EU JCA and national HTA: Where methodological differences begin after the JCA

The Joint Clinical Assessment harmonizes parts of clinical evidence assessment across Europe, but it does not harmonize all methodological requirements of national HTA processes. A comparative analysis of EU HTAR and HTA systems in Germany, France, the Netherlands and Spain identifies common ground in core evidence standards, alongside relevant differences in scoping, indirect comparisons, non-randomized evidence and the handling of uncertainty.

For health technology developers, this creates a new planning challenge: an evidence package must meet JCA requirements while remaining suitable for subsequent national HTA processes. This interface determines which analyses can be used across Europe and where national requirements call for additional evidence or analyses.

What Sarri et al. examined across EU JCA and national HTA systems

Sarri et al. examined methodological similarities and differences between EU HTAR and selected national HTA systems. The study was based on an environmental scan of publicly available guidance documents conducted in March 2024 and updated in December 2024.

The authors included 31 methodological documents. In addition to guidance from the European Commission and EUnetHTA, they reviewed documents from IQWiG and G-BA in Germany, HAS in France, ZIN in the Netherlands, and AEMPS and AQuAS in Spain.

The comparison focused on three areas:

1. Scoping and the definition of PICO questions
2. Evidence identification and selection
3. Evidence synthesis and comparative analyses

The analysis therefore does not represent every national HTA system in the EU. It covers selected countries with established HTA structures and comparatively extensive methodological guidance. The findings are particularly useful for identifying concrete methodological interfaces between JCA and national HTA.

EU JCA harmonizes clinical assessment, not national HTA requirements

The EU JCA creates a common European framework for comparative clinical assessment, while Member States retain their own assessment and decision-making requirements.

The JCA brings together and assesses available information on the comparative clinical effectiveness and safety of a new health technology. Final judgments on the additional benefit or value of a technology, as well as reimbursement and pricing decisions, remain the responsibility of Member States.

This division of responsibilities is critical for evidence planning. A clinical analysis may form part of the joint European assessment without automatically meeting every requirement of a national HTA process.

The publication shows that there is a shared methodological core. EU HTAR and the national systems examined favor a systematically identified and as unbiased as possible evidence base. Randomized controlled trials and direct comparisons have a prominent role. Transparent documentation of assumptions and uncertainty is also reflected across several systems.

Differences become particularly relevant when these general principles are applied to specific national assessment questions.

JCA scoping already introduces different national evidence requirements

PICO scoping translates Member State requirements into specific research questions for the JCA. Differences between national HTA systems therefore become relevant before the JCA is completed, starting with the definition of its assessment scope.

A JCA PICO must accommodate different national questions

Population, intervention, comparator and outcomes define the methodological framework for JCA evidence requirements. Member States can contribute their national requirements to the scoping process. These requirements are subsequently consolidated into one or more PICOs.

Population and comparator requirements can differ between Member States. A population relevant to a national HTA may not fully correspond to the EMA label population. The relevant comparator can also depend on the national standard of care.

This is particularly relevant for Germany because the Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA) determines the appropriate comparator therapy (zweckmäßige Vergleichstherapie, zVT) for the early benefit assessment. The publication explicitly identifies this as a difference from the European level.

A joint JCA therefore does not necessarily mean a single clinical research question for the whole of Europe. Scoping must accommodate different national requirements within a European assessment.

National PICO requirements can require additional analyses

A JCA PICO can differ from the original research question addressed by a clinical study. The requested population may represent only a subgroup of the trial population, for example, or a relevant comparator may not have been directly investigated in the pivotal trial.

In such situations, the available trial evidence cannot necessarily be used unchanged for every PICO question. Additional subgroup analyses, re-analyses of existing studies or indirect comparisons may be required.

PICO planning therefore becomes a question of analytical feasibility. Manufacturers need to assess not only which questions may emerge from Member States, but also which data and methods can answer them.

EU JCA and national HTA share core principles for evidence selection

EU JCA and the national HTA systems examined favor high-quality evidence with the lowest possible risk of bias. However, specific requirements for evidence identification, evidence selection and study assessment differ.

For the JCA, the guidance sets out detailed requirements for systematic evidence identification. The evidence base should be developed using predefined criteria and the relevant PICOs. The publication highlights requirements relating to database searches, study registries and the recency of searches, among other areas.

At national level, requirements for literature searches and acceptable evidence sources may differ. This means that even the question of which evidence is included in an assessment can be answered differently by JCA and national HTA systems.

