Lessons for Oncology, Rare Disease, and ATMP Developers
If you look closely at the new EU HTA Regulation, you’ll notice something subtle but far-reaching: it doesn’t just change how evidence is assessed; it changes how evidence must be created.
And nowhere is this more apparent than in clinical trial design.
For programs in oncology, rare diseases, and advanced therapies, the shift is profound. Regulatory approval remains the primary purpose of the pivotal trial and always will. But early HTA alignment creates three critical advantages.
First, it sharpens the overall development strategy, ensuring that the program is moving toward a position where patient access will be achievable at a viable price.
Second, it enables teams to design pivotal studies that meet EMA requirements while being optimized for HTA where feasible, avoiding design choices that would later undermine comparative assessment.
And third, it allows sponsors to plan supplementary evidence generation early — natural history data, indirect comparisons, real-world evidence — so these components are ready in time for the JCA and national assessments.
This integrated approach does not ask the pivotal trial to do “double duty”, but to be part of a coherent evidence strategy.
This dual purpose is the new reality.
Trial design is changing under the EU HTA Regulation because evidence now has to stand up for access as well as approval.
In brief:The EU HTA Regulation affects trial design because it changes the questions evidence must answer—not just how evidence is reviewed. For oncology, rare disease, and ATMP programs, early alignment helps teams anticipate comparator shifts, endpoint expectations, and where supplementary evidence (natural history, ITCs, RWE, long-term follow-up) will be needed. The goal isn’t to make the pivotal trial do everything—it’s to build an evidence plan that holds up at access.
Oncology: A Moving Target
Few therapeutic areas evolve as quickly as oncology. New approvals redefine standards of care every year. Biomarker-driven stratification creates subpopulations that didn’t exist a decade ago. Treatment sequencing varies across Europe in ways that challenge a one-size-fits-all development strategy.
We often meet oncology teams who designed trials around current practice, only to find that the JCA will evaluate them against a different reality.
An FDA-aligned trial might compare against a therapy that is no longer the dominant choice in Germany. A pivotal trial may focus on endpoints that the EMA supports, while HTA assessors emphasize durability, quality of life, or overall survival.
The lesson is clear: oncology programs need foresight — not because every future HTA requirement can be engineered into the pivotal trial, but because early insight helps teams optimize what is feasible, understand remaining gaps, and plan complementary evidence that will be essential by the time of the JCA.
Rare Disease: When Evidence Is Scarce
Rare disease programs face different challenges. Small populations, heterogeneity, and ethical constraints often lead to single-arm studies or reliance on surrogate endpoints. These designs are scientifically justified, but HTA bodies expect a level of contextualization that goes beyond regulatory norms.
This raises a central question: how to prove relative effectiveness when the evidence is inherently constrained?
In this setting, natural history studies, real-world evidence, and creative statistical approaches become indispensable. But these aren’t retroactive fixes, they must be planned early and executed intentionally.
ATMPs: The Problem of Time
Advanced therapies introduce yet another complexity: time. Durability of effect often cannot be demonstrated within the confines of a traditional regulatory timeline. HTA bodies, rightly, want to understand long-term outcomes, even when long-term data doesn’t yet exist.
Programs relying on short-term endpoints must justify how early signals translate into meaningful, sustained benefit. Post-market commitments, real-world evidence strategies, and long-term follow-up plans are essential components of an ATMP development program, particularly when durability data are still emerging.
We’ve seen ATMP teams who navigated the FDA pathway smoothly only to encounter resistance in Europe because their still immature durability data couldn’t answer HTA questions.
What matters is a long-term evidence plan built early enough to answer the questions that will come later.
Designing for Both Worlds
The core challenge, and opportunity, in the new HTA landscape is designing trials that can thrive in both regulatory and HTA reviews. EMA may focus on benefit–risk. HTA bodies focus on relative value. These are different lenses, and trial design must accommodate both.
In our experience, dual-purpose trial design doesn’t slow programs down.
- It strengthens them.
- It clarifies decision-making.
- It reduces rework later.
- And it positions companies for success both at approval, and at access.
The Takeaway
The EU HTA Regulation reshapes not only how evidence is assessed, but how it is created. It requires development teams to anticipate the European landscape not as it is today, but as it will be at the time of review.
The companies who adopt this mindset early will design trials that can adapt as evidence and context change. They’ll anticipate comparators, build relevant endpoints, and collect contextual evidence that resonates with payers and clinicians.
And most importantly, they’ll enter Europe with evidence strong enough to support both the science and the story of their innovation.
Related reading
Explore the guide: EU HTA Regulation guide
Continue reading: Should you pursue a Joint Scientific Consultation (JSC)?
