Real‐world evidence (RWE) has an increasing role in both pre-, and post- approval applications to support the authorization of new medicines and indications, or to address post-marketing safety concerns. Therefore, the use of Real-World Data (RWD) in regulatory processes at the European Medicines Agency (EMA) varies depending on whether it is being used for marketing applications or post-approval submissions. While RWD is increasingly recognized as valuable in both contexts, the goals, methodologies, and regulatory expectations differ significantly.
1. Purpose and Context of RWD Use
Marketing Application (Pre-Approval):
- Purpose: During the marketing application phase, RWD can support evidence from clinical trials to demonstrate the safety and efficacy of a new medicinal product. It is typically used to supplement data from Randomized Controlled Trials (RCTs) when specific questions cannot be fully addressed by RCTs alone.
- Context: RWD may be used in cases where conducting RCTs is not feasible or ethical, such as for rare diseases, or where additional RWE is needed to demonstrate effectiveness in broader populations or in specific subgroups not well-represented in clinical trials.
Post-Approval Submissions:
- Purpose: Post-approval, RWD is primarily used for ongoing monitoring of a product’s safety, effectiveness, and utilization in the broader patient population. This can include pharmacovigilance activities, safety updates, and periodic benefit-risk assessments.
- Context: RWD is crucial in understanding long-term safety, real-world effectiveness, and off-label use in diverse patient populations. It can also be used to fulfill post-authorization safety or efficacy studies (PASS/PAES) required by the EMA.
2. Types of RWD Used
Marketing Application:
- Types of Data: RWD used in marketing applications might include data from expanded access programs, observational studies, registries, and sometimes historical control data. The focus is on data that can provide comparative effectiveness or complement clinical trial data to meet specific regulatory requirements.
- Regulatory Expectations: The EMA expects RWD used in this context to be of high quality, with a clear rationale for its use, and to be supported by robust methodologies to minimize bias. The integration of RWD with RCT data must be scientifically justified and capable of withstanding regulatory scrutiny.
Post-Approval Submissions:
- Types of Data: Post-approval RWD includes data from electronic health records (EHRs), insurance claims databases, patient registries, and spontaneous reporting systems. This data is used for ongoing safety monitoring, risk management, and real-world effectiveness studies.
- Regulatory Expectations: The EMA is particularly focused on the completeness, accuracy, and timeliness of RWD in the post-approval phase. RWD must be continuously updated and capable of identifying new safety signals, monitoring adverse events, and assessing the long-term benefit-risk profile of the product.
3. Methodological Considerations
Marketing Application:
- Methodology: When used in marketing applications, the methodologies for RWD analysis must be rigorously designed to ensure the data’s validity and reliability. This includes careful consideration of study design, data sources, and statistical methods to control for confounding factors and biases.
- Regulatory Submission: The EMA requires that any RWD used in a marketing application be thoroughly validated and that the submission clearly explains how the RWD complements or supplements traditional clinical trial data. The focus is on demonstrating that the product is safe and effective for its intended use.
Post-Approval Submissions:
- Methodology: In the post-approval phase, the emphasis is on continuous data collection and analysis. Methodologies may include cohort studies, case-control studies, and surveillance programs designed to detect rare or long-term adverse effects. The methods used must be flexible enough to accommodate the dynamic nature of real-world settings.
- Regulatory Submission: The EMA expects detailed periodic safety update reports (PSURs) and post-authorization safety studies (PASS) that incorporate RWD to monitor ongoing safety. These submissions should demonstrate how the product performs in a broader population over time and whether any new risks have emerged.
4. Regulatory Challenges
Marketing Application:
- Challenges: The primary challenge is ensuring that RWD is of sufficient quality and relevance to support regulatory decision-making. There can be concerns about the comparability of RWD with clinical trial data, especially if the data is derived from less controlled environments and patient inclusion/exclusion criteria do not have a good match.
- Regulatory Acceptance: The EMA is cautious in accepting RWD in marketing applications, requiring strong justification for its use and clear evidence that it meets regulatory standards for quality and reliability.
Post-Approval Submissions:
- Challenges: The main challenges involve managing the large volume of data, ensuring data integrity, and effectively identifying and interpreting safety signals. Additionally, there is the need to harmonize data from different sources and countries to provide a consistent picture of the product’s safety and effectiveness.
- Regulatory Acceptance: The EMA is more accustomed to using RWD in the post-approval phase, particularly for safety monitoring. However, the agency still requires that the data be robust and that any findings are actionable and contribute to the ongoing assessment of the product’s benefit-risk profile.
5. Impact on Regulatory Decisions
Marketing Application:
- Impact: RWD in marketing applications can influence the approval process, particularly in cases where traditional RCT data is limited or when additional evidence is needed to support a broader label or indication. However, the impact is often supplementary, and RCTs remain the cornerstone of regulatory approval.
Post-Approval Submissions:
- Impact: Post-approval, RWD plays a critical role in shaping regulatory decisions related to label updates, risk management plans, and even product withdrawals if significant safety concerns arise. The ongoing collection and analysis of RWD can lead to changes in clinical practice recommendations and regulatory actions based on real-world use.
In conclusion, the use of RWD differs significantly between marketing applications and post-approval submissions at the EMA. In marketing applications, RWD is often supplementary, used to support or enhance the evidence from RCTs. Post-approval, RWD is integral to ongoing safety monitoring, risk management, and assessing the real-world effectiveness of a product. The methodologies, regulatory expectations, and impact on decision-making vary accordingly, reflecting the different stages of a product’s lifecycle and the evolving role of RWD in regulatory science.