For years, real-world evidence (RWE) has remained central to European market access planning. It was employed to describe disease burden, treatment pathways, and unmet medical needs, but it rarely decides the result of a clinical assessment. The EU Joint Clinical Assessment (JCA) is now bringing a transformation in this situation. As oncology medicines and advanced therapy medicinal products (ATMPs) go through the initial JCA cycles, RWE is being used for scoping, selecting comparators, conducting indirect comparisons, and managing uncertainty. It is no longer only extra evidence added after approval.
The JCA continues to focus on relative clinical effectiveness, and non-randomised evidence is more vulnerable to bias when used to estimate treatment effects. However, when pivotal trials are single-arm, involve narrow patient populations, lack comparators, or have limited follow-up, RWE helps address the resulting evidence gaps. It can determine whether the evidence package simply describes a product or answers the questions posed by Member States.
Real-World Evidence Has Moved From Context to Evidence Design
Under Regulation (EU) 2021/2282, drug developers were asked to respond to a single set of Population, Intervention, Comparator and Outcome (PICO) questions across Member States. This requirement highlights the weakness in conventional evidence planning. Although pivotal trials are planned many years before the JCA scope is defined, the deadline for submitting the dossier depends on the specific JCA procedure and its key milestones. The 100-day standard and shorter timelines applicable to certain procedures should therefore be stated in line with the appropriate procedural guidance and not treated as a general deadline calculated from the date of the scoping request.
This timing mismatch makes RWE strategically important before launch. Recent analysis of RWE use across the EU HTA system identifies four practical roles:
- Informing PICO simulations
- Mapping the disease landscape
- Identifying prognostic factors and effect modifiers
- Directly or indirectly supporting comparative clinical assessment
The analysis also recommends developers to start their PICO simulation and real-world evidence planning at least 1.5 years before the deadline for submitting to the JCA, and preferably during the Phase II-to-Phase III transition.
It represents a real shift in operating model. RWE is no longer just a ‘supporting evidence’ workstream owned by a late-stage HEOR team. it is now included in the product’s overall evidence-generation plan and must be aligned with clinical development, regulatory strategy, medical affairs, and market access from the point at which decisions regarding the comparator and the endpoint can still be made.
Why JCA Raises the Bar for RWE?
Acceptance of observational evidence is not necessarily easier under the JCA. In fact, the initial implementation has established a high methodological standard. Developers must explain why a comparator is relevant, address confounding and effect modification, and clearly state their analytical assumptions and residual uncertainty.
In practice, having registry data does not constitute an RWE strategy. In order to produce a JCA-ready package, it is necessary to have a pre-specified research question linked to a plausible PICO. The data source must be justified with respect to the target population and the treatment pathway. There must be clear definitions of the index date, exposure, outcomes, and follow-up period; and an analysis plan that anticipates confounding, missing data, immortal-time bias, and transportability.
This is especially important in cases where the evidence body is limited. In the context of rare diseases, ATMPs and later-line oncology, randomised comparator groups may be impossible, unethical, or unavailable. In such situations, RWE may support external comparator groups to create synthetic controls, benchmark against the natural history, or provide context for the results of single-arm trials. However, these methods are not interchangeable with indirect treatment comparisons based on clinical trials. An external-control study employs a different cohort as the comparator; a matching-adjusted indirect comparison (MAIC) usually reweights the individual patient data from one trial so that it matches the overall baseline characteristics from another study. Both of these approaches have limitations, and a comparison that is not anchored requires particularly strong assumptions if a causal interpretation is to be made.
Read More: Global Pharma Evidence Strategy: Approval to Reimbursement
Early JCA Experience Shows the Evidence Gap
The fact is clearly shown by the first JCAs. The drug tovorafenib, which was evaluated for use in children with low-grade glioma, was based on a non-comparative Phase 2 study. Although the consolidated scope included eight PICOs, comparative results were provided for only two; one unanchored matching-adjusted indirect comparison was included, while several of the PICOs could not be evaluated since there was no suitable comparator data available. The assessors also noted significant uncertainties, such as the small effective sample size and confounders that could not be fully dealt with.
The lesson is not that RWE failed. Rather, it’s that RWE arrived too late, in a fragmented state, and without sufficient pre-planned comparator data to deal with the comparative questions identified in the scope. For sponsors, this implies that RWE should be an asset that is planned from the beginning, not something added on afterwards. The choice of data source, comparator cohort, endpoint definitions and method of analysis must be made before the pivotal programme is locked.
Early JCA signals also show recurring problems related to disconnected evidence networks, imbalance in effect modifiers, and comparisons that are only weakly justified. Such issues are serious in rare diseases because small samples, varied patient populations, and limited natural-history data hinder both traditional indirect treatment comparisons and RWE-based methods.
Where Real-World Evidence Creates Value Across the JCA Lifecycle?
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Before Scoping: Anticipating the questions
The most valuable use of real-world evidence usually takes place before a formal scope is established. It estimates existing treatment sequences, identifies the types of treatments that are likely to be used in normal clinical practice, quantifies different patient subgroups, and checks whether the populations eligible for trials are similar to those who will actually receive the medicine. This allows sponsors to carry out PICO simulations in major markets and prioritise the evidence gaps most likely to affect reimbursement.
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During Dossier Preparation: Strengthening comparative interpretation
In the absence of direct head-to-head evidence, RWE can be used to identify external comparators, provide data needed for comparative analyses that are properly designed, and assist with transportability assessments. Its role is to ensure the comparison is interpretable by demonstrating that the real-world cohort is similar to the trial population with respect to measurable characteristics, by highlighting any remaining differences, and by measuring the direction and magnitude of likely bias.
This is where the difference between considering real-world evidence as a “plan” and as “a part of the strategy” becomes apparent. Although a retrospective chart review produced after the JCA scope has been determined can offer some background information, it is very unlikely to eliminate a comparator gap. A prospectively designed external-control study, with eligibility criteria, endpoints and statistical analysis all defined in the protocol, could considerably enhance the evidence package, on the condition that its limitations are clearly stated.
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After Authorisation: Maintaining the value case
The JCA is not the end of evidence generation. Further clinical questions can arise again because of conditional approvals, the fact that survival data is still immature, changing standards of care, and the introduction of new comparators. RWE is necessary for lifecycle evidence concerning long-term effectiveness, safety in more widespread populations, changes in treatment patterns, performance among subgroups, and the effect of a therapy on real-world care pathways.
For ATMPs, where durable follow-up is central to the value proposition, registry-based evidence may be necessary. For oncology products, real-world outcomes can test whether benefits observed in tightly controlled trials persist in routine practice. For devices and diagnostics, where randomised evidence is less common, the gap between performance evidence and clinical utility is even wider, making real-world outcome data central to any future JCA-relevant case.
For medical devices and in-vitro diagnostics, the JCA framework also applies to selected technologies, with the first devices selected for assessment in October 2026. RWE may help demonstrate clinical utility and outcomes in relevant settings, but it should not be presented as mandatory or central to every device assessment. The appropriate evidence depends on the technology, intended use and assessment question.
Real-World Examples Point Towards a More Confident Role
Recent evidence from Europe shows that real-world evidence can go beyond just providing background information. For example, in the case of von Hippel-Lindau disease, natural-history data for belzutifan were used to put the response rates from a small single-arm trial into context since a randomised comparator was not available. In patients with heavily pretreated multiple myeloma, real-world cohorts from outside the trial were combined with the trial data for elranatamab in order to assess effectiveness in a group where conventional comparisons were difficult.
It’s important to note that these examples illustrate a particular pattern. RWE is most effective when it addresses a specific uncertainty, such as natural history, comparator context, treatment pathway, or an external benchmark; rather than when it is presented as a broad “real-world validation” exercise. The same principle will apply under JCA. Sponsors should define the decision that RWE is intended to inform, then design the data and analysis around that decision.
The infrastructure is likewise becoming more developed. Through DARWIN EU, the European Medicines Agency’s federated network consisting of hospitals, registries, and other real-world data sources; enables regulators to request analyses that place the evidence provided by the sponsor in context. Although this does not eliminate the sponsor’s responsibility to put forward a coherent RWE strategy, it does indicate that real-world data are becoming an integral part of the European evidence infrastructure rather than remaining an optional addition.
Also Read: European RWE and Market Access 2026
What Should C-Level Executives and Market Access Leaders Change?
The strategic question for biopharma leadership is not whether real-world evidence can support JCA; instead, it is whether the organisation can generate RWE that is good enough to support decisions, early enough, at acceptable cost, and with enough methodological rigor to withstand review in several countries.
- First, RWE planning should proceed to the decision stage going from Phase II to Phase III. Before protocol lock, comparator feasibility, the viability of using an external control, registry readiness, and endpoint availability should be evaluated since the JCA will have to assess the evidence in response to questions that may not yet be formally stated.
- Second, companies should develop a PICO options library organised by disease area. This library should map the likely comparators, subpopulations, outcome measures, data sources and methods of evidence synthesis for the major European markets. Once the formal 100-day dossier period begins, the focus should be on retrieving, adapting and validating the existing material, not on starting evidence planning.
- Third, RWE should be treated as an asset and should have defined owners, budgets, and quality standards. This involves clear accountability in all areas of clinical development, HEOR, regulatory affairs, medical affairs, and data science, as well as documented data provenance, pre-specified analyses, and a realistic understanding of what each data source can and cannot support.
- Fourth, the national HTA requirements must be taken into account. Although the JCA carries out a single EU-wide clinical assessment, national organisations still have the responsibility for pricing, reimbursement and access. The acceptability and use of RWE can differ from one national system to another and depending on the specific decision context. As a result, it is still necessary to plan for the individual country evidence requirements, especially in cases where national agencies ask for extra analyses or use different methodological standards. Instead of saying that one country is generally more or less open to real-world evidence, sponsors should examine the requirements of the appropriate national HTA bodies and adjust their evidence strategy accordingly.
How Ingenious e-Brain Supports JCA-Ready Real-World Evidence?
Ingenious e-Brain supports biopharma and medtech companies in developing evidence strategies that address European clinical assessment and market access requirements.
Our team conducts multi-country evidence-gap assessments using published clinical guidelines, HTA reports, trial registries, and available JCA scopes. These assessments help clients evaluate comparator feasibility, identify relevant patient populations and outcomes, and prioritise uncertainties that may require additional evidence generation.
We also support the methodological development of RWE-based evidence by evaluating external comparator feasibility, real-world benchmarking, transportability analyses and indirect treatment comparisons. Our work includes identifying fit-for-purpose registries, electronic health record networks and claims databases, alongside developing transparent evidence-synthesis approaches that document analytical assumptions, limitations and potential sources of bias.
For products approaching EU filing, Ingenious e-Brain helps align real-world evidence, clinical, regulatory and market-access workstreams around one integrated evidence roadmap. This includes preparing JCA dossier components, supporting national HTA adaptations after the JCA report, and ensuring that the same evidence base can be carried consistently into AMNOG, HAS and other national reimbursement discussions.
For medical devices, diagnostics and companion diagnostics, we help clients define the real-world outcomes, clinical utility measures and comparator context needed to support a future JCA-relevant value case.
Future Outlook
Over the next two to three JCA cycles, RWE is expected to become more formalised rather than optional. As orphan medicines enter scope from 13 January 2028, followed from 13 January 2030 by the other medicinal products falling within Article 7 of Regulation (EU) 2021/2282. Pressure will grow for clearer methodologies on external comparators, registry-based evidence, transportability and lifecycle evidence generation.
For healthcare leaders, the advantage will depend on their ability to integrate evidence: the ability to combine data from clinical trials, registries, electronic health records (EHRs), patient-generated data and indirect comparisons into a single, coherent and auditable package. Companies which develop this capability early will not just be able to respond to JCA scopes more efficiently; they will be in a position to set the evidence questions that their products can realistically answer and to turn real-world evidence into a major factor in access, differentiation and lifecycle value.
Conclusion
If you’re preparing for the EU Joint Clinical Assessment (JCA), we help you integrate real-world evidence (RWE) into your market access strategy. From anticipating PICO requirements and identifying comparator gaps to evaluating relevant data sources, our team helps align clinical development and market access planning with evolving European and national HTA requirements.
Connect with our market access team to explore how our JCA support and RWE capabilities can help address assessment requirements and strengthen your market access approach.
For more information, visit our Market Access service page.
