Raising the Bar: What EMA, FDA, and HTAs Want from Real-World Evidence Today

The use of real-world data in regulatory submissions is no longer novel. It is expected. But as agencies like the FDA and EMA signal increasing openness to observational evidence, a more pressing question emerges: Is this shift substantive, or simply cosmetic? 

Amid the rhetoric of innovation, Target Trial Emulation (TTE) and Quantitative Bias Analysis (QBA) have entered the regulatory lexicon. TTE offers a structured way to design and simulate hypothetical trials using observational data. QBA, as an advanced application of TTE, takes on the less glamorous task of quantifying bias the confounding, misclassification, and selection problems that haunt most real-world analyses.

Both TTE and QBA are sophisticated, defensible, and technically sound. But are they being taken seriously?

In cases of gene therapies, rare disease treatments, oncology programs with external controls, regulators have nodded approvingly at TTE-like frameworks. EMA’s Parallel Consultation pilots and recent FDA approvals suggest a willingness to engage. HTA bodies, too, are beginning to probe not just what real-world data are used, but how methodological limitations are addressed.

Yet much of the activity remains in exploratory discussions, and not necessarily translates itself to full inclusion in actual submissions. The story is similar with QBA. HTA agencies increasingly ask for sensitivity analyses and bias quantification. Still, methodological depth is often limited to surface-level gestures; in most cases we acknowledge uncertainty without truly accounting for it.

What appears to be changing is not the science, which in most cases has been here for some time, but the expectation of accountability. Regulatory and HTA audiences are less interested in abstract assurances and more focused on defensible logic chains:

Why this population? Why this endpoint? What does uncertainty really mean in practice? This is not just a statistical discussion. It is a strategic one. 

On June 9th, Adigens Health will host a webinar examining what’s real and what’s rhetorical in the regulatory response to TTE and QBA. Are we seeing a broader adoption of these approaches into mainstream evidence frameworks? Are review bodies evolving their expectations?

For stakeholders developing evidence strategies, the answer increasingly appears to be yes.