PICO scoping determines which clinical questions will be addressed in a Joint Clinical Assessment (JCA). The assessment scope is developed from the requirements of EU Member States and may cover multiple populations, comparators and outcomes. For health technology developers, it determines which clinical evidence needs to be addressed in the JCA dossier and where additional analyses may be necessary.
The scope of a JCA can extend considerably beyond the questions investigated in the pivotal trials supporting marketing authorisation. Differences in national standards of care, clinically relevant subpopulations and comparators may result in several PICOs within the same therapeutic indication.
Preparations therefore need to begin before the final assessment scope is communicated. Identifying potential populations, comparators and outcomes early allows developers to assess the available evidence, identify methodological gaps and prepare additional analyses.
PICO scoping in JCA: Purpose and regulatory framework
PICO scoping brings together Member States' clinical assessment requirements in a common assessment scope. This provides the basis for the comparative clinical assessment under Regulation (EU) 2021/2282 on health technology assessment.
A JCA examines the relative clinical effectiveness and safety of a health technology. It does not determine added benefit under national assessment systems, nor does it decide pricing or reimbursement. These decisions remain the responsibility of Member States.
Member States contribute their clinical assessment requirements to the European process. These requirements inform a common assessment scope defining the questions to be addressed in the JCA dossier.
Population, intervention, comparator and outcome in JCA
The PICO framework structures clinical assessment questions around four elements.
|
PICO element |
Role in JCA |
|---|---|
|
Population (P) |
Patients for whom relative clinical effectiveness and safety are to be assessed |
|
Intervention (I) |
The health technology being assessed, such as a new medicinal product |
|
Comparator (C) |
The treatment or intervention against which clinical outcomes are compared |
|
Outcome (O) |
Clinical outcomes used to assess effectiveness and safety |
Each PICO represents a specific clinical question. Differences in populations, comparators or outcomes may require several PICOs to be addressed within one JCA.
The PICO framework also supports the allocation of studies and analyses to the relevant questions. For each comparison, developers need to make clear which evidence is available and what methodological limitations remain.
How the EMA indication differs from the JCA assessment scope
The EMA marketing authorisation indication and the JCA assessment scope serve different purposes. Regulatory assessment examines a medicine's quality, safety and efficacy in the proposed indication. The JCA specifies the questions on relative clinical effectiveness and safety relevant to Member States.
A broad indication can therefore lead to several PICO questions. Different lines of therapy, clinical subpopulations or national standards of care may be relevant within the same indication.
Evidence generated for marketing authorisation will not necessarily address every question in the JCA assessment scope. A study may be adequate for regulatory purposes without providing a direct comparison against each comparator requested for JCA.
The role of Member States and the HTA Coordination Group
Member States participate in the European assessment through the Health Technology Assessment Coordination Group (HTA Coordination Group, HTACG) and its relevant working structures.
The Coordination Group coordinates joint work among national HTA bodies. The subgroup responsible for JCA, together with the appointed assessors and co-assessors, contributes to developing the assessment scope and conducting the clinical assessment.
Participation by multiple Member States is intended to ensure that different national requirements concerning populations, comparators and outcomes can be reflected in the European assessment.
The resulting assessment scope is not a collection of national benefit assessments. It defines the common clinical questions to be examined in the JCA.
Developing the JCA assessment scope and consolidating PICOs
The JCA assessment scope is developed from Member States' clinical assessment requirements and consolidated into a common set of questions. Scoping takes place alongside the European marketing authorisation process and is completed before the developer submits the final JCA dossier.
Consolidation is a central part of the process. Different national requirements must be brought together so that relevant clinical questions can be addressed in the joint assessment.
How Member States contribute PICO requirements
Member States may propose requirements concerning populations, comparators and outcomes based on their healthcare context and assessment needs.
Differences may arise from:
National treatment standards
Available therapeutic alternatives
Definitions of clinical subpopulations
Requirements for clinical outcomes
The place of a new therapy in existing treatment pathways
A medicine might be compared with an established active treatment in one Member State, while individualised treatment is relevant in another. Both requirements may need to be reflected in the common assessment scope.
Consolidating national PICO requirements
PICO consolidation brings Member States' requirements together into a common assessment scope. Clinically comparable questions are considered together, and overlaps between national requirements are identified.
