The First 18 Months of EU Joint Clinical Assessment Exposed a Problem Sponsors Did Not Anticipate
High-Impact Journals
- What 18 Months of EU JCA Implementation Actually Produced
- The First Completed JCA Report: What the Tovorafenib Assessment Established
- Why Oncology JCAs Can Require Indirect Comparisons
- Comparator Variability: The Problem JCA Was Supposed to Solve
- Progression-Free Survival as a Primary Endpoint: Regulatory Acceptance vs HTA Interpretation
- When JCA Evidence Does Not Satisfy National HTA Requirements
- Germany-Specific: JCA-AMNOG Interaction and National Supplements
- Orphan Medicines: Evidence Constraints and JCA Planning
- External Control Data and Real-World Evidence Demands
- Evidence Planning: What Sponsors Must Do Differently
- Pubrica JCA Evidence-Readiness Assessment Framework
- How Pubrica Would Map Your Evidence Gaps Before Submission
- Reference
Interesting topics
The First 18 Months of EU Joint Clinical Assessment Exposed a Problem Sponsors Did Not Anticipate
Early oncology JCA experience indicates that sponsors may need to address evidence gaps when pivotal trials do not directly answer all comparator, population or outcome questions included in the consolidated PICO scope. Indirect comparisons, network meta-analysis and external evidence may therefore become important components of evidence planning, depending on the available data and methodological feasibility.
Pubrica | HTA and Market Access Evidence Series | October 2026
1. What 18 Months of EU JCA Implementation Actually Produced
Regulation (EU) 2021/2282 established the EU HTA framework and provides for joint clinical assessments at EU level. The Regulation applies from 12 January 2025. Cancer medicines and ATMPs were among the first medicinal products brought into scope, while orphan medicinal products are scheduled for inclusion from 13 January 2028.
The objective of the JCA is to reduce duplication in the clinical evidence assessment conducted across Member States. The EU-level JCA produces a common assessment of relative clinical effectiveness and safety for the defined scope, while Member States continue to conduct their national HTA and pricing and reimbursement processes.
Early JCA experience highlights three evidence-planning issues that sponsors should address before the assessment scope is finalised:
- PICO breadth: A single product may be assessed against multiple populations, comparators and outcomes.
- Evidence alignment: The pivotal trial may not directly answer every scoped PICO.
- National follow-through: The JCA report feeds into national HTA processes rather than replacing them.
The rest of this article looks at why that is happening, where it can go wrong, and what sponsors can do before they submit.
2. The First Completed JCA Report: What the Tovorafenib Assessment Established
The European Commission published the first completed medicinal-product JCA report for tovorafenib (Ojemda) on 9 June 2026. The report provides a practical example of how the JCA process evaluates evidence against the defined assessment scope, including situations in which available clinical evidence does not directly answer every relevant PICO question.
- The report describes, it does not decide. The JCA assesses relative clinical effectiveness and safety. It does not give a value judgement, an economic view or a reimbursement recommendation. Those remain national.
- Scope drives everything. The assessment answers the PICO questions in the final scope, even where the pivotal trial was designed for a different question. Where the trial does not map to a PICO, the report records the evidence gap rather than closing it.
- Methods are held to published guidance. European JCA methodological guidance addresses direct and indirect treatment comparisons and sets out the assumptions and considerations relevant to assessing the validity and applicability of comparative evidence. [2,3] Indirect comparisons without a common comparator require particular methodological justification because they rely on stronger assumptions than anchored comparisons. Sponsors should therefore assess their feasibility against the applicable JCA methodological guidance and the requirements of the relevant national HTA methodology rather than assume that an unanchored analysis will be accepted.
