Anticipating EU HTA expectations: Insights from our PICO simulation framework

Authored by: Cécile Rémuzat, Malek Dimassi, Eric Faulkner, Clément François, Nour Grioui, Eve Hanna, Shrividya Iyer, Agnieszka Kocwin, Ulrike Kuchenbecker, Anna Kuciara, Simon Pannett, Radoslaw Skowron

As the EU Joint Clinical Assessment (JCA) becomes a central component of market access strategy, anticipating likely Health Technology Assessment (HTA)-relevant Population, Indication, Comparator and Outcomes (PICO)s has never been more critical. Early planning before pivotal trial design is essential to ensure that trial endpoints, comparators, subpopulation and subgroup definitions are prospectively aligned with HTA expectations, rather than requiring post hoc adaptations that may weaken the evidence package.

At Inizio Ignite, Putnam, we have developed a structured PICO simulation framework to proactively model potential population, intervention, comparator, and outcome expectations ahead of JCA and national HTA submissions. Our current simulations across multiple oncology and rare disease assets highlight both the methodological complexity and the strategic value of early PICO anticipation.

What is the Putnam PICO Simulation Framework?

Our PICO simulation approach is a structured, evidence-anchored process designed to anticipate HTA-relevant PICOs prior to formal assessment.

It integrates:

• European and national clinical guidelines
• Regulatory context and anticipated EU label
• Pivotal clinical trial evidence
• HTA precedents across key EU Member States
• Real-world clinical practice insights
• Emerging pipeline competitors expected to be relevant at the time of assessment

The objective is to define a range of plausible PICOs that may be required by HTA bodies.

How the Simulation Works

The framework follows an iterative process that progressively refines PICO hypotheses by integrating the evidence and contextual factors most likely to influence HTA decision-making.

1. Define the intervention profile

• Anticipated EU label
• Intended positioning within the treatment pathway
• Development timelines

2. Establish a baseline EU PICO

A first reference PICO set is defined based primarily on European clinical guidelines.

3. Integrate multi-level evidence

Evidence that will be typically considered by HTA bodies is progressively layered in:

• European and then national clinical guidelines
• Approved and reimbursed comparators
• Previous HTA reports
• Country-specific practice patterns
• Emerging pipeline competitors

Global or non-EU guidelines are considered only when they are recent and explicitly relevant to the EU context.

4. Explicitly document variability

At each stage, differences across countries and over time are systematically identified and documented. PICOs are iteratively updated and, where needed, expanded through tracked revisions.

5. Consolidate and validate

The result is a consolidated set of PICO hypotheses supported by documented assumptions and evidence sources, validated through expert input (including internal experts and, where relevant, proxy HTA experts and Key Opinion Leaders (KOLs), and structured to enable systematic tracking of both EU-level and country-specific PICO.

What We Are Seeing in Current Simulations?

Across current oncology and rare disease assets, the number of potential PICOs varies substantially.

Depending on comparator grouping (e.g., “OR” vs. “AND”), subpopulation definition, and country variation, we observed:

• As few as 2-4 PICOs in focused settings
• Up to 14-20 PICOs in more complex or heterogeneous indications
• Variability driven primarily by comparator structuring and subpopulation splits

This range highlights why early anticipation is essential: the difference between a narrowly scoped PICO and a conservatively separated PICO set can dramatically alter evidence requirements.

Key Lessons Learned from Current Simulations

Across assets, several recurring themes have emerged.

1. European clinical guidelines are necessary but could be insufficient

European guidelines remain foundational but can be:

• Often outdated in fast-moving areas
• Inconsistent with national guidelines
• Insufficiently granular for specific subpopulations

Cross-referencing national clinical guidelines and HTA precedents is essential to ensure alignment with country-specific standards and evidence requirements. Populations and comparators should be validated early with national KOLs and HTA experts to clarify local expectations and anticipate potential areas of challenge. In parallel, conducting real-world evidence (RWE) analyses to characterize treatment patterns and patient population characteristics can further strengthen the simulation.

2. Comparator structuring (“OR” vs “AND”) drives PICO inflation

When multiple comparators are listed in guidelines:

• Grouping them under one PICO reduces complexity
• Separating them into distinct PICOs increases rigor but multiplies evidence needs

While a conservative separation approach is necessary to anticipate HTA scrutiny, it can substantially increase the number of potential PICOs. In such cases, a structured prioritization process becomes important to ensure that evidence planning is focused first on the PICOs most likely to shape JCA conclusions.

3. Trial design does not always align with real-world SoC

When trial comparators reflect mechanistic or scientific constraints rather than routine clinical practice, HTA relevance may be questioned.

This is particularly common when:

• The investigational product requires a specific backbone therapy for pharmacologic reasons
• The trial comparator is not widely used in routine practice (e.g., not EMA-approved for the indication and/or not supported by treatment guidelines)
• The asset aims to introduce a new sequencing logic rather than compete within the existing pathway

Assets positioned to shift the treatment paradigm create additional uncertainty in:

• Comparator expectations (which backbone is considered relevant?)
• Population definitions (which patients truly reflect the intended positioning?)
• Generalizability (does the trial reflect real-world practice?)

Any deviation from established standards of care should be clearly documented and justified, distinguishing between scientific trial requirements and real-world clinical practice.

At the same time, applying a conservative HTA lens by identifying all relevant PICOs and validating populations and comparators early with national KOLs and HTA experts helps ensure alignment with country expectations and reduces submission risk.

4. Population definitions are sometimes ambiguous

Clinical terminology, such as “platinum-resistant,” is not always defined consistently across sources; without clarification, this can overestimate eligible populations, misalign comparator selection, and undermine credibility in HTA discussions, so population definitions should be verified at the protocol or regulatory level wherever possible.

5. Rare diseases require broader evidence triangulation

In rare diseases without approved therapeutic options or clear HTA precedent, clinical guidance is often sparse, and disease management frequently depends on supportive care or off-label use of therapies, with comparator relevance differing across Member States. Under these conditions, analogue disease benchmarks, burden-of-illness evidence, anticipated pipeline developments, and careful identification and justification of clinically relevant outcomes play a critical role in shaping defensible PICOs, with expert validation ensuring their relevance and robustness.

Strategic Implications for Manufacturers

The key takeaway from our current simulation exercises is clear: The real risk is not identifying too many PICOs; it is failing to identify the few that will ultimately shape HTA conclusions.

A structured, transparent, and conservative simulation approach should:

• Anticipates HTA expectations rather than reacting to them
• De-risks evidence generation strategy
• Identifies early gaps in population/comparator/outcome coverage and prepares the appropriate mitigation plan
• Supports more robust EU and national submissions

Looking Ahead

As EU JCA implementation progresses, structured PICO anticipation will become a standard component of development strategy.

Inizio Ignite, Putnam’s PICO simulation framework provides:

• Transparency
• Reproducibility
• Early risk identification

In an increasingly complex HTA landscape, anticipating the right questions is just as important as generating the right data.

Want to understand how your asset may be assessed under EU JCA? Learn how Inizio Ignite, Putnam’s PICO simulation framework can help you anticipate HTA expectations before critical development decisions are made.