Five Theses on EU HTA and National HTA Processes: Why One JCA Requires Different National Evidence Strategies

The Joint Clinical Assessment (JCA) establishes a common European assessment of comparative clinical effectiveness and safety under the EU HTA Regulation. National HTA processes, however, remain decisive for subsequent appraisal, reimbursement and pricing. The first JCA reports and their implementation in Germany and France show that differences in PICO, comparators, endpoints, evidence methods and national evidence appraisal need to be considered early in evidence planning.

This creates a dual requirement for health technology developers: clinical evidence must meet the requirements of the JCA while remaining fit for purpose in the relevant national HTA processes. National requirements therefore do not become relevant only when local dossiers are prepared. They already affect PICO scoping, study design, comparators, endpoints and the planning of direct and indirect comparisons.

Germany and France illustrate two different forms of this interface. In Germany, JCA evidence meets the requirements of the AMNOG early benefit assessment. In France, the evidence assessed in the JCA is considered within the appraisal by the Transparency Committee (Commission de la transparence, CT) of the French National Authority for Health (Haute Autorité de santé, HAS) for SMR and ASMR. A common JCA therefore does not lead to a common national appraisal pathway.

The Joint Clinical Assessment and national HTA processes serve different purposes

The Joint Clinical Assessment evaluates comparative clinical effectiveness and safety at European level. National HTA processes subsequently consider this evidence within their respective appraisal and reimbursement systems.

The JCA therefore provides a common clinical assessment basis, but not a single European decision on added benefit, reimbursement or price. A study or analysis may form part of the JCA without automatically meeting all requirements of a national HTA process.

In Germany, requirements concerning the relevant population, the appropriate comparator therapy, patient-relevant endpoints and the assessment of added benefit remain applicable. In France, the Transparency Committee addresses two key national questions: whether the Service médical rendu (SMR) is sufficient to support reimbursement and what additional therapeutic progress compared with available alternatives is reflected by the Amélioration du service médical rendu (ASMR).

The five theses on JCA and national HTA processes at a glance

JCA and national HTA are interconnected levels of assessment, but they answer different questions. This creates five key requirements for European and national evidence planning.

Thesis 1: The JCA provides a common clinical assessment but does not replace national HTA processes

The Joint Clinical Assessment provides a common European clinical assessment but does not replace national HTA appraisals or national decisions on reimbursement and pricing.

Member States use the common clinical assessment basis within their respective national processes. The EU HTA process is intended to reduce duplication in clinical assessment without harmonising national appraisal standards and decision-making processes.

Germany assesses JCA evidence according to AMNOG requirements

In Germany, the early benefit assessment under Section 35a of the German Social Code Book V remains the national appraisal framework. Relevant requirements include the target population, the appropriate comparator therapy, patient-relevant endpoints, subgroups, analytical methods and the currency of the evidence.

Tovorafenib provides the first practical illustration of this distinction. The JCA dossier and the AMNOG dossier draw partly on the same clinical evidence but address different assessment questions. In the German process, issues including implementation of the intention-to-treat principle, patient relevance and operationalisation of endpoints, patient-reported outcomes and safety analyses were considered according to national requirements.

Indirect comparisons also illustrate the difference. MAIC analyses from the JCA context were mentioned in the German process but were not presented accordingly as evidence for the AMNOG assessment.

France assesses JCA evidence according to the requirements of the Transparency Committee

In France, the Transparency Committee assesses the clinical benefit of a medicine for the reimbursement decision and its therapeutic progress compared with available alternatives. The CT distinguishes between SMR and ASMR.

SMR takes into account factors including efficacy and adverse effects, the medicine's place in the therapeutic strategy, disease severity and medical need. ASMR assesses therapeutic progress compared with existing alternatives and also informs the framework for subsequent price negotiations.

The French assessment question therefore goes beyond the description of relative clinical effects in the JCA. What matters is the significance of the evidence relative to clinically relevant alternatives in the French healthcare context.

Germany and France therefore illustrate the same underlying principle: the JCA provides a common clinical assessment basis, while the national significance of that evidence continues to be determined by the respective HTA system.

Thesis 2: National evidence requirements begin during JCA scoping

National differences do not emerge only after publication of the JCA report. Populations, comparators and outcomes submitted by Member States already influence the assessment scope of the Joint Clinical Assessment.

JCA scoping translates Member State requirements into specific PICO questions covering population, intervention, comparator and outcomes. Differences in treatment pathways and national comparators can therefore generate multiple PICO questions within a single JCA.

The first published JCA reports illustrate the practical scale of this issue. Eight PICOs were defined for tovorafenib, seven for tarlatamab and 14 for onasemnogene abeparvovec. Multiple PICOs may require additional evidence searches, subgroup analyses and indirect comparisons.