What the first report established | Why it matters to sponsors |
Assessment follows the consolidated scope, not the trial protocol | Trial design choices made years earlier are tested against questions the sponsor did not write |
Uncertainty is reported openly, including where evidence is missing | A gap in the JCA becomes a visible gap in every national dossier |
No economic or value conclusions | National HTA bodies still run their own full assessments |
Strict timelines | Late evidence generation cannot be repaired inside the process |
3. Why Oncology JCAs Can Require Indirect Comparisons
Indirect comparisons become important when the pivotal trial does not directly answer one or more comparator questions included in the JCA scope. This can occur when multiple comparators are relevant, the pivotal study is single-arm, treatment crossover affects interpretation, or the standard of care has changed since trial initiation.
This finding highlights a structural evidence-planning challenge. A pivotal oncology trial may provide direct evidence against one comparator, while the consolidated JCA scope may require assessment against additional comparators or populations. Where direct evidence is unavailable, sponsors may need to evaluate the feasibility of an indirect comparison, network meta-analysis or external-control approach.
Several recurring evidence-design situations can increase the likelihood that an indirect comparison will need to be considered:
Then retain your bullets, but slightly tighten them:
- Multiple comparators in scope: Additional relevant comparators can require evidence beyond the pivotal head-to-head comparison.
- Single-arm evidence: Single-arm studies do not provide a concurrent randomized comparator and may require alternative comparative evidence.
- Treatment crossover: Crossover can complicate interpretation of treatment effects, particularly for overall survival.
- Changing standards of care: A comparator selected when a trial begins may differ from the standard of care relevant at the time of assessment.
Established methods include Bucher adjusted indirect comparisons, network meta-analysis (NMA), and population-adjusted approaches such as matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC) [1]. Their applicability depends on the available evidence and the assumptions required by each method. The HTACG methodological guidance places particular emphasis on similarity, heterogeneity and consistency when assessing indirect evidence.
4. Comparator Variability: The Problem JCA Was Supposed to Solve
The JCA framework is designed to reduce duplication in EU-level clinical evidence assessment while accommodating differences in national HTA requirements. Comparator variability remains a practical challenge because different assessment contexts may identify different relevant comparators.
Two Member States can look at the same patient population and name different standards of care. One may use a regimen that is not reimbursed in another. One may treat an older sequence of therapy that elsewhere has been replaced. When these differences enter the JCA scoping process, the consolidated scope tends to include all of them.
That creates a trade-off sponsors did not fully anticipate:
- If the scope is wide, the evidence package must be wide, and indirect comparisons multiply.
- Each indirect comparison carries its own assumptions, and each assumption can be challenged by assessors.
- A shared evidence package that is strong against comparator A and weak against comparator B leaves some Member States with a usable report and others with an unusable one.
A harmonised EU assessment process does not necessarily eliminate differences in the clinical questions considered relevant across Member States. Where different standards of care contribute to the consolidated PICO scope, comparator variability can therefore remain an important evidence-planning issue for sponsors, particularly when the pivotal trial does not directly address every scoped comparator.
Figure 1. How Comparator Variability Affects the JCA Evidence Package
Step | What happens | Risk created |
1. National input | Each Member State states its preferred comparator | Divergent standards of care enter the process |
2. Scope consolidation | Assessors merge requests into a set of PICOs | Number of comparators grows |
3. Sponsor evidence plan | Sponsor builds direct and indirect evidence for each PICO | Reliance on indirect comparison rises |
4. Assessor review | Assumptions tested against HTACG guidance | Weak similarity or heterogeneity weakens the result |
5. National use | Member States take the report into local HTA | Evidence is strong for some comparators, thin for others |
5. Progression-Free Survival as a Primary Endpoint: Regulatory Acceptance vs HTA Interpretation
Progression-free survival (PFS) is an important endpoint in oncology development, particularly when overall-survival data are immature. However, regulatory acceptance of PFS does not automatically establish the strength of evidence for patient-relevant outcomes in HTA.
Surrogate endpoints may support regulatory decision-making in oncology when their evidentiary role is appropriate to the disease, intervention and available clinical evidence. HTA assessments address a different question: whether the available evidence supports relative clinical effectiveness and patient-relevant outcomes with sufficient confidence for the assessment. Consequently, regulatory acceptance of an endpoint does not by itself establish its evidentiary value for HTA. [2].