Randomized controlled trials remain the preferred evidence standard

Randomized controlled trials retain a central position in both the EU HTAR framework and the national systems examined. Direct comparative evidence with a low risk of bias is the preferred basis for estimating relative treatment effects.

The practical challenge arises when such evidence is not available for a specific PICO question. This can occur for new therapies without a direct comparison against a nationally relevant comparator or in indications where randomized evidence is limited.

Indirect comparisons and, where appropriate, non-randomized evidence then become more important. At the same time, methodological differences between HTA systems become more pronounced.

Non-randomized evidence is treated differently in EU JCA and national HTA

Non-randomized evidence is subject to substantial methodological requirements under EU HTAR. The publication discusses its use particularly in situations where evidence gaps exist or randomized evidence is unavailable.

Confounding is a major concern. In non-randomized comparisons, relevant confounders, prognostic factors and effect modifiers need to be considered. If the necessary information is unavailable, uncertainty around estimated treatment effects can increase substantially.

National requirements also differ. Sarri et al. describe Germany and the Netherlands as more restrictive in their use of non-randomized evidence, while local real-world evidence can play a greater role in certain contexts in France and Spain.

For manufacturers, the implication is clear: the availability of an additional evidence source does not by itself determine whether it can be used in the same way for JCA and national HTA.

Indirect comparisons are a central methods gap between EU JCA and national HTA

Indirect comparisons are among the areas in which Sarri et al. identify relevant differences between EU HTAR and national HTA requirements. At the same time, multiple PICO questions in a JCA can increase the need for indirect comparisons.

When no direct comparison is available between a new therapy and a requested comparator, it is necessary to assess whether the question can be addressed through an evidence network or population-adjusted methods.

At this point, selecting a statistical method alone is not sufficient. The first question is whether the assumptions required for a robust indirect comparison are met.

EU HTAR sets demanding requirements for indirect comparisons

EU HTAR guidance requires a detailed assessment of exchangeability across the included studies. This includes similarity, homogeneity and, where relevant to the evidence network, consistency.

Effect modifiers should be identified a priori where possible. The publication refers to literature reviews, expert input and subgroup analyses as potential sources. Assumptions, missing information and the potential direction of bias should be documented transparently.

These requirements become particularly relevant when study populations differ. The greater the differences between studies in prognostic factors or effect modifiers, the more difficult the interpretation of an indirect treatment effect becomes.

The methodological focus therefore shifts from “Which ITC method can we use?” to a more fundamental question: “Can a robust indirect comparison be conducted for this PICO question at all?”

MAIC, STC and ML-NMR are not automatically transferable to national HTA

EU HTAR guidance discusses several methods for indirect and population-adjusted comparisons, including matching-adjusted indirect comparisons (MAIC), simulated treatment comparisons (STC) and multilevel network meta-regression (ML-NMR).

The publication shows, however, that national guidance differs in its treatment of these methods. Requirements for controlling confounding and effect modification become particularly demanding for unanchored comparisons and non-randomized evidence.

This creates a practical challenge for evidence planning: an analytical method considered for a European PICO question is not automatically suitable in the same way for every national HTA question.

Manufacturers therefore need to plan more than the statistical approach itself. They need to assess early which analyses are likely to remain robust under the methodological requirements of the relevant national HTA systems.

EU JCA and national HTA handle uncertainty differently

EU HTAR distinguishes between internal validity, statistical precision and external validity when considering uncertainty. The transferability of findings to the relevant healthcare context remains particularly important at national HTA level.

Internal validity concerns potential systematic bias within the underlying evidence. Statistical precision reflects uncertainty resulting from random variation. External validity addresses how well findings can be generalized to the relevant context of use.

For the JCA, sources of uncertainty should be presented transparently and explored through appropriate sensitivity analyses. National HTA systems can subsequently interpret this uncertainty in light of their own assessment requirements.

The publication highlights an important distinction: within the JCA, the medical context of a PICO question should not in itself be used to justify a generally lower evidence standard. National systems may apply different assessment considerations, for example in rare diseases or situations of high unmet medical need.

Evidence appraisal remains a national responsibility

The JCA is intended to assess comparative clinical evidence, not to pre-empt a final national value judgment. Parts of evidence appraisal therefore remain at Member State level.

Sarri et al. illustrate this through differences in the use of GRADE, thresholds for clinical relevance and other national assessment criteria.

This is more than a procedural distinction. The same clinical treatment effect can be described at European level and analyzed in terms of its uncertainty, while its relevance to a specific national HTA decision is subsequently assessed using national criteria.