The aim is to make a joint assessment practicable while retaining clinically relevant assessment questions.
The consolidated scope may still contain several PICOs. A common assessment scope does not mean that every Member State uses the same population or comparator.
For developers, the practical question is which comparisons must ultimately be addressed in the JCA dossier once consolidation is complete.
Finalising and communicating the assessment scope
The final assessment scope is communicated to the health technology developer as part of the JCA process and provides the basis for the requested clinical evidence.
The standard time limit for submitting the JCA dossier is 100 days from the first formal request for dossier submission; it is generally 60 days in accelerated authorisation procedures. The triggering event is the formal request in the individual assessment, rather than simply the communication of the assessment scope.
These timelines make early evidence planning particularly important. Systematic literature reviews, indirect comparisons and additional analyses may not be feasible to develop from scratch once the final assessment scope is known.
The calculation of deadlines and the remaining procedural milestones are covered in the guide to the JCA process.
Populations and subgroups in JCA scoping
Population definitions determine which patients are included in each JCA question on relative clinical effectiveness and safety. Differences within the marketing authorisation indication may lead to multiple PICOs and additional evidence requirements.
The way a population is defined directly affects which studies are eligible and whether their findings can be applied to the population of interest.
Clinical populations within the authorised indication
A JCA PICO population may be defined by characteristics such as:
Disease stage and severity
Previous treatments
Line of therapy
Biomarker status or genetic alterations
Eligibility for specific treatment options
Other prognostic or treatment-relevant characteristics
Such criteria may substantially narrow the available evidence. A randomised trial may enrol a broad population, while a JCA PICO requests a comparison in a more narrowly defined subgroup.
Developers then need to establish whether suitable subgroup analyses are available and whether the results are methodologically reliable for the requested population.
Biomarkers and genetically defined subpopulations
Molecular or genetic characteristics can be central to defining relevant populations for targeted therapies and medicines for rare diseases.
This is particularly important when treatment eligibility or prognosis differs across genetic subpopulations.
Studies in these settings often involve small patient numbers. Further subdivision may reduce statistical precision and make direct comparisons more difficult.
Evidence planning should therefore examine early whether clinical studies adequately represent the subpopulations likely to be relevant to JCA.
How population definitions affect evidence availability
The narrower the population, the more important it becomes to establish whether suitable comparative evidence exists for that specific question. A clinically meaningful population definition does not guarantee that matching study data are available.
Small subgroups can create challenges through limited sample sizes, missing comparator arms and differences in eligibility criteria.
The JCA of onasemnogene abeparvovec (Itvisma) illustrates the difficulties associated with genetically defined populations in a rare disease.
Developers should therefore compare anticipated population definitions against the actual study evidence at an early stage.
Comparators in JCA: Different standards of care and treatment alternatives
Different national standards of care may lead to several comparators being included in the JCA assessment scope for the same intervention. Comparator selection affects evidence requirements and may necessitate additional direct or indirect comparisons.
Comparator requirements are a major determinant of JCA dossier scope and methodological complexity.
National standards of care and comparator selection
Member States may consider different treatment alternatives relevant. Reasons include differences in the availability of authorised medicines, clinical guidelines, routine practice and the positioning of therapies within treatment pathways.
A comparator may represent established standard care in one Member State, while another treatment is relevant elsewhere.
The common JCA assessment scope needs to accommodate these differences. Developers should therefore examine available clinical evidence beyond the comparator used in the pivotal registration trial.
Individualised treatment as a comparator
Individualised treatment may encompass several therapeutic options selected according to patient characteristics.
The comparative assessment then needs to consider which treatments are actually included in that individualised approach and whether the underlying data reflect the requested comparison.
Comparability depends, among other factors, on the treatment mix, patient population and available outcomes. A broad comparison against a heterogeneous control group may raise additional methodological questions.
When direct comparative evidence is unavailable
Not every comparator in the assessment scope will have been investigated directly in the pivotal trials.
Where direct comparative data are unavailable, indirect treatment comparisons or other evidence syntheses may be needed.
Feasibility depends on the available studies. Situations without a common comparator, or with substantial differences between study populations, are particularly challenging.
