The European Union Health Technology Assessment Regulation has created a common framework for assessing the relative clinical effectiveness and safety of eligible health technologies.
However, the introduction of Joint Clinical Assessment does not establish a single European pricing, reimbursement or market-access decision.
A JCA report provides a scientific analysis of comparative clinical evidence. It does not determine:
- Whether a medicine represents added clinical value in a particular country
- Whether it is cost-effective
- What price should be accepted
- Whether it is affordable
- Which patient population should receive reimbursement
- How it should be positioned within a national treatment pathway
- Whether additional national evidence or analyses will be required
This distinction has important operational consequences. Pharmaceutical companies must develop an integrated evidence strategy that supports the EU-level JCA while simultaneously preparing for national HTA, economic evaluation, pricing and reimbursement.
1. The Legal Boundary Between JCA and National HTA
Joint Clinical Assessments are governed by Regulation (EU) 2021/2282 on health technology assessment.
The Regulation applies progressively:
- From 12 January 2025: new oncology medicines and Advanced Therapy Medicinal Products
- From 13 January 2028: orphan medicinal products
- From 13 January 2030: all centrally authorised new medicinal products falling within the Regulation’s scope
The JCA analyses the available clinical evidence concerning the relative effects of a health technology on health outcomes.
According to Article 9 of Regulation (EU) 2021/2282, a JCA report must not contain:
- A value judgement
- A conclusion on the overall clinical added value of the technology
- A conclusion regarding the technology’s position in the treatment pathway
- A conclusion on the target population in which the technology should be used
These judgements remain within the responsibility of Member States.
The Regulation therefore separates two activities:
EU-level JCA | National HTA and reimbursement |
Relative clinical effectiveness | National judgement of clinical added value |
Relative safety | Applicability to national clinical practice |
PICO-based clinical assessment | Local positioning in the treatment pathway |
Direct and indirect clinical comparisons | Cost-effectiveness |
Description of evidence certainty and limitations | Budget impact and affordability |
Assessment of submitted clinical evidence | Pricing and reimbursement decision |
Description of transferability issues | Reimbursement restrictions |
Common EU-level scientific report | National negotiation and implementation |
The European Commission explains that JCAs support national HTA processes by providing a scientific analysis of the relative effects of a health technology. They do not replace national pricing and reimbursement responsibilities. See the European Commission’s JCA overview.
2. What Happens When the JCA Process Begins?
For an eligible medicinal product, the developer must submit certain information when submitting its marketing-authorisation application to the European Medicines Agency.
This includes:
- The summary of product characteristics
- The clinical overview included in the marketing-authorisation application
- Information necessary to determine the product’s eligibility and establish the JCA assessment scope
The JCA process formally begins when an assessor and co-assessor are appointed and the health technology developer is informed by the HTA Secretariat.
The detailed interaction between the developer, assessors, Member States and the HTA Secretariat is governed by Commission Implementing Regulation (EU) 2024/1381.
Once the consolidated assessment scope is communicated, the health technology developer is generally required to submit its JCA dossier within 100 days.
The 100-day period is not simply a general target for completing all EU HTA work. It is the defined period for submitting the required dossier following the formal request.
The developer should therefore have the following substantially prepared before the final scope is received:
- Anticipated PICO scenarios
- Systematic literature reviews
- Clinical-study documentation
- Direct-comparison analyses
- Indirect treatment comparisons
- Subgroup analyses
- Outcome-level evidence tables
- Risk-of-bias assessments
- Evidence-gap analyses
- Statistical-analysis documentation
- Justification for missing or unavailable evidence
- Internal review and governance processes
The official process and timeline are summarised in the European Commission JCA factsheet.
3. The Consolidated PICO Scope Creates Evidence Complexity
The JCA assessment scope is based on the PICO framework:
- P: Patient population
- I: Intervention
- C: Comparator
- O: Health outcomes
Member States submit their information needs during the scoping process. These requests are consolidated into one or more PICOs for the assessment.