In JCA, this has practical consequences:
- The scope typically lists patient-relevant outcomes such as overall survival, health-related quality of life and severe toxicity.
- A surrogate-only evidence base can be described, but the report is likely to note high uncertainty on the outcomes that matter.
- Indirect comparisons on a surrogate add a second layer of uncertainty: the comparison may be valid on progression-free survival and still say little about survival.
Sponsors should therefore distinguish regulatory acceptance of a surrogate endpoint from the evidence required to establish its relevance to patient-relevant outcomes in an HTA context. Where possible, the evidence package should explain the relationship between the surrogate and outcomes such as overall survival or health-related quality of life. Evidence of the surrogate-to-final-outcome relationship at trial level, ideally from meta-analyses in the same tumour type and treatment class, needs to be in the dossier from the start.
6. When JCA Evidence Does Not Satisfy National HTA Requirements
The JCA report does not replace national assessment. It feeds into it. Several gaps can appear between what the JCA delivers and what a Member State needs.
Gap | Where it arises | Typical national consequence |
Comparator not in the JCA scope | Local standards of care differ from the consolidated PICOs | National body requests additional analysis or its own evidence review |
Population differs | Local reimbursed population is narrower than the licensed one | Subgroup analyses requested |
Outcome not covered | National methods require outcomes the JCA scope did not include | Additional endpoints or quality of life data demanded |
Method not accepted nationally | National guidance differs from HTACG on indirect comparison methods | JCA analysis set aside or re-run |
Timing | Data cut used in JCA is outdated at national appraisal | Updated analyses requested |
The practical risk is that sponsors may need additional analyses or evidence for national assessments when the JCA evidence package does not fully address national requirements.
This illustrates an important planning limitation: the EU-level JCA can reduce duplication in clinical evidence assessment, but it does not eliminate all national evidence requirements or methodological differences. Sponsors should therefore plan the JCA evidence package together with the requirements of priority national HTA markets.
7. Germany-Specific: JCA-AMNOG Interaction and National Supplements
Germany provides an important national case study because its AMNOG benefit-assessment process operates alongside the EU JCA framework and applies national methodological and evidence requirements. The Federal Joint Committee (G-BA) appoints an appropriate comparator therapy (zweckmäßige Vergleichstherapie), and the benefit dossier is assessed against it, with added benefit categories that drive price negotiation. [3]
Three interaction points deserve attention:
- Comparator alignment. The comparator relevant to the German national benefit assessment may not fully correspond to every comparator represented in the JCA scope. Sponsors should therefore compare the German national evidence requirements with the final JCA PICOs early enough to identify potential gaps and additional analyses.
- Evidence standards. Sponsors should assess the acceptability of indirect evidence under the applicable German methodological framework rather than assume that evidence considered in the JCA will automatically satisfy the requirements for a national added-benefit assessment. Evidence that passes JCA review may still be judged insufficient for an added benefit claim.
- National requirements. Sponsors should assess which national evidence elements remain relevant to the German benefit-assessment process alongside the JCA report, including applicable patient-relevant outcome and subgroup analyses under the current G-BA framework.
Sponsors targeting Germany should build the evidence plan for both processes at once. A single analysis plan that serves the JCA and the G-BA saves time. Two plans written separately usually do not reconcile.
8. Orphan Medicines: Evidence Constraints and JCA Planning
Orphan medicinal products have a broader inclusion date of 13 January 2028 under the EU HTA Regulation. Cancer medicines, however, entered the JCA framework from 12 January 2025. An orphan oncology medicine may therefore already fall within the earlier cancer-medicine scope where it meets the applicable eligibility criteria.
Rare disease evidence has well-known limits:
- Small populations make randomised comparison against several comparators impractical.
- Single-arm trials are common, and natural history data are often the only reference.
- Between-trial heterogeneity is hard to assess when each study is small, and populations are defined differently.