The availability of a statistical method alone does not establish that a comparison is valid. The methodological assumptions and limitations of these approaches are examined in the guide to JCA evidence assessment.
Comparator requirements and JCA dossier complexity
The number of relevant comparators directly affects the work required to prepare the evidence.
Each additional comparison requires an assessment of available studies, population comparability and the analyses needed.
The JCA of tarlatamab (Imdylltra), for example, illustrates how different treatment settings and comparators within one indication can lead to several PICO questions.
Identifying plausible comparators early is therefore an important part of JCA dossier planning.
Outcomes in JCA scoping and their implications for evidence planning
The outcomes specified in the assessment scope determine which clinical results are to be examined for each PICO. Differences in outcome requirements may call for additional analyses and affect the availability of suitable evidence.
Developers should consider potential European outcome requirements while clinical studies are still being designed.
Clinical outcomes and patient-reported outcomes
Relevant JCA outcome domains may include mortality, morbidity, health-related quality of life and safety.
Available studies need to be assessed to establish whether they collected the requested outcomes and provide suitable comparative results.
Patient-reported outcomes can provide important information on health-related quality of life or disease symptoms. Their interpretability, however, depends on the measurement instrument, completeness of data and statistical analysis.
Gaps between requested and available outcomes
Not every outcome included in the assessment scope will necessarily have been collected in the relevant studies. Further difficulties arise when studies measure similar clinical concepts using different instruments or definitions.
Three questions are particularly important:
Was the requested outcome measured in the available studies?
Are the outcome definitions and measurement methods sufficiently comparable across studies?
Are appropriate results available for the relevant population and comparator?
Missing outcomes cannot be recovered simply by performing additional statistical analyses.
Where suitable data are unavailable, the gap and its implications for the relevant PICO should be documented transparently.
Planning outcomes during clinical development
The availability of clinical outcomes for a later JCA is largely determined by study design.
It may therefore be useful to consider potential European outcome requirements during pivotal trial planning.
This includes the choice of measurement instruments, analysis populations, data cut-offs and statistical methods.
A Joint Scientific Consultation can provide an opportunity to discuss evidence generation plans in relation to anticipated requirements for a future clinical assessment.
What the first JCAs show about PICO coverage
The first published JCAs demonstrate that the number of requested PICOs and the availability of suitable comparative evidence can differ substantially. Developers face the challenge of addressing the assessment scope while clearly explaining the limitations of the available evidence.
Across the first four published JCAs, the assessment scope ranged from one PICO for lurbinectedin to 14 for onasemnogene abeparvovec. Coverage also varied: all requested PICOs were addressed for lurbinectedin and tarlatamab, while coverage was partial for tovorafenib and onasemnogene abeparvovec.
The number of PICOs addressed does not, by itself, indicate the methodological quality of the submitted evidence. Even a PICO that is formally addressed may involve considerable uncertainty if a direct comparison is unavailable or the assumptions underlying an indirect comparison are not sufficiently met.
For scoping, these early experiences reinforce the importance of checking potential comparators and available comparative data before the final scope is communicated.
The methodological findings from these four assessments are examined in detail in the separate insight, Joint Clinical Assessment: What the first four JCA reports reveal about evidence assessment.
PICO simulation and early evidence planning for developers
Simulating potential JCA PICOs before the final assessment scope is available can help identify additional comparator requirements and evidence gaps. This allows developers to prepare literature searches, feasibility assessments and potential evidence syntheses.
PICO simulation does not replace the official assessment scope. It is a planning tool for anticipating different clinical assessment requirements.
Anticipating potential PICO requirements
A PICO simulation can start from the proposed marketing authorisation indication, the planned studies and anticipated requirements across Member States.
Potential populations, comparators and outcomes can then be identified.
Particular attention should be paid to questions where national standards of care differ or where no direct evidence is available against a potential comparator.
The simulation should consider several plausible scenarios without treating any anticipated scope as final.
Prioritising PICO scenarios
Not every conceivable PICO requires the same level of advance preparation. Three criteria can support prioritisation.
|
Criterion |
Planning question |
|---|---|
|
Likelihood |
How likely is this PICO to be included in the assessment scope? |
|
Assessment relevance |
How important might this question be for the clinical assessment and subsequent national HTA? |
|
Feasibility |
Are suitable data and methods available to address the question? |
Prioritisation can help direct limited resources towards the most relevant and resource-intensive evidence questions.
