 2023, provides a common foundation for regulatory expectations. It builds on recommendations from TEHDAS and consolidates existing approaches, outlining principles for assessing data sources and suggesting metrics to evaluate reliability and completeness. Meanwhile, other agencies such as the FDA have issued tailored guidance based on specific data types, including electronic health records (EHRs), insurance claims, and registries.

Improving transparency in NIS

The use of RWD in NIS was another area addressed by all agencies in the review. Common regulatory expectations include a clearly defined research question, justification for the chosen study design, defined exposure and outcome measures, and approaches to address confounding and bias.

To support consistency in this area, the drafting group developed a reflection paper on the use of RWD in NIS to generate RWE. The document discusses the design, conduct, and analysis of such studies, while also covering legal, governance, and transparency considerations. It was open for public consultation between May and August 2024, receiving nearly 700 comments from stakeholders including academia, industry, patient groups, and regulatory authorities. After revisions, the final version was adopted by the CHMP in March 2025.

Addressing gaps in clinical trial guidance

In contrast to the more established areas of data quality and NIS, guidance on the use of RWD in clinical trials remains limited. Regulatory bodies such as the FDA and NICE have issued guidance on externally controlled trials using RWD, with a focus on ensuring comparability between trial participants and RWD-derived controls. These documents recommend pre-specification of study protocols and strategies to mitigate bias, noting the importance of transparency in trial design and analysis.

The UK’s MHRA has also published guidance on pragmatic randomized controlled trials using RWD. These studies follow conventional RCT principles but may require particular attention to data collection and endpoint measurement when conducted in routine care settings.

More broadly, RWD considerations for clinical trials are also addressed in the ICH E6(R3) Annex 2 Guideline for Good Clinical Practice, which includes aspects related to data quality and format, such as terminologies and data standards.

Incorporating RWD into regulatory submissions

Some agencies have also begun to address how RWD is submitted in regulatory dossiers. For example, the FDA recommends use of Clinical Data Interchange Standards Consortium (CDISC) standards and provides guidance on file formats for datasets. Swissmedic offers similar recommendations for identifying and referencing RWD and RWE in submissions.

Next steps in guidance development

Of the four areas identified in the review, two; data quality and the use of RWD in NIS; have already resulted in adopted guidance. The MWP has now prioritized the development of guidance on the use of RWD in clinical trials, with externally controlled trials considered the most immediate focus.

The MWP workplan for 2025 to 2027 includes the development of a concept paper on externally controlled trials. Since external controls may be drawn from both prior trials and RWD sources, the initiative will involve collaboration between RWE experts, biostatisticians, and the Scientific Advice Working Party (SAWP). The concept paper is intended to inform future guidance in this area.

Other areas under consideration for future development include augmented control trials, which supplement small trial control arms with RWD, and pragmatic trials in real-world clinical settings. Guidance on data standards for regulatory submissions may also be explored, depending on evolving needs.

Annual updates to the MWP workplan will continue to reflect the priorities of the EU medicines regulatory network. These ongoing efforts aim to ensure that guidance evolves in step with scientific and technical advancements, supporting the effective and transparent use of RWE in regulatory decision-making.