Why Comparator Choices in Europe Catch US Companies Off Guard
There are few moments more disorienting for a US-based biotech team than seeing their first European PICO. The assumptions that made perfect sense for FDA alignment suddenly look mismatched in a European context. Comparators appear that were never part of earlier discussions. Subpopulations come into focus that had not been viewed as meaningful. These shifts reflect how value is assessed for access and reimbursement in Europe. Unlike the US, Europe runs evidence review through formal HTA pathways. Under JCA, the clinical assessment is now centralized at EU level, while national HTA decisions continue.
In brief: Under EU HTA, comparators are anchored in real clinical practice - not regulatory precedent - and that difference shows up sharply in PICO scope. One indication can translate into multiple PICOs across lines of therapy, subpopulations, or country-specific standards of care. Teams get caught off guard when comparator strategy is treated as fixed at trial start, rather than monitored and stress-tested as practice evolves.
Where the Disconnect Begins
Trial design typically revolves around regulatory requirements (FDA and EMA). Sponsors choose comparators based on scientific rationale, feasibility, ethics, and FDA input. The goal is to demonstrate safety and efficacy in a controlled framework that can withstand regulatory scrutiny.
Europe, however, brings HTA expectations into the equation.
HTA bodies choose comparators based on clinical practice, not regulatory guidance. They ask, “What is the most relevant treatment option patients are actually receiving?” That answer varies — sometimes dramatically — across countries.
France may expect one comparator.
Germany another.
The Nordics something different still.
And all of these expectations can influence the PICO assessment scope chosen for the JCA.
The Surprise of Multiple PICOs
One of the most challenging parts of the new system is that a single label indication may turn into several PICOs. If a therapy is used differently across lines of treatment or across clinical subpopulations, HTA assessors can split the PICO to reflect that complexity.
A biotech developing an oncology therapy may suddenly find itself facing:
- A PICO comparing against first-line standard of care (SOC) option 1
- A PICO comparing against first-line standard of care (SOC) option 2
- A PICO comparing against a second-line option
- A PICO focused on biomarker-positive subgroups
- A PICO for patients who progressed on prior therapy
Each requiring separate analysis.
Regulatory approval asks whether a drug works and is safe.
JCA asks how much better it is versus the relevant SOC, and it asks that question multiple times.
Why It’s So Easy to Get Caught Off Guard
The root issue isn’t that US companies “miss” something. Europe formalizes real-world clinical practice into scope and comparator requirements, a moving target that evolves faster than regulatory guidance.
When you design a trial three years before filing, the SOC at that moment may be completely different by the time you reach the JCA.
We’ve seen companies blindsided when a new therapy entered the market just months before their review. We’ve seen comparators chosen based on regional usage patterns that were invisible during trial design. We’ve seen subpopulations that were scientifically sound for FDA but insufficiently granular for European payers. European HTA decisions follow clinical practice, and practice changes quickly — with regional variation in treatment pathways, new entrants to the market, and differing views on which patient groups matter most.
When development planning does not reflect this variation, the PICO can expose gaps that are difficult to close later.
How Teams Can Get Ahead of the PICO Curve
Success in this new environment comes from thinking like a European HTA assessor long before submission. That means understanding:
- How treatment pathways are evolving
- Which comparators are reimbursed where
- How guidelines differ by country
- How clinical practice diverges from label
- How value is defined in each context
When we partner with teams, we help them see these patterns early, before evidence is locked and before trial design becomes inflexible.
The Bottom Line
The PICO follows a different evidentiary logic, one that reflects how Europe makes access decisions.
Companies who understand this lens early will design stronger trials, prepare better evidence, and avoid the costly surprises that derail European launches.
What comes next is a different kind of preparation — one that builds evidence able to stand across Europe’s access decisions.
Related reading
Explore the guide: EU HTA Regulation guide
Continue reading: How EU HTA reform will change trial design
