In healthcare regulation, external controls regulation is emerging as a vital approach to generating evidence for drug approvals when traditional randomised controlled trials (RCTs) are impractical. This method uses data from outside trial protocols, such as real-world data (RWD), to form comparisons. In this update, I examine the European Medicines Agency’s (EMA) latest draft concept paper (linked below) and its impact on policy and market access.

Background and Context

RCTs remain the benchmark for proving drug safety and efficacy. Yet, in cases like rare diseases, ethical or logistical barriers often hinder their use. External controls, sourced from other trials or RWD, provide an alternative. Specific guidance on this method is absent in Europe which is driving the need for a structured framework to enable comparisons.

Core Challenges and Insights

Defining the Scope

The proposed external controls regulation seeks to clarify when and how such data can support regulatory decisions. The EMA aims to set minimum standards for its use in assessing efficacy or safety. Importantly, this excludes uses like historical data for context or network meta-analyses, which other guidelines cover.

Methodological Barriers

Using external controls poses risks of bias and confounding due to the lack of randomisation. Therefore, robust statistical methods are crucial to address these issues. Here are key concerns:

• Data must be relevant, reliable, and timely for credibility.
• Prospective planning reduces bias compared to retrospective analysis.
• Operational hurdles, like data access, need resolution for practical use.

Global and Local Perspectives

While the EMA focuses on Europe, parallels exist with the US FDA’s RWD frameworks. Nevertheless, regional differences, such as data privacy laws like GDPR, demand tailored approaches. For instance, EU-based data sources might take precedence to reflect local patient demographics.

Implications for Policy and Access

External controls could speed up access to therapies for unmet needs. However, alignment with Health Technology Assessment (HTA) bodies is essential to avoid reimbursement delays. Moreover, this approach may support value-based pricing by showcasing real-world outcomes. The EMA’s consultation, open until 31 October 2025, offers a chance to shape these policies.

Recommendations for Stakeholders

First, invest in quality data systems to enable robust external control studies. Second, adopt advanced statistical tools to ensure valid results. Finally, engage with regulators early to align on expectations. The EMA’s workshop on 3 November 2025 provides a forum for such dialogue.

Conclusion

In summary, proposed external controls regulation stands to transform evidence generation in healthcare. It promises faster drug development while demanding strict methodological standards. Industry leaders must contribute to ongoing discussions to refine this framework. Together, we can balance innovation with patient safety for better outcomes.