A single technology may therefore need to address multiple:
- Patient populations
- Subpopulations
- Comparators
- Treatment settings
- Lines of therapy
- Outcomes
- Follow-up periods
This can create a substantial evidence burden.
For example, a pivotal clinical trial may compare the new medicine with Comparator A. However, the consolidated JCA scope may include Comparators B, C and D because different treatments represent relevant standards of care across Member States.
The dossier may then require:
- Direct evidence for Comparator A
- Network meta-analysis for Comparator B
- Matching-adjusted indirect comparison for Comparator C
- A clear explanation of why no valid comparison is available for Comparator D
The company cannot assume that the comparator selected for regulatory development will address every PICO required for JCA.
The HTACG guidance on filling in the JCA dossier template requires developers to provide detailed descriptions and justifications for the direct and indirect comparison methods used.
4. Evidence Must Be Mapped at PICO and Outcome Level
A common mistake is to assess evidence readiness only at the overall product level.
For JCA, evidence readiness should be evaluated separately for each PICO and each requested outcome.
A practical evidence matrix could contain:
PICO element | Evidence question | Required assessment |
Population | Does the trial population match the | Eligibility criteria, baseline characteristics and effect modifiers |
Intervention | Does the study reflect the final | Dose, administration, treatment duration and treatment sequence |
Comparator | Is the comparator | Direct evidence, common comparator or population-adjusted comparison |
Outcomes | Were all requestedoutcomes collected? | Definitions, measurement instruments, timepoints and missing data |
Study validity | Is the evidence internally valid? | Randomisation, allocation, blinding, attrition and selective reporting |
External validity | Can the results apply to the target setting? | PICO mismatch, standard of care and healthcare-setting differences |
Statistical precision | How uncertain is the effect estimate? | Confidence intervals, sample size and event counts |
Subgroups | Are requested subgroup results credible? | Prespecification, interaction testing and statistical power |
This matrix should be completed before dossier preparation begins. Waiting for the final assessment scope to identify every evidence gap leaves little time to generate new evidence or build defensible analyses.
5. Internal Validity and Risk of Bias
JCA does not assess evidence solely according to whether a study is randomised or observational.
The assessors examine whether the estimated treatment effect may have been influenced by systematic bias.
Relevant issues include:
- Randomisation methods
- Allocation concealment
- Blinding
- Deviations from intended treatment
- Missing outcome data
- Outcome-measurement bias
- Selective reporting
- Confounding in non-randomised studies
- Immortal-time bias
- Misclassification
- Informative censoring
- Publication bias
The HTACG recommends using recognised study-design-specific tools when assessing internal validity.
For observational evidence, it is not sufficient to state that statistical adjustment was performed. The dossier should explain:
- How confounders were identified
- Which variables were available
- Which important variables were unavailable
- How missing data were handled
- Whether treatment assignment could be predicted by measured characteristics
- Whether residual or unmeasured confounding remains
- How sensitive the results are to modelling assumptions
The HTACG Guidance on the Validity of Clinical Studies describes requirements covering internal validity, external validity, statistical precision and risk-of-bias assessment.
6. External Validity Remains a National Question
One of the most important technical boundaries between JCA and national HTA concerns external validity.
The JCA can identify potential mismatches between:
- The assessed population and the national population
- Trial comparators and national standards of care
- Trial outcomes and national decision needs
- Study settings and routine clinical practice
- Treatment administration in the trial and national implementation
However, the final judgement about whether the evidence is applicable to a national healthcare system remains with the Member State.
The HTACG validity guidance explicitly recognises that external validity can differ between Member States because healthcare settings and relevant PICOs may differ.
This means national Market Access teams must investigate:
- Whether the trial population represents local patients
- Whether baseline risks differ
- Whether treatment-effect modifiers differ
- Whether the comparator reflects local clinical practice
- Whether diagnostic and monitoring infrastructure is available
- Whether treatment adherence is likely to differ
- Whether the outcome measures are relevant to local decision-makers
- Whether the resource requirements can be supported locally
A statistically valid European-level result may still have limited national relevance if the study setting differs materially from local practice.