A shared clinical evidence base therefore does not necessarily result in the same national assessment.

Germany shows close methodological alignment between IQWiG and EU JCA

Among the national HTA systems examined by Sarri et al., IQWiG methodology shows the closest alignment with EU HTAR methods. The authors also relate this finding to Germany's influential role during the preparation of the European HTA methodology.

Areas of alignment include the prominent role of randomized evidence, systematic evidence identification, transparent planning of statistical analyses and requirements for assessing heterogeneity and uncertainty.

This methodological proximity does not mean that JCA evidence can be transferred into the German benefit assessment without further review.

National requirements remain relevant in Germany. These include the population relevant to the benefit assessment and the appropriate comparator therapy determined by the G-BA. Requirements concerning outcomes, subgroups, indirect comparisons and the assessment of submitted evidence also need to be considered for the specific AMNOG procedure.

The close methodological alignment therefore requires a differentiated interpretation. Many analyses may in principle be transferable, but whether they actually answer the German assessment question depends on the specific PICO, the available evidence and national requirements.

What the methods gaps mean for JCA and national evidence planning

The findings by Sarri et al. argue against a purely sequential approach of “JCA first, national HTA afterwards.” National requirements can already influence which European PICO questions arise and which analyses need to be prepared to address them.

JCA and national HTA should not be planned as separate evidence projects

An evidence package does not need to be developed twice from scratch. The more important question is which elements of the evidence can support both European and national assessments and where requirements diverge.

This assessment should take place early. Relevant areas include:

• populations and potential subgroups
• European and national comparator requirements
• availability of direct comparative evidence
• structure of evidence networks
• relevant effect modifiers
• feasibility of indirect comparisons
• additional analyses required nationally

The earlier these interfaces are understood, the more effectively common analyses and national additions can be planned.

Multiple JCA PICOs can require multiple analytical scenarios

Multiple PICO questions can require the same clinical evidence to be analyzed in different ways. Sarri et al. explicitly discuss the potential need for parallel analytical scenarios based on the same evidence sources to address different methodological requirements.

This is particularly relevant when different comparators need to be considered or when a PICO population does not fully correspond to the trial population.

For biostatistics, evidence synthesis and market access teams, this creates a shared planning task. Analyses need to be statistically valid while also answering the specific European or national decision question.

National transferability should be assessed during European evidence planning

For Germany, the preparation of the JCA should already include an assessment of which parts of the European evidence are likely to support the subsequent early benefit assessment.

This does not mean pre-empting the national procedure. The objective is to identify foreseeable differences early. If, for example, the German appropriate comparator therapy is not directly represented in the pivotal trials, the need for additional analyses may become apparent well before the AMNOG procedure begins.

This is where the connection to the delta dossier becomes particularly relevant. The quality of the later national dossier depends substantially on how well European evidence and German requirements have been considered together in advance.

EU JCA and national HTA differ across the evidence pathway

The methodological differences are therefore not confined to a single step. They can become relevant from scoping and evidence selection through statistical analysis and final national assessment.

What manufacturers can take from the comparison of EU JCA and national HTA

The challenge of EU JCA is not limited to producing a European evidence package. The key question is whether the same evidence can subsequently support the methodological requirements of the relevant national HTA systems.

Three practical preparation points follow:

1. Consider national requirements during JCA scoping. Different populations and comparators can determine which evidence and analyses will later be required.
2. Assess indirect comparisons early for methodological transferability. The availability of MAIC, STC or other methods does not automatically make an analysis suitable for every national question.
3. Identify national additional analyses early. If additional subgroups, comparators or evidence sources are likely to become relevant, preparation should not wait until the JCA has been completed.

For Germany, this transferability becomes particularly visible in the delta dossier. The relevant question is not only which evidence is available in the JCA, but whether it addresses the questions of the German benefit assessment and where additional evidence or analyses are required.

Primary source on EU JCA and national HTA methods

Sarri G, Vinals L, Leisle L, Claverie Chau I, Smalbrugge D, Lucassen K, Jemiai Y. Mapping methods gaps between EU joint clinical assessments and local health technology assessment decision-making: an environmental scan of guidance in select EU markets and harmonization challenges. Journal of Comparative Effectiveness Research. 2025; e240240. DOI: 10.57264/cer-2024-0240.

The publication is based on an environmental scan of methodological guidance for EU HTAR and selected HTA systems in Germany, France, the Netherlands and Spain.