When Real-World Evidence Gets Real: Lessons from the Frontlines of Target Trial Emulation

It’s not every day that three leaders in epidemiology, health technology assessment, and regulatory science gather to discuss what might become the new standard in evidence generation. But that’s exactly what happened on June 9th, when Adigens Health co-founders Miguel Hernán and Radek Wasiak were joined by Uwe Siebert , Professor of Public Health, Medical Decision Making and Health Technology Assessment at UMIT TIROL – University for Health Sciences and Technology, Austria, and Director of the Continuing Education Program on HTA & Decision Science (www.htads.org) as well as President-Elect of ISPOR, for a lively and timely webinar.

The topic? How decision-makers are responding to Target Trial Emulation (TTE) and more generally, to advanced methodological approaches in regulatory and HTA submissions, and if these methods are truly ready for primetime.

From Method to Movement

The past decade has seen a dramatic shift in how real-world evidence (RWE) is viewed. Once considered a supplement (or worse, a soft substitute) for randomized controlled trials (RCTs), RWE is increasingly expected to answer tough, causal questions. The FDA, EMA, NICE, and other HTA bodies are adapting their guidance, slowly but surely, to this new reality.

TTE has emerged as a central framework in this evolution. As Miguel Hernán explained, TTE isn’t just rebranding observational studies. It’s a structured, principled way of asking: “If we had run a randomized trial, how would we have done it?” And then approximating that trial using observational data without skipping on rigor or transparency.

Why This Matters Now

Parallel regulatory and HTA assessments in Europe, especially under the EU Joint Clinical Assessment (JCA), are changing the rules of engagement. Submissions must now be designed with comparative evidence front and center. This means early planning, better use of real-world data, and clearer articulation of bias and uncertainty.

As Uwe Siebert highlighted, TTE and advanced methods offer a way forward. They allow sponsors to explicitly define the estimand, control for confounding, and quantify residual bias. But, as he cautioned, methodology isn’t everything. Fit-for-purpose data, clinical validity, and trust-building with agencies are just as important.

The Politics of Credibility

A question was posed by Radek Wasiak who noted that even well-executed studies using TTE can fail to influence decisions if stakeholders don’t trust the methods or the data. There’s a human and institutional layer to evidence that can’t be ignored.

Do regulators and HTA bodies judge the sponsor more than the science? Does unfamiliarity breed skepticism, even when the methods are sound? These are the questions we need to ask, especially in high-stakes therapeutic areas where RCTs are infeasible.

So… Will This Become the New Standard?

The consensus was cautious optimism. TTE is gaining traction. Advanced methods are no longer just the domain of epidemiologists and statisticians focused on observational data. And real-world data, when used carefully, is becoming essential in modern evidence packages.

But a dominant theme emerged: this is not a plug-and-play revolution. It’s a shift in culture, expectations, and collaboration. If we want TTE to be the new standard, we need:

• Better training across functions

• Earlier conversations with regulators and HTA bodies

• High-quality, transparent data

• And a willingness to move beyond precedent when the science calls for it

As the discussion closed, all three speakers agreed: it’s not about replacing RCTs. It’s about knowing when and how to augment them with the real-world insights that patients, payers, and providers urgently need.

📌 Missed the webinar? Stay tuned: Adigens Health will continue to explore these themes in future blogs, publications, and workshops.