The Fast Lane to Evidence? What the New EMA Report Means for Trial Emulation

The European Medicines Agency (EMA) just released its third annual report on real-world evidence (RWE) in regulatory decision-making and the signal is clear: Target Trial Emulation (TTE) is no longer experimental. It’s on the regulatory radar.

While much of the report focuses on the operational growth of the DARWIN EU® network, a quieter but more meaningful development emerges from the methodology section: EMA is actively exploring how target trial emulation and estimand frameworks can strengthen regulatory-grade RWE.

What the New EMA Report Tells Us

The third RWE experience report (Feb 2024–Feb 2025) paints a picture of growing maturity and expanding ambition:

🔹The number of completed regulator-led RWE studies more than doubled over the previous year.

🔹Median study timelines dropped to just 4 months, largely thanks to DARWIN EU®.

🔹Feasibility success rates rose to 78%, as more data partners came online and outcome definitions were refined.

Crucially, the role of RWE has expanded far beyond its traditional niche in pharmacovigilance. Studies now routinely support marketing authorisation applications (MAAs), HTA joint clinical assessments (JCAs), and public health and policy decisions.

"Real-world data are now used not only for safety questions but increasingly for understanding patterns of use, estimating treatment effectiveness, and supporting clinical trial designs."

This evolution reflects a strategic shift: RWE is becoming a forward-looking tool for evidence generation, not just a retrospective signal detection mechanism.

Advanced Methods Moving to the Forefront

To support this expanded scope, EMA has turned its attention to methodology. The latest report notes an increasing use of modern causal inference techniques:

"Several methodological advancements have been developed or applied in the context of these studies, including approaches to adjust for immortal time bias, marginal structural models, and time-varying confounding."

These are not cosmetic improvements. They represent a deeper commitment to ensuring RWE can answer causal questions with the same clarity and credibility expected of trials.

This is where frameworks like target trial emulation and estimands bring structure, transparency, and reproducibility to RWD-based studies.

"Building on the potential of modern causal inference methods, including target trial emulation, is a core goal of the joint TARGET-EU project between the EMA and the Methodology Working Party."

Target Trial Emulation: From Method to Expectation

TTE asks a simple question: If we could run a randomized trial, what would it look like? Then it builds a study using observational data that mirrors that design, from eligibility criteria and treatment assignment to timing and follow-up.

TTE provides a framework for pre-specifying protocols, aligning with estimands, and reducing common biases. It’s increasingly viewed as the gold standard for RWE intended to support regulatory or HTA decision-making.

"The need to move towards decision-grade RWE requires strengthening study design, not only through data quality improvements but also by building more robust and transparent causal inference strategies."

What Sponsors Should Do Next

If you're preparing a submission with real-world evidence, it may no longer be enough to rely on retrospective comparisons or simple matching.

You need to:

🔹Define your target trial explicitly

🔹Justify why an RCT is infeasible

🔹Specify your estimand and causal contrast

🔹Ensure time zero, exposure, and outcomes are consistently aligned

🔹Pre-register your protocol or make it available for review

In short, you need to treat RWE as if you're running a real trial.  If you don’t, regulators will. 

Final Thought: Time to Lean In

The EMA's latest report may not have put TTE on the cover, but make no mistake: the framework is gaining traction where it matters most. As regulators move from passively accepting RWE to actively designing with it, trial emulation will become not just accepted, but expected.

Sponsors who move early to embrace this shift will be better positioned to influence decisions, not just respond to them.

At Adigens Health, we're helping clients do just that. We embed methodological rigour early, ask better questions, and design studies that regulators and HTA bodies can trust.

To learn more about how to apply TTE in your development strategy or build a fit-for-purpose external control, explore our recent blogs and events at www.adigenshealth.com.