For these products, indirect comparisons often depend on assumptions that cannot be tested. The HTACG guidance accepts that evidence may be limited but the report will still say so in plain terms. Sponsors with orphan oncology products should plan for the likelihood that the JCA will describe their evidence as uncertain and should prepare to explain, in each national dossier, why more data were not feasible.
9. External Control Data and Real-World Evidence Demands
Where no comparator data exist inside the trial, external control arms and real-world evidence (RWE) are the next option. Their use in JCA is growing, and so is scrutiny of them.
Assessors tend to ask the same questions about any external control:
- Were the external data selected before the trial results were known, or after?
- Do the populations match on prognostic factors and treatment-effect modifiers, and are the key variables captured with the same definitions?
- How much residual confounding could remain after adjustment for measured prognostic factors and treatment-effect modifiers? Have appropriate sensitivity analyses been conducted to assess the robustness of the estimated treatment effect to potential unmeasured confounding?
- Is the data source fit for purpose, with complete follow-up and verified outcomes?
External controls rarely replace randomised evidence in an HTA setting. They are used to put a range around a plausible effect. Pre-specification in the statistical analysis plan, transparent data provenance and sensitivity analyses that stress the main assumption are what make the difference between a usable comparison and one that is set aside.
10. Evidence Planning: What Sponsors Must Do Differently
The first 18 months point to a handful of changes in how sponsors plan.
- Map likely PICO scenarios early. Identify plausible populations, comparators and outcomes across priority Member States before pivotal results are available, then test whether the planned evidence can answer each scenario directly.
- Pre-specify the indirect-comparison strategy where feasible. Define the evidence network, effect modifiers, similarity assumptions and planned sensitivity analyses before results are available rather than selecting the method retrospectively.
- Test comparative-evidence feasibility before committing to an analysis. Assess network connectivity, population similarity, effect modifiers, heterogeneity and data availability before concluding that NMA, anchored comparison or population-adjusted methods are defensible.
- Build the surrogate-evidence case. Include evidence supporting the relationship between the surrogate endpoint and patient-relevant outcomes such as overall survival and health-related quality of life, rather than relying only on the regulatory rationale.
- Run one analysis plan for several audiences. Align the JCA dossier with the national requirements in the key target markets, particularly Germany, France and Italy.
- Plan for post-JCA data. Decide in advance which data cuts, long-term follow-up and real-world datasets will be available for national appraisals.
- Document assumptions plainly. Assessors read the limitations section first. A candid statement of what the evidence cannot show is more credible than one that avoids the point.
11. Pubrica JCA Evidence-Readiness Assessment Framework
Pubrica’s JCA Evidence-Readiness Assessment is designed as a pre-submission decision framework. It maps the anticipated PICO scope against available clinical evidence, tests the feasibility of indirect and external comparisons, identifies endpoint and national HTA gaps, and converts those findings into a prioritised evidence-action plan. The framework scores the evidence package across six domains and highlights where the dossier is most exposed.
Domain | Key questions | Typical output |
1. Scope alignment | Which comparators and populations are likely to appear in the final scope? | Comparator and PICO map by Member State |
2. Direct evidence | Does the pivotal trial answer any scoped PICO directly? | Coverage matrix of PICOs against trial data |
3. Indirect comparison feasibility | Is there a connected network, and are effect modifiers measurable? | Feasibility report and recommended method |
4. Endpoint validity | Are surrogate endpoints supported by evidence of surrogacy? | Surrogate evidence summary |
5. External and real-world data | Are external controls fit for purpose and pre-specified? | Data source and bias assessment |
6. National readiness | Where will the JCA package fall short in key markets? | Gap list by country with proposed fixes |
Each domain is rated on a simple scale of ready, partly ready or not ready, with a note on what evidence would change the rating. The aim is a short, practical output a clinical and market access team can act on, not a long audit document.