It must not be confused with unilaterally narrowing the official assessment scope. Once the scope is finalised, the requirements of the European process apply.
Early assessment of comparator evidence
Potential comparators should be identified alongside a structured review of available evidence.
This should establish whether direct comparative studies exist, which additional studies might support indirect comparisons, and whether relevant prognostic factors are adequately documented.
The availability of individual patient data can also affect the feasibility of population-adjusted analyses.
Where essential information is missing, a methodologically credible evidence synthesis may not be possible even when some relevant studies exist.
Preparing systematic literature reviews and evidence syntheses
Systematic literature reviews and indirect comparisons require sufficient time for planning, execution, quality assurance and documentation.
Starting preparatory work before the final assessment scope is published may therefore be valuable, particularly when several potential comparators are involved.
Preparations may include developing search strategies, identifying relevant studies and assessing the feasibility of indirect comparisons.
Once the assessment scope is finalised, these analyses need to be aligned with the actual questions requested and updated where necessary.
Detailed documentation, completeness and submission requirements are covered in the guide to the JCA dossier.
Addressing PICOs without suitable comparative evidence
Suitable comparative evidence may not be identifiable for every requested PICO.
In such cases, the available data and their limitations need to be presented transparently.
Developers should distinguish gaps caused by a lack of studies, unavailable comparator data, differences between populations and comparisons that are not methodologically feasible.
Clear documentation supports interpretation of the evidence base and helps developers respond to questions raised during the JCA process.
Connecting JCA scoping with national HTA processes
The JCA assessment scope reflects clinical assessment requirements from several Member States, while national HTA processes retain their own criteria for evaluating and using the evidence. Developers therefore need to identify which European PICO questions correspond to subsequent national assessment questions.
The JCA provides a common clinical evidence base. It does not replace national decisions on added benefit, reimbursement or pricing.
National relevance of individual JCA PICOs
Not every PICO included in the European assessment scope has the same relevance in every Member State.
National differences may concern the target population, comparator and assessment of clinical outcomes.
Developers should therefore identify early which European PICOs are likely to matter most for the national procedures they anticipate.
JCA scoping and the appropriate comparator therapy in German AMNOG
In Germany, the appropriate comparator therapy (zweckmäßige Vergleichstherapie, zVT) remains central to early benefit assessment under AMNOG where such a comparator is to be specified.
German requirements may already inform the European scoping process. This does not mean that the European assessment scope replaces subsequent national determinations or assessment criteria.
When preparing a delta dossier, developers need to identify which European PICOs reflect German benefit assessment requirements and whether the available evidence is suitable for those questions.
The specific German requirements concerning comparators, outcomes and national dossier content are covered in the AMNOG guides, in particular the guides to the AMNOG dossier and G-BA consultation.
Preparing for JCA scoping: Key checks for developers
Structured JCA scoping preparation connects anticipated clinical assessment questions with the evidence actually available. Early identification of potential comparators and an assessment of whether planned studies cover the relevant populations and outcomes are particularly important.
Seven checks can guide preparation:
Populations: Have the likely relevant clinical populations and subpopulations been identified?
Comparators: Which treatments might be requested because of differences in national standards of care?
Outcomes: Do planned studies adequately cover the clinical outcomes likely to be requested?
Direct evidence: Which potential PICOs can be supported by randomised direct comparisons?
Indirect evidence: Which additional comparisons may be necessary, and are they methodologically feasible?
Evidence gaps: Which questions are unlikely to be addressed with the available data?
Timelines: Which literature reviews, analyses and documentation tasks should begin before the final assessment scope is communicated?
This checklist supports operational planning and complements the PICO simulation described in this guide. It does not replace the final assessment scope or a methodologically sound appraisal of the available evidence.
Sources and regulatory references
Regulation (EU) 2021/2282 on health technology assessment.
European Commission and HTA Coordination Group: methodological and procedural guidance on JCA scoping.
European Commission: Joint Clinical Assessment reports for tovorafenib, lurbinectedin, tarlatamab and onasemnogene abeparvovec, 2026.