National comparators increase the complexity of the JCA assessment scope

Different comparators can mean that a clinical development programme does not directly answer every PICO question in the JCA.

The relevant standard of care may differ between Member States. A phase III study with a direct comparator may therefore provide robust direct evidence for one PICO while no direct evidence is available for another comparator.

In these situations, network meta-analyses, matching-adjusted indirect comparisons or external comparator data may be required. The availability and methodological feasibility of these analyses should therefore be assessed before the final assessment scope is established.

JCA PICOs can differ in their relevance to national HTA processes

PICO coverage in the JCA and national PICO relevance are not the same thing. Not every European PICO question has the same relevance for every national HTA process.

Tarlatamab illustrates this difference. The JCA included seven PICOs covering different populations, comparators and evidence methods. Three of these PICOs were relevant to the French early access assessment.

This creates an additional planning dimension for manufacturers: alongside European PICO coverage, teams need to assess early which PICO scenarios may become decision-relevant in priority national HTA processes.

Thesis 3: JCA evidence does not automatically meet the requirements of national HTA processes

A study or analysis can be considered in the JCA without fully meeting the methodological or decision-related requirements of a national HTA process.

The JCA and national HTA systems share fundamental methodological principles but apply them to different assessment questions. Randomised direct evidence is highly valued, evidence should be identified systematically, and uncertainty should be presented transparently. Differences arise when these principles are applied to national decision questions.

Indirect comparisons can be interpreted differently in the JCA and national HTA processes

Indirect comparisons may be required when direct comparative evidence is unavailable for individual JCA PICOs. Their robustness depends on factors including similarity or exchangeability, prognostic factors, effect modifiers and potential confounders.

A MAIC, NMA or other indirect analysis presented in the JCA is therefore not automatically equally suitable for every national HTA process.

Germany assesses JCA evidence against national AMNOG requirements

Tovorafenib shows that evidence prepared for the JCA must be considered in Germany against the national assessment question.

The German process focused on issues including patient relevance and endpoint operationalisation, ITT analyses, response rates for patient-reported outcomes and safety analyses. Indirect comparisons submitted in the JCA context did not automatically answer the German assessment question.

The case therefore demonstrates a key distinction between a common clinical assessment and national usability: evidence assessed in the JCA remains relevant, but it must address the specific national assessment question.

France assesses JCA evidence against its requirements for the quality of clinical demonstration

The French Transparency Committee assesses not only whether comparative evidence is available, but whether the evidence meets national requirements for the quality of the clinical demonstration.

For ASMR, relevant factors include a clinically relevant comparator, the quality of the study design, an appropriate study population, clinically relevant endpoints, and the magnitude and clinical relevance of the effect. A statistically significant difference alone is not necessarily clinically relevant.

A direct randomised comparison against a clinically relevant comparator remains the preferred evidence standard. If a direct randomised comparison is absent even though the CT considers such a comparison to have been feasible, this may limit the ASMR. Methodologically appropriate indirect comparisons can be considered, but their assumptions and remaining uncertainties are assessed separately.

Tarlatamab and lurbinectedin illustrate these differences in practice. For tarlatamab, the relevant population and direct randomised evidence were particularly important in France. For lurbinectedin, the appraisal additionally considered the relevant data cut-off, PFS and OS, and a change in the statistical methodology.

The same evidence base can therefore serve different functions in the JCA and in national HTA processes.

Thesis 4: The JCA-to-national HTA gap is country-specific

The JCA-to-national HTA gap describes the difference between the clinical evidence prepared and assessed in the JCA and the additional requirements of a national HTA and market access process.

This gap does not consist solely of missing evidence. JCA content may need to be reused, adapted, updated or supplemented at national level. Which of these tasks is required depends on the respective HTA system.

Germany translates JCA evidence into the requirements of the AMNOG process

In Germany, this interface can be described using the working term delta dossier. The term does not refer to a separate regulatory dossier template. It describes the content and evidence that need to be prepared between the JCA dossier and the requirements of the German AMNOG process.

Depending on the procedure, this may include national requirements concerning the appropriate comparator therapy, patient-relevant endpoints, subgroups, epidemiology, the target population within the statutory health insurance system, costs and evidence currency.

The German delta therefore does not arise solely from missing data. It results from the difference between the assessment questions addressed in the JCA and the requirements of the German benefit assessment.

France combines reuse, adaptation and supplementation of JCA content

The French local dossier neither adopts the JCA dossier in full nor recreates the clinical evidence from scratch. National preparation combines reuse, adaptation and supplementation.

Parts of the JCA dossier can be transferred into the French dossier. Other content needs to be adapted to the French assessment question. For results on relative effectiveness and safety, the JCA dossier can be referenced while relevant updated data may be added.