Where direct randomised evidence addresses the PICO, it will generally provide the strongest basis for estimating relative treatment effects.
However, developers may need indirect comparisons when the required comparator was not included in the pivotal trial.
Possible approaches include:
- Conventional pairwise meta-analysis
- Bucher indirect comparison
- Network meta-analysis
- Network meta-regression
- Matching-adjusted indirect comparison
- Simulated treatment comparison
- Multilevel network meta-regression
Each method requires different assumptions.
Network meta-analysis
Network meta-analysis generally requires:
- A connected evidence network
- Sufficient similarity between included studies
- Transitivity across comparisons
- Consistency between direct and indirect evidence
- Appropriate handling of heterogeneity
- Assessment of effect modifiers
A network can be mathematically connected but clinically unreliable if studies differ substantially in patient characteristics, treatment lines, outcome definitions or follow-up periods.
Matching-adjusted indirect comparison
MAIC may be used when individual patient data are available for the sponsor’s study but only aggregate data are available for the comparator study.
The assessment should report:
- Variables included in the weighting model
- Rationale for selecting prognostic variables and effect modifiers
- Pre- and post-weighting balance
- Effective sample size
- Weight distribution
- Population overlap
- Sensitivity analyses
- Remaining unobserved differences
A severe reduction in effective sample size may indicate poor overlap and unstable effect estimates.
The HTACG methodological guideline on direct and indirect comparisons and its practical guideline provide detailed methodological expectations.
The first published JCA reports demonstrate that a completed assessment does not necessarily mean every PICO has been fully answered.
In the JCA summary report for tovorafenib, the assessment scope included multiple PICOs. However, results for several PICOs were not included because relevant comparative evidence was unavailable.
For one PICO, the assessment considered an unanchored MAIC. The report highlighted major uncertainties related to:
- The evidence-synthesis method
- Small effective sample size
- Differences between study populations
- Limited availability of relevant comparative data
- The inability to interpret effect estimates automatically as causal effects
This provides a practical lesson: submitting an analysis does not remove uncertainty. The credibility of the result depends on the clinical and statistical assumptions supporting the comparison.
Market Access teams should study the published JCA report for tovorafenib as an early example of how PICO coverage, missing evidence and indirect comparisons are documented.
Under Article 13 of Regulation (EU) 2021/2282, Member States must give due consideration to published JCA reports during national HTA processes.
National authorities should also attach the JCA report to the national assessment and report how it was considered.
However, Member States retain responsibility for:
- Drawing conclusions on national clinical added value
- Assessing national applicability
- Conducting economic evaluation
- Determining budget impact
- Assessing organisational consequences
- Considering ethical and social factors
- Establishing price and reimbursement conditions
- Determining reimbursement populations and restrictions
National authorities should not repeat the same analysis of information already assessed within the JCA without justification. Nevertheless, they may require complementary clinical analyses necessary for the national HTA process.
This creates a technical distinction between:
- Duplicating the EU-level relative clinical assessment, and
- Conducting complementary analyses required for national decision-making
Market Access teams must understand that distinction for every target market.
The following workstreams may still be required nationally.
Local epidemiology
Country-specific estimates may include:
- Incidence and prevalence
- Diagnosed population
- Eligible population
- Biomarker-positive population
- Treatment-line distribution
- Contraindications
- Expected treatment uptake
These estimates should reconcile clinical eligibility with real-world access conditions.
Local standard of care
Teams should establish:
- Which treatments are actually used
- Treatment shares
- Sequencing
- Duration of therapy
- Variation between national guidelines and routine practice
- Regional differences
- Off-label treatment patterns
The JCA comparator set may not fully resolve the national treatment-pathway question.
Cost-effectiveness
Depending on national requirements, the model may need to incorporate:
- Overall survival
- Progression-free survival
- Health-state utilities
- Treatment discontinuation
- Adverse events
- Subsequent therapies
- Treatment waning
- Extrapolation beyond observed trial follow-up
- Local costs
- Discount rates
- Probabilistic sensitivity analysis
- Structural uncertainty
If indirect comparisons feed the economic model, their uncertainty should be propagated rather than treated as fixed.
