Real-World Data (RWD) and Real-World Evidence (RWE) to Support Medicinal Product Development
The use of Real-World Data (RWD) and Real-World Evidence (RWE) is playing an increasingly important role in the development, authorization, and monitoring of medicinal products. To move forward, the European Medicines Agency (EMA) has published a comprehensive document explaining how RWE, derived from RWD, can support regulatory decision-making. The document focuses on the practical applications of RWE, such as filling evidence gaps, improving efficiency in regulatory processes, and generating evidence in a timely manner to aid in the decision-making processes of regulators. Furthermore, the EMA can assist in identifying the best resources to answer specific research questions, conducting targeted analyses, and ensuring independent and transparent evidence generation.
Applications and Benefits of RWD/RWE
One of the major advantages of utilizing RWE is that it can complement evidence gathered from traditional clinical trials, particularly in areas where data gaps exist throughout the product lifecycle. The use of RWE allows for multiple products to be monitored simultaneously, avoiding unnecessary duplication of studies and streamlining processes for marketing authorization holders (MAHs). The speed and efficiency of evidence generation are enhanced, which in turn may shorten the approval steps for specific studies.
EMA’s document (Real-world evidence provided by EMA - Support for regulatory decision-making) published on the agency’s Big Data website highlights that scientific questions can currently be addressed using three main RWE approaches:
1. DARWIN EU® (Data Analysis and Real-World Interrogation Network)
2. Internal Electronic Health Databases from various EU countries
3. Studies conducted under EMA framework contracts
These approaches allow rapporteurs, assessors, or national regulatory representatives to submit questions to the EMA, aiding in the evaluation of medicinal products by providing additional data to support their assessments with regard to efficacy and safety.
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European GMPs and the Role of the Qualified Person (QP): Clinical Trial Supplies (Day 3 only) – Live Online Training
EMA's Technological Advancements: Scientific Ex- plorer
In March 2024, the EMA introduced the Scientific Explorer, an AIenabled tool designed to assist EU regulators in navigating regulatory scientific information. The tool offers focused and precise searches of the EMA network's sources, simplifying and accelerating decision-making processes. This AI-driven tool is part of EMA's broader efforts to modernize its regulatory practices and improve access to relevant RWD and RWE.
Insights from EMA’s Pilot Study on RWE
Between September 2021 and February 2023, the EMA conducted a pilot project to generate RWE to support regulatory evaluations. This initiative, detailed in an article published in Clinical Pharmacology & Therapeutics (Real-World Evidence to Support EU Regulatory Decision Making Results from a Pilot of Regulatory Use Cases), provided key insights into how RWE can be integrated into regulatory decision-making.
The pilot study revealed several important lessons:
- Complementarity with Clinical Trials: RWD and RWE can enhance the evidence provided by traditional clinical trials, helping to fill evidence gaps at various stages of a product’s lifecycle.
- Timely Evidence Generation: There is a need for faster access to representative data to meet regulatory timelines.
- Collaboration and Communication: Early and close interaction with stakeholders, including the agency's scientific Committees, is crucial for understanding research questions and ensuring the relevance of studies conducted.
The agency aims to leverage these insights to maximize the potential of RWE in future regulatory frameworks.
Harmonization Efforts
The EMA has taken steps to harmonize the use of RWE in regulatory environments. One key initiative is the ICH Reflection Paper on Real-World Evidence (RWE) and Real-World Data (RWD) to support regulatory decision-making, which aims to standardize terminology and converge principles for planning and reporting RWD-based studies. The paper, which was revised following a public consultation from June to September 2023, outlines the following areas for harmonization:
- Standardization of Terminology: Aligning definitions for RWD and RWE to ensure consistency across regulatory frameworks.
- Protocol and Report Format: Establishing a common format for study protocols and reports submitted throughout the lifecycle of a medicinal product.
- Study Registration: Encouraging the registration of protocols and reports to promote transparency and accountability.
Additionally, an annex in the reflection paper summarizes existing regulatory guidance and resources related to RWD and RWE.
RWD in Non-Interventional Studies (NIS)
Non-interventional studies (NIS) or so-called "observational studies", which do not involve randomization or blinding, are increasingly recognized as valuable sources of RWD for regulatory purposes. While clinical trials remain the primary source for assessing the benefits and risks of investigational medicinal products (IMPs), NIS have gained traction in post-authorization safety assessments. The EMA has published a draft Reflection Paper on the use of RWD in NIS to generate RWE, which was open for public comment until August 2024. The draft addresses the methodological challenges of NIS and explores ways to improve their acceptance for efficacy assessments. The EMA's ongoing projects aim to generate more structured RWD and incorporate this data into regulatory decision-making processes, thereby expanding the role of NIS in evaluating medicinal products.
Furthermore, following the previously published ICH reflection paper on Real-World Evidence (RWE) and Real-World Data (RWD) to support regulatory decision-making, the ICH M14 Guideline on General Principles on Plan, Design and Analysis of Pharmacoepidemiological Studies that utilize Real-World Data for Safety Assessment of Medicines has been published in May 2024 for public consultation. This guideline focuses on non-interventional studies using RWD, offering recommendations for the safety assessment of medicines, including drugs, vaccines, and other biological products.
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The ICH M14 Guideline aims to align international best practices on planning and conducting safety studies with RWD, while expanding the potential for using RWE to assess medicine effectiveness and utilization in routine clinical practice. The guideline also connects with other ICH efforts, such as the ICH E6(R3) (Good Clinical Practice (GCP)) and the ICH M11 (CeSHarP) guideline, which focuses on clinical trials and the corresponding protocols.
Conclusion
The European Medicines Agency’s initiatives around RWD and RWE reflect a significant shift towards integrating real-world data into the regulatory framework for medicinal product development. By harmonizing standards, utilizing advanced technologies like artificial intelligence (AI), and expanding the scope of non-interventional studies, the EMA is streamlining processes and enhancing the robustness of evidence used in regulatory decisions. These efforts not only promise faster and more comprehensive evaluations but also enable a more responsive regulatory environment that can adapt to the evolving regulatory landscape of (investigational) medicinal products.
About the Author
Dr Andrea Kühn-Hebecker is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the area packaging, herbal medicinal products, development and Lifecycle Management.
