EUnetHTA 21 Publishes Final Guidance on Evidence Submission Requirements

EUnetHTA 21—the consortium responsible for supporting the implementation of the EU HTA Regulation—has released its final consolidated guidance on evidence submission requirements for Joint Clinical Assessments (JCAs). This publication represents one of the most important methodological milestones leading up to the Regulation’s enforcement in 2025.

The guidance provides a harmonized framework for preparing clinical evidence packages for EU-level assessments, and is expected to serve as the foundational reference for manufacturers submitting oncology medicines and ATMPs under the first wave of mandatory JCAs.

Key elements of the final guidance

The document consolidates methodological expectations across several critical domains, offering detailed instructions for manufacturers preparing evidence dossiers. Among the most notable sections are:

1. Systematic Literature Review Standards

EUnetHTA 21 emphasizes that literature reviews included in JCA submissions must:

• follow a transparent, reproducible methodology,
• conform to PRISMA reporting standards,
• include clearly documented search strategies,
• provide explicit risk-of-bias assessments using accepted tools,
• and demonstrate justification for inclusion/exclusion criteria.

The guidance stresses that SLRs must be complete and submitted fully at the time of dossier delivery—late updates or post-hoc amendments will not be accepted except under exceptional circumstances.

2. Endpoint Selection and Outcome Reporting

Manufacturers are expected to align clinical endpoints with:

• relevance to patient-centred outcomes,
• established HTA agency preferences across Europe,
• and disease-specific core outcome sets when available.

The guidance urges consistency between primary endpoints used for regulatory approval and those included in HTA evidence packages. Any divergence must be justified with methodological clarity.

3. Comparator Justification Requirements

One of the more challenging aspects for industry is the requirement to justify comparator selection across multiple Member States. The guidance outlines that submissions should include:

• evidence of clinical practice variation across countries,
• rationale for each comparator’s relevance,
• and documentation of standard-of-care differences where applicable.

Indirect treatment comparisons (ITCs) are permitted but must follow strict methodological standards regarding heterogeneity assessment and model transparency.

4. Evidence Quality and Bias Assessment

The final guidance reiterates the need for:

• structured risk-of-bias evaluation (e.g. RoB 2, ROBINS-I),
• clear discussion of study limitations,
• explicit assessment of indirectness,
• and transparent reporting of missing data handling.

The document also encourages early dialogue to reduce the risk of avoidable evidence gaps.

Updates from previous draft versions

Compared to earlier drafts, the final guidance includes:

• expanded sections on real-world evidence (RWE),
• more detailed examples of acceptable search strategies,
• clarifications on handling immature survival data,
• and stronger requirements for documenting deviations from study protocols.

Additionally, the guidance provides enhanced structure for manufacturer dossiers, including specification of mandatory annexes and checklist-based quality controls.

Implications for manufacturers preparing for 2025 JCAs

The release of this final guidance gives companies greater clarity on what will be expected for JCA submissions. However, it also highlights several challenges:

Earlier Alignment with HTA Expectations

Since JCA timelines will run parallel to EMA regulatory reviews, manufacturers must anticipate HTA requirements much earlier in development.

Greater Methodological Rigor

HTA bodies across the EU are shifting towards more uniform methodological standards. Manufacturers with historically variable SLR or ITC practices will need to upgrade internal methods to meet baseline expectations.

Reduced Flexibility in Evidence Submission

The guidance makes clear that dossiers must be complete and methodologically robust at the moment of submission—there will be limited opportunity to amend or expand evidence afterwards.

Role of the guidance in the broader EU HTA landscape

The final EUnetHTA 21 guidance is expected to serve as the primary methodological reference until the Coordination Group publishes its own legally binding procedures. While the guidance itself is not regulatory, it will heavily influence:

• national HTA bodies’ expectations,
• cross-country assessment alignment,
• and the interpretation of evidence quality in the early years of the Regulation.

Most Member States have already indicated that they will adopt this guidance as a standard reference for their own parallel assessments.

IS4Health’s perspective

For companies preparing for the first wave of JCAs, early readiness is crucial. At IS4Health, we support manufacturers in:

• designing PRISMA-compliant reviews,
• ensuring comparator justification meets EU-wide expectations,
• preparing endpoint strategies aligned with both regulatory and HTA needs,
• and developing high-quality clinical evidence summaries.

We will continue to track updates from EUnetHTA 21 and the HTA Coordination Group as the EU prepares for the 2025 implementation.