Budget impact
Budget-impact analysis should distinguish:
- Prevalent and incident populations
- Gross and net budget impact
- Treatment acquisition cost
- Administration cost
- Monitoring and diagnostic costs
- Adverse-event costs
- Displaced comparator costs
- Market uptake
- Duration of treatment
- Potential cost offsets
The population calculation should be reproducible and linked to local data sources.
Local RWE
RWE may be required to address:
- Treatment patterns
- Comparator use
- Baseline risk
- Long-term effectiveness
- Adherence and persistence
- Healthcare-resource utilisation
- Underrepresented populations
- Patient-reported outcomes
- Managed-entry agreement endpoints
Every RWE activity should be connected to a defined national decision uncertainty.
Before receiving the final JCA scope, companies should be able to answer:
PICO readiness
- Have we predicted the most likely populations and subpopulations?
- Have we mapped standards of care across Member States?
- Can every anticipated comparator be connected to the evidence network?
- Are the requested outcomes available at relevant timepoints?
- Are outcome definitions consistent across studies?
Comparative evidence
- Do we have direct evidence for each comparator?
- If not, is a connected network available?
- Have effect modifiers been identified before analysis?
- Is population adjustment methodologically defensible?
- What is the effective sample size after weighting?
- Have heterogeneity, inconsistency and residual confounding been evaluated?
Study validity
- Has risk of bias been assessed using suitable tools?
- Are analyses prespecified?
- Are missing-data methods justified?
- Have multiplicity and selective reporting been addressed?
- Are effect estimates accompanied by confidence intervals?
National readiness
- Has each country assessed external validity?
- Is the comparator relevant to local clinical practice?
- Is the national epidemiological model complete?
- Are economic models locally adapted?
- Has uncertainty from indirect evidence been incorporated?
- Is the budget-impact population calculation reproducible?
- Is there a post-launch RWE plan linked to payer uncertainty?
Companies should not operate separate and disconnected JCA and national HTA programmes.
A more effective structure is an integrated evidence plan with two linked layers.
EU-level layer
- PICO scenario planning
- Comparative clinical evidence
- Risk-of-bias assessment
- Direct and indirect comparisons
- Outcome-level evidence mapping
- Uncertainty documentation
- JCA dossier preparation
National layer
- External-validity assessment
- Local epidemiology
- Treatment-pathway mapping
- Economic modelling
- Budget-impact analysis
- National value communication
- Pricing and reimbursement strategy
- Additional RWE generation
The evidence base should remain scientifically consistent, but its interpretation and application must be adapted to national decision contexts.
Joint Clinical Assessment creates a common European scientific foundation, but it does not produce a common Market Access decision.
The JCA describes the relative clinical evidence and its limitations. Member States still determine:
- Whether the results are applicable locally
- Whether the medicine delivers added clinical value
- Whether the price is justified
- Whether the healthcare system can afford it
- Which patients should receive reimbursement
- What additional evidence or risk-sharing arrangements are required
The central challenge for pharmaceutical companies is therefore not simply completing the JCA dossier within 100 days.
It is building evidence that remains methodologically credible across multiple PICOs and can then be translated into country-specific clinical, economic and reimbursement decisions.
Companies that connect PICO planning, comparative evidence, HEOR, RWE and national Market Access preparation early will be better positioned to manage uncertainty and accelerate patient access across Europe.
The practical relationship between JCA, national HTA, PICO strategy, comparative evidence, RWE, pricing and reimbursement will be explored at the:
European RWE & Market Access Summit 2026 – JCA & PICO Strategy Edition
Date: 21–22 October 2026
Venue: Inntel Hotels Amsterdam Landmark
Location: Amsterdam, Netherlands
The summit will bring together professionals from pharmaceutical and biotechnology companies, HTA organisations, payer bodies, Market Access, HEOR, RWE, Medical Affairs, Regulatory Affairs, Pricing and Reimbursement, and evidence technology providers.