For Pharma/Biotech companies advancing innovative therapies toward European markets, understanding the PICO framework is central to successful Health Technology Assessment (HTA) submissions. Under the EU Health Technology Assessment Regulation (HTAR), the Joint Clinical Assessment (JCA) process relies heavily on the PICO framework to define the scope of clinical evidence to be submitted.
Failure to anticipate and address relevant PICOs can lead to incomplete dossiers, delays, or weaker positioning for national reimbursement decisions.
This article explains the PICO framework in the specific context of EU HTA submissions, with practical insights tailored for developers preparing Marketing Authorisation Application (MAA) and HTA pathways.
What is the PICO Framework?
PICO is a structured method for formulating clear, answerable research questions for evidence synthesis and assessment. In HTA, it translates policy and clinical needs into precise data requirements. The four components are:
- P – Population (or Patient population)
- I – Intervention
- C – Comparator(s)
- O – Outcomes
In the EU JCA process, PICO is not driven solely by the data the company has generated. It is shaped by the policy needs and clinical practices of the 27 EU Member States. The final assessment scope consolidates these national inputs into one or more PICOs that the Health Technology Developer (HTD) must address in the JCA dossier.
The JCA is a clinical relative-effectiveness and safety assessment that runs in parallel with the EMA review. Economic evaluation and final reimbursement decisions remain at the national level, but the JCA report heavily influences those downstream processes.
Breaking Down Each Element for HTA
Population (P)
This defines the patient group(s) for which the technology is assessed. It typically starts from the claimed indication/intended use submitted to the EMA but frequently expands into clinically relevant subpopulations.
Examples of common splits include:
- Line of therapy (first-line vs later-line)
- Biomarker or mutation status
- Disease severity or stage
- Prior treatment exposure
- Age or specific high-need subgroups
Member States may request assessment in populations that differ from the broad label population if local clinical practice or reimbursement decisions focus more narrowly.
Intervention (I)
This is usually the technology under assessment (the product and its dosing/administration as applied for). Variations in dose, formulation, or combination use are generally treated as potential effect modifiers rather than separate interventions requiring their own full PICO, unless they substantially change the clinical question.
Comparator(s) (C)
This is often the most challenging and variable element for US developers. Comparators are selected based on actual clinical practice and relevance in individual Member States, not solely on regulatory approval status. They can include:
- Standard of care (which may differ by country)
- Off-label treatments commonly used in practice
- Best supportive care
- Multiple alternative options (sometimes as “OR” or “AND” logic)
Unlike the US, where ICER or payer reviews often focus on a more limited set of comparators, EU Member States can request several distinct comparators, leading to multiple PICOs. Indirect treatment comparisons (ITCs) or network meta-analyses frequently become necessary when head-to-head data are absent.
Outcomes (O)
Outcomes must be patient-relevant and free of ranking or judgment at the scoping stage. Typical categories include:
- Overall survival and progression-free survival (especially in oncology)
- Response rates
- Quality of life / patient-reported outcomes
- Safety and tolerability endpoints
- Functional or symptom-specific measures
Surrogate endpoints may be accepted if well-justified and validated, but HTA bodies often place greater emphasis on hard clinical and patient-centred outcomes than pure regulatory endpoints.
How PICO Works in the EU JCA Process
The scoping process is a critical early step:
- Assessors draft an initial scope proposal.
- Member States respond via a PICO survey, indicating their national needs.
- Inputs are consolidated into the lowest feasible number of PICOs while remaining inclusive of Member State requirements.
- The final assessment scope is communicated to the HTD.
- The company then has a limited window (typically up to 100 days, or 60 days under accelerated procedures) to submit the full JCA dossier addressing every PICO.
Simulations and early experience have shown that the number of PICOs can range from a handful to 10–13 or more in complex indications such as oncology. Each PICO generally requires its own evidence presentation, including systematic literature reviews, critical appraisal, and (where needed) comparative analyses.
Importantly, PICO definition is policy-driven rather than purely data-driven. If evidence is unavailable for a requested PICO, the HTD must still address it and justify the gap.
Why This Matters for Pharma/Biotech Clients
US companies are accustomed to FDA-centric development and ICER-style reviews that often use a narrower set of comparators and populations. In Europe:
- Multiple PICOs create significant evidence-generation and analysis burdens.
- Tight timelines after final scope finalisation leave little room for new data collection.
- Indirect comparisons and real-world evidence considerations become more prominent.
- National clinical practice variations (especially in comparator choice) introduce uncertainty that must be managed proactively.
Early JCA experience has already highlighted risks when comparator data are missing or indirect comparisons carry high uncertainty. Assessors flag these limitations clearly in reports.
Practical Recommendations for Preparation
- Start PICO prediction early – Ideally 18–24 months before planned MAA submission. Map current and evolving treatment landscapes across major EU markets, review national HTA reports, clinical guidelines, and prior assessments of similar products.
- Conduct systematic PICO scenario exercises – Identify possible populations, likely comparators, and core outcomes. Prioritise those with highest probability and greatest impact on market access.
- Align clinical development with HTA needs – Consider Joint Scientific Consultation (JSC) opportunities and ensure pivotal trials support potential subpopulations and relevant comparators where feasible.
- Build robust evidence packages – Plan systematic literature reviews, feasibility of ITCs, and strategies for handling evidence gaps. Prepare justifications and sensitivity analyses in advance.
- Integrate regulatory and HTA workstreams – Because MAA and JCA timelines are linked, treat PICO readiness as part of overall European launch planning rather than a separate activity.
- Monitor evolving practice – National clinical practice and HTA preferences continue to evolve; regular landscape updates are essential.
Conclusion: The PICO Framework Explained
The PICO framework is the cornerstone of EU Joint Clinical Assessment scoping. For Pharma/Biotech companies, mastering it means moving from a regulatory-focused evidence mindset to one that anticipates multi-country clinical practice and policy needs. Companies that invest early in PICO prediction, evidence planning, and cross-functional alignment are better positioned to submit complete, high-quality JCA dossiers and support stronger national HTA and reimbursement outcomes.
Understanding and preparing for PICO is one of the highest-leverage activities a developer can undertake when planning European market entry. Early engagement with experienced EU HTA specialists can significantly reduce uncertainty and improve readiness for this critical step. Speak with us for more information.