Figure 1. Pubrica JCA Evidence-Readiness Workflow
Stage | Activity | Output |
Inputs | Trial data, protocols, SAPs, literature, national HTA guidance | Evidence inventory |
Assessment | Score six domains against JCA and national requirements | Readiness rating |
Gap analysis | Identify missing comparators, outcomes and methods | Prioritised gap list |
Action plan | Define analyses, literature reviews and data generation | Timed evidence plan |
Pre-submission check | Re-score after actions are complete | Final readiness report |
12. How Pubrica Would Map Your Evidence Gaps Before Submission
A gap map is most useful when it is built early enough to act on. Pubrica’s approach has four steps.
- Collect and review. We gather clinical study reports, statistical analysis plans, systematic literature reviews and any existing HTA correspondence.
- Map against scope. We compare what exists against the likely JCA PICOs and the national requirements of the target Member States.
- Rate and prioritise. Each gap is rated by how much it could change the assessment and how feasible it is to close in the time available.
- Plan the fix. For each priority gap we propose a specific action, such as a targeted literature review, a feasibility analysis for an indirect comparison, a surrogate validation summary or a pre-specified external control analysis.
The output is a prioritised evidence-gap and action plan that can be used by regulatory, clinical, biostatistics and market-access teams. It identifies which gaps are realistically addressable before submission, which require additional analysis or evidence generation, and which should instead be transparently characterised as residual uncertainty.
Get expert support from Pubrica for addressing reviewer comments, preparing point-by-point rebuttals, and strengthening manuscripts for journal resubmission. Prepare your revised manuscript with confidence.
Conclusion
What is a Joint Clinical Assessment (JCA)?
A Joint Clinical Assessment (JCA) is an EU-level assessment of the relative clinical effectiveness and safety of certain health technologies. The assessment is based on consolidated PICO questions and does not make national pricing, reimbursement, or economic decisions.
Why are indirect comparisons important in oncology JCAs?
An indirect comparison may need to be considered when the pivotal trial does not directly compare the intervention with one or more relevant comparators included in the JCA scope. Multiple comparators, single-arm evidence, treatment crossover and changes in standard of care can create situations where direct comparative evidence is unavailable.
How does comparator variability affect JCA evidence packages?
Different Member States may identify different standards of care. When these preferences are consolidated into JCA PICOs, sponsors may need to provide evidence for several comparators. This can increase reliance on indirect comparisons and create different levels of evidence strength across comparators.
Does a JCA report replace national HTA assessments?
No. The JCA report feeds into national HTA and pricing and reimbursement processes. Member States may still require additional analyses because of differences in comparators, populations, outcomes, methodology, or data-cut timing.
How can sponsors prepare for EU JCA evidence requirements?
Sponsors should map likely PICO scenarios early, assess whether pivotal evidence directly answers each relevant comparator question, test the feasibility of indirect comparisons, document assumptions and effect modifiers, assess surrogate-endpoint evidence, and align the EU evidence plan with priority national HTA requirements. They should also identify post-JCA data and analysis needs before submission.
References
- Bucher, H. C., Guyatt, G. H., Griffith, L. E., & Walter, S. D. (1997). The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. Journal of Clinical Epidemiology, 50(6), 683-691. https://doi.org/10.1016/S0895-4356(97)00049-8
- Kemp, R., & Prasad, V. (2017). Surrogate endpoints in oncology: When are they acceptable for regulatory and clinical decisions, and are they currently overused? BMC Medicine, 15, Article 134. https://doi.org/10.1186/s12916-017-0902-9
- Schweitzer, M. K., Dold, M. N., Genet, A., Gossens, K., Klein-Hessling, T., Löffler, N., Rabel, M., Rasch, A., Reuter, E. M., Schmelcher, J., Wolfram, N., & Werner, S. (2024). Shaping a suitable EU HTA dossier template: why the German template is not fit for purpose. The European journal of health economics : HEPAC : health economics in prevention and care, 25(5), 877–888. https://doi.org/10.1007/s10198-023-01631-5