At the same time, specific national content remains necessary. This includes the French healthcare context, disease and epidemiology, clinical management, burden and unmet need, clinically relevant comparators, therapeutic strategy and target population.

The French translation of the JCA therefore involves three core tasks:

1. Reuse JCA content when the European material directly addresses the French assessment question.
2. Adapt or update JCA content when the French appraisal requires a different interpretation or more recent evidence.
3. Add national content when the French healthcare context and the requirements of SMR, ASMR and market access require additional information.

The comparison between the JCA dossier and the French local dossier shows that national implementation involves different forms of reuse. Clinical content can partly be transferred or referenced, while the French healthcare context and other national appraisal content require separate preparation.

Germany and France show different JCA-to-national HTA gaps

Germany and France draw on content and evidence from the JCA but translate them into different national appraisal frameworks.

The German concept of the delta dossier should therefore not simply be transferred to other countries. The JCA-to-national HTA gap is the broader category; the German delta dossier and the French local dossier represent different national manifestations of that gap.

Thesis 5: JCA and national HTA require an integrated evidence strategy

JCA and national HTA should not be planned sequentially as a European evidence project followed by a local one. Some evidence gaps can be addressed later through additional analyses. Others arise from decisions in the clinical development programme and are difficult to correct once the pivotal study is complete.

This distinction is central to evidence strategy.

Comparator, population and endpoints are among the evidence decisions that are difficult to correct later

A missing decision-relevant comparator, an endpoint that was not collected or an unsuitable study population can only be addressed to a limited extent once the pivotal study has been completed.

In Germany, for example, the absence of a direct comparison against the relevant appropriate comparator therapy can materially affect the subsequent benefit assessment. In France, the CT generally expects a direct randomised comparison against a clinically relevant comparator when such a comparison is feasible. Clinically relevant endpoints and an appropriate study population are also part of the quality of the clinical demonstration.

These requirements should therefore be assessed against expected European and national assessment questions before the pivotal study design is finalised.

Indirect comparisons and additional data can address some evidence gaps

Other evidence gaps can be addressed at least partly after the pivotal study has been completed. Options may include indirect comparisons, additional subgroup analyses, external data, real-world evidence or updated data cut-offs.

These options have methodological limits. An indirect comparison can usefully supplement missing direct evidence only if the assumptions required for the comparison are met. Real-world evidence can describe the healthcare context, use in clinical practice or remaining uncertainties, but it does not automatically replace a randomised comparative study when such evidence is expected for the assessment question.

The French CT explicitly states that observational studies cannot replace randomised clinical trials in situations where randomised evidence is expected. Real-world evidence can, however, contribute to describing actual use, therapeutic strategy and remaining uncertainties.

PICO simulation should begin before the final JCA assessment scope

PICO simulation allows expected populations and comparators to be assessed for their evidence requirements before the final assessment scope is published.

Potential PICO scenarios can be prioritised early according to their likelihood, decision relevance and analytical feasibility. Systematic literature reviews, evidence gap assessments and potential indirect comparisons can then be prepared for likely scenarios.

This reduces the risk that core evidence components need to be developed only within the compressed JCA timeline.

National HTA requirements should be assessed in parallel with JCA evidence planning

An integrated evidence strategy connects the expected JCA assessment scope with the requirements of priority national HTA systems.

For Germany, this assessment may include population, appropriate comparator therapy and patient-relevant endpoints. For France, it includes the relevant population, clinically relevant comparator, quality of demonstration, clinical endpoints and the requirements for SMR and ASMR.

Prioritisation should focus in particular on how relevant an evidence requirement is to the subsequent national decision and how difficult it will be to address after clinical development is complete. A missing comparator or an endpoint that was never collected requires different early planning from contextual information, additional analyses or national healthcare data that can be added later.

The JCA becomes the common starting point for different national HTA pathways

The Joint Clinical Assessment becomes a common starting point for different national HTA pathways. The EU HTA process is intended to reduce duplication in clinical assessment, but it does not remove differences between national HTA systems. The clinical evidence prepared and assessed in the JCA subsequently meets different national assessment questions, methods and healthcare contexts.

Germany and France already illustrate how different this national fit can be. Germany translates JCA evidence into the requirements of the AMNOG benefit assessment. France combines reuse of JCA content with adaptations and specific national content for the assessment of SMR and ASMR.

For manufacturers, this creates one connected evidence task: anticipate likely JCA PICOs, prepare methodologically robust evidence for the JCA, identify national requirements that are difficult to address later, and manage the remaining country-specific gaps.

The JCA therefore does not replace national evidence planning. It provides a common European starting point from which evidence must be translated into different national HTA processes.