The implementation of EU Joint Clinical Assessments (JCA) represents a momentum shift in how comparative evidence is submitted for new health technologies and scrutinized during local health technology assessment (HTA) across the Member States (MS) in Europe. Central to this new architecture is the precision required in defining comparators.¹

Most PICO frameworks assume there is a clearly defined comparator, one treatment, or a short, fixed list of treatments combined as an “OR” or “AND” scenario, which applies to every patient in the targeted population or a subpopulation thereof (Table 1).¹ Clinical reality does not always follow this logic. In some therapeutic areas, especially in rare and very rare indications, no well-defined standard of care (SoC) exists. Instead, the most appropriate treatment depends on individual patient characteristics, such as prior treatment history, disease severity, and comorbidities. When this is the case and the full population cannot be split into a “limited number of meaningful subpopulations” (e.g., when the deciding factors are overlapping, not well-defined, or apply to small number of patients), the EU JCA PICO scope introduces an additional comparator scenario: a bundle of treatment options, the so-called “individualised treatment comparator.”¹

“There might be situations in which a single treatment suitable for all patients in a given population does not exist. … Actual treatments for individual patients are chosen based on patients’ individual characteristics.” ¹

However, the definition of “meaningful subpopulations” is still up to interpretation and may vary across the different MS when defining their policy-driven PICO requests, creating a grey zone for decision-making between the OR and the individualized treatment scenario. Moreover, the EU HTA Regulation (HTAR) guidance on the scoping process does not present well-defined rules for the consolidation of PICOs with individualised treatment comparators, introducing additional challenges for the JCA readiness in terms of preparatory activities.

“If several individualised treatment comparators are requested by MS, a discussion between assessor, co-assessor and MS should explore the opportunity to adjust the components of the individualised treatment to consolidate the individualised treatment options. However, this process should always consider the needs of all MS. If individualised treatment options differ, different PICO(s) might have to be formulated.” ¹

Table 1: Comparator scenarios in EU JCA PICOs¹

What evidence do you need to provide to address a PICO with the individualised treatment comparator?

In rare diseases, off-label treatments may need inclusion due to limited options, whereas in areas with many therapies, licensed and guideline-recommended treatments may suffice. Overall, the comparator set (bundle of treatment options) may include²:

• Licensed treatments for the indication
• Guideline-recommended options
• Commonly used treatments within the healthcare system
• Evidence-supported treatments from RCTs or registries

A key challenge is that treatment landscapes may vary across MS, so the defined comparator set can differ depending on which local perspective “dominates” PICO scoping discussions — often without health technology developer (HTD) being aware.

“In the interests of achieving the lowest possible number of PICOs, while still addressing MS needs, individual MS may consider whether a broader/narrower range of treatment options within the individualised treatment comparator specification would be acceptable.” ²

What if the HTD’s trial covers only some of the bundle treatment options?

This is where the complexity emerges. The HTA Coordination Group’s (CG) Q&A (May 2026) exactly addresses this issue — and its conclusion is deliberately nuanced. If the HTD’s trial captures only a subset of treatments within the individualised treatment comparator, this alone does not invalidate the use of such evidence — but it does materially shape how that evidence can be used in the EU JCA submission.

The key determinant is clinical relevance of the trial’s comparator arm in the EU MS. Where the subset of treatments included in the HTD’s SoC reflects the most meaningful treatment options in EU practice, direct trial evidence may be considered. However, the JCA submission will be correspondingly considered narrower in scope and the JCA assessors will explicitly acknowledge what is missing.

The implications of JCA critique vary depending on the extent of trial’s comparator arm coverage:

• Broad but incomplete coverage: If the SoC arm includes most options — particularly those most used — the JCA assessors are likely to accept these analyses, albeit with clearly stated limitations.
• Limited and unrepresentative coverage: If only a small number of options are included, and these do not reflect the predominant treatments across EU MS, the assessment risks losing clinical relevance for the defined PICO.
• Single-option comparator: If the SoC reduces to just one treatment, the analysis effectively shifts away from the target population and instead describes a de facto subpopulation. In such cases, the results may no longer meaningfully address the full PICO.

In all cases, the JCA report does not resolve these drawbacks — it documents it. The ultimate judgement on whether such evidence is fit for purpose rests with national HTA bodies, who will determine its acceptability for local decision-making.

Where does the indirect treatment comparison (ITC) fit?

The ITC serves as a methodological “reserve” when the HTD trial comparator does not meet the individualised treatment comparator requirement — as mentioned above, common in heterogeneous diseases, rare conditions with limited therapies, or heavily pre-treated populations lacking a clear standard of care. Furthermore, global trials designed to satisfy multiple market requirements where no single SoC is defined.

Strategically, the ITC is a “moving target,” shaped by clinical guidelines and available evidence. This creates challenges for HTDs, who must compare against a fragmented and variable treatment landscape, increasing analytical complexity and the need for robust justification. A hierarchical approach is recommended, prioritizing relevant trial comparators and, where needed, constructing external control arms from registries or real-world data.

How do the ITC results fit in the JCA Dossier?

When the assessment scope mandates an ITC, HTDs must align their evidence with clinical reality while maintaining strict adherence to the PICO requirements.^3,4 It is important that HTDs follow these strategic directives:

• PICO alignment and informative value: HTDs must aim to meet PICO requirements as closely as possible based on the evidence availability and comparability with the technology’s trial base. Where data deviations occur (e.g., mismatched subgroup definitions), the developer must provide the closest possible analysis and explicitly justify why the data provided remains informative given the assessment scope.

• Justification for deviations or non-response: Any departure from the requested scope must be supported by robust literature searches. This is not optional; a lack of literature-backed justification can jeopardize the confirmation of the dossier. Evidence from literature searches may also build up robust justifications.

• What JCA assessors will check: Which treatment options were available in the comparator arm? How was treatment selection made for individual patients? Does the study protocol give investigators discretion to select based on patient characteristics? Were reasons for treatment choices documented?

Conclusion and final takeaways

Successfully navigating the individualised comparator situation in the EU JCAs requires more than just clinical data; it requires a sophisticated strategy that anticipates MS needs and addresses evidence gaps before they become “incompleteness” issues in the dossier.

References

1. Guidance on the Scoping Process v1.0, HTA Coordination Group, adopted on 28 November 2024.

2. Questions and Answers on general methodological and procedural issues for joint clinical assessments, HTA Coordination Group, 18 May 2026.

3. Methodological Guideline for Quantitative Evidence Synthesis: Direct and Indirect Comparisons, HTA Coordination Group, 8 March 2024.

4. Practical Guideline for Quantitative Evidence Synthesis: Direct and Indirect Comparisons, HTA Coordination Group, 8 March 2024.

Navigating the individualised treatment comparator